Vesta Lai - Academia.edu (original) (raw)

Papers by Vesta Lai

Research paper thumbnail of Effects of Oral Contraceptive Use on the Renal and Systemic Vascular Response to Angiotensin II Infusion

Journal of the American Society of Nephrology, Mar 1, 2004

We have previously shown that users of oral contraceptive (OC) medications exhibit increased plas... more We have previously shown that users of oral contraceptive (OC) medications exhibit increased plasma levels of angiotensin II (Ang II) with only modest hemodynamic consequences, suggesting estrogen-mediated Ang II type 1 (AT 1 ) receptor downregulation. Accordingly, in 10 women who were OC users and 10 women who, as OC nonusers, served as controls, all mean age 26 Ϯ 1 yr, we examined the renal and peripheral hemodynamic response to graded Ang II infusion, plasma and urine cyclic guanosine monophosphate (cGMP) levels as a surrogate marker for AT 1 and/or AT 2 receptormediated activation of the nitric oxide pathway, and AT 1 receptor expression in skin biopsies. The OC nonusers were studied during the follicular and luteal phases of the menstrual cycle, whereas OC users were studied once during the 21-d medication phase. Subjects ingested a controlled sodium diet for 7 d before each study. Renal hemodynamic function was assessed using standard inulin and p-aminohippurate clearance techniques. AT 1 receptor mRNA levels in skin biopsy samples were assessed using a real-time PCR protocol. In response to graded Ang II infusion, OC users exhibited renal and peripheral hemodynamic responses that were augmented compared with those of OC nonusers, in conjunction with evidence of increased tissue AT 1 receptor expression. Plasma cGMP levels and 24-h urinary cGMP excretion did not differ. These data suggest that, contrary to our original hypothesis, OC use does not appear to be associated with AT 1 receptor downregulation. The factor protecting OC users from the hemodynamic impact of increased Ang II levels remains elusive.

Research paper thumbnail of Effect of Protein Kinase C Inhibition on Renal Hemodynamic Function and Urinary Biomarkers in Humans With Type 1 Diabetes: A Pilot Study

Diabetes Care, 2009

OBJECTIVE -The aim of this study was to examine the effect of protein kinase C␤ inhibition with r... more OBJECTIVE -The aim of this study was to examine the effect of protein kinase C␤ inhibition with ruboxistaurin on renal hemodynamic function and urinary biomarkers (monocyte chemoattractant protein-1 [MCP-1] and epidermal growth factor) in renin angiotensin system blockade-treated type 1 diabetic subjects.

Research paper thumbnail of Variation in the renin angiotensin system throughout the normal menstrual cycle

Journal of the American Society of Nephrology Jasn, Feb 1, 2002

It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components pea... more It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components peak when plasma estrogen levels are highest, during the luteal phase of the normal menstrual cycle. This phenomenon has been attributed to "activation" of the RAS. The end-organ vasoconstrictive response to this phenomenon has not been well established. In two related experiments, the RAS was studied in healthy, premenopausal women during predefined phases of the normal menstrual cycle. In the first experiment, the circulating components of the RAS and the systemic hemodynamic response to incremental lower body negative pressure (LBNP) during the follicular and luteal phases of the menstrual cycle were examined. Response variables included mean arterial pressure (MAP), renin, plasma renin activity (PRA), angiotensin II (AngII), and aldosterone. Baseline levels of renin, PRA, and aldosterone were significantly higher in the luteal phase. In response to LBNP, there were significant increases in all variables in both phases; however, the humoral response to this stimulus was significantly augmented in the luteal phase compared with the follicular phase. Despite these elevations in circulating components of the RAS during the luteal phase, subjects were unable to maintain MAP in response to LBNP, exhibiting a dramatic depressor response that did not occur during the follicular phase. In the second experiment, renal and peripheral hemodynamic function at baseline, and in response to AngII blockade with losartan, were examined in women during these high and low estrogen phases of the menstrual cycle. The renal and peripheral hemodynamic responses were similar in the luteal phase and the follicular phase. These results demonstrate that, despite an increase in circulating RAS components during the luteal phase of the menstrual cycle, the system is blunted rather than "activated," at least at a tissue level. Further studies are needed to clarify this mechanism.

Research paper thumbnail of Glomerular haemodynamic profile of patients with Type 1 diabetes compared with healthy control subjects

Diabetic medicine : a journal of the British Diabetic Association, Jan 7, 2015

To evaluate the glomerular haemodynamic profile of patients with Type 1 diabetes with either rena... more To evaluate the glomerular haemodynamic profile of patients with Type 1 diabetes with either renal hyperfiltration (GFR ≥ 135 ml/min/1.73 m(2) ) or renal normofiltration (GFR 90-134 ml/min/1.73 m(2) ) during euglycaemic and hyperglycaemic conditions, and to compare this profile with that of a similar group of healthy control subjects. Gomez's equations were used to derive afferent and efferent arteriolar resistances, glomerular hydrostatic pressure and filtration pressure. At baseline, during clamped euglycaemia, patients with Type 1 diabetes and hyperfiltration had lower mean ± sd afferent arteriolar resistance than both those with Type 1 diabetes and normofiltration (914 ± 494 vs. 2065 ± 597 dyne/s/cm(5) ; P < 0.001) and healthy control subjects (1676 ± 707 dyne/s/cm(5) ; p < 0.001). By contrast, efferent arteriolar resistance was similar in the three groups. Patients with Type 1 diabetes and hyperfiltration also had higher mean ± sd glomerular hydrostatic pressure than ...

