Augmented Pulmonary Vascular and Venous Constrictions to NG-Nitro-L-Arginine Methyl Ester in Rats with Monocrotaline-Induced Pulmonary Hypertension (original) (raw)
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Role of inhibition of nitric oxide production in monocrotaline-induced pulmonary hypertension
Journal of Applied Physiology, 1997
induced pulmonary hypertension (PH) is associated with impaired endothelium-dependent nitric oxide (NO)-mediated relaxation. To examine the role of NO in PH, Sprague-Dawley rats were given a single subcutaneous injection of normal saline [control (C)], 80 mg/kg MCT, or the same dose of MCT and a continuous subcutaneous infusion of 2 mg • kg 21 • day 21 of molsidomine, a NO prodrug (MCT1MD). Two weeks later, plasma NO 3 2 levels, pulmonary arterial pressure (Ppa), ratio of right-to-left ventricular weights (RV/LV) to assess right ventricular hypertrophy, and pulmonary histology were evaluated. The plasma NO 3 2 level in the MCT group was reduced to 9.2 6 1.5 µM (n 5 12) vs. C level of 17.7 6 1.8 µM (n 5 8; P , 0.02). In the MCT1MD group, plasma NO 3 2 level was 12.3 6 2.0 µM (n 5 8). Ppa and RV/LV in the MCT group were increased compared with C [Ppa, 34 6 3.4 mmHg (n 5 6) vs. 19 6 0.8 mmHg (n 5 8) and 0.41 6 0.01 (n 5 9) vs. 0.25 6 0.008 (n 5 8), respectively; P , 0.001]. In the MCT1MD group, Ppa and RV/LV were not different when compared with C [19 6 0.5 mmHg (n 5 5) and 0.27 6 0.01 (n 5 9), respectively; P , 0.001 vs. MCT]. Medial wall thickness of lung vessels in the MCT group was increased compared with C [31 6 1.5% (n 5 9) vs. 13 6 0.66% (n 5 9); P , 0.001], and MD partially prevented MCT-induced pulmonary vascular remodeling [22 6 1.2% (n 5 11); P , 0.001 vs. MCT and C]. These results indicate that a defect in the availability of bioactive NO may play an important role in the pathogenesis of MCT-induced PH. molsidomine; pulmonary vascular remodeling ENDOTHELIAL DYSFUNCTION is thought to underlie various clinical and experimental forms of pulmonary hypertension. The absence of a relaxation response to nitroglycerin in pulmonary microvessels in vitro is reported to be associated with a high mortality rate in children with congenital heart defect and pulmonary hypertension. Reduced nitric oxide (NO) generation in the lungs has been shown in this clinical group (8, 23). Impaired endothelium-dependent NO-mediated relaxation has been shown in isolated pulmonary arteries (PA) from humans suffering from Eisenmenger syndrome (9). However, there are conflicting reports about NO production in experimental models of pulmonary hypertension. There have been findings suggestive of increased NO production in chronic hypoxia-induced pulmonary hypertension in rats (16, 36) and monocrotaline (MCT)-induced pulmonary hypertension (20),
The Journal of physiology, 1994
1. The actions of inhibitors of the release or action of nitric oxide (NO) on pulmonary vascular resistance (PVR) were investigated in lungs isolated from pig, sheep, dog and man. 2. In pig, sheep and human lungs perfused with Krebs-dextran solution, both N omega-nitro-L-arginine methyl ester (L-NAME; 10(-5) M) and Methylene Blue (10(-4) M) increased basal PVR. This increase was reversed by sodium nitroprusside (10(-5) M). In pig lungs N omega-monomethyl-L-arginine (10(-4) M) increased PVR by 154%. This increase was partially reversed by L-arginine (10(-3) M). L-NAME had no effect in dog lungs. 3. Pulmonary artery pressure-flow (PPA/Q) relationships were studied over a wide range of flows. In pigs, sheep and human lungs perfused with Krebs-dextran solution, L-NAME increased the PPA/Q slope. This increase was reversed by sodium nitroprusside. In dog lungs L-NAME had no effect. 4. In blood-perfused lungs, the respective responses to L-NAME were similar to those observed with saline. A...
