Endothelial control of the pulmonary circulation in normal and chronically hypoxic rats (original) (raw)
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AJP: Heart and Circulatory Physiology, 2013
Chronic hypoxia (CH)-induced pulmonary hypertension is characterized by vasoconstriction and vascular remodeling, leading to right ventricular dysfunction. Given the role of arterial compliance ( Ca) in right ventricular work, a decrease in Ca would add to right ventricular work. Nitric oxide (NO) is a potent vasodilator made by NO synthases from l-arginine (l-Arg). However, little is known of the effect of l-Arg on vascular compliance ( Cv) in the lung. We hypothesized that exposure to CH would decrease Ca and that this effect would be reversed by exogenous l-Arg. Sprague-Dawley rats were exposed to either normoxia or CH for 14 days; the lungs were then isolated and perfused. Vascular occlusions were performed and modeled using a three-compliance, two-resistor model. Pressure-flow curves were generated, and a distensible vessel model was used to estimate distensibility and a vascular resistance parameter ( R0). Hypoxia resulted in the expected increase in arterial resistance ( Ra) ...
American Journal of Physiology-heart and Circulatory Physiology, 2013
Chronic hypoxia (CH)-induced pulmonary hypertension is characterized by vasoconstriction and vascular remodeling, leading to right ventricular dysfunction. Given the role of arterial compliance (Ca) in right ventricular work, a decrease in Ca would add to right ventricular work. Nitric oxide (NO) is a potent vasodilator made by NO synthases from L-arginine (L-Arg). However, little is known of the effect of L-Arg on vascular compliance (Cv) in the lung. We hypothesized that exposure to CH would decrease Ca and that this effect would be reversed by exogenous L-Arg. Sprague-Dawley rats were exposed to either normoxia or CH for 14 days; the lungs were then isolated and perfused. Vascular occlusions were performed and modeled using a three-compliance, two-resistor model. Pressure-flow curves were generated, and a distensible vessel model was used to estimate distensibility and a vascular resistance parameter (R0). Hypoxia resulted in the expected increase in arterial resistance (Ra) as well as a decrease in both Ca and Cv. L-Arg had little effect on Ra, Ca, or Cv in isolated lungs from normoxic animals. L-Arg decreased Ra in lungs from CH rats and redistributed compliance to approximately that found in normoxic lungs. CH increased R0, and L-Arg reversed this increase in R0. L-Arg increased exhaled NO, and inhibition of L-Arg uptake attenuated the L-Arg-induced increase in exhaled NO. These data demonstrate that the CH-induced decrease in Ca was reversed by L-Arg, suggesting that L-Arg may improve CH-induced right ventricular dysfunction.
Pharmacology, 2003
The hemodynamic effects of N G -nitro-L-arginine methyl ester (L-NAME, inhibitor of nitric oxide (NO) synthase) were examined in thiobutabarbital-anesthetized controlrats and rats with monocrotaline-induced pulmonary hypertension. L-NAME (1-16 mg/kg i.v.) increased mean arterial pressure, systemic vascular resistance, venous resistance and pulmonary vascular resistance, and decreased cardiac output in both the control and pulmonary hypertensive rats. Relative to the controls, L-NAME (16 mg/kg) caused a smaller increase ("50% of control) in mean arterial pressure in the pulmonary hypertensive rats, but greater increases in venous ("200%) as well as pulmonary vascular ("400%) resistances and a greater decrease in cardiac output ("140%). The results show that NO is an important dilator within the arterial, venous and pulmonary circulation; its pulmonary and venous dilator roles are augmented in pulmonary hypertension.
American Journal of Physiology-Heart and Circulatory Physiology, 1999
The present study was aimed at examining the role of nitric oxide (NO) in the hypoxic contraction of isolated small pulmonary arteries (SPA) in the rat. Animals were treated with either saline (sham experiments) or Escherichia coli lipolysaccharide [LPS, to obtain expression of the inducible NO synthase (iNOS) in the lung] and killed 4 h later. SPA (300- to 600-μm outer diameter) were mounted as rings in organ chambers for the recording of isometric tension, precontracted with PGF2α, and exposed to either severe (bath [Formula: see text] 8 ± 3 mmHg) or milder (21 ± 3 mmHg) hypoxia. In SPA from sham-treated rats, contractions elicited by severe hypoxia were completely suppressed by either endothelium removal or preincubation with an NOS inhibitor [ N G-nitro-l-arginine methyl ester (l-NAME), 10−3 M]. In SPA from LPS-treated rats, contractions elicited by severe hypoxia occurred irrespective of the presence or absence of endothelium and were largely suppressed by l-NAME. The milder hy...
