Kafait Malik | University of Tennessee Health Science Center (original) (raw)

Papers by Kafait Malik

PubMed, Oct 1, 1988

This study was performed to determine the subtype of M2 muscarinic receptor that is involved in t... more This study was performed to determine the subtype of M2 muscarinic receptor that is involved in the action of cholinergic agents on prostaglandin (PG) synthesis as well as on the mechanical function of the isolated rabbit heart perfused at a constant flow rate with Krebs-Henseleit buffer. The increase in PG output elicited by acetylcholine (ACh) or arecaidine propargyl ester (APE), a selective M2 agonist was attenuated by both 11-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl-5,11-dihydro-6H- pyrido-[2,3-b][1,4]-benzodiazepine-6-one (AF-DX 116), an M2 alpha antagonist, and hexahydro-sila-difenidol (HHSiD), an M2 beta antagonist. The coronary vasodilating effect of ACh and APE was inhibited by HHSiD, but not by AF-DX 116, whereas the vasoconstrictor effect was blocked by AF-DX 116, but not by HHSiD. The decrease in heart rate produced by ACh or APE was blocked by AF-DX 116, but not by HHSiD; however, the decrease in developed tension produced by the cholinergic stimuli was abolished by all these muscarinic receptor antagonists. The increase in PG output or changes in the mechanical parameters of the heart produced by ACh or APE were not altered by adrenergic receptor antagonists, phentolamine and propranolol, or by the nicotinic receptor antagonist, hexamethonium. The effect of isoproterenol or exogenous arachidonic acid to enhance PG output was not altered by these M2 receptor antagonists; however, the cyclooxygenase inhibitor indomethacin abolished the output of PG elicited by these agents or by ACh or APE. These data indicate that the effect of cholinergic stimuli to promote cardiac PG synthesis and decrease developed tension is mediated through the activation of both M2 alpha and M2 beta subtypes of muscarinic receptors. The cholinergically induced vasodilating component of the coronary response is mediated through the activation of M2 beta, whereas the coronary vasoconstriction and the decrease in heart rate is mediated through the activation of M2 alpha muscarinic receptors.

PubMed, Apr 1, 1988

This study was performed to determine the subtype of muscarinic receptors involved in the action ... more This study was performed to determine the subtype of muscarinic receptors involved in the action of cholinergic stimuli on prostaglandin (PG) synthesis in the isolated rabbit heart perfused at a constant flow rate with Krebs Hanseleit buffer. Acetylcholine (ACh, 1.0-10.0 nmol), an M1 and M2 receptor agonist, and arecaidine propargyl ester (APE, 1.0-5.0 nmol), a selective M2 agonist, produced a dose-related increase in the output of 6-keto-PGF1 alpha and a decrease in heart rate, whereas 4-[m-chlorophenyl carbamoyl]-2-butynyl-trimethylammonium chloride (McN-A-343, 10 nmol-1.0 mumol), a selective M1 receptor agonist, did not alter PG output. The increase in PG output or the decrease in heart rate elicited by ACh or APE was abolished by atropine (0.1 microM), an M1 and M2 receptor antagonist, and by 11-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6-H-pyrido-[2,3-b] [1,4]-benzodiazepine-6-one (AF-DX-116, 1.0 microM), a selective M2 antagonist, but not by pirenzepine (1.0 microM), a selective M1 antagonist. The developed tension, which was also reduced by ACh and APE, but not by McN-A-343, was minimized by AF-DX-116 and not by lower concentrations of pirenzepine that attenuated the coronary vasodilator effect of McN-A-343. Lower doses of ACh (1.0-5.0 nmol) caused coronary vasodilation, whereas higher doses of ACh (10.0 nmol) and lower as well as higher doses of APE produced a biphasic effect--an initial vasodilation followed by vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Circulation Research, Oct 1, 1974