Some Aspects of Role of Nitric Oxide in the Mechanisms of Hypertension (Experimental Study)
Cardiology Research
Background: Modulation of endothelial function is a therapeutic option to reduce some of the significant complications of hypertension. However, the relationship between endothelial dysfunction reduced nitric oxide (NO) production, and the development of hypertension is not fully understood. To establish a potential pathogenetic link between impaired NO synthesis and hypertension, we investigated the results of competitive interaction of the substrate of NO synthase, Larginine, and its analog, an non-selective inhibitor of NO synthase, N-nitro-methyl ether-L-arginine (L-NAME), in experimental rats. Methods: Arterial hypertension was induced in male Wistar rats by intraperitoneal administration of L-NAME (Sigma-Aldrich) for 4-7 weeks. During the last 3 weeks, to a separate group of animals simultaneously with L-NAME, L-arginine (Sigma-Aldrich) was administered. In animals monitored for systolic and diastolic pressure, the level of NO in blood samples was determined spectrophotometrically using a Griess reagent. Results: Administration of L-NAME for 4-7 weeks induced an irreversible decrease of NO content in blood, a reversible increase of systolic pressure (SP) and diastolic pressure (DP), and an irreversible increase in pulse pressure (PP). In rats against the background of 7 weeks of intraperitoneal administration of L-NAME, during the last 3 weeks, they were injected with L-arginine, the SP and DP indices returned to their initial values, PP decreased and the NO content in arterial blood increased. Conclusions: The results of the study indicate the presence of residual endothelial dysfunction (characterized by insufficient NO) after the correction of hypertension. Therefore, in developing the new therapeutic approaches for the treatment of hypertension, it is necessary to include drugs that, in addition to correcting blood pressure, will support normalization, and potentiation of endothelial function and endogenous NO synthesis.
Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension
Nitric Oxide, 2012
Pulmonary hypertension (PH) is a rare disorder that without treatment is progressive and often fatal within 3 years. The treatment of PH involves the use of a diverse group of drugs and lung transplantation. Although nitrite was once thought to be an inactive metabolite of endothelial-derived nitric oxide (NO), there is increasing evidence that nitrite may be useful in the treatment of PH, but the mechanism by which nitrite exerts its beneficial effect remains uncertain. The purpose of this study was to investigate the effect of chronic sodium nitrite treatment in a PH model in the rat. Following induction of PH with a single injection of monocrotaline, 60 mg; daily ip injections of sodium nitrite (3 mg/kg) starting on day 14 and continuing for 21 days, resulted in a significantly lower pulmonary arterial pressure on day 35 when compared to values in untreated animals with monocrotaline-induced PH. In monocrotaline-treated rats, daily treatment with ip nitrite injections for 21 days decreased right ventricular mass and pathologic changes in small pulmonary arteries. Nitrite therapy did not change systemic arterial pressure or cardiac output when values were measured on day 35. The decreases in pulmonary arterial pressure in response to iv injections of sodium nitroprusside, sodium nitrite, and BAY 41-8543 were not different in rats with monocrotaline-induced pulmonary hypertension and rats with chronic nitrite therapy when compared to responses in animals in which pulmonary arterial pressure was increased with U46619. These findings are consistent with the hypothesis that the mechanisms that convert nitrite to vasoactive NO, activate soluble guanylyl cyclase and mediate the vasodilator response to NO or an NO derivative are not impaired. The present data are consistent with the results of a previous study in monocrotaline-induced PH in which systemic arterial pressure and cardiac output were not evaluated and are consistent with the hypothesis that nitrite is effective in the treatment of monocrotaline-induced PH in the rodent.
