Abstract P405: Cardioprotective Actions Of Nitroxyl Donor Angeli's Salt Are Preserved In The Diabetic Heart And Vasculature In The Face Of Nitric Oxide Resistance

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Anida Velagic ◽  
Jasmin Chendi Li ◽  
Chengxue Helena Qin ◽  
Mandy Li ◽  
Minh Deo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Therapeutic Potential ◽  
Left Ventricular ◽  
Maximal Rate ◽  
Sprague Dawley ◽  
Response Curves ◽  
No Donor ◽  
Coronary Vasculature ◽  
Acute Ischaemia ◽  
Angeli's Salt

Introduction: The risk of fatal cardiovascular events is increased in patients with type 2 diabetes mellitus (T2DM). A major contributor to poor prognosis is impaired nitric oxide (NO•) signalling at the level of tissue responsiveness, termed NO• resistance. Nitroxyl (HNO) induces positive inotropic and lusitropic effects in healthy and failing hearts. Hypothesis: We hypothesised that in a rodent model, T2DM will promote, and HNO will circumvent, NO• resistance in the myocardium and coronary vasculature. Methods: At 8 weeks of age, male Sprague-Dawley rats commenced a high-fat diet. After two weeks, the rats received low-dose streptozotocin (two intraperitoneal injections, 35 mg/kg, over two consecutive days), and continued the diet. Twelve weeks later, hearts were Langendorff-perfused to assess responses to the NO• donor diethylamine NONOate (DEA/NO) and the HNO donor Angeli’s salt. Results: Inotropic, lusitropic and coronary vasodilator responses to DEA/NO were impaired, and responses to Angeli’s salt were preserved or enhanced, in T2DM hearts compared with non-diabetic hearts. Conclusions: This is the first evidence that inotropic and lusitropic responses are preserved, and NO• resistance in the coronary vasculature is circumvented, by the HNO donor Angeli’s salt in T2DM. These findings highlight the cardiovascular therapeutic potential of HNO donors, especially in cardiac emergencies such as acute ischaemia or heart failure. Figure 1. Dose-response curves and maximal responses to DEA/NO or Angeli's salt in diabetic or non-diabetic hearts. (A-C) LV+dP/dt, (D-F) LV-dP/dt and (G-I) coronary flow rate. Data expressed as change from baseline (denoted by Δ), mean ± SEM. Data analysed by two-way RM ANOVA with Sidak's post-hoc test. *P<0.05 vs. non-diabetic. LV, left ventricular; LV+dP/dt, maximal rate of rise in LV pressure; LV-dP/dt, maximal rate of fall in LV pressure.

Abstract 156: The Nitroxyl Donor Angeli's Salt Elicits Concomitant Concentration-Dependent Coronary Vasodilatory and Inotropic Actions in the Intact Rat Heart

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Rebecca H Ritchie ◽  
Kai Yee Chin ◽  
Chengxue Qin ◽  
Nga Cao ◽  
Barbara K Kemp-Harper ◽  
...  
Keyword(s):  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Soluble Guanylyl Cyclase ◽  
High Reactivity ◽  
Left Ventricular ◽  
Lv Function ◽  
Sprague Dawley ◽  
Response Curves ◽  
Ventricular Systolic Pressure ◽  
Angeli's Salt

Nitroxyl (HNO) is a novel redox sibling of NO• that elicits vasodilator, antihypertrophic and superoxide-suppressing actions. HNO is however resistant to scavenging by superoxide, and has high reactivity with thiols (enabling potent enhancement of LV function). In the present study, hearts from adult male Sprague-Dawley rats were Langendorff-perfused at constant pressure. Dose-response curves to the HNO donor Angeli’s salt were performed following preconstriction with U46619 to ∼50% of baseline coronary flow (CF). Angeli’s salt (10pmol-10µmol, n=6) elicited significant dose-dependent increases in left ventricular systolic pressure (LVSP), LV developed pressure (LVDP), LV end-diastolic pressure (LVEDP), LV±dP/dt, and CF. The effects of the highest dose of Angeli's salt studied on LV function are shown in the Table; these were significantly inhibited by co-administration of the HNO scavenger L-cysteine (4mM, n=6) or the soluble guanylyl cyclase inhibitor ODQ (10µM, n=5). The EC 50 for Angeli's salt-induced vasodilatation was increased from -8.6±0.3mol to -7.5±0.2mol (p<0.01) and -7.6±0.3mol (p<0.05) by L-cysteine and ODQ, respectively. Although CGRP is a putative mediator of HNO actions, both the inotropic and vasodilator actions of Angeli's salt were insensitive to the CGRP antagonist CGRP 8-37 (0.1µM, n=5). The vehicle for Angeli’s salt, 0.01M NaOH, had no effect on any of these parameters (n=3, results not shown). Our results demonstrate that the cardiac effects of Angeli’s salt are thiol-sensitive, and mediated by HNO and cGMP, but not CGRP. HNO donors represent potential therapy for the failing heart, alone or in addition to standard care.