PubMed, Oct 1, 1976

Prostaglandins are primarily local or tissue hormones that have their effects at, or near to, the... more Prostaglandins are primarily local or tissue hormones that have their effects at, or near to, the site of synthesis. Some blood vessels synthesize prostaglandins intramurally, where their local release influences vascular tone and reactivity. Endogenous prostaglandins (primarily prostaglandin E2 (PGE2) participate in the regulation of vascular reactivity by opposing the vasoconstrictor and antinatriuretic actions of circulating pressor hormones; and by braking the release of norepinephrine from vasoconstrictor nerves. The proposal that one or more prostaglandins affect vascular reactivity is supported by the following observations: enhanced vascular reactivity to pressor stimuli occurs in organs with low basal rates of prostaglandin synthesis and after inhibition of prostaglandin synthetase in organs with high biosynthetic capacity; and exogenous PGE2 reversibly inhibits the vasoconstrictor activity of pressor stimuli.

Prostaglandins, May 1, 1973

Abstract In chloralose-anesthetized dogs, either PGE 2 , PGA 2 or acetylcholine (ACh) infused int... more Abstract In chloralose-anesthetized dogs, either PGE 2 , PGA 2 or acetylcholine (ACh) infused into a renal artery inhibited reversibly in the experimental kidney vasoconstriction-antidiuresis produced by renal nerve stimulation (RNS) or by pressor hormones given intravenously. The renal actions of RNS were reversed by PGE 2 and PGA 2 , whereas, those of norepinephrine were least affected. PGF 2α did not modify the renal actions of pressor stimuli. ACh inhibited the renal effects of RNS and norepinephrine to the same degree. PGE 2 (100 ng/min) inhibited the renal actions of adrenergic stimuli and angiotensin II to the same degree as PGA 2 , at a dose one-fifth that of PGA 2 , and at concentrations (ca 0.5 ng/ml blood) comparable to those of a substance, having the properties of PGE 2 , reported in renal venous effluent during escape from the renal vasoconstrictor-antidiuretic actions of pressor hormones.

Circulation Research, Jul 1, 1972

Renal vasodilation produced by two dissimilar vasodepressor polypeptides, bradykinin and eledoisi... more Renal vasodilation produced by two dissimilar vasodepressor polypeptides, bradykinin and eledoisin, was correlated with changes in renal venous concentrations of substances having the properties of prostaglandins of the E and F series in anesthetized dogs. Samples of renal venous blood were extracted for acidic lipids, and the prostaglandin E and prostaglandin F zones of the chromatographed extracts were eluted and assayed in vitro for prostaglandins of the E and F series by a parallel bioassay system (sensitivity 0.015 ng/ml blood). During the first 2 minutes of infusion, bradykinin increased the concentration of a prostaglandin E-like substance in renal venous blood from a mean control level of 0.16 ng/ml to 1.05 ng/ml (P <0.01); this increase occurred simultaneously with the greatest increase in renal blood flow to 432 ml/min from a control value of 282 ml/min. After 12 minutes of bradyldnin infusion, the concentration of the prostaglandin E-like substance had decreased to 0.30 ng/ml, and renal blood flow had fallen to 398 ml/min. In contrast, eledoisin infused in equidilator doses did not increase the concentration of the prostaglandin E-like substance. The concentration of prostaglandin F-like substances was not affected by either polypepride. A transient increase in urine flow occurred during the first 2 minutes of bradykinin infusion only. These results suggest that a prostaglandin E-like substance participates in the renal vasodilator and the diuretic responses to bradykinin. KEY WORDS renal vasodilation renal blood flow renal prostaglandins vasodilator polypeptides bioassay tissue hormones renal lipids

