Monocrotaline‐induced Pulmonary Hypertension Impairs Diaphragm Vasomotor Function

Abstract

INTRODUCTIONPulmonary hypertension (PH) is a chronic and progressive disease characterized by high arterial blood pressure and compensatory vascular remodeling in the pulmonary circulation. Mounting evidence suggests that the effects of PH extend beyond the pulmonary circulation. In humans and animals, PH induces diaphragm contractile dysfunction and diaphragm muscle atrophy. While the mechanistic bases for the PH‐induced diaphragm dysfunction is relatively unknown, alterations in the vasomotor control of the diaphragm resistance vasculature (i.e. arterioles) may play a key role. Therefore, we tested the hypothesis that PH increases the vasoconstrictor responsiveness and impairs the vasorelaxation of diaphragm arterioles.METHODSAdult female Sprague‐Dawley rats (n=8) were divided into healthy control (HC; n=2), ovariectomized (OVX; n=3), and PH + OVX (n=3). PH + OVX animals were given a single intraperitoneal injection of monocrotaline (MCT; 50mg/kg) to induce PH. Disease progression was then monitored via echocardiography. Once animals developed PH (~3 weeks post injection), the diaphragm was removed and first‐order arterioles (1A) from the medial costal diaphragm were isolated, cannulated, and pressurized at 90 cmH2O. After a 60 min equilibration period and spontaneous tone development, vasoconstrictor responses to potassium chloride (KCl) (10‐100 mM) and endothelium‐dependent and ‐independent vasorelaxation responses to cumulative doses of acetylcholine (ACh) and sodium nitroprusside (SNP) (10‐9 to 10‐4 M) were determined.RESULTSSpontaneous tone (%) development was not different across all three groups (HC: 36 ± 9%; OVX: 33 ± 9%; PH + OVX: 39 ± 2%; P>0.05). Compared to control vessels, maximal percent vasoconstriction with KCl was decreased with OVX (67 ± 2 versus 50 ± 1%; P<0.05). Maximal vasoconstriction (%) was reduced with PH + OVX (36 ± 4%) compared to vessels from both healthy control and OVX groups (P<0.05). Ovariectomy had no effect on endothelium‐dependent vasodilation responses to ACh versus intact control animals (P>0.05). The maximal ACh‐mediated vasodilation with PH + OVX (29 ± 9%) was decreased versus both healthy (45 ± 6%; P<0.05) and OVX animals (41 ± 4%; P<0.05). Across all three groups, there were no differences in percent relaxation with SNP (P>0.05).CONCLUSIONThese findings suggest that estrogen plays a role in the maintenance of K+ channel activity and/or the contribution of K+ channels to diaphragm vasomotor tone, and that PH further disrupts K+ channel function in diaphragm arterioles. In addition, the absence of estrogen in OVX animals had no effect on endothelial function whereas PH + OVX impaired endothelium‐dependent vasorelaxation of diaphragm resistance vessels. These findings suggest that PH, at least in the rodent model utilized herein, elicits endothelial dysfunction in the diaphragm vasculature and provide a potential mechanism for the impaired diaphragm contractile dysfunction in PH patients.