scholarly journals Selective estrogen receptor-α and estrogen receptor-β agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism

2008 ◽  
Vol 295 (5) ◽  
pp. R1486-R1493 ◽  
Author(s):  
Tim Lahm ◽  
Paul R. Crisostomo ◽  
Troy A. Markel ◽  
Meijing Wang ◽  
Yue Wang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Estrogen Receptor ◽  
Pulmonary Artery ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Organ Bath ◽  
Sprague Dawley ◽  
Response Curves ◽  
Vascular Effects ◽  
M 10 ◽  
Dependent Mechanism

Both endogenous and exogenous estrogen decrease pulmonary artery (PA) vasoconstriction. Whether these effects are mediated via estrogen receptor (ER)-α or ER-β, and whether the contribution of ERs is stimulus-dependent, remains unknown. We hypothesized that administration of the selective ER-α agonist propylpyrazole triol (PPT) and/or the selective ER-β agonist diarylpropiolnitrile (DPN) rapidly decreases PA vasoconstriction induced by pharmacologic and hypoxic stimuli via a nitric oxide (NO)-dependent mechanism. PA rings ( n = 3–10/group) from adult male Sprague-Dawley rats were suspended in physiologic organ baths. Force displacement was measured. Vasoconstrictor responses to phenylephrine (10−8M − 10−5M) and hypoxia (Po2 35–45 mmHg) were determined. Endothelium-dependent and -independent vasorelaxation were measured by generating dose-response curves to acetylcholine (10−8M − 10−4M) and sodium nitroprusside (10−9M − 10−5M). PPT or DPN (10−9M − 5 × 10−5M) were added to the organ bath in the presence and absence of the NO-synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) (10−4M). Selective ER-α activation (PPT, 5 × 10−5M) rapidly (<20 min) decreased phenylephrine-induced vasoconstriction. This effect, as well as PPT's effects on endothelium-dependent vasorelaxation, were neutralized by l-NAME. In contrast, selective ER-β activation (DPN, 5 × 10−5M) rapidly decreased phase II of hypoxic pulmonary vasoconstriction (HPV). l-NAME eliminated this phenomenon. Lower PPT or DPN concentrations were less effective. We conclude that both ER-α and ER-β decrease PA vasoconstriction. The immediate onset of effect suggests a nongenomic mechanism. The contribution of specific ERs appears to be stimulus specific, with ER-α primarily modulating phenylephrine-induced vasoconstriction, and ER-β inhibiting HPV. NO inhibition eliminates these effects, suggesting a central role for NO in mediating the pulmonary vascular effects of both ER-α and ER-β.

Maturational changes in the regulation of pulmonary vascular tone by nitric oxide in neonatal rats

2007 ◽  
Vol 293 (5) ◽  
pp. L1261-L1270 ◽  
Author(s):  
Louis G. Chicoine ◽  
Michael L. Paffett ◽  
Mark R. Girton ◽  
Matthew J. Metropoulus ◽  
Mandar S. Joshi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Guanylyl Cyclase ◽  
Vascular Tone ◽  
Age Groups ◽  
Soluble Guanylyl Cyclase ◽  
No Production ◽  
Sprague Dawley ◽  
No Donor ◽  
Early Postnatal Development ◽  
Old Rats