ID 51393 Poster Board 312 Hypertension is a major risk factor that contributes to kidney injury i... more ID 51393 Poster Board 312 Hypertension is a major risk factor that contributes to kidney injury in women. While the female sex hormone 17b-estradiol (E2) has been shown to be cardioprotective in experimental models of cardiovascular diseases, E2 replacement therapy in postmenopausal women has been controversial. We have shown previously that ovariectomy (used as a tool to deplete endogenous E2) augments angiotensin (Ang) II-induced increase in blood pressure and plasma level of 12(S)-hydroxyeicosatetraenoic acid (HETE), a major arachidonic acid metabolite produced by 12/15-lipoxygenase (ALOX15). ALOX15 and its arachidonic acid-derived metabolite 12(S)-HETE is implicated in cardiovascular and renal diseases. This study was conducted to investigate the contribution of ALOX15 to Ang II-induced renal dysfunction in intact and ovariectomized (OVX) female mice. Ang II (700 ng/kg/min) infused subcutaneously by osmotic pumps for 2 weeks caused a marked increase in water intake (mL; 10.5±0.64 vs 5.0±0.40), and renal dysfunction as evidenced by increased urine output (mL; 5.06±0.43 vs 1.56±0.15), decreased urine osmolality (mOm/Kg; 1.27±0.04 vs 2.10±0.06) and increased urinary excretion of vasopressin prosegment copeptin (pg/mL; 149.53±3.47 vs 122.13±1.00) measured by ELISA in OVX but not intact (with ovaries intact) wild type (WT) mice (n=4/group, p<0.05). These effects of Ang II were attenuated in intact and OVX Alox15 knockout (ALOX15KO) female mice (water intake: 4.0±0.41 and 5.25±0.47; urine output: 1.18±0.11 and 1.00±0.10; urine osmolality: 2.56±0.27 and 1.78±0.07; urinary excretion of copeptin: 122.9±0.56 and 118.03±3.76; n=4/group, p<0.05). Moreover, in OVX-WT mice with depleted plasma E2 (pg/mL; 1.00±0.26 vs 14.71±1.38; n=4, p<0.05, measured by ELISA), the effects of Ang II on renal hypertrophy expressed as total kidney/body weight ratio (mg/g; 12.19±0.55 vs 9.16±0.22; n=6, p<0.05) and reactive oxygen species production measured by increased 2-hydroxyethidium fluorescence on staining with dihydroethidium (arbitrary unit; 16.73±0.63 vs 4.33±0.09, n=4, p<0.05), were also enhanced compared to intact WT mice. These effects of Ang II were attenuated in both intact and OVX-ALOX15KO mice (plasma E2: 13.96±1.75 and 1.29±0.44, kidney/body weight: 9.48±0.18 and 10.10±0.33, reactive oxygen species: 1.55±0.07 and 1.82±0.02). These data suggest that ovariectomy or lack of 17b-estradiol promotes Ang II-induced hypertension and renal dysfunction, most likely by a mechanism dependent on ALOX15/12 (S)-HETE. Therefore, the selective inhibitors of ALOX15 or 12 (S)-HETE receptor antagonists could be useful for treating hypertension and associated pathogenesis in postmenopausal, hypoestrogenic women or females with ovarian failure. Furthermore, it has been reported that that two single-nucleotide polymorphisms in the Alox12 gene, rs9904779 and rs434473 (encoding a replacement of asparagine by serine in the protein), was associated with onset of natural menopause in a small set of white women studied. Therefore, it would be important to explore ALOX15 gene polymorphism further in a larger population of diverse groups of normal aging and pre-and postmenopausal females to determine its impact on the contribution of arachidonic acid-ALOX15 derived 12(S)-HETE in hypertension and its pathogenesis.