Research paper thumbnail of A randomized cross-over comparison of short-term exposure of once-daily extended release tacrolimus and twice-daily tacrolimus on renal function in healthy volunteers

Transplant international : official journal of the European Society for Organ Transplantation, 2014

Calcineurin inhibitor nephrotoxicity remains an issue for transplant recipients. The pharmacokine... more Calcineurin inhibitor nephrotoxicity remains an issue for transplant recipients. The pharmacokinetic profile (PK) of the once-daily tacrolimus extended release (Tac-ER) includes equivalent exposure [AUC(0-24 h) ] but lower Cmax versus twice-daily tacrolimus immediate release (Tac-IR). We hypothesized that the unique PK profiles would result in pharmacodynamic differences in renal function. Nineteen healthy male subjects were allocated to once-daily Tac-ER and twice-daily Tac-IR in a prospective, randomized, two period, cross-over study. Tacrolimus was titrated to achieve trough levels of 8-12 ng/ml. Twenty four hours ERPF and GFR estimated by para-aminohippurate and sinistrin clearance were performed at baseline and at the end of each 10-day dosing period. Mean Tac C0 was 11.0 ± 2.2 and 11.3 ± 1.8 ng/ml for Tac-ER and Tac-IR, respectively. The mean Effective 24 h renal plasma flow (ERPF) was significantly higher with Tac-ER compared with Tac-IR (658 ± 127 vs. 610 ± 93 ml/min/1.73 m(...

Research paper thumbnail of Endothelial nitric oxide synthase gene polymorphisms and the renal hemodynamic response to L-arginine

Kidney International, 2009

Nitric oxide is generated from L-arginine by nitric oxide synthase (NOS), an enzyme that exists i... more Nitric oxide is generated from L-arginine by nitric oxide synthase (NOS), an enzyme that exists in several isoforms. Some studies found that a polymorphism (G894T) in the endothelial NOS gene was associated with decreased nitric oxide bioactivity and vascular complications. However, it is not known whether the enzyme had a reduced activity. Here we measured the effect of an infusion

Research paper thumbnail of Variation in the renin angiotensin system throughout the normal menstrual cycle

Journal of the American Society of Nephrology : JASN, 2002

It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components pea... more It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components peak when plasma estrogen levels are highest, during the luteal phase of the normal menstrual cycle. This phenomenon has been attributed to "activation" of the RAS. The end-organ vasoconstrictive response to this phenomenon has not been well established. In two related experiments, the RAS was studied in healthy, premenopausal women during predefined phases of the normal menstrual cycle. In the first experiment, the circulating components of the RAS and the systemic hemodynamic response to incremental lower body negative pressure (LBNP) during the follicular and luteal phases of the menstrual cycle were examined. Response variables included mean arterial pressure (MAP), renin, plasma renin activity (PRA), angiotensin II (AngII), and aldosterone. Baseline levels of renin, PRA, and aldosterone were significantly higher in the luteal phase. In response to LBNP, there were significant...

Research paper thumbnail of Transdermal Contraception and the Renin Angiotensin Aldosterone System (RAAS) in Pre-Menopausal Women

American Journal of Physiology - Renal Physiology, 2015

The oral contraceptive pill (OCP) activates the renin-angiotensin-aldosterone system (RAAS) throu... more The oral contraceptive pill (OCP) activates the renin-angiotensin-aldosterone system (RAAS) through first-pass hepatic metabolism. Although usually benign, RAAS activation may have detrimental effects on renal and hemodynamic function in some women. Since combined hormonal contraception with the transdermal patch (EVRA) does not undergo first-pass hepatic metabolism, we hypothesized that the RAAS response would be different from that of OCP subjects. Thirty-five nonsmoking, premenopausal women (15 control subjects, 10 OCP subjects, and 10 contraceptive patch subjects) without evidence of cardiovascular disease, renal disease, or diabetes were studied. Baseline angiotensinogen, renin, angiotensin II, aldosterone, and plasma renin activity were assessed along with hormonal and hemodynamic responses to simulated orthostatic stress using incremental lower body negative pressure (LBNP; -15, -25, and -40 mmHg). Baseline levels of angiotensinogen, angiotensin II, and plasma renin activity were significantly higher in OCP subjects compared with normotensive control and contraceptive patch subjects (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), whereas aldosterone was significantly higher in OCP versus control subjects only (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Plasma renin levels were significantly lower at baseline in contraceptive patch subjects compared with normotensive control and OCP subjects (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). In response to LBNP, increases in renin, angiotensin II, and aldosterone were attenuated in contraceptive patch subjects in conjunction with an exaggerated decline in mean arterial pressure (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05 vs. control and OCP subjects). The contraceptive patch in healthy premenopausal women is associated with an impaired ability to maintain blood pressure in response to LBNP, possibly due to insensitivity of the endogenous RAAS. Further evaluation may be beneficial in women with kidney disease.

Research paper thumbnail of The angiotensin II receptor type 2 polymorphism influences haemodynamic function and circulating RAS mediators in normotensive humans

Nephrology Dialysis Transplantation, 2010

Background. The haemodynamic responses to angiotensin II type 1 (AT1) receptor blockade may be me... more Background. The haemodynamic responses to angiotensin II type 1 (AT1) receptor blockade may be mediated in part by interactions between angiotensin II and the angiotensin II type 2 receptor (AT2R). An AT2R G1675A gene polymorphism has been described, but the functional effects of this polymorphism are unknown. Methods. Haemodynamic function, circulating reninangiotensin system mediators and norepinephrine were measured in young healthy subjects at baseline and at 2 and 4 weeks after treatment with irbesartan. Subjects were divided into two groups on the basis of the AT2R G1675A gene polymorphism: GG subjects (n = 12) and AA/GA subjects (n = 22). Results. AA/AG subjects exhibited hypotensive and renal vasodilatory responses to irbesartan at 4 weeks, but GG subjects did not. In accord with haemodynamic effects, circulating aldosterone levels were suppressed in AA/AG, while circulating norepinephrine levels were augmented only in GG subjects. In contrast, increases in circulating renin, angiotensin II and plasma renin activity after irbesartan were exaggerated in AA/AG subjects. Conclusions. The AT2R G1675A polymorphism is a determinant of haemodynamic responses to AT1 receptor blockade, an effect that may be due to influences on aldosterone escape.