Nitric oxide (NO) is an important regulator of vasomotor tone in the pulmonary circulation. We tested the hypothesis that the role NO plays in regulating vascular tone changes during early postnatal development. Isolated, perfused lungs from 7- and 14-day-old Sprague-Dawley rats were studied. Baseline total pulmonary vascular resistance (PVR) was not different between age groups. The addition of KCl to the perfusate caused a concentration-dependent increase in PVR that did not differ between age groups. However, the nitric oxide synthase (NOS) inhibitor Nω-nitro-l-arginine augmented the K+-induced increase in PVR in both groups, and the effect was greater in lungs from 14-day-old rats vs. 7-day-old rats. Lung levels of total endothelial, inducible, and neuronal NOS proteins were not different between groups; however, the production rate of exhaled NO was greater in lungs from 14-day-old rats compared with those of 7-day-old rats. Vasodilation to 0.1 μM of the NO donor spermine NONOate was greater in 14-day lungs than in 7-day lungs, and lung levels of both soluble guanylyl cyclase and cGMP were greater at 14 days than at 7 days. Vasodilation to 100 μM of the cGMP analog 8-(4-chlorophenylthio)guanosine-3′,5′-cyclic monophosphate was greater in 7-day lungs than in 14-day lungs. Our results demonstrate that the pulmonary vascular bed depends more on NO production to modulate vascular tone at 14 days than at 7 days of age. The observed differences in NO sensitivity may be due to maturational increases in soluble guanylyl cyclase protein levels.

Abstract P607: Nitric Oxide (NO) Regulates Paracellular Permselectivity in Isolated, Perfused Rat Thick Ascending Limbs through Claudin-19

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Casandra M Monzon ◽  
Jeffrey Garvin
Keyword(s):  
Nitric Oxide ◽  
Control Period ◽  
Sprague Dawley ◽  
Permeability Ratio ◽  
Ionic Selectivity ◽  
No Donor ◽  
Sprague Dawley Rats ◽  
Spermine Nonoate ◽  
Dilution Potential ◽  
Cl Permeability

About 50% of the Na reabsorbed in thick ascending limbs (TALs) traverses the paracellular pathway. The ionic selectivity of this route is regulated by claudins in the tight junctions. TALs express claudin-19 which has been reported to regulate TAL Na permeability. We showed that nitric oxide (NO) decreases Na/Cl permeability ratio (PNa/PCl) in TALs by increasing the absolute permeabilities of both ions though PCl increased more. However, whether NO affects paracellular permeability via claudin-19 is unknown. We hypothesize that NO regulates the paracellular permselectivity in TALs through this claudin. To test this we perfused TALs from Sprague Dawley rats and measured dilution potentials (a measure of permselectivity) with and without exogenously-added or endogenously-produced NO in the presence or absence of an antibody against an extracellular domain of claudin-19 or Tamm-Horsfall protein (control). Dilution potentials were generated by reducing bath NaCl from 141 to 32 mM. For the NO donor spermine NONOate (SPM): during the control period, the dilution potential was -9.3 ± 1.8 mV. After SPM (200 μM), it was -6.7 ± 1.6 mV (n = 6; p < 0.003). In the presence of the claudin-19 antibody, SPM had no significant effect on dilution potentials (claudin-19 antibody alone: -12.7 ± 2.1 mV vs claudin-19 antibody + SPM: -12.9 ± 2.4 mV; n = 6). The claudin-19 antibody alone had no effect on dilution potentials. In the presence of the Tamm-Horsfall protein, the effect of SPM was still present (Tamm-Horsfall protein antibody alone: -9.7 ± 1.0 mV; Tamm-Horsfall protein antibody + SPM: -6.3 ± 1.1 mV, p<0.006, n = 6). For experiments with endogenously-produced NO, L-arginine the substrate for NO synthase was added. During the control period, the dilution potential was -11.0 ± 1.1 mV. After L-arginine (500 μM) treatment, they were -9.0 ± 1.2 mV (n = 9; p < 0.05). In the presence of the claudin-19 antibody, L-arginine had no significant effect on dilution potentials (claudin-19 antibody alone: -10.1 ± 0.9 mV vs claudin-19 antibody + L-arginine: -10.1 ± 1.0 mV; n = 9). In the presence of the Tamm-Horsfall protein, the effect of L-arginine was still present. We conclude that the actions of NO on the paracellular permselectivity in thick ascending limbs are at least in part mediated by claudin-19.