Circulation Research, Aug 1, 1976

American Journal of Physiology-regulatory Integrative and Comparative Physiology, Feb 1, 1984

We have investigated the role of prostaglandins (PG) in the modulation of adrenergic neuroeffecto... more We have investigated the role of prostaglandins (PG) in the modulation of adrenergic neuroeffector events by examining the effect of PGI2 and PGE2 and their precursor, arachidonic acid, on the decrease in renal blood flow elicited by renal nerve stimulation or by injected norepinephrine in pentobarbital-anesthetized rats, with or without pretreatment with the cyclooxygenase inhibitor, sodium meclofenamate. Administration of PGI2 or PGE2 (0.4 micrograms X kg-1 X min-1) or arachidonic acid (5 micrograms X kg-1 X min-1) into the renal artery reduced vascular resistance and inhibited the vasoconstrictor response elicited by renal nerve stimulation or by injected norepinephrine. In contrast, administration of sodium meclofenamate (10 mg/kg iv + 30 micrograms X kg-1 X min-1) into the renal artery increased renal vascular resistance and enhanced the renal vasoconstrictor response to both adrenergic stimuli. In animals pretreated with the cyclooxygenase inhibitor, the ability of arachidonic acid, but not that of either PGE2 or PGI2, to reduce renal vascular resistance and the vasoconstrictor response to either nerve stimulation or injected norepinephrine was abolished. These data indicate that one or more prostaglandins, probably PGE2 or PGI2, formed in the kidney reduce renal vascular tone by their direct action on the vascular smooth muscle and by attenuating the influence of adrenergic stimuli on renal vasculature.

American Journal of Physiology-renal Physiology, Apr 1, 1984

We studied the contribution of prostaglandins to the actions of bradykinin at the renal vascular ... more We studied the contribution of prostaglandins to the actions of bradykinin at the renal vascular adrenergic neuroeffector junction by examining the effect of the peptide on the decrease in renal blood flow elicited by renal nerve stimulation and injected norepinephrine in pentobarbital-anesthetized rats with or without pretreatment with the cyclooxygenase inhibitors sodium meclofenamate or indomethacin. Infusion of bradykinin, 10 ng X kg-1 X min-1, into the renal artery reduced both the basal and the rise in renal vascular resistance produced by nerve stimulation or norepinephrine. The prostaglandin precursor arachidonic acid, 5 micrograms X kg-1 X min-1, infused into the renal artery, also reduced renal vascular resistance and the vasoconstrictor response elicited by either adrenergic stimulus. In animals pretreated with either sodium meclofenamate or indomethacin, the effect of arachidonic acid, but not that of bradykinin, to produce renal vasodilation and to attenuate adrenergically induced renal vasoconstriction was abolished. These data suggest that bradykinin produces renal vasodilation and inhibits the renal vasoconstrictor effect of adrenergic stimuli in the rat kidney in vivo by a mechanism unrelated to prostaglandin synthesis.

American Journal of Physiology, Nov 1, 1972

The APS Journal Legacy Content is the corpus of 100 years of historical scientific research from ... more The APS Journal Legacy Content is the corpus of 100 years of historical scientific research from the American Physiological Society research journals. This package goes back to the first issue of each of the APS journals including the American Journal of Physiology, first published in 1898. The full text scanned images of the printed pages are easily searchable. Downloads quickly in PDF format.

The FASEB Journal, May 1, 2022

Polycystin-1 (PC-1, PKD1), a receptor-like protein expressed by the Pkd1 gene, is present in a wi... more Polycystin-1 (PC-1, PKD1), a receptor-like protein expressed by the Pkd1 gene, is present in a wide variety of cell types, but its cellular location, signaling mechanisms, and physiological functions are poorly understood. Here, by studying tamoxifen-inducible, endothelial cell (EC)-specific Pkd1 knockout (Pkd1 ecKO) mice, we show that flow activates PC-1-mediated, Ca2+-dependent cation currents in ECs. EC-specific PC-1 knockout attenuates flow-mediated arterial hyperpolarization and vasodilation. PC-1-dependent vasodilation occurs over the entire functional shear stress range and via the activation of endothelial nitric oxide synthase (eNOS) and intermediate (IK)- and small (SK)-conductance Ca2+-activated K+ channels. EC-specific PC-1 knockout increases systemic blood pressure without altering kidney anatomy. PC-1 coimmunoprecipitates with polycystin-2 (PC-2, PKD2), a TRP polycystin channel, and clusters of both proteins locate in nanoscale proximity in the EC plasma membrane. Knockout of either PC-1 or PC-2 (Pkd2 ecKO mice) abolishes surface clusters of both PC-1 and PC-2 in ECs. Single knockout of PC-1 or PC-2 or double knockout of PC-1 and PC-2 (Pkd1/Pkd2 ecKO mice) similarly attenuates flow-mediated vasodilation. Flow stimulates nonselective cation currents in ECs that are similarly inhibited by either PC-1 or PC-2 knockout or by interference peptides corresponding to the C-terminus coiled-coil domains present in PC-1 or PC-2. In summary, we show that PC-1 regulates arterial contractility through the formation of an interdependent signaling complex with PC-2 in ECs. Flow stimulates PC-1/PC-2 clusters in the EC plasma membrane, leading to eNOS, IK channel, and SK channel activation, vasodilation, and a reduction in blood pressure.

