diabetes Effects of ACE inhibition and AT1-receptor blockade on haemodynamic responses to L-arginine in Type 1 (original) (raw)
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Journal of the renin-angiotensin-aldosterone system : JRAAS, 2004
Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve endothelial function in Type 1 diabetes. However, the potential of ACE inhibitors (ACE-I) to enhance the haemodynamic effects of L-arginine (L-arg), the precursor of nitric oxide (NO), has not been evaluated. Furthermore, angiotensin receptor blockers (ARBs), another group of inhibitors of the renin-angiotensin system (RAS), have not been studied in this context.
AJP: Renal Physiology, 2013
The objective is to elucidate the effect of nitric oxide (NO)-renin-angiotensin system (RAS) interactions on renal hemodynamic function in uncomplicated, type 1 diabetes mellitus (DM). In 14 salt-replete, male healthy volunteers (C) and 9 male DM patients on euglycemia, glomerular filtration rate (GFR), renal blood flow (RBF), filtration fraction (FF), and sodium excretion (UNaV) were measured at baseline and during a 90-min infusion of 3.0 μg·kg−1·min−1 NG-nitro-l-arginine-methyl-ester (l-NAME) after 3 days of pretreatment with either placebo (PL) or 50 mg losartan (LOS). Baseline GFR, RBF, and FF were higher in DM ( P < 0.005). In the C group, PL + l-NAME caused declines in GFR (101 ± 3 to 90 ± 3 ml·min−1·1.73 m−2), RBF (931 ± 22 to 754 ± 31 ml·min−1·1.73 m−2), and UNaV (158 ± 12 to 82 ± 18 μmol/min) and an increase in FF (0.19 ± 0.02 to 0.21 ± 02; P < 0.001), which were not influenced by LOS pretreatment ( P > 0.05 for LOS + l-NAME-C vs. PL + l-NAME-C). In DM, PL + l-NAM...
Kidney International, 2005
ACE and non-ACE pathways in the renal vascular response to RAS interruption in type 1 diabetes mellitus. Background. The enormous contribution of reninangiotensin system (RAS) interruption with ACE (angiotensinconverting enzyme) inhibitors and angiotensin II receptor blockers (ARB) in the treatment of diabetic nephropathy has led to interest in the factors involved in angiotensin II (Ang II) generation. In normal subjects, RAS interruption using an ARB produced a 50% greater renal plasma flow (RPF) rise than with an ACE inhibitor, suggesting a substantial contribution of non-ACE pathways. Moreover, immunohistochemistry studies in kidneys of overtly proteinuric diabetic subjects showed up-regulation of chymase, an alternative Ang II-generating enzyme. Our aim was to determine the degree to which the non-ACE pathways contribute to RAS activation in type 1 diabetes mellitus (DM). Methods. Type 1 DM patients (N = 37, 14 M/23 F; age 31 ± 2 years; DM duration 16 ± 1.7 years; HbA1c 7.7.0 ± 0.3%) were studied on a high-salt diet. They received captopril 25 mg po one day and candesartan 16 mg po the next day. RPF and glomerular filtration rate (GFR) were measured before and up to 4 hours after drug administration. Results. Both captopril and candesartan induced a significant rise in RPF (baseline vs. peak <0.0001 for both), and the rise was concordant for the 2 drugs (r = 0.77, P < 0.001). However, the RPF responses were not significantly different between the 2 drugs (captopril 72 ± 11 mL/min/1.73m 2 , candesartan 75 ± 12, P = 0.841). Conclusion. In predominantly normoalbuminuric, normotensive type 1 DM, activation of the intrarenal RAS reflects a mechanism involving primarily the classic ACE pathway. The enormous contribution of renin-angiotensin system (RAS) interruption with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor block
Dual Blockade of the Renin-Angiotensin System in Diabetic Nephropathy
Diabetes Care, 2002
OBJECTIVE-Many patients with diabetic nephropathy (DN) have levels of albuminuria Ͼ1 g/day and blood pressure Ͼ135/85 mmHg, despite antihypertensive combination therapy, including recommended doses of ACE inhibitors, e.g., lisinopril/enalapril at 20 mg daily. We tested the concept that such patients might benefit from dual blockade of the renin-angiotensin system (RAS). RESEARCH DESIGN AND METHODS-We performed a randomized double-blind crossover study of 2 months treatment with candesartan cilexetil 8 mg once daily and placebo in addition to previous antihypertensive treatment. We included 18 type 2 diabetic patients with DN fulfilling the above-mentioned criteria. All received recommended doses of ACE inhibitor and, in addition, 15 patients received diuretics, 11 received a calcium channel antagonist, and 3 received a -blocker. At the end of each treatment period, we measured the glomerular filtration rate (GFR), 24-h blood pressure, albuminuria, and IgGuria. RESULTS-The addition of candesartan to usual antihypertensive therapy induced a mean (95% CI) reduction in albuminuria of 25% (2-58), P ϭ 0.036 (geometric mean [95% CI] from 1,764 mg/24 h [1,225-2,540] to 1,334 mg/24 h [890-1,998]). It also produced a mean reduction of 35% (9-53) in the fractional clearance of albumin (P ϭ 0.016), a reduction of 32% (1-54) in fractional clearance of IgG (P ϭ 0.046), a reduction in 24-h systolic blood pressure of 10 mmHg (2-18) (P ϭ 0.019) (mean Ϯ SE) from 148 Ϯ 3 to 138 Ϯ 5 mmHg, and a mean reduction in GFR of 5 ml ⅐ min Ϫ1 ⅐ 1.73 m Ϫ2 (0.1-9) (P ϭ 0.045). CONCLUSIONS-Dual blockade of the RAS reduces albuminuria and blood pressure in type 2 diabetic patients with DN responding insufficiently to previous antihypertensive therapy, including ACE inhibitors in recommended doses.