Research paper thumbnail of Endothelial nitric oxide synthase gene polymorphisms and the renal hemodynamic response to L-arginine

Kidney International, 2009

Research paper thumbnail of Long-term hemodynamic and molecular effects persist after discontinued renin–angiotensin system blockade in patients with type 1 diabetes mellitus

Kidney International, 2013

Animal studies suggest temporary renin-angiotensin system (RAS) blockade enhances long-term vascu... more Animal studies suggest temporary renin-angiotensin system (RAS) blockade enhances long-term vascular protective effects; however, this is not established in humans. Here we evaluated the long-term effects of prior RAS blockade on hemodynamic function, urinary measures of inflammation, and tissue antioxidant mRNA expression in patients with type 1 diabetes mellitus (T1DM) who participated in the 5-year Renin Angiotensin System Study (RASS). At 4 years after completing the RASS and discontinuing study medication, renal hemodynamic responses to clamped hyperglycemia were significantly greater in 18 patients in the RAS blockade group compared to 9 patients of the placebo-treated group. Individuals who had received RAS blockade also exhibited higher flow-mediated vasodilatation, reduced urinary cytokine excretion in response to hyperglycemia, and increased skin mRNA expression of superoxide dismutase-1 and catalase. Thus, patients with uncomplicated T1DM who received prior RAS blockade for 5 years maintain long-term effects on renal hemodynamic and systemic vascular function, inflammatory pathways in the kidney, and antioxidant enzyme expression in skin 4 years after discontinuation of therapy. Our findings suggest that sustained long-term protective effects of finite RAS inhibition requires further study.

Research paper thumbnail of Endothelial Nitric Oxide Synthase Gene/Gender Interactions and the Renal Hemodynamic Response to Angiotensin II

Journal of the American Society of Nephrology, 2005

Endothelial function is dependent on the generation of nitric oxide (NO) by the enzyme endothelia... more Endothelial function is dependent on the generation of nitric oxide (NO) by the enzyme endothelial NO synthase (eNOS). One functional coding polymorphism of the eNOS gene (G8943 T) is associated with reduced enzyme activity, increased coronary heart disease, and the development of end-stage renal failure. Because gender and renin-angiotensin system activation also play key roles in the development of renal and cardiovascular disease and because NO plays a role in the response to angiotensin II (AngII), it was hypothesized that the eNOS gene G8943 T polymorphism would be a determinant of the systemic and renal vascular response to AngII. Fifty young, healthy, normotensive individuals who were on a controlled sodium and protein diet for 1 wk underwent assessment of BP and renal hemodynamic function at baseline and during AngII infusion (4 ng/kg per min for 45 min). Participants were genotyped for the eNOS gene G8943 T polymorphism and then segregated into groups on the basis of gender and genotype (GG versus GT/TT). Baseline values for renal blood flow, effective renal plasma flow, and GFR were lower in men with the T allele compared with men who were homozygous for the G allele (P ‫؍‬ 0.03), but the polymorphism was not associated with renal hemodynamic function in women. The BP responses to AngII were similar in men and women regardless of genotype. Both multivariate linear regression and analysis of covariance (ANCOVA) revealed a relationship between gender and genotype. Men with the GT/TT genotype exhibited a significantly greater decrease in GFR (P ‫؍‬ 0.04) in response to AngII than did those with the GG genotype. This association was not observed in women. The eNOS gene G8943 T polymorphism is a determinant of both baseline renal hemodynamic function and the hemodynamic response to AngII in men but not in women.

Research paper thumbnail of Effects of Oral Contraceptive Use on the Renal and Systemic Vascular Response to Angiotensin II Infusion

Journal of the American Society of Nephrology, 2004

We have previously shown that users of oral contraceptive (OC) medications exhibit increased plas... more We have previously shown that users of oral contraceptive (OC) medications exhibit increased plasma levels of angiotensin II (Ang II) with only modest hemodynamic consequences, suggesting estrogen-mediated Ang II type 1 (AT 1 ) receptor downregulation. Accordingly, in 10 women who were OC users and 10 women who, as OC nonusers, served as controls, all mean age 26 Ϯ 1 yr, we examined the renal and peripheral hemodynamic response to graded Ang II infusion, plasma and urine cyclic guanosine monophosphate (cGMP) levels as a surrogate marker for AT 1 and/or AT 2 receptormediated activation of the nitric oxide pathway, and AT 1 receptor expression in skin biopsies. The OC nonusers were studied during the follicular and luteal phases of the menstrual cycle, whereas OC users were studied once during the 21-d medication phase. Subjects ingested a controlled sodium diet for 7 d before each study. Renal hemodynamic function was assessed using standard inulin and p-aminohippurate clearance techniques. AT 1 receptor mRNA levels in skin biopsy samples were assessed using a real-time PCR protocol. In response to graded Ang II infusion, OC users exhibited renal and peripheral hemodynamic responses that were augmented compared with those of OC nonusers, in conjunction with evidence of increased tissue AT 1 receptor expression. Plasma cGMP levels and 24-h urinary cGMP excretion did not differ. These data suggest that, contrary to our original hypothesis, OC use does not appear to be associated with AT 1 receptor downregulation. The factor protecting OC users from the hemodynamic impact of increased Ang II levels remains elusive.

Research paper thumbnail of Gender Differences in the Renal Response to Renin-Angiotensin System Blockade

Journal of the American Society of Nephrology, 2006

Evidence suggests that gender differences exist in renin-angiotensin system (RAS) function. It wa... more Evidence suggests that gender differences exist in renin-angiotensin system (RAS) function. It was hypothesized that women may differ also in their response to RAS blockade. The renal and peripheral hemodynamic responses to incremental dosages of an angiotensin receptor blocker and the degree of angiotensin II (AngII) insensitivity achieved during 8 wk were examined in men and women. Participants were 30 young healthy men (n ‫؍‬ 15; mean age 27 ؎ 2) and women (n ‫؍‬ 15; mean age 28 ؎ 2) who were on a controlled sodium and protein diet for 1 wk before each study. The humoral, renal, and systemic response to incremental dosages of irbesartan (75 mg for 4 wk, then 150 mg for 4 wk) was assessed, as was the pressor response to AngII (3 ng/kg per min), at 2-wk intervals. AngII type 1 receptor expression in skin biopsies was assessed at baseline and after 8 wk by a real-time PCR protocol. Men and women both exhibited significant declines in BP. Women achieved significantly reduced AngII sensitivity compared with men at lower dosages, showing no pressor response at 4 wk of 75 mg/d irbesartan, whereas men continued to exhibit a pressor response at 4 wk of 150 mg/d. Receptor expression at baseline did not differ between men and women but by 8 wk was significantly decreased in women and unchanged in men. Our findings indicate that men may require larger dosages of angiotensin receptor blocker than do women and that the BP response cannot be used as a surrogate marker for adequate RAS blockade of the renal microvasculature.