bioRxiv (Cold Spring Harbor Laboratory), Jun 6, 2023

Endothelial cells (ECs) regulate vascular contractility to control regional organ blood flow and ... more Endothelial cells (ECs) regulate vascular contractility to control regional organ blood flow and systemic blood pressure. Several cation channels are expressed in ECs which regulate arterial contractility. In contrast, the molecular identity and physiological functions of anion channels in ECs is unclear. Here, we generated tamoxifen-inducible, EC-specific TMEM16A knockout (TMEM16A ecKO) mice to investigate the functional significance of this chloride (Cl-) channel in the resistance vasculature. Our data demonstrate that TMEM16A channels generate calcium-activated Clcurrents in ECs of control (TMEM16A fl/fl) mice that are absent in ECs of TMEM16A ecKO mice. Acetylcholine (ACh), a muscarinic receptor agonist, and GSK101, a TRPV4 agonist, activate TMEM16A currents in ECs. Single molecule localization microscopy data indicate that surface TMEM16A and TRPV4 clusters locate in very close nanoscale proximity, with ~18% exhibiting overlap in ECs. ACh stimulates TMEM16A currents by activating Ca 2+ influx through surface TRPV4 channels without altering the size or density of TMEM16A or TRPV4 surface clusters, their spatial proximity or colocalization. ACh-induced activation of TMEM16A channels in ECs produces hyperpolarization in pressurized arteries. ACh, GSK101 and intraluminal ATP, another vasodilator, all dilate pressurized arteries through TMEM16A channel activation in ECs. Furthermore, EC-specific knockout of TMEM16A channels elevates systemic blood pressure in conscious mice. In summary, these data indicate that vasodilators stimulate TRPV4 channels, leading to Ca 2+-dependent activation of nearby TMEM16A channels in ECs to produce arterial hyperpolarization, vasodilation and a reduction in blood pressure. We identify TMEM16A as an anion channel present in ECs that regulates arterial contractility and blood pressure. One sentence summary: Vasodilators stimulate TRPV4 channels, leading to calcium-dependent activation of nearby TMEM16A channels in ECs to produce arterial hyperpolarization, vasodilation and a reduction in blood pressure.

