Effects of hydralazine on the pulmonary vasculature and respiratory control in humans

Abstract

This study sought: (1) to clarify the effects of hydralazine on both the pulmonary vasculature and respiratory control in euoxia and hypoxia in healthy humans; and (2) to determine whether hydralazine alters the expression of genes regulated by hypoxia-inducible factor 1 (HIF-1). Ten volunteers participated in two 2 day protocols. Hydralazine (25 mg) or placebo was administered at 1 pm and 11 pm on the first day, and at 1 pm on the second day. In the mornings and afternoons of both days, we measured plasma vascular endothelial growth factor (VEGF) and erythropoietin (EPO) concentrations (both HIF-1-regulated gene products), systemic arterial blood pressure, and changes in heart rate, cardiac output, maximal systolic pressure difference across the tricuspid valve (ΔP max ) and ventilation in response to 20 min of isocapnic hypoxia. Recent hydralazine: (1) decreased diastolic blood pressure; (2) increased heart rate and cardiac output in euoxia and hypoxia whilst having no effect on ΔP max ; and (3) increased the ventilatory sensitivity to hypoxia. Hydralazine had no effect on plasma EPO or VEGF concentration. We conclude that hydralazine increases the sensitivity of the ventilatory response to hypoxia, but lacks any effect on the pulmonary vasculature at the dose studied. It did not affect the expression of HIF-1-regulated genes. Hydralazine is a vasodilator (Stunkard et al. 1954) whose mode of action remains uncertain. It has been employed in the treatment of pulmonary hypertension, where some authors have found that it reduces pulmonary vascular resistance (Packer et al. 1982;Keller et al. 1984;Groves et al. 1985), but others have found that it has no such effect (Lupi-Herrera et al. 1984). One possible explanation for these differences is that they simply relate to heterogeneity within the disease states studied, for example underlying differences in ventilation-perfusion matching. Despite the uncertaintly surrounding the effects of hydralazine on the pulmonary circulation, there is nevertheless agreement that hydralazine improves oxygenation through its effect as a respiratory stimulant (Rubin et al. 1982;Miller et al. 1983;Keller et al. 1984;Corriveau et al. 1987;Corriveau et al. 1988). However, this effect of hydralazine complicates the interpretation of its effects on the pulmonary circulation still further, because, in those studies where a reduction in pulmonary vascular resistance was detected, it cannot be determined whether it arose from a direct effect of hydralazine on the vasculature or from an indirect effect through the increase in oxygenation.The first purpose of this study was to clarify the effects of hydralazine on both the pulmonary vasculature and respiratory control in humans. The study sought to do this in normal, healthy volunteers so that the complicating effects of heterogeneous disease states would be removed. Furthermore, it sought to do this under tightly regulated conditions for partial pressures of O 2 (P O 2 ) and CO 2 (P CO 2 ) so that any secondary effects of hydralazine on the...

Effects of Pregnancy, Hypertension and Nitric Oxide Inhibition on Rat Uterine Artery Myogenic Reactivity

“…Since hydralazine induces vascular smooth muscle (VSM) relaxation via multiple mechanisms [31,32,33], the pathways by which it affects remodeling and activation of tone are not known. Moreover, recent studies have demonstrated that hydralazine augments flow-induced remodeling through a mechanism linked to reactive oxygen species [34].…”