Research paper thumbnail of Postpartum Assessment of the Renin Angiotensin System in Women with Previous Severe, Early-Onset Preeclampsia

The Journal of Clinical Endocrinology & Metabolism, 2011

Women with a history of severe preeclampsia are at an increased risk for the development of vascu... more Women with a history of severe preeclampsia are at an increased risk for the development of vascular disease. We hypothesized that abnormalities in the renin-angiotensin system (RAS) may be a predisposing factor. Physiological assessments were conducted at an academic center. Sixteen women with previous severe preeclampsia (PPE) were compared with nine previously pregnant controls (PPC) and 11 never-pregnant controls (NPC). Baseline circulating components of the RAS and expression of angiotensin (ANG) II type I (AT1) and type II (AT2) receptors in the skin were assessed along with the response to simulated orthostatic stress using incremental lower-body negative pressure (LBNP: -15, -25, and -40 mm Hg) and a graded ANG II infusion (1 and 3 ng/kg · min). Response to LBNP and ANG II was evaluated. RAS components were not different between previously pregnant groups, but were decreased compared with NPC subjects. In response to LBNP, there were significant increases in RAS components in all three groups, but the response to this stimulus was significantly lower and delayed in PPE subjects. Despite the blunted rise in circulating RAS mediators in PPE subjects, their blood pressure was maintained in 88% compared with only 33 and 55% in the PPC and NPC groups, respectively (P = 0.014). All three groups responded to the graded ANG II infusion with an increase in blood pressure that was significantly more pronounced in PPE subjects (P = 0.037) correlating with AT1/AT2 receptor expression. Alterations in the RAS in formerly preeclamptic patients may contribute to future vascular disease.

Research paper thumbnail of The effect of sex on endothelial function responses to clamped hyperglycemia in type 1 diabetes

Hypertension Research, 2014

Although the female sex is associated with renal protection in non-diabetic nephropathy, men and ... more Although the female sex is associated with renal protection in non-diabetic nephropathy, men and women with type 1 diabetes mellitus (T1D) have a similar risk of developing nephropathy. As hyperglycemia is associated with exaggerated effects on blood pressure and renal hyperfiltration in women versus men with T1D, we examined the influence of clamped hyperglycemia on flow mediated vasodilatation (FMD) to determine if this parameter contributes to sex-related differences in the vascular function. After a controlled diet for seven days, blood pressure, ultrasound derived FMD and circulating renin angiotensin system mediators were measured in men (n=30) and women (n=28) with T1D during clamped euglycemia and hyperglycemia. Men and women were similar in pre-study dietary parameters, age, diabetes duration, body mass index, HbA1c, renal function and proteinuria. The systolic blood pressure (SBP) was higher in men during clamped euglycemia (121±2 vs. 108±2 mm Hg, P&amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001) and hyperglycemia (121±2 vs. 111±2 mm Hg, P&amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001), as were the circulating levels of angiotensin II (P&amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). SBP increased in response to hyperglycemia in women but not in men. Consistently with differences in blood pressure during clamped euglycemia, FMD was higher in women than in men (8.06±0.55 vs. 4.15±0.52%, P&amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001). In contrast, between-group differences in FMD during clamped hyperglycemia did not reach significance owing to a decline in FMD in women, versus men, in response to clamped hyperglycemia (P=0.040 for between-group change in FMD). Clamped hyperglycemia suppresses FMD in women, but not in men, with uncomplicated T1D, which may contribute to the relative loss of protection against renal disease progression in women with T1D.

Research paper thumbnail of Renal Hyperfiltration and Arterial Stiffness in Humans With Uncomplicated Type 1 Diabetes

Diabetes Care, 2010

OBJECTIVE -We have reported that renal hyperfiltration is associated with endothelial dysfunction... more OBJECTIVE -We have reported that renal hyperfiltration is associated with endothelial dysfunction in early type 1 diabetes. However, the relationship between renal hyperfiltration and arterial stiffness is unknown. Accordingly, we measured arterial stiffness in type 1 diabetic subjects with hyperfiltering (n ϭ 20) or normofiltering (n ϭ 18).

Research paper thumbnail of The Effect of Direct Renin Inhibition Alone and in Combination With ACE Inhibition on Endothelial Function, Arterial Stiffness, and Renal Function in Type 1 Diabetes

Diabetes Care, 2012

OBJECTIVEdDiabetes is associated with renin-angiotensin system (RAS) activation, leading to renal... more OBJECTIVEdDiabetes is associated with renin-angiotensin system (RAS) activation, leading to renal and systemic vascular dysfunction that contribute to end-organ injury and significant morbidity. RAS blockade with ACE inhibitors reduces, but does not abolish, RAS effects. Accordingly, our aim was to determine if direct renin inhibition alone, and in combination with an ACE inhibitor, corrects early hemodynamic abnormalities associated with type 1 diabetes.

Research paper thumbnail of Effect of Protein Kinase C  Inhibition on Renal Hemodynamic Function and Urinary Biomarkers in Humans With Type 1 Diabetes: A Pilot Study

Diabetes Care, 2009

OBJECTIVE -The aim of this study was to examine the effect of protein kinase C␤ inhibition with r... more OBJECTIVE -The aim of this study was to examine the effect of protein kinase C␤ inhibition with ruboxistaurin on renal hemodynamic function and urinary biomarkers (monocyte chemoattractant protein-1 [MCP-1] and epidermal growth factor) in renin angiotensin system blockade-treated type 1 diabetic subjects.

Research paper thumbnail of Effect of Direct Renin Inhibition on Renal Hemodynamic Function, Arterial Stiffness, and Endothelial Function in Humans With Uncomplicated Type 1 Diabetes: A pilot study

Diabetes Care, 2010

OBJECTIVE -Blockade of the renin-angiotensin system (RAS) plays an important role in preventing e... more OBJECTIVE -Blockade of the renin-angiotensin system (RAS) plays an important role in preventing end-organ injury associated with diabetes. The recent development of direct renin inhibitors (DRIs) provides a new approach to block the RAS, but the effects of DRIs on renal and systemic vascular function in uncomplicated type 1 diabetes have not been elucidated.