Hypertension, Sep 1, 2018

Previously we showed that the protection against angiotensin (Ang) II-induced hypertension and as... more Previously we showed that the protection against angiotensin (Ang) II-induced hypertension and associated pathophysiological changes in female mice are mediated by cytochrome P450 (CYP) 1B1-estradiol (E2) generated metabolite 2-methoxyestradiol (2-ME). Also, we demonstrated that Ang II-induced hypertension is mediated by group IV cytosolic phospholipase A 2 α (cPLA 2 α) activation resulting in arachidonic acid (AA) release, and generation predominantly of eicosanoids with pro-hypertensive effects in male mice. This study was conducted to determine the contribution of cPLA 2 α/AA system, and its relationship to CYP1B1 in Ang II-induced hypertension in the female mice. Ang II infusion (700 ng/kg/min, s.c. micro-osmotic pump) for 14 days increased the systolic blood pressure (SBP), measured by tail-cuff in wild-type mice (cPLA 2 α +/+ ) but not in cPLA 2 α gene-disrupted mice (cPLA 2 α -/- ) (151±8 vs. 126±9 mmHg, P &lt;0.05, n=4-5). Ang II markedly increased SBP in ovariectomized (OVX) cPLA 2 α +/+ mice but not in OVX cPLA 2 α -/- mice (175±3 vs. 121±2 mmHg, P &lt;0.05, n=4-5). AA metabolism inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA, 50 mg/kg, i.p. every 3 rd day) attenuated ( P &lt;0.05) the Ang II-induced increase in SBP in intact (124±5 mmHg, n=5) and OVX cPLA 2 α +/+ mice (124±5 mmHg, n=4). E2 attenuated Ang II-induced increase in SBP in OVX Cyp1b1 +/+ mice, but not in OVX Cyp1b1 -/- mice (125±5 vs. 158±4 mmHg, P &lt;0.05, n=3-4). Ang II-induced increase in SBP was also attenuated by ETYA in the Cyp1b1 -/- mice (129±7 vs. 185±7 mmHg, P &lt;0.05, n=4). Ang II-induced increase in cPLA 2 α +/+ activity examined in the kidneys was inhibited in Cyp1b1 -/- mice treated with 2-ME. Antagonists of prostaglandin (PG) E2 receptors EP1 (SC19220) and EP3 (L-798106) (28 μg/g, s.c. every 2 nd day) minimized Ang II-induced increase in SBP in OVX cPLA 2 α +/+ mice (126±2 and 127±5 vs. 175±3 mmHg, respectively, n=5). These data suggest that CYP1B1-E2 generated metabolite 2-ME protects against Ang II-induced hypertension by inhibiting cPLA 2 α activity and production of AA-derived PGE2 that exerts pro-hypertensive effects by stimulating EP1 and EP3 receptors. Thus, 2-ME and the drugs that selectively block EP1 and EP3 receptors could be useful for the treatment of hypertension and its pathogenesis in females.

Hypertension, Sep 1, 2013

Previously we have shown that Group IV cytosolic phospholipase A 2 α (cPLA 2 α) is critical for t... more Previously we have shown that Group IV cytosolic phospholipase A 2 α (cPLA 2 α) is critical for the development of angiotensin (Ang) II-induced hypertension, cardiovascular dysfunction and fibrosis. This study was conducted to determine the role of cPLA 2 α in renal dysfunction and end organ damage associated with Ang II-induced hypertension. Eight weeks old male wild type (cPLA 2 α +/+ ) and cPLA 2 α knockout (cPLA 2 α -/- ) mice were infused with Ang II (700 ng/kg/min) or its vehicle for 2 weeks and systolic blood pressure (SBP) was measured weekly by the tail cuff method. Ang II increased SBP (mmHg) in cPLA 2 α +/+ mice to a greater degree than in cPLA 2 α -/- mice (125 ± 2 to 186 ± 7 vs. 125 ± 2 to 132 ± 2 respectively, P&lt; 0.05). Ang II caused renal fibrosis as indicated by accumulation of α-smooth muscle actin, transforming growth factor-β-positive cells and collagen deposition in the kidneys of cPLA 2 α +/+ but not cPLA 2 α -/- mice. Ang II infusion increased reactive oxygen species production in the kidney measured by 2-hydroxyethidium fluorescence (AU), in cPLA 2 α +/+ mice (16.14 ± 0.61 vehicle vs. 24.08 ± 0.61 Ang II P &lt; 0.05) but not in cPLA 2 α -/- mice (16.93 ± 0.58 vehicle vs. 17.19 ± 0.93 Ang II). Mice were placed in metabolic cages to monitor their water intake and urine output. After 13 days of Ang II infusion, 24 hr water intake was increased (4.33 ± 0.14 ml to 8.17 ± 0.27 ml P &lt; 0.05) in cPLA 2 α +/+ mice but not in cPLA 2 α -/- mice (4.87 ± 0.22 ml to 4.8 ± 0.27 ml). Twenty-four hr urine output (μl) was increased to a greater extent in cPLA 2 α +/+ mice (423.33 ± 67.26 to 2030.94 ± 191.58 P &lt; 0.05) vs. cPLA 2 α -/- mice (374.37 ± 66.89 to 787.37 ± 126.50). Urine osmolality (mOsm/kg) was decreased (3778.33 ± 240.21 to 1620 ± 129.23 P &lt; 0.05) in cPLA 2 α +/+ but not in cPLA 2 α -/- mice (4042 ± 306.07 to 3372.5 ± 43.27), and proteinuria (mg/24hr) increased to a greater extent in cPLA 2 α +/+ mice (2.07 ± 0.11 to 6.99 ± 0.34 P &lt; 0.05) vs. cPLA 2 α -/- mice (1.95 ± 0.07 to 3.03 ± 0.20 in cPLA 2 α -/- ). These data suggest that cPLA 2 α contributes to Ang II-induced hypertension, associated renal dysfunction and end organ damage, most likely due to release of arachidonic acid, activation of NADPH oxidase and generation of ROS. Thus, cPLA 2 α could serve as a potential therapeutic target in the treatment of hypertension and end organ damage.