Bronchoconstriction and endogenous nitric oxide in isolated lungs of spontaneously hypertensive rats
European Journal of Pharmacology, 2004
Bronchoconstrictor responses were measured in lungs isolated from spontaneously hypertensive (SHR) and normotensive rats, perfused via the airways. Lungs from SHRs were more responsive than lungs from normotensive rats to methacholine, 5-hydroxytryptamine (5-HT), arachidonic acid or prostaglandin H 2 . The responses of SHR airways to methacholine or 5-HT were unaffected by pretreatment in vivo with an inhibitor of nitric oxide (NO) synthase, N N -nitro-L-arginine methyl ester hydrochloride (L-NAME, 30 mg kg À 1 ), although responses in normotensive airways to methacholine, but not to 5-HT, were enhanced. Antigen challenge of isolated lungs from actively sensitized rats elicited bronchoconstriction, not different between strains. Pretreatment with L-NAME increased the response to antigen challenge only in normotensive lungs. Compound 48/80 induced bronchoconstriction in lungs from either strain, equally. These responses to compound 48/80 were unaffected by L-NAME pretreatment. Thus, SHR airways lack relaxing factors and degranulation of mast cells in SHR lungs was not affected by endogenous NO. D
Journal of Pharmacology and Experimental Therapeutics, 2010
Pulmonary hypertension (PH) is a life-threatening disease with unclear vascular mechanisms. We tested whether PH involves abnormal pulmonary vasoconstriction and impaired vasodilation. Male Sprague-Dawley rats were exposed to hypoxia (9% O 2 ) for 2 weeks or injected with single dose of monocrotaline (MCT, 60 mg/kg s.c.). Control rats were normoxic or injected with saline. After the hemodynamic measurements were performed, pulmonary and mesenteric arteries were isolated for measurement of vascular function. Hematocrit was elevated in hypoxic rats. Right ventricular systolic pressure and Fulton's Index [right/(left ϩ septum) ventricular weight] were greater in hypoxic and MCT-treated rats than in normoxic rats. Pulmonary artery contraction by phenylephrine and 96 mM KCl was less in hypoxic and MCT-treated rats than in normoxic rats. Acetylcholine-induced relaxation was less in the pulmonary arteries of hypoxic and MCT-treated rats than of normoxic rats, suggesting reduced effects of endothelium-derived vasodilators. The nitric oxide synthase inhibitor, N -nitro-L-arginine methyl ester, and the guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3a]quinoxalin-1-one, inhibited acetylcholine relaxation, suggesting that it was mediated by nitric oxide (NO)-cGMP. The NO donor sodium nitroprusside caused less relaxation in the pulmonary arteries of hypoxic and MCT-treated than of normoxic rats, suggesting decreased responsiveness of vascular smooth muscle cells (VSMCs) to vasodilators. Phenylephrine and KCl contraction and acetylcholine and sodium nitroprusside relaxation were not different in the mesenteric arteries from all groups. In lung tissue sections, the wall thickness of pulmonary arterioles was greater in hypoxic and MCT-treated rats than in normoxic rats. The specific reductions in pulmonary, but not systemic, arterial vasoconstriction and vasodilation in hypoxiaand MCT-induced PH are consistent with the possibility of de-differentiation of pulmonary VSMCs to a more proliferative/ synthetic and less contractile phenotype in PH.
Inhaled nitric oxide is not a negative inotropic agent in a porcine model of pulmonary hypertension
The Journal of Thoracic and Cardiovascular Surgery, 1997
Background: Reports of pulmonary edema complicating inhaled nitric oxide therapy in patients with chronic heart failure and pulmonary hypertension have raised the concern that inhaled nitric oxide may have negative inotropic effects. Methods and results: We investigated the effect of multiple doses of inhaled nitric oxide (20, 40 and 80 ppm) on left ventricular contractile state in 10 open-chest pigs. Pressure-volume loops were generated during transient preload reduction to determine the end-systolic pressure-volume relationship and the stroke work-end-diastolic volume relation. Inhaled nitric oxide had no effect on systemic vascular resistance, cardiac output, end-systolic pressure-volume relationship or stroke workend-diastolic volume relation under normal conditions. After induction of pulmonary hypertension (intravenous thromboxane A z analog), inhalation of nitric oxide (80 ppm) resulted in a reduction in pulmonary vascular resistance (mean-standard error of the mean) from 10.4-3 to 6.5-2 Wood units (p < 0.001) and in pulmonary artery pressure from 44-4 to 33-4 mm Hg (p < 0.05). Left ventricular end-diastolic volume rose from 53-9 ml to 57-10 ml (p = 0.02). No statistically significant change in cardiac output or