Research paper thumbnail of Effects of Oral Contraceptive Use on the Renal and Systemic Vascular Response to Angiotensin II Infusion

Journal of the American Society of Nephrology, Mar 1, 2004

We have previously shown that users of oral contraceptive (OC) medications exhibit increased plas... more We have previously shown that users of oral contraceptive (OC) medications exhibit increased plasma levels of angiotensin II (Ang II) with only modest hemodynamic consequences, suggesting estrogen-mediated Ang II type 1 (AT 1 ) receptor downregulation. Accordingly, in 10 women who were OC users and 10 women who, as OC nonusers, served as controls, all mean age 26 Ϯ 1 yr, we examined the renal and peripheral hemodynamic response to graded Ang II infusion, plasma and urine cyclic guanosine monophosphate (cGMP) levels as a surrogate marker for AT 1 and/or AT 2 receptormediated activation of the nitric oxide pathway, and AT 1 receptor expression in skin biopsies. The OC nonusers were studied during the follicular and luteal phases of the menstrual cycle, whereas OC users were studied once during the 21-d medication phase. Subjects ingested a controlled sodium diet for 7 d before each study. Renal hemodynamic function was assessed using standard inulin and p-aminohippurate clearance techniques. AT 1 receptor mRNA levels in skin biopsy samples were assessed using a real-time PCR protocol. In response to graded Ang II infusion, OC users exhibited renal and peripheral hemodynamic responses that were augmented compared with those of OC nonusers, in conjunction with evidence of increased tissue AT 1 receptor expression. Plasma cGMP levels and 24-h urinary cGMP excretion did not differ. These data suggest that, contrary to our original hypothesis, OC use does not appear to be associated with AT 1 receptor downregulation. The factor protecting OC users from the hemodynamic impact of increased Ang II levels remains elusive.

Research paper thumbnail of Effect of Protein Kinase C Inhibition on Renal Hemodynamic Function and Urinary Biomarkers in Humans With Type 1 Diabetes: A Pilot Study

Diabetes Care, 2009

OBJECTIVE -The aim of this study was to examine the effect of protein kinase C␤ inhibition with r... more OBJECTIVE -The aim of this study was to examine the effect of protein kinase C␤ inhibition with ruboxistaurin on renal hemodynamic function and urinary biomarkers (monocyte chemoattractant protein-1 [MCP-1] and epidermal growth factor) in renin angiotensin system blockade-treated type 1 diabetic subjects.

Research paper thumbnail of Variation in the renin angiotensin system throughout the normal menstrual cycle

Journal of the American Society of Nephrology Jasn, Feb 1, 2002

It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components pea... more It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components peak when plasma estrogen levels are highest, during the luteal phase of the normal menstrual cycle. This phenomenon has been attributed to "activation" of the RAS. The end-organ vasoconstrictive response to this phenomenon has not been well established. In two related experiments, the RAS was studied in healthy, premenopausal women during predefined phases of the normal menstrual cycle. In the first experiment, the circulating components of the RAS and the systemic hemodynamic response to incremental lower body negative pressure (LBNP) during the follicular and luteal phases of the menstrual cycle were examined. Response variables included mean arterial pressure (MAP), renin, plasma renin activity (PRA), angiotensin II (AngII), and aldosterone. Baseline levels of renin, PRA, and aldosterone were significantly higher in the luteal phase. In response to LBNP, there were significant increases in all variables in both phases; however, the humoral response to this stimulus was significantly augmented in the luteal phase compared with the follicular phase. Despite these elevations in circulating components of the RAS during the luteal phase, subjects were unable to maintain MAP in response to LBNP, exhibiting a dramatic depressor response that did not occur during the follicular phase. In the second experiment, renal and peripheral hemodynamic function at baseline, and in response to AngII blockade with losartan, were examined in women during these high and low estrogen phases of the menstrual cycle. The renal and peripheral hemodynamic responses were similar in the luteal phase and the follicular phase. These results demonstrate that, despite an increase in circulating RAS components during the luteal phase of the menstrual cycle, the system is blunted rather than "activated," at least at a tissue level. Further studies are needed to clarify this mechanism.

Research paper thumbnail of Glomerular haemodynamic profile of patients with Type 1 diabetes compared with healthy control subjects

Diabetic medicine : a journal of the British Diabetic Association, Jan 7, 2015

To evaluate the glomerular haemodynamic profile of patients with Type 1 diabetes with either rena... more To evaluate the glomerular haemodynamic profile of patients with Type 1 diabetes with either renal hyperfiltration (GFR ≥ 135 ml/min/1.73 m(2) ) or renal normofiltration (GFR 90-134 ml/min/1.73 m(2) ) during euglycaemic and hyperglycaemic conditions, and to compare this profile with that of a similar group of healthy control subjects. Gomez's equations were used to derive afferent and efferent arteriolar resistances, glomerular hydrostatic pressure and filtration pressure. At baseline, during clamped euglycaemia, patients with Type 1 diabetes and hyperfiltration had lower mean ± sd afferent arteriolar resistance than both those with Type 1 diabetes and normofiltration (914 ± 494 vs. 2065 ± 597 dyne/s/cm(5) ; P < 0.001) and healthy control subjects (1676 ± 707 dyne/s/cm(5) ; p < 0.001). By contrast, efferent arteriolar resistance was similar in the three groups. Patients with Type 1 diabetes and hyperfiltration also had higher mean ± sd glomerular hydrostatic pressure than ...

Research paper thumbnail of A randomized cross-over comparison of short-term exposure of once-daily extended release tacrolimus and twice-daily tacrolimus on renal function in healthy volunteers

Transplant international : official journal of the European Society for Organ Transplantation, 2014

Calcineurin inhibitor nephrotoxicity remains an issue for transplant recipients. The pharmacokine... more Calcineurin inhibitor nephrotoxicity remains an issue for transplant recipients. The pharmacokinetic profile (PK) of the once-daily tacrolimus extended release (Tac-ER) includes equivalent exposure [AUC(0-24 h) ] but lower Cmax versus twice-daily tacrolimus immediate release (Tac-IR). We hypothesized that the unique PK profiles would result in pharmacodynamic differences in renal function. Nineteen healthy male subjects were allocated to once-daily Tac-ER and twice-daily Tac-IR in a prospective, randomized, two period, cross-over study. Tacrolimus was titrated to achieve trough levels of 8-12 ng/ml. Twenty four hours ERPF and GFR estimated by para-aminohippurate and sinistrin clearance were performed at baseline and at the end of each 10-day dosing period. Mean Tac C0 was 11.0 ± 2.2 and 11.3 ± 1.8 ng/ml for Tac-ER and Tac-IR, respectively. The mean Effective 24 h renal plasma flow (ERPF) was significantly higher with Tac-ER compared with Tac-IR (658 ± 127 vs. 610 ± 93 ml/min/1.73 m(...

