Inhibition Of Pulmonary Vasoconstriction Research Articles

Loss of prolyl hydroxylase 1 and 2 in SM22α-expressing cells prevents Hypoxia-Induced pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a disease characterized by increased vasoconstriction and vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) highly express the transcription factor hypoxia-inducible factor-1α (HIF-1α), yet the role of PASMC HIF-1α in the development of PAH remains controversial. To study the role of SMC HIF-1α in the pulmonary vascular response to acute and chronic hypoxia, we used a gain-of-function strategy to stabilize HIF-1α in PASMC by generating mice lacking prolyl hydroxylase domain (PHD) 1 and 2 in SM22α-expressing cells. This strategy increased HIF-1α expression and transcriptional activity under conditions of normoxia and hypoxia. Acute hypoxia increased right ventricular systolic pressure (RVSP) in control, but not in SM22α-PHD1/2-/- mice. Chronic hypoxia increased RVSP and vascular remodeling more in control SM22α-PHD1/2+/+ than in SM22α-PHD1/2-/- mice. In vitro studies demonstrated increased contractility and myosin light chain phosphorylation in isolated PHD1/2+/+ compared with PHD1/2-/- PASMC under both normoxic and hypoxic conditions. After chronic hypoxia, there was more p27 and less vascular remodeling in SM22α-PHD1/2-/- compared with SM22α-PHD1/2+/+ mice. Hypoxia increased p27 in PASMC isolated from control patients, but not in cells from patients with idiopathic pulmonary arterial hypertension (IPAH). These findings highlight an SM22α-expressing cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling. Modulating HIF-1α expression in PASMC may represent a promising preventative and therapeutic strategy for patients with PAH.NEW & NOTEWORTHY In a mouse model wherein hypoxia-inducible factor 1 alpha (HIF-1α) is stabilized in vascular smooth muscle cells, we found that HIF-1α regulates vasoconstriction by limiting phosphorylation of myosin light chain and regulates vascular remodeling through p27 induction. These findings highlight a cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling.

Pentobarbital attenuates pulmonary vasoconstriction in isolated sheep lungs

Pentobarbital sodium is a widely used anesthetic agent that has been demonstrated to attenuate systemic vascular responses to multiple pressors. To determine whether pentobarbital affected pulmonary vasoreactivity we determined the pulmonary vascular response to hypoxia and potassium in isolated in situ perfused sheep lungs. The flow resistive characteristics of the pulmonary vasculature were assessed by determining mean instantaneous pressure-flow relationships over a wide range of flows (20-120 ml.min-1.kg body wt-1) with PIO2 of 200 and 30 Torr, with and without pentobarbital. Pentobarbital attenuated hypoxic pulmonary vasoconstriction (P less than 0.001) in a concentration-dependent fashion (50% effective concentration = 0.42 mM). In addition, the pulmonary constrictor response to potassium was markedly blunted by pentobarbital (P less than 0.001). We conclude that pentobarbital inhibits hypoxic pulmonary vasoconstriction in a concentration-dependent fashion and that this inhibition of pulmonary vasoconstriction in isolated sheep lungs is not specific for hypoxia.

Pulmonary Vasoconstriction and Profound Leukopenia in TWo Sheep Experimental Models: Effects of Complement Depletion

In the awake sheep, the acute and transient increase of pulmonary vascular resistance following either veno-venous cardiopulmonary bypass or E coli endotoxin infusion is primarily mediated by pulmonary synthesis of thromboxane.1-3 Inhibition of pulmonary vasoconstriction by pretreatment with either cyclooxygenase or thromboxane synthetase inhibitors does not prevent the leukopenia resulting from either bypass or endotoxin.1-3 Thus, certain metabolic similarities exist between these two models, although their fundamental mechanisms probably differ.