Endothelin-1-induced vasoconstriction does not require intracellular Ca2+ waves in arteries from rats exposed to intermittent hypoxia

Abstract

Sleep apnea is associated with cardiovascular disease, and patients with sleep apnea have elevated plasma endothelin (ET)-1 concentrations. Rats exposed to intermittent hypoxia (IH), a model of sleep apnea, also have increased plasma ET-1 concentrations and heightened constriction to ET-1 in mesenteric arteries without an increase in global vascular smooth muscle cell Ca2+ concentration ([Ca2+]). Because ET-1 has been shown to increase the occurrence of propagating Ca2+ waves, we hypothesized that ET-1 increases Ca2+ wave activity in mesenteric arteries, rather than global [Ca2+], to mediate enhanced vasoconstriction after IH exposure. Male Sprague-Dawley rats were exposed to sham or IH conditions for 7 h/day for 2 wk. Mesenteric arteries from sham- and IH-exposed rats were isolated, cannulated, and pressurized to 75 mmHg to measure ET-1-induced constriction as well as changes in global [Ca2+] and Ca2+ wave activity. A low concentration of ET-1 (1 nM) elicited similar vasoconstriction and global Ca2+ responses in the two groups. Conversely, ET-1 had no effect on Ca2+ wave activity in arteries from sham rats but significantly increased wave frequency in arteries from IH-exposed rats. The ET-1-induced increase in Ca2+ wave frequency in arteries from IH rats was dependent on phospholipase C and inositol 1,4,5-trisphosphate receptor activation, yet inhibition of phospholipase C and the inositol 1,4,5-trisphosphate receptor did not prevent ET-1-mediated vasoconstriction. These results suggest that although ET-1 elevates Ca2+ wave activity after IH exposure, increases in wave activity are not associated with increased vasoconstriction.