Research paper thumbnail of Endothelial nitric oxide synthase gene polymorphisms and the renal hemodynamic response to L-arginine

Kidney International, 2009

Nitric oxide is generated from L-arginine by nitric oxide synthase (NOS), an enzyme that exists i... more Nitric oxide is generated from L-arginine by nitric oxide synthase (NOS), an enzyme that exists in several isoforms. Some studies found that a polymorphism (G894T) in the endothelial NOS gene was associated with decreased nitric oxide bioactivity and vascular complications. However, it is not known whether the enzyme had a reduced activity. Here we measured the effect of an infusion

Research paper thumbnail of Variation in the renin angiotensin system throughout the normal menstrual cycle

Journal of the American Society of Nephrology : JASN, 2002

It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components pea... more It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components peak when plasma estrogen levels are highest, during the luteal phase of the normal menstrual cycle. This phenomenon has been attributed to "activation" of the RAS. The end-organ vasoconstrictive response to this phenomenon has not been well established. In two related experiments, the RAS was studied in healthy, premenopausal women during predefined phases of the normal menstrual cycle. In the first experiment, the circulating components of the RAS and the systemic hemodynamic response to incremental lower body negative pressure (LBNP) during the follicular and luteal phases of the menstrual cycle were examined. Response variables included mean arterial pressure (MAP), renin, plasma renin activity (PRA), angiotensin II (AngII), and aldosterone. Baseline levels of renin, PRA, and aldosterone were significantly higher in the luteal phase. In response to LBNP, there were significant...

Research paper thumbnail of Transdermal Contraception and the Renin Angiotensin Aldosterone System (RAAS) in Pre-Menopausal Women

American Journal of Physiology - Renal Physiology, 2015

The oral contraceptive pill (OCP) activates the renin-angiotensin-aldosterone system (RAAS) throu... more The oral contraceptive pill (OCP) activates the renin-angiotensin-aldosterone system (RAAS) through first-pass hepatic metabolism. Although usually benign, RAAS activation may have detrimental effects on renal and hemodynamic function in some women. Since combined hormonal contraception with the transdermal patch (EVRA) does not undergo first-pass hepatic metabolism, we hypothesized that the RAAS response would be different from that of OCP subjects. Thirty-five nonsmoking, premenopausal women (15 control subjects, 10 OCP subjects, and 10 contraceptive patch subjects) without evidence of cardiovascular disease, renal disease, or diabetes were studied. Baseline angiotensinogen, renin, angiotensin II, aldosterone, and plasma renin activity were assessed along with hormonal and hemodynamic responses to simulated orthostatic stress using incremental lower body negative pressure (LBNP; -15, -25, and -40 mmHg). Baseline levels of angiotensinogen, angiotensin II, and plasma renin activity were significantly higher in OCP subjects compared with normotensive control and contraceptive patch subjects (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), whereas aldosterone was significantly higher in OCP versus control subjects only (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Plasma renin levels were significantly lower at baseline in contraceptive patch subjects compared with normotensive control and OCP subjects (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). In response to LBNP, increases in renin, angiotensin II, and aldosterone were attenuated in contraceptive patch subjects in conjunction with an exaggerated decline in mean arterial pressure (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05 vs. control and OCP subjects). The contraceptive patch in healthy premenopausal women is associated with an impaired ability to maintain blood pressure in response to LBNP, possibly due to insensitivity of the endogenous RAAS. Further evaluation may be beneficial in women with kidney disease.

Research paper thumbnail of The angiotensin II receptor type 2 polymorphism influences haemodynamic function and circulating RAS mediators in normotensive humans

Nephrology Dialysis Transplantation, 2010

Background. The haemodynamic responses to angiotensin II type 1 (AT1) receptor blockade may be me... more Background. The haemodynamic responses to angiotensin II type 1 (AT1) receptor blockade may be mediated in part by interactions between angiotensin II and the angiotensin II type 2 receptor (AT2R). An AT2R G1675A gene polymorphism has been described, but the functional effects of this polymorphism are unknown. Methods. Haemodynamic function, circulating reninangiotensin system mediators and norepinephrine were measured in young healthy subjects at baseline and at 2 and 4 weeks after treatment with irbesartan. Subjects were divided into two groups on the basis of the AT2R G1675A gene polymorphism: GG subjects (n = 12) and AA/GA subjects (n = 22). Results. AA/AG subjects exhibited hypotensive and renal vasodilatory responses to irbesartan at 4 weeks, but GG subjects did not. In accord with haemodynamic effects, circulating aldosterone levels were suppressed in AA/AG, while circulating norepinephrine levels were augmented only in GG subjects. In contrast, increases in circulating renin, angiotensin II and plasma renin activity after irbesartan were exaggerated in AA/AG subjects. Conclusions. The AT2R G1675A polymorphism is a determinant of haemodynamic responses to AT1 receptor blockade, an effect that may be due to influences on aldosterone escape.