Vascular endothelial function is improved by oral glycine treatment in aged rats

2015 ◽  
Vol 93 (6) ◽  
pp. 465-473 ◽  
Author(s):  
Jaime H. Gómez-Zamudio ◽  
Rebeca García-Macedo ◽  
Martha Lázaro-Suárez ◽  
Maximiliano Ibarra-Barajas ◽  
Jesús Kumate ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mrna Expression ◽  
Interleukin 1 ◽  
Aged Rats ◽  
Sprague Dawley ◽  
Response Curves ◽  
Proinflammatory Mediators ◽  
Nadph Oxidase 4 ◽  
Tnf Α ◽  
Cox 2

Glycine has been used to reduce oxidative stress and proinflammatory mediators in some metabolic disorders; however, its effect on the vasculature has been poorly studied. The aim of this work was to explore the effect of glycine on endothelial dysfunction in aged rats. Aortic rings with intact or denuded endothelium were obtained from untreated or glycine-treated male Sprague–Dawley rats at 5 and 15 months of age. Concentration–response curves to phenylephrine (PHE) were obtained from aortic rings incubated with NG-nitro-l-arginine methyl ester (l-NAME), superoxide dismutase (SOD), indomethacin, SC-560, and NS-398. Aortic mRNA expression of endothelial nitric oxide synthase (eNOS), NADPH oxidase 4 (NOX-4), cyclooxygenase 1 (COX-1), cyclooxygenase 2 (COX-2), tumour necrosis factor (TNF)-α, and interleukin-1 β was measured by real time RT–PCR. The endothelial modulation of the contraction by PHE was decreased in aortic rings from aged rats. Glycine treatment improved this modulator effect and increased relaxation to acetylcholine. Glycine augmented the sensitivity for PHE in the presence of l-NAME and SOD. It also reduced the contraction by incubation with indomethacin, SC-560, and NS-398. Glycine increased the mRNA expression of eNOS and decreased the expression of COX-2 and TNF-α. Glycine improved the endothelium function in aged rats possibly by enhancing eNOS expression and reducing the role of superoxide anion and contractile prostanoids that increase the nitric oxide bioavailability.

scholarly journals The Effect of Mitochondrial Complex I-Linked Respiration by Isoflurane Is Independent of Mitochondrial Nitric Oxide Production

2018 ◽  
Vol 8 (2) ◽  
pp. 113-122 ◽  
Author(s):  
Fuqi Xu ◽  
Shigang Qiao ◽  
Hua Li ◽  
Yanjun Deng ◽  
Chen Wang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mitochondrial Respiration ◽  
Complex I ◽  
Adenosine Diphosphate ◽  
Sprague Dawley ◽  
No Donor ◽  
Anesthetic Preconditioning ◽  
Rat Hearts ◽  
Nos Inhibitor

Background: Anesthetic preconditioning (APC) of the myocardium is mediated in part by reversible alteration of mitochondrial function. Nitric oxide (NO) inhibits mitochondrial respiration and may mediate APC-induced cardioprotection. In this study, the effects of isoflurane on different states of mitochondrial respiration during the oxidation of complex I-linked substrates and the role of NO were investigated. Methods: Mitochondria were isolated from Sprague-Dawley rat hearts. Respiration rates were measured polarographically at 28ºC with a computer-controlled Clark-type O2 electrode in the mitochondria (0.5 mg/mL) with complex I substrates glutamate/malate (5 mM). Isoflurane (0.25 mM) was administered before or after adenosine diphosphate (ADP)-initiated state 3 respiration. The NO synthase (NOS) inhibitor L-N5-(1-iminoethyl)-ornithine (L-NIO, 10 μM) and the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 1 μM) were added before or after the addition of ADP. Results: Isoflurane administered in state 2 increased state 2 respiration and decreased state 3 respiration. This attenuation of state 3 respiration by isoflurane was similar when it was given during state 3. L-NIO did not alter mitochondrial respiration or the effect of isoflurane. SNAP only, added in state 3, decreased state 3 respiration and enhanced the isoflurane-induced attenuation of state 3 respiration. Conclusion: Isoflurane has clearly distinguishable effects on different states of mitochondrial respiration during the oxidation of complex I substrates. The uncoupling effect during state 2 respiration and the attenuation of state 3 respiration may contribute to the mechanism of APC-induced cardioprotection. These effects of isoflurane do not depend on endogenous mitochondrial NO, as the NOS inhibitor L-NIO did not alter the effects of isoflurane on mitochondrial respiration.

