β2-Adrenergic Receptor-Dependent Attenuation of Hypoxic Pulmonary Vasoconstriction Prevents Progression of Pulmonary Arterial Hypertension in Intermittent Hypoxic Rats (original) (raw)
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Antioxidants, 2021
Chronic sustained hypoxia (CSH), as found in individuals living at a high altitude or in patients suffering respiratory disorders, initiates physiological adaptations such as carotid body stimulation to maintain oxygen levels, but has deleterious effects such as pulmonary hypertension (PH). Obstructive sleep apnea (OSA), a respiratory disorder of increasing prevalence, is characterized by a situation of chronic intermittent hypoxia (CIH). OSA is associated with the development of systemic hypertension and cardiovascular pathologies, due to carotid body and sympathetic overactivation. There is growing evidence that CIH can also compromise the pulmonary circulation, causing pulmonary hypertension in OSA patients and animal models. The aim of this work was to compare hemodynamics, vascular contractility, and L-arginine-NO metabolism in two models of PH in rats, associated with CSH and CIH exposure. We demonstrate that whereas CSH and CIH cause several common effects such as an increase...
Cardiovascular Research, 2007
Aims b-adrenoceptor (b-AR)-mediated relaxation was characterized in pulmonary arteries from normoxic and hypoxic (as model of pulmonary hypertension) mice. The endothelial NO synthase (eNOS) pathway was especially investigated because of its potential vasculoprotective effects. Methods Pulmonary arteries from control or hypoxic (0.5 atm for 21 days) wild-type or eNOS 2/2 mice were used for pharmacological characterization of b-AR-mediated relaxation in myograph, and for immunohistochemistry using anti-b-AR antibodies. Results In pulmonary arteries from normoxic mice, isoproterenol (b-AR agonist) and procaterol (selective b 2 -AR agonist) elicited relaxation, while cyanopindolol and CL316243 (b 3 -AR agonists) were ineffective. The effect of isoproterenol was antagonized by CGP20712A and ICI118551 (b 1 -or b 2 -AR antagonists, respectively) and also partially inhibited by N v -nitro-L-arginine methylester (L-NAME, a NOS inhibitor), endothelium denudation, or eNOS gene deletion. Relaxation to procaterol was abolished by L-NAME or endothelium removal. In eNOS 2/2 mice, procaterol-induced relaxation was decreased but was insensitive to L-NAME, this residual effect involving other endothelium-dependent relaxant factors as compensatory mechanisms. Immunostaining for b 2 -AR was observed in the endothelial layer, but not the medial layer of pulmonary arteries. Pulmonary arteries from hypoxic mice exhibited decreased endothelial NO-dependent relaxation to acetylcholine. However, in these arteries, relaxation to procaterol was either unaffected (extralobar segments) or even increased (intralobar segments) and was still abolished by L-NAME or endothelium removal. Conclusion b 1 -and b 2 -AR, but not b 3 -AR, mediate relaxation of mice pulmonary arteries. The b 2 -AR component is dependent on eNOS activity and is preserved following chronic hypoxia. These data highlight the role of the b 2 -AR as a pharmacological target to induce/restore endothelial NO-dependent protective effects in pulmonary circulation.
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.
AJP: Heart and Circulatory Physiology, 2007
Excessive proliferation of vascular wall cells underlies the development of elevated vascular resistance in hypoxic pulmonary hypertension (PH), but the responsible mechanisms remain unclear. Growth-promoting effects of catecholamines may contribute. Hypoxemia causes sympatho-excitation, and prolonged stimulation of 1 -adrenoceptors induces hypertrophy and hyperplasia of arterial smooth muscle cells and adventitial fibroblasts. Catecholamine trophic actions in arteries are enhanced when other conditions favoring growth or remodeling are present, eg injury, altered shear stress and, notably, in isolated pulmonary arteries from rats with hypoxic PH. The present study examined the hypothesis that catecholamines contribute to pulmonary vascular remodeling in vivo in hypoxic PH. Mice genetically deficient in norepinephrine and epinephrine production (dopamine -hydroxylase -/-, DBH -/-) or 1 -adrenoceptors were examined for alterations in PH, cardiac hypertrophy and vascular remodeling after 21 days exposure to normobaric 0.1 FIO 2 . Decrease in lumen area and increase in wall thickness of arteries were strongly inhibited in knockout mice (order of extent of inhibition: D H -/-= 1D -AR -/-> 1B -AR -/-). Distal muscularization of small arterioles was also reduced (D H -/-> 1D -AR -/-> 1B -AR -/mice). Despite these reductions, increases in right ventricular pressure and hypertrophy were not attenuated in D H -/and 1B -AR -/-
Hypoxia-induced pulmonary hypertension: Different impact of iloprost, sildenafil, and nitric oxide
Respiratory Medicine, 2007
Objectives: Chronic alveolar hypoxia induces pulmonary hypertension, evident from elevated pulmonary artery pressure (PAP), pulmonary vascular resistance, right ventricular hypertrophy (RVH), and increased muscularization of the pulmonary vasculature. Additionally, the vasoconstrictor response to acute hypoxia (HPV) may be reduced in the remodeled vasculature. However, no direct comparison of different treatments on the various parameters characterizing pulmonary hypertension has been performed yet. Against this background, we compared the effects of inhaled NO, infused iloprost, a stable prostacyclin analogue, and oral sildenafil, a phosphodiesterase 5 inhibitor, on hypoxiainduced pulmonary hypertension. Methods: Exposure of rabbits to chronic hypoxia (FiO 2 ¼ 0.10) for 42 days. Treatment with infused iloprost, oral sildenafil, and inhaled nitric oxide. Results: We quantified PAP, pulmonary vascular resistance, RVH, vascular remodeling, vasoreactivity, and the strength of HPV. Chronic hypoxia resulted in an increase in (a) the right ventricle/(left ventricle+septum) ratio from 0.2670.01 to 0.4470.01, (b) PAP, and (c) the degree of muscularization from 14.074.0% to 43.575.3%. Treatment with iloprost and sildenafil, but not with NO, prevented the increase in muscularization. In contrast, RVH was strongly inhibited by sildenafil, whereas NO had some minor, and iloprost had no effect. Only iloprost reduced PAP compared to NO and sildenafil. The downregulation of HPV was abrogated only by NO.
