Endothelin and prostaglandin H2/thromboxane A2 enhance myogenic constriction in hypertension by increasing Ca2+ sensitivity of arteriolar smooth muscle

The myogenic response of skeletal muscle arterioles is enhanced in hypertension because of the release of endothelin (ET) and prostaglandin H-2 (PGH(2))/thromboxane A(2) (TxA(2)) from the endothelium. We hypothesized that ET and PGH(2)/TxA(2) modulate Ca2+ signaling in arteriolar smooth muscle and thereby enhance myogenic constriction. Thus, simultaneous changes in intracellular Ca2+ concentration in smooth muscle ([Ca2+](i)), measured by fura 2 microfluorometry (expressed as Ca2+ fluorescence ratio [R-Ca]), and diameter were obtained as a function of intraluminal pressure (P-i), in isolated cannulated gracilis muscle arterioles (diameter approximate to 120 mum) of normotensive Wistar rats (WR) and spontaneously hypertensive rats (SHR). In the absence of extracellular Ca2+, increases in P-i from 20 to 160 mm Hg increased the passive diameter of arterioles without changes in R-Ca. In the presence of extracellular Ca2+ and endothelium, increases in P-i elicited similar increases in R-Ca (30+/-7% for control and 33+/-8% for SHR at 160 mm Hg) but at significantly (P<0.05) greater constriction of SHR arterioles compared with WR arterioles (at 160 mm Hg, 55+/-4% versus 38+/-2%, respectively, of passive diameter). In the absence of the endothelium, P-i-induced changes in the R-Ca and diameter of SHR and WR arterioles did not differ significantly. Also, a step increase in P-i (from 80 to 140 mm Hg) elicited a similar increase in R-Ca but greater constrictions in SHR versus WR arterioles. In the presence of the TxA(2) receptor inhibitor SQ29,548 and the ETA receptor inhibitor BQ123, there was no difference between responses of SHR and WR arterioles. In WR arterioles, increasing concentrations of KC1 elicited a significant increase in R-Ca (38+/-7% at 80 mmol/L) and completely constricted the arterioles; In contrast, constrictions to ET (52+/-7% at 3X10(-1)2 mol/L) and the TxA(2) agonist U46619 (40+/-8% at 3X10(-9) mol/L) were not accompanied by increases in R-Ca at submaximal concentrations. Collectively, these findings suggest that in hypertension, endothelium-derived ET and PGH(2)/TxA(2) increase the Ca2+ sensitivity of the contractile apparatus of arteriolar smooth muscle; thus, the similar increases in [Ca2+](i) in response to the elevation of intraluminal pressure elicit greater myogenic constriction.