Functional changes in vascular smooth muscle have long been hypothesized to contribute to elevated peripheral resistance, the final common pathway that characterizes hypertension, regardless of its etiology (1-8). For such changes to be relevant, however, they must occur in arterial resistance vessels, where peripheral vascular resistance is determined. While many studies of perfused vascular beds in spontaneously hypertensive rats (SHR) and their normotensive control Wistar Kyoto rats (WKY) have suggested increased contractile responses in SHR, in isolated large arteries either no change or even decreased contractility has often been found (4, 5, 7). This discrepancy may occur because of the participation of arterial resistance vessels in the perfusion preparations. Studies presented herein of isolated mesenteric resistance vessels (mrv's; ca. 110 Mum i.d.) have revealed that increased responses to norepinephrine and high K+ depolarization in SHR as compared to WKY vessels are associated with increased 45Ca influx into the SHR arteriolar smooth muscle cells.
The aims of the present proposal are to further characterize changes in tension responses in SHR mrv's and to determine how these changes are related to Ca2+ entry, intracellular Ca2+ release or buffering, and Ca2+-contractile protein interactions. To these ends, I will study Ca2+ entry and intracellular release by 45Ca influx and efflux measurements, membrane potential using intracellular microelectrodes, cytoplasmic free Ca2+ using the fluorescent indicator Fura-2, Ca2+ conductance in single channels incorporated into lipid bilayers, and tension responses in saponin skinned vessels. Recent evidence has indicated that increased dietary Ca can lower blood pressure (29,44), perhaps through a membrane stabilizing effect of raised extracellular Ca2+ on vascular smooth muscle (8). I will test the hypothesis that the membrane stabilizing effect of raised extracellular Ca2+ is defective in SHR vessels. Additionally, the effects of some Ca2+ regulating hormones (e.g., Vitamin D3) on the resistance vessels will be determined. It is hoped that these studies will help to clarify the nature of the abnormalities in arteriolar Ca2+ handling in SHR, since increased Ca2+ is the intracellular signal for contraction.