The Indian Journal of Pediatrics, 1963

Amongst the cases of subacute bacterial endocarditis in children, 75 per cent. are seen in eases ... more Amongst the cases of subacute bacterial endocarditis in children, 75 per cent. are seen in eases of congenital heart disease. The common congenital deformities invoved are bicuspid aortic valve, patent ducts arteriosus, coarctation of the aolta, ventricular septal defect, pulmonary stenosis or aortic stenosis at times. The incidence ofsubacute bacterial endocarditis reported is 6.5 per cent. among all cases having congenital heart diseases according to CULFMAN and LE~INA.

Molecular Psychiatry, Aug 10, 2022

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia afte... more Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer's disease (AD). Currently, the mechanistic insights into the evolution and progression of VCID remain elusive. White matter change represents an invariant feature. Compelling clinical neuroimaging and pathological evidence suggest a link between white matter changes and neurodegeneration. Our prior study detected hypoperfused lesions in mice with partial deficiency of endothelial nitric oxide (eNOS) at very young age, precisely matching to those hypoperfused areas identified in preclinical AD patients. White matter tracts are particularly susceptible to the vascular damage induced by chronic hypoperfusion. Using immunohistochemistry, we detected severe demyelination in the middle-aged eNOS-deficient mice. The demyelinated areas were confined to cortical and subcortical areas including the corpus callosum and hippocampus. The intensity of demyelination correlated with behavioral deficits of gait and associative recognition memory performances. By Evans blue angiography, we detected blood-brain barrier (BBB) leakage as another early pathological change affecting frontal and parietal cortex in eNOS-deficient mice. Sodium nitrate fortified drinking water provided to young and middle-aged eNOS-deficient mice completely prevented non-perfusion, BBB leakage, and white matter pathology, indicating that impaired endothelium-derived NO signaling may have caused these pathological events. Furthermore, genome-wide transcriptomic analysis revealed altered gene clusters most related to mitochondrial respiratory pathways selectively in the white matter of young eNOS-deficient mice. Using eNOS-deficient mice, we identified BBB breakdown and hypoperfusion as the two earliest pathological events, resulting from insufficient vascular NO signaling. We speculate that the compromised BBB and mild chronic hypoperfusion trigger vascular damage, along with oxidative stress and astrogliosis, accounting for the white matter pathological changes in the eNOS-deficient mouse model. We conclude that eNOS-deficient mice represent an ideal spontaneous evolving model for studying the earliest events leading to white matter changes, which will be instrumental to future therapeutic testing of drug candidates and for targeting novel/specific vascular mechanisms contributing to VCID and AD.