The Chinese journal of physiology, 2006
Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia on the protein expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), nitric oxide (NO) production, and hypoxic pulmonary vasoconstriction (HPV) in rat lung. Twenty-four male rats were divided into hyperoxic and normoxic groups. Hyperoxic rats were placed in > 90% F1O2 for 60 h prior to experiments. After baseline in vitro analysis, the rats underwent isolated, perfused lung experiments. Two consecutive hypoxic challenges (10 min each) were administered with the administration of a non-specific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), in between. We measured intravascular NO production, pulmonary arterial pressure, and protein expression of eNOS and iNOS by immunohistochemistry. We found that hyperoxia rats exhibited increased baseline NO production (P < 0.001) and blunted HPV response (P < 0.001) during hypoxic challeng...
Reduced Hypoxic Pulmonary Vascular Remodeling by Nitric Oxide From the Endothelium
Hypertension, 2001
We examined whether overproduction of endogenous nitric oxide (NO) can prevent hypoxia-induced pulmonary hypertension and vascular remodeling by using endothelial NO-overexpressing (eNOS-Tg) mice. Male eNOS-Tg mice and their littermates (wild-type, WT) were maintained in normoxic or 10% hypoxic condition for 3 weeks. In normoxia, eNOS protein levels, Ca 2ϩ -dependent NOS activity, and cGMP levels in the lung of eNOS-Tg mice were higher than those of WT mice. Activity of eNOS and cGMP production in the lung did not change significantly by hypoxic exposure in either genotype. Chronic hypoxia did not induce iNOS expression nor increase its activity in either genotype. Plasma and lung endothelin-1 levels were increased by chronic hypoxia, but these levels were not significantly different between the 2 genotypes. In hemodynamic analysis, right ventricular systolic pressure (RVSP) in eNOS-Tg mice was similar to that in WT mice in normoxia. Chronic hypoxia increased RVSP and induced right ventricular hypertrophy in both genotypes; however, the degrees of these increases were significantly smaller in eNOS-Tg mice. Histological examination revealed that hypoxic mice showed medial wall thickening in pulmonary arteries. However, the increase of the wall thickening in small arteries (diameter Ͻ80 m) by chronic hypoxia was inhibited in eNOS-Tg mice. Furthermore, muscularization of small arterioles was significantly attenuated in eNOS-Tg mice. Thus, we demonstrated directly that overproduction of eNOS-derived NO can inhibit not only the increase in RVSP associated with pulmonary hypertension but also remodeling of the pulmonary vasculature and right ventricular hypertrophy induced by chronic hypoxia. (Hypertension. 2001;37:322-327.)
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...
Role of endothelial nitric oxide in pulmonary and systemic arteries during hypoxia
Nitric Oxide, 2014
Our aim was to investigate the role played by endothelial nitric oxide (NO) during acute vascular response to hypoxia, as a modulator of both vascular tone (through guanylate cyclase (sGC) activation) and mitochondrial O 2 consumption (through competitive inhibition of cytochrome-c-oxydase (CcO)). Organ bath experiments were performed and O 2 consumption (Clark electrode) was determined in isolated aorta, mesenteric and pulmonary arteries of rats and eNOS-knockout mice. All pre-contracted vessels exhibited a triphasic hypoxic response consisting of an initial transient contraction (not observed in vessels from eNOS-knockout mice) followed by relaxation and subsequent sustained contraction. Removal of the endothelium, inhibition of eNOS (by L-NNA) and inhibition of sGC (by ODQ) abolished the initial contraction without altering the other two phases. The initial hypoxic contraction was observed in the presence of L-NNA+NO-donors. L-NNA and ODQ increases O 2 consumption in hypoxic vessels and increases the arterial tone in normoxia but not in hypoxia. When L-NNA+mitochondrial inhibitors (cyanide, rotenone or myxothiazol) were added, the increase in tone was similar in normoxic and hypoxic vessels, which suggests that inhibition of the binding of NO to reduced CcO restored the action of NO on sGC. CONCLUSION: A complex equilibrium is established between NO, sGC and CcO in vessels in function of the concentration of O 2 : as O 2 falls, NO inhibition of mitochondrial O 2 consumption increases and activation of sGC decreases, thus promoting a rapid increase in tone in both pulmonary and systemic vessels, which is followed by the triggering of NOindependent vasodilator/vasoconstrictor mechanisms.