Angiotensin receptor blockers in diabetic nephropathy: renal and cardiovascular end points
Seminars in Nephrology, 2004
The activity of the renin-angiotensin-aldosterone system (RAAS) is elevated both in the circulation and in the renal tissue of diabetic and nondiabetic nephropathies. The increased RAAS activity plays an important role in the hemodynamic and nonhemodynamic pathogenetic mechanisms involved in kidney disease. Previous studies have demonstrated that albuminuria is not only a marker of glomerular lesions, but also a progression promoter, and finally a powerful predictor of the long-term beneficial effect of blood pressure-lowering therapy. Randomized crossover and parallel blind studies in patients with diabetic nephropathy have demonstrated that angiotensin II receptor blockers (ARB) induce favorable changes in systemic blood pressure, renal hemodynamics, and proteinuria similar to those induced by angiotensin-converting enzyme (ACE) inhibition. Studies have revealed the optimal renoprotective dose for some ARBs; however, additional dose titration studies are urgently needed to obtain the maximum benefit of this valuable new class of compounds. The combination of ARB and ACE inhibition is well tolerated and even more effective than monotherapy in reducing systemic blood pressure and albuminuria in diabetic nephropathy. In addition, dual RAAS blockade is safe and well tolerated. Impaired autoregulation of glomerular filtration rate (GFR); demonstrated with some blood pressure-lowering agents implies disturbances in the downstream transmission of the systemic blood pressure into the glomerulus, leading to capillary hypertension or hypotension depending of the level of blood pressure. ARB does not interfere with GFR autoregulation in hypertensive diabetic patients. In contrast to previous observational studies with ACE inhibition, long-term treatment with ARB has similar beneficial renoprotective effect on progression of diabetic kidney disease in hypertensive diabetic patients with ACE II and DD genotypes. ARB can prevent/delay development of diabetic nephropathy independently of its beneficial blood pressure-lowering effect in patients with type 2 diabetes and microalbuminuria. Recently, two landmark studies led to the following conclusion: "Losartan and Irbesartan conferred significant renal benefit in patients with type 2 diabetes and nephropathy. This protection is independent of the reduction in blood pressure it causes. The ARB is generally safe and well tolerated." A recent metaanalysis indicates that ARBs reduce cardiovascular events mainly because of reduction in first hospitalization for congestive heart failure in hypertensive type 2 diabetic patients with albuminuria. The studies mentioned here suggest that ARB represents a beneficial treatment of hypertension and proteinuria in incipient and overt diabetic nephropathy.
Blockade of the renin–angiotensin system for the primary prevention of diabetic nephropathy
Diabetes management, 2012
The prevention of chronic kidney disease is a primary goal for diabetes management. Lowering blood pressure can reduce the incidence of microalbuminuria in Type 1 or Type 2 diabetes, especially in patients with hypertension. Blockade of the renin-angiotensin system (RAS) is an effective strategy to reduce blood pressure in diabetic patients, but no more so than other antihypertensive strategies. RAS blockers have a more favorable side-effects profile compared to other antihypertensive agents, meaning that generally patients are more likely to take them. Any 'independent' effect of RAS blockade for the primary prevention of diabetic nephropathy, beyond blood-pressure control, remains to be clearly established. New combination strategies using renin inhibitors or aldosterone antagonists, to achieve a more complete RAS blockade, have the potential to improve renal outcomes in patients with diabetes. Summary There is clear evidence for the pathogenic role of the renin-angiotensin system (RAS) in the progression of diabetic kidney. Treatment with either an a ngiotensin-converting enzyme inhibitor or angiotensin receptor blocker have been shown to reduce proteinuria and preserve renal function in patients with diabetes and chronic kidney disease. While such data provide a strong rationale for early and sustained blockade of the RAS for the primary prevention of kidney disease, clinical trial evidence to support this goal is limited and inconsistent. By contrast, data from observational and clinical trials clearly demonstrate the primacy of blood-pressure control in the development of diabetic kidney disease, especially in hypertensive patients. Whether RAS blockade offers additional benefits for primary prevention, over-and-above blood-pressure control, remains contentious. At best, any 'independent effects' on primary prevention are modest, and certainly not the panacea envisaged by many practitioners. However, the better tolerability, efficacy and side-effects profile of RAS blockers, and other actions on retinopathy and cardiovascular disease, means that most patients with diabetes currently receive RAS blockers as first line antihypertensive agents. The future development of more effective 'escape-proof' regimens currently offers the best way forward to realize the hope that RAS blockade will ultimately prevent diabetic kidney disease in the clinic as effectively as it does in animal models.