2000
Aims b-adrenoceptor (b-AR)-mediated relaxation was characterized in pulmonary arteries from normoxic and hypoxic (as model of pulmonary hypertension) mice. The endothelial NO synthase (eNOS) pathway was especially investigated because of its potential vasculoprotective effects. Methods Pulmonary arteries from control or hypoxic (0.5 atm for 21 days) wild-type or eNOS 2/2 mice were used for pharmacological characterization of b-AR-mediated relaxation in myograph, and for immunohistochemistry using anti-b-AR antibodies. Results In pulmonary arteries from normoxic mice, isoproterenol (b-AR agonist) and procaterol (selective b 2 -AR agonist) elicited relaxation, while cyanopindolol and CL316243 (b 3 -AR agonists) were ineffective. The effect of isoproterenol was antagonized by CGP20712A and ICI118551 (b 1 -or b 2 -AR antagonists, respectively) and also partially inhibited by N v -nitro-L-arginine methylester (L-NAME, a NOS inhibitor), endothelium denudation, or eNOS gene deletion. Relaxation to procaterol was abolished by L-NAME or endothelium removal. In eNOS 2/2 mice, procaterol-induced relaxation was decreased but was insensitive to L-NAME, this residual effect involving other endothelium-dependent relaxant factors as compensatory mechanisms. Immunostaining for b 2 -AR was observed in the endothelial layer, but not the medial layer of pulmonary arteries. Pulmonary arteries from hypoxic mice exhibited decreased endothelial NO-dependent relaxation to acetylcholine. However, in these arteries, relaxation to procaterol was either unaffected (extralobar segments) or even increased (intralobar segments) and was still abolished by L-NAME or endothelium removal. Conclusion b 1 -and b 2 -AR, but not b 3 -AR, mediate relaxation of mice pulmonary arteries. The b 2 -AR component is dependent on eNOS activity and is preserved following chronic hypoxia. These data highlight the role of the b 2 -AR as a pharmacological target to induce/restore endothelial NO-dependent protective effects in pulmonary circulation.
Allopurinol inhibits hypoxic pulmonary vasoconstriction. Role of toxic oxygen metabolites
Acta Anaesthesiologica Scandinavica, 1990
The exact mechanism whereby hypoxic pulmonary vasoconstriction (HPV) is elicited is still unsettled. We have evaluated a possible role for toxic oxygen metabolites (TOM), employing a setup of blood-perfused isolated rat lungs. HPV reflected as pulmonary arterial pressor responses, was evoked by alternately challenging the airways with a hypoxic-and a normoxic gas mixture, resulting in gradually increasing responses until a maximum was obtained. In a sequence of responses (mean f s.e.mean) increasing from 2.5 ? 0.2 kPa to 3.2 f 0.1 kPa, administration to the perfusate of the inhibitor of xanthine oxidase (XO), allopurinol (AP) reduced the subsequent response to 2.5 f 0.2 kPa (P<O.OOl). By contrast, AP did not affect vasoconstriction induced by serotonin or bradykinin. In control experiments responses continued to increase after administration of hypoxanthine (substrate of XO). Neither pretreatment with daily injections of the antioxidant vitamin E for 3 days in advance, nor addition to the perfusate of the scavenger enzymes superoxide dismutase and catalase, or dimethylsulfoxide had any impact on HPV; the subsequent responses rose at the same rate and in the same way as before. Thus, the present study has shown that AP inhibition of XO depresses HPV. This could be due either to reduced production of TOM or to accumulation of purine metabolites. The absence of inhibitory effects of quenchers of T O M refutes a role for these metabolites in the elicitation of HPV. More likely, AP inhibits HPV by interfering with the purine metabolism
In Rats With Hypoxic Pulmonary Hypertension
Right-ventricular myocardial hypertrophy during hypoxic pulmonary hypertension is associated with local renin-angiotensin-system activation. The expression of angiotensin II type 1 (AT 1 ) and type 2 (AT 2 ) receptors in this setting has never been investigated. We have therefore examined the chronic hypoxia pattern of AT 1 and AT 2 expression in the right and left cardiac ventricles, using in situ binding and RT-PCR assays. Hypoxia produced right but not left ventricular hypertrophy after 7, 14 and 21 days, respectively. Hypoxia for 2 days was associated in each ventricle with a simultaneous and transient increase (P < 0.05) in AT 1 binding and AT 1 mRNA levels, in the absence of any significant change in AT 2 expression level. Only after 14 days of hypoxia, AT 2 binding increased (P < 0.05) in the two ventricles, concomitantly with a right ventricular decrease (P < 0.05) in AT 2 mRNA. Along these data, AT 1 and AT 2 binding remained unchanged in both the left and hypertrophied right ventricles from rats treated with monocrotaline for 30 days. These results indicate that chronic hypoxia induces modulations of AT 1 and AT 2 receptors in both cardiac ventricles probably through direct and indirect mechanisms, respectively, which modulations may participate in myogenic (at the level of smooth or striated myocytes) rather than in the growth response of heart to hypoxia.