systemic vascular resistance was observed. Inhaled nitric oxide had no effect on end-systolic pressure-volume relationship or stroke work-end-diastolic volume relation. Conclusions: In a porcine model of pulmonary hypertension, inhaled nitric oxide does not impair left ventricular contractile function. Therefore the cause of pulmonary edema observed in some patients receiving inhaled nitric oxide is not due to a negative inotropic action of this therapy. (J Thorac Cardiovasc Surg 1997; 114:461-6) nhaled nitric oxide (NO) is currently being used in a number of clinical situations to selectively reduce 12 pulmonary vascular resistance. ' When given by the inhaled route, NO reduces pulmonary vascular resistance while leaving systemic vascular resistance From the Departments of Surgery, a Anesthesiology, b and Medicine,
Pediatric Research, 2005
Persistent pulmonary hypertension of the newborn is characterized by elevated pulmonary vascular resistance after birth leading to right-to-left shunting and systemic arterial hypoxemia. Inhaled nitric oxide (NO) is effective in reducing the need for extracorporeal membrane oxygenation, but it has potential toxicities, especially in an oxygen-rich environment. A number of other NO-based molecules have been given by inhalation, but their structure-function relationships have not been established. Recent studies have raised the idea that toxic and beneficial properties can be separated. We synthesized a novel organic nitrate [ethyl nitrate (ENO 2 )], tested it in vitro, and administered it to hypoxic piglets. ENO 2 lowered pulmonary artery pressure and raised the PO 2 in arterial blood but did not alter systemic vascular resistance or methemoglobin levels. In addition, we tested the effect of ENO 2 in the presence of the thiol glutathione, both in vivo and in vitro, and found its action to be enhanced. Although ENO 2 is less potent than inhaled NO on a doseequivalency basis, pretreatment of hypoxic animals with glutathione, which may be depleted in injured lungs, led to a markedly enhanced effect (largely mitigating the difference in potency).
INHIBITION OF ENDOTHELIAL NITRIC OXIDE BIOSYNTHESIS BY N-NITRO-l-ARGININE
Clinical and Experimental Pharmacology and Physiology, 1990
1. The actions of N-nitro-L-arginine (NOLA) on the release of nitric oxide (NO) from arterial endothelial cells was studied in rat isolated thoracic aortic rings and by bioassay of NO derived from cultured bovine aortic endothelial cells. 2. NOLA (3-10 mumol/L) caused concentration-dependent inhibition of acetylcholine-induced relaxation of phenylephrine-contracted rat aortic rings, which is dependent on the release of NO from the endothelium. The inhibitory actions of NOLA could be prevented by pre- and co-incubation with L-arginine (1 mmol/L). 3. Endothelium-independent relaxation induced by sodium nitroprusside was not affected by NOLA. 4. The release of NO from bovine aortic endothelial cells, induced by bradykinin (10 nmol/L), was detected by bioassay on pre-contracted rabbit aortic strips. NOLA (1-3 mumol/L, given through the cell column) reduced or abolished the release of NO, but did not affect relaxations of the bioassay tissues induced by glyceryl trinitrate or authentic NO. 5. These data indicate that NOLA potently inhibits the biosynthesis of NO from L-arginine, and thus prevents its release from arterial endothelial cells. It may be a useful pharmacological tool for probing the significance of NO biosynthesis in cardiovascular function.
Nitric oxide and pulmonary arterial pressures in pulmonary hypertension
Free Radical Biology and Medicine, 2004
Decreased production of vasodilator substances such as nitric oxide (NO) has been proposed as important in development of pulmonary arterial hypertension (PAH). We hypothesize that NO measured over time serves as a non invasive marker of severity of PAH and response to therapy. We prospectively and serially measured exhaled NO and carbon monoxide (CO), a vasodilator and anti-inflammatory product of heme oxygenases, in 17 PAH patients in conjunction with hemodynamic parameters over 2 years. Although pulmonary artery pressures and NO were similar in all patients at entry to the study, NO increased in the 12 individuals who survived to complete the study, and correlated with change in pulmonary artery pressures. In contrast, CO did not change or correlate with hemodynamic parameters. Investigation of NO-oxidant reaction products in PAH in comparison to controls suggests that NO synthesis is impaired in the lung and that reactive oxygen species may be involved in the pathophysiology of pulmonary hypertension. Endogenous NO is inversely related to pulmonary artery pressure in PAH, with successful therapy of PAH associated with increase in NO. D