Research paper thumbnail of Endothelial nitric oxide synthase gene polymorphisms and the renal hemodynamic response to L-arginine

Kidney International, 2009

Research paper thumbnail of Long-term hemodynamic and molecular effects persist after discontinued renin–angiotensin system blockade in patients with type 1 diabetes mellitus

Kidney International, 2013

Animal studies suggest temporary renin-angiotensin system (RAS) blockade enhances long-term vascu... more Animal studies suggest temporary renin-angiotensin system (RAS) blockade enhances long-term vascular protective effects; however, this is not established in humans. Here we evaluated the long-term effects of prior RAS blockade on hemodynamic function, urinary measures of inflammation, and tissue antioxidant mRNA expression in patients with type 1 diabetes mellitus (T1DM) who participated in the 5-year Renin Angiotensin System Study (RASS). At 4 years after completing the RASS and discontinuing study medication, renal hemodynamic responses to clamped hyperglycemia were significantly greater in 18 patients in the RAS blockade group compared to 9 patients of the placebo-treated group. Individuals who had received RAS blockade also exhibited higher flow-mediated vasodilatation, reduced urinary cytokine excretion in response to hyperglycemia, and increased skin mRNA expression of superoxide dismutase-1 and catalase. Thus, patients with uncomplicated T1DM who received prior RAS blockade for 5 years maintain long-term effects on renal hemodynamic and systemic vascular function, inflammatory pathways in the kidney, and antioxidant enzyme expression in skin 4 years after discontinuation of therapy. Our findings suggest that sustained long-term protective effects of finite RAS inhibition requires further study.

Research paper thumbnail of Endothelial Nitric Oxide Synthase Gene/Gender Interactions and the Renal Hemodynamic Response to Angiotensin II

Journal of the American Society of Nephrology, 2005

Endothelial function is dependent on the generation of nitric oxide (NO) by the enzyme endothelia... more Endothelial function is dependent on the generation of nitric oxide (NO) by the enzyme endothelial NO synthase (eNOS). One functional coding polymorphism of the eNOS gene (G8943 T) is associated with reduced enzyme activity, increased coronary heart disease, and the development of end-stage renal failure. Because gender and renin-angiotensin system activation also play key roles in the development of renal and cardiovascular disease and because NO plays a role in the response to angiotensin II (AngII), it was hypothesized that the eNOS gene G8943 T polymorphism would be a determinant of the systemic and renal vascular response to AngII. Fifty young, healthy, normotensive individuals who were on a controlled sodium and protein diet for 1 wk underwent assessment of BP and renal hemodynamic function at baseline and during AngII infusion (4 ng/kg per min for 45 min). Participants were genotyped for the eNOS gene G8943 T polymorphism and then segregated into groups on the basis of gender and genotype (GG versus GT/TT). Baseline values for renal blood flow, effective renal plasma flow, and GFR were lower in men with the T allele compared with men who were homozygous for the G allele (P ‫؍‬ 0.03), but the polymorphism was not associated with renal hemodynamic function in women. The BP responses to AngII were similar in men and women regardless of genotype. Both multivariate linear regression and analysis of covariance (ANCOVA) revealed a relationship between gender and genotype. Men with the GT/TT genotype exhibited a significantly greater decrease in GFR (P ‫؍‬ 0.04) in response to AngII than did those with the GG genotype. This association was not observed in women. The eNOS gene G8943 T polymorphism is a determinant of both baseline renal hemodynamic function and the hemodynamic response to AngII in men but not in women.

Research paper thumbnail of Effects of Oral Contraceptive Use on the Renal and Systemic Vascular Response to Angiotensin II Infusion

Journal of the American Society of Nephrology, 2004

We have previously shown that users of oral contraceptive (OC) medications exhibit increased plas... more We have previously shown that users of oral contraceptive (OC) medications exhibit increased plasma levels of angiotensin II (Ang II) with only modest hemodynamic consequences, suggesting estrogen-mediated Ang II type 1 (AT 1 ) receptor downregulation. Accordingly, in 10 women who were OC users and 10 women who, as OC nonusers, served as controls, all mean age 26 Ϯ 1 yr, we examined the renal and peripheral hemodynamic response to graded Ang II infusion, plasma and urine cyclic guanosine monophosphate (cGMP) levels as a surrogate marker for AT 1 and/or AT 2 receptormediated activation of the nitric oxide pathway, and AT 1 receptor expression in skin biopsies. The OC nonusers were studied during the follicular and luteal phases of the menstrual cycle, whereas OC users were studied once during the 21-d medication phase. Subjects ingested a controlled sodium diet for 7 d before each study. Renal hemodynamic function was assessed using standard inulin and p-aminohippurate clearance techniques. AT 1 receptor mRNA levels in skin biopsy samples were assessed using a real-time PCR protocol. In response to graded Ang II infusion, OC users exhibited renal and peripheral hemodynamic responses that were augmented compared with those of OC nonusers, in conjunction with evidence of increased tissue AT 1 receptor expression. Plasma cGMP levels and 24-h urinary cGMP excretion did not differ. These data suggest that, contrary to our original hypothesis, OC use does not appear to be associated with AT 1 receptor downregulation. The factor protecting OC users from the hemodynamic impact of increased Ang II levels remains elusive.

Research paper thumbnail of Gender Differences in the Renal Response to Renin-Angiotensin System Blockade

Journal of the American Society of Nephrology, 2006

Evidence suggests that gender differences exist in renin-angiotensin system (RAS) function. It wa... more Evidence suggests that gender differences exist in renin-angiotensin system (RAS) function. It was hypothesized that women may differ also in their response to RAS blockade. The renal and peripheral hemodynamic responses to incremental dosages of an angiotensin receptor blocker and the degree of angiotensin II (AngII) insensitivity achieved during 8 wk were examined in men and women. Participants were 30 young healthy men (n ‫؍‬ 15; mean age 27 ؎ 2) and women (n ‫؍‬ 15; mean age 28 ؎ 2) who were on a controlled sodium and protein diet for 1 wk before each study. The humoral, renal, and systemic response to incremental dosages of irbesartan (75 mg for 4 wk, then 150 mg for 4 wk) was assessed, as was the pressor response to AngII (3 ng/kg per min), at 2-wk intervals. AngII type 1 receptor expression in skin biopsies was assessed at baseline and after 8 wk by a real-time PCR protocol. Men and women both exhibited significant declines in BP. Women achieved significantly reduced AngII sensitivity compared with men at lower dosages, showing no pressor response at 4 wk of 75 mg/d irbesartan, whereas men continued to exhibit a pressor response at 4 wk of 150 mg/d. Receptor expression at baseline did not differ between men and women but by 8 wk was significantly decreased in women and unchanged in men. Our findings indicate that men may require larger dosages of angiotensin receptor blocker than do women and that the BP response cannot be used as a surrogate marker for adequate RAS blockade of the renal microvasculature.