Hypertension, Sep 1, 2016

Men and post-menopausal females are more prone to develop hypertension and renal dysfunction as c... more Men and post-menopausal females are more prone to develop hypertension and renal dysfunction as compared to pre-menopausal females. It is well documented that in various experimental models of hypertension, the protection against hypertension in females is lost following ovariectomy (OVX). Recently we have shown that CYP1B1 protects against angiotensin II (Ang II)-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol (2-ME). This study was conducted to determine if 2-ME reduces Ang II-induced hypertension, renal dysfunction and end organ damage in OVX female, and intact male mice. Treatment of OVX Cyp1b1 +/+ and Cyp1b1 -/- female mice with 2-ME (1.5 mg/kg/day i.p., for 2 weeks) reduced Ang II-induced increase in systolic blood pressure (SBP) (182±5.1 vs. 143± 2.4 mmHg, 179±6.4 vs. 140± 8.6 mmHg, P &lt; 0.05, n= 5), water consumption, urine output and osmolality, and proteinuria (5.5±0.7 vs. 3.3±0.5 mg/24 hrs, 8.4±1.3 vs. 4.4 ±0.9 mg/24 hrs) respectively. 2-ME also reduced Ang II-induced increase in SBP (188±2.6 vs. 143± 2.7 mmHg, P &lt; 0.05, n= 5) in intact male mice. 2-ME did not alter water consumption and urine osmolality, but reduced urine output and sodium excretion, and proteinuria (14.4±2.0 vs. 6.0±0.5 mg/24 hrs) in intact Cyp1b1 +/+ male mice. Treatment with 2-ME attenuated Ang II-induced end-organ damage (actin and collagen accumulation) in OVX Cyp1b1 +/+ and Cyp1b1 -/- female and Cyp1b1 +/+ male mice. 2-ME mitigated urinary excretion of angiotensinogen in OVX Cyp1b1 +/+ and Cyp1b1 -/- female mice infused with Ang II. These data suggest that 2-ME reduces Ang II- induced hypertension and associated renal dysfunction and end-organ damage in OVX Cyp1b1 +/+ and Cyp1b1 -/- female, and intact male mice. Therefore, 2-ME could serve as a therapeutic agent for treatment of hypertension and associated pathogenesis in post-menopausal females, and intact males.

PubMed, Dec 1, 1983

We studied the effect of intracoronary angiotensin II (AII) infusion on the coronary sinus output... more We studied the effect of intracoronary angiotensin II (AII) infusion on the coronary sinus output of norepinephrine (NE) elicited by left cardiac sympathetic nerve stimulation in pentobarbital-anesthetized dogs pretreated with a prostaglandin synthesis inhibitor (indomethacin) or its vehicle. The NE output from the heart was determined from the NE levels in coronary sinus blood before and during cardiac sympathetic nerve stimulation. In both indomethacin- and vehicle-pretreated animals, infusion of AII (30 ng kg-1 min-1) into the left coronary artery augmented the coronary sinus output of NE elicited by sympathetic nerve stimulation, but had no effect on the basal output of NE from the heart. In both groups of animals, the AII-induced increase in NE output was associated with an increase in the effect of cardiac sympathetic nerve stimulation on left ventricular contractility (LVdP/dt max). All did not alter the removal of exogenous NE by the heart and moreover the AII-induced increase in the output of NE elicited by cardiac sympathetic nerve stimulation was also observed during blockade of neuronal and extraneuronal uptake with cocaine and normetanephrine, respectively. Therefore, the All-induced increase in the coronary sinus output of NE and LVdPl dt max elicited by cardiac sympathetic nerve stimulation is most likely due to enhanced NE release from adrenergic nerve terminals in the heart. The ability of All to increase the coronary sinus output of NE and the positive inotropic response elicited by cardiac sympathetic nerve stimulation was enhanced in animals pretreated with the cyclooxygenase inhibitor, indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)