The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction

2010 ◽  
Vol 299 (6) ◽  
pp. H2037-H2045 ◽  
Author(s):  
Lennart G. Bongartz ◽  
Branko Braam ◽  
Marianne C. Verhaar ◽  
Maarten Jan M. Cramer ◽  
Roel Goldschmeding ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Low Dose ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Dysfunction ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
No Synthase ◽  
Nitric Oxide Donor ◽  
No Production ◽  
No Donor

We recently developed a rat model of cardiorenal failure that is characterized by severe left ventricular systolic dysfunction (LVSD) and low nitric oxide (NO) production that persisted after temporary low-dose NO synthase inhibition. We hypothesized that LVSD was due to continued low NO availability and might be reversed by supplementing NO. Rats underwent a subtotal nephrectomy and were treated with low-dose NO synthase inhibition with Nω-nitro-l-arginine up to week 8. After 3 wk of washout, rats were treated orally with either the long-acting, tolerance-free NO donor molsidomine (Mols) or vehicle (Veh). Cardiac and renal function were measured on weeks 11, 13, and 15. On week 16, LV hemodynamics and pressure-volume relationships were measured invasively, and rats were killed to quantify histological damage. On week 15, blood pressure was mildly reduced and creatinine clearance was increased by Mols (both P < 0.05). Mols treatment improved ejection fraction (53 ± 3% vs. 37 ± 2% in Veh-treated rats, P < 0.001) and stroke volume (324 ± 33 vs. 255 ± 15 μl in Veh-treated rats, P < 0.05). Rats with Mols treatment had lower end-diastolic pressures (8.5 ± 1.1 mmHg) than Veh-treated rats (16.3 ± 3.5 mmHg, P < 0.05) and reduced time constants of relaxation (21.9 ± 1.8 vs. 30.9 ± 3.3 ms, respectively, P < 0.05). The LV end-systolic pressure-volume relationship was shifted to the left in Mols compared with Veh treatment. In summary, in a model of cardiorenal failure with low NO availability, supplementing NO significantly improves cardiac systolic and diastolic function without a major effect on afterload.

Abstract 12177: Inhaled Nitric Oxide During Cardiopulmonary Resuscitation Improves Functional Outcome and Increases 7-Day-Survival After Prolonged Cardiac Arrest in Rats

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Anne Brücken ◽  
Christian Bleilevens ◽  
Matthias Derwall ◽  
Michael Fries
Keyword(s):  
Nitric Oxide ◽  
Cardiac Arrest ◽  
Cardiopulmonary Resuscitation ◽  
Functional Outcome ◽  
Statistical Significance ◽  
Spontaneous Circulation ◽  
Left Ventricular ◽  
Inhaled Nitric Oxide ◽  
Sprague Dawley ◽  
Pulmonary Vasodilator

Introduction: Precordial compressions during cardiac arrest (CA) increase pulmonary vascular resistance (PVR), potentially impeding survival by limiting left ventricular preload. Although used as selective pulmonary vasodilator there is accumulating evidence that inhaled nitric oxide (iNO) also attenuates I/R injury. Hypothesis: Applying iNO during cardiopulmonary resuscitation (CPR) increases resuscitation rates and improves functional outcome after cardiac arrest in rats. Methods: Thirty male Sprague-Dawley rats were subjected to 10 mins of CA and 3 mins of CPR. Animals were randomized to receive either 20 ppm or 40 ppm iNO during CPR until 30 mins after ROSC (return of spontaneous circulation) or no iNO treatment. For all animals a neurological deficit score (NDS) was calculated daily for seven days following the experiment. Results: Inhalation of 20 ppm iNO increased ROSC rates in comparison to animals treated with 40 ppm or without iNO treatment, however this failed to reach statistical significance (control: 7/10; 20ppm iNO: 10/10; 40ppm iNO 6/10). 20 ppm iNO significantly decreased time to ROSC, resulting in a significant reduction of post-arrest lactate levels. Also, significantly higher mean arterial pressures in comparison to control animals were observed. Furthermore, 20 ppm iNO resulted in a significantly higher seven-day-survival in comparison to controls (control: 4/10; 20 ppm iNO: 10/10). All iNO treated animals showed better neurological outcomes, being significant in animals treated with 20 ppm iNO on postoperative day 2- 7. Conclusions: Our study demonstrates that 20 ppm but not 40 ppm iNO during CPR significantly decreases time to ROSC. Furthermore, significantly better seven-day-survival and neurological outcome was noted for 20 ppm iNO in comparison to controls.

scholarly journals Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 inhibition in thick ascending limbs