Research paper thumbnail of Postpartum Assessment of the Renin Angiotensin System in Women with Previous Severe, Early-Onset Preeclampsia

The Journal of Clinical Endocrinology & Metabolism, 2011

Women with a history of severe preeclampsia are at an increased risk for the development of vascu... more Women with a history of severe preeclampsia are at an increased risk for the development of vascular disease. We hypothesized that abnormalities in the renin-angiotensin system (RAS) may be a predisposing factor. Physiological assessments were conducted at an academic center. Sixteen women with previous severe preeclampsia (PPE) were compared with nine previously pregnant controls (PPC) and 11 never-pregnant controls (NPC). Baseline circulating components of the RAS and expression of angiotensin (ANG) II type I (AT1) and type II (AT2) receptors in the skin were assessed along with the response to simulated orthostatic stress using incremental lower-body negative pressure (LBNP: -15, -25, and -40 mm Hg) and a graded ANG II infusion (1 and 3 ng/kg · min). Response to LBNP and ANG II was evaluated. RAS components were not different between previously pregnant groups, but were decreased compared with NPC subjects. In response to LBNP, there were significant increases in RAS components in all three groups, but the response to this stimulus was significantly lower and delayed in PPE subjects. Despite the blunted rise in circulating RAS mediators in PPE subjects, their blood pressure was maintained in 88% compared with only 33 and 55% in the PPC and NPC groups, respectively (P = 0.014). All three groups responded to the graded ANG II infusion with an increase in blood pressure that was significantly more pronounced in PPE subjects (P = 0.037) correlating with AT1/AT2 receptor expression. Alterations in the RAS in formerly preeclamptic patients may contribute to future vascular disease.

Research paper thumbnail of The effect of sex on endothelial function responses to clamped hyperglycemia in type 1 diabetes

Hypertension Research, 2014

Although the female sex is associated with renal protection in non-diabetic nephropathy, men and ... more Although the female sex is associated with renal protection in non-diabetic nephropathy, men and women with type 1 diabetes mellitus (T1D) have a similar risk of developing nephropathy. As hyperglycemia is associated with exaggerated effects on blood pressure and renal hyperfiltration in women versus men with T1D, we examined the influence of clamped hyperglycemia on flow mediated vasodilatation (FMD) to determine if this parameter contributes to sex-related differences in the vascular function. After a controlled diet for seven days, blood pressure, ultrasound derived FMD and circulating renin angiotensin system mediators were measured in men (n=30) and women (n=28) with T1D during clamped euglycemia and hyperglycemia. Men and women were similar in pre-study dietary parameters, age, diabetes duration, body mass index, HbA1c, renal function and proteinuria. The systolic blood pressure (SBP) was higher in men during clamped euglycemia (121±2 vs. 108±2 mm Hg, P&amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001) and hyperglycemia (121±2 vs. 111±2 mm Hg, P&amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001), as were the circulating levels of angiotensin II (P&amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). SBP increased in response to hyperglycemia in women but not in men. Consistently with differences in blood pressure during clamped euglycemia, FMD was higher in women than in men (8.06±0.55 vs. 4.15±0.52%, P&amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001). In contrast, between-group differences in FMD during clamped hyperglycemia did not reach significance owing to a decline in FMD in women, versus men, in response to clamped hyperglycemia (P=0.040 for between-group change in FMD). Clamped hyperglycemia suppresses FMD in women, but not in men, with uncomplicated T1D, which may contribute to the relative loss of protection against renal disease progression in women with T1D.

Research paper thumbnail of Renal Hyperfiltration and Arterial Stiffness in Humans With Uncomplicated Type 1 Diabetes

Diabetes Care, 2010

OBJECTIVE -We have reported that renal hyperfiltration is associated with endothelial dysfunction... more OBJECTIVE -We have reported that renal hyperfiltration is associated with endothelial dysfunction in early type 1 diabetes. However, the relationship between renal hyperfiltration and arterial stiffness is unknown. Accordingly, we measured arterial stiffness in type 1 diabetic subjects with hyperfiltering (n ϭ 20) or normofiltering (n ϭ 18).

Research paper thumbnail of The Effect of Direct Renin Inhibition Alone and in Combination With ACE Inhibition on Endothelial Function, Arterial Stiffness, and Renal Function in Type 1 Diabetes

Diabetes Care, 2012

OBJECTIVEdDiabetes is associated with renin-angiotensin system (RAS) activation, leading to renal... more OBJECTIVEdDiabetes is associated with renin-angiotensin system (RAS) activation, leading to renal and systemic vascular dysfunction that contribute to end-organ injury and significant morbidity. RAS blockade with ACE inhibitors reduces, but does not abolish, RAS effects. Accordingly, our aim was to determine if direct renin inhibition alone, and in combination with an ACE inhibitor, corrects early hemodynamic abnormalities associated with type 1 diabetes.

Research paper thumbnail of Effect of Protein Kinase C  Inhibition on Renal Hemodynamic Function and Urinary Biomarkers in Humans With Type 1 Diabetes: A Pilot Study

Diabetes Care, 2009

OBJECTIVE -The aim of this study was to examine the effect of protein kinase C␤ inhibition with r... more OBJECTIVE -The aim of this study was to examine the effect of protein kinase C␤ inhibition with ruboxistaurin on renal hemodynamic function and urinary biomarkers (monocyte chemoattractant protein-1 [MCP-1] and epidermal growth factor) in renin angiotensin system blockade-treated type 1 diabetic subjects.

Research paper thumbnail of Effect of Direct Renin Inhibition on Renal Hemodynamic Function, Arterial Stiffness, and Endothelial Function in Humans With Uncomplicated Type 1 Diabetes: A pilot study

Diabetes Care, 2010

OBJECTIVE -Blockade of the renin-angiotensin system (RAS) plays an important role in preventing e... more OBJECTIVE -Blockade of the renin-angiotensin system (RAS) plays an important role in preventing end-organ injury associated with diabetes. The recent development of direct renin inhibitors (DRIs) provides a new approach to block the RAS, but the effects of DRIs on renal and systemic vascular function in uncomplicated type 1 diabetes have not been elucidated.