Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

Abstract

Christou H, Reslan OM, Mam V, Tanbe AF, Vitali SH, Touma M, Arons E, Mitsialis SA, Kourembanas S, Khalil RA. Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 302: L875-L890, 2012. First published January 27, 2012; doi:10.1152/ajplung.00293.2011.-Pulmonary hypertension (PH) is characterized by pulmonary arteriolar remodeling with excessive pulmonary vascular smooth muscle cell (VSMC) proliferation. This results in decreased responsiveness of pulmonary circulation to vasodilator therapies. We have shown that extracellular acidosis inhibits VSMC proliferation and migration in vitro. Here we tested whether induction of nonhypercapnic acidosis in vivo ameliorates PH and the underlying pulmonary vascular remodeling and dysfunction. Adult male Sprague-Dawley rats were exposed to hypoxia (8.5% O2) for 2 wk, or injected subcutaneously with monocrotaline (MCT, 60 mg/kg) to develop PH. Acidosis was induced with NH4Cl (1.5%) in the drinking water 5 days prior to and during the 2 wk of hypoxic exposure (prevention protocol), or after MCT injection from day 21 to 28 (reversal protocol). Right ventricular systolic pressure (RVSP) and Fulton's index were measured, and pulmonary arteriolar remodeling was analyzed. Pulmonary and mesenteric artery contraction to phenylephrine (Phe) and high KCl, and relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) were examined ex vivo. Hypoxic and MCT-treated rats demonstrated increased RVSP, Fulton's index, and pulmonary arteriolar thickening. In pulmonary arteries of hypoxic and MCT rats there was reduced contraction to Phe and KCl and reduced vasodilation to ACh and SNP. Acidosis prevented hypoxia-induced PH, reversed MCT-induced PH, and resulted in reduction in all indexes of PH including RVSP, Fulton's index, and pulmonary arteriolar remodeling. Pulmonary artery contraction to Phe and KCl was preserved or improved, and relaxation to ACh and SNP was enhanced in NH4Cl-treated PH animals. Acidosis alone did not affect the hemodynamics or pulmonary vascular function. Phe and KCl contraction and ACh and SNP relaxation were not different in mesenteric arteries of all groups. Thus nonhypercapnic acidosis ameliorates experimental PH, attenuates pulmonary arteriolar thickening, and enhances pulmonary vascular responsiveness to vasoconstrictor and vasodilator stimuli. Together with our finding that acidosis decreases VSMC proliferation, the results are consistent with the possibility that nonhypercapnic acidosis promotes differentiation of pulmonary VSMCs to a more contractile phenotype, which may enhance the effectiveness of vasodilator therapies in PH. pulmonary artery; pulmonary circulation; nitric oxide; vascular smooth muscle PULMONARY HYPERTENSION (PH) is a serious disease and a major and expanding public health problem with ϳ1,000 new patients diagnosed every year in the United States (6,20). PH is characterized by increased pulmonary arterial pre...

Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-α

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The Role of Activin Receptor-Like Kinase 1 Signaling in the Pulmonary Vasculature of Experimental Diaphragmatic Hernia

“…These cellular processes account for increased medial and adventitial thickening of the arterial wall leading to pathological obstructive changes in the pulmonary microvasculature of the diseased. 2,3 Recently, activin receptor-like kinase 1 (ALK-1), an EC receptor for the transforming growth factor-β (TGF-β) family has been implicated in the pathogenesis of PH. ALK-1 mRNA has been reported to be most abundantly expressed in rat lungs as well as in kidney, brain, and heart.…”

Extracellular acidosis contracts coronary but neither renal nor mesenteric artery via modulation of H+,K+‐ATPase, voltage‐gated K+ channels and L‐type Ca2+ channels

“…), rat pulmonary arteries (Christou et al . ) and rabbit mesenteric arteries (Nakanishi et al . ) and aorta (Celotto et al .…”

“…Although it is well known that pH i plays crucial roles in determining vascular tone (Wakabayashi et al 2006), the reported effects of acidosis on vascular tone are inconsistent and even conflicting. It has been reported that acidosis produced vasodilatation or inhibition of contraction in many vascular beds, including human internal mammary arteries (Rohra et al 2005), porcine cerebral (Kokubun et al 2009), coronary (Ishizaka & Kuo, 1996) and pulmonary arteries (Nilsson et al 2012), rat pulmonary arteries (Christou et al 2012) and rabbit mesenteric arteries (Nakanishi et al 1996) and aorta (Celotto et al 2011). On the contrary, it has also been reported that acidosis induced contraction in rabbit pulmonary (Ketabchi et al 2009), basilar (Cho et al 2007) and mesenteric arteries (Nakanishi et al 1996), rat coronary artery (RCA; Phillis et al 2000) and aorta (Furukawa et al 1996) and dog coronary artery (Goodyer et al 1961).…”