2016 ◽  
Vol 310 (8) ◽  
pp. F748-F754 ◽  
Author(s):  
Vanesa D. Ramseyer ◽  
Pablo A. Ortiz ◽  
Oscar A. Carretero ◽  
Jeffrey L. Garvin
Keyword(s):  
Nitric Oxide ◽  
Pde5 Inhibitor ◽  
Cell Types ◽  
No Production ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
No Donor ◽  
Induced Hypertension ◽  
Stimulation Of

In thick ascending limbs (THALs), nitric oxide (NO) decreases NaCl reabsorption via cGMP-mediated inhibition of Na-K-2Cl cotransporter (NKCC2). In angiotensin (ANG II)-induced hypertension, endothelin-1 (ET-1)-induced NO production by THALs is impaired. However, whether this alters NO's natriuretic effects and the mechanisms involved are unknown. In other cell types, ANG II augments phosphodiesterase 5 (PDE5)-mediated cGMP degradation. We hypothesized that NO-mediated inhibition of NKCC2 activity and stimulation of cGMP synthesis are blunted via PDE5 in ANG II-induced hypertension. Sprague-Dawley rats were infused with vehicle or ANG II (200 ng·kg−1·min−1) for 5 days. ET-1 reduced NKCC2 activity by 38 ± 13% ( P < 0.05) in THALs from vehicle-treated rats but not from ANG II-hypertensive rats (Δ: −9 ± 13%). A NO donor yielded similar results as ET-1. In contrast, dibutyryl-cGMP significantly decreased NKCC2 activity in both vehicle-treated and ANG II-hypertensive rats (control: Δ−44 ± 15% vs. ANG II: Δ−41 ± 10%). NO increased cGMP by 2.08 ± 0.36 fmol/μg protein in THALs from vehicle-treated rats but only 1.06 ± 0.25 fmol/μg protein in ANG II-hypertensive rats ( P < 0.04). Vardenafil (25 nM), a PDE5 inhibitor, restored NO's ability to inhibit NKCC2 activity in THALs from ANG II-hypertensive rats (Δ: −60 ± 9%, P < 0.003). Similarly, NO's stimulation of cGMP was also restored by vardenafil (vehicle-treated: 1.89 ± 0.71 vs. ANG II-hypertensive: 2.02 ± 0.32 fmol/μg protein). PDE5 expression did not differ between vehicle-treated and ANG II-hypertensive rats. We conclude that NO-induced inhibition of NKCC2 and increases in cGMP are blunted in ANG II-hypertensive rats due to PDE5 activation. Defects in the response of THALs to NO may enhance NaCl retention in ANG II-induced hypertension.

Age-dependent augmentation of cardiac endothelial NOS in a genetic rat model of heart failure

1997 ◽  
Vol 273 (3) ◽  
pp. H1223-H1230 ◽  
Author(s):  
F. H. Khadour ◽  
R. H. Kao ◽  
S. Park ◽  
P. W. Armstrong ◽  
B. J. Holycross ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Left Ventricular ◽  
Shr Rats ◽  
Sprague Dawley ◽  
Spontaneously Hypertensive ◽  
Nitrite Level ◽  
Sd Rats ◽  
Enhanced Expression ◽  
Nitrate And Nitrite

Alterations in nitric oxide (NO) biosynthesis in the heart have been implicated in the pathophysiology of heart failure. We compared changes in cardiac nitric oxide synthase (NOS) activity and expression in genetically heart failure-prone (SHHF) rats at 6, 12, and 18 mo of age with those in age-matched spontaneously hypertensive (SHR) and Sprague-Dawley (SD) rats. Systolic blood pressure was significantly higher in SHHF and SHR rats compared with SD rats; however, it declined with age in SHHF rats only. Left ventricular mass increased with age in SHR and SHHF, but not in SD rats. Plasma nitrate and nitrite level was elevated in SHHF and SHR rats at 18 mo only. In left ventricular homogenates from SHHF rats, Ca(2+)-dependent NOS activity increased markedly with age and was accompanied by enhanced expression of endothelial NOS (eNOS). In contrast, SHR rats showed a much smaller increase in Ca(2+)-dependent NOS activity over time without changes in eNOS expression; neither parameter was altered with age in SD rats. Ca(2+)-independent NOS activity was not detected in any heart. This is the first report of a unique alteration in myocardial NOS activity in hypertensive rats genetically prone to heart failure.

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