The vascular muscle of the spontaneously hypertensive rat (SHR) plays an important role in the etiology of genetic hypertension. Not only is peripheral vascular resistance elevated in the SHR as compared to the normotensive Wistar Kyoto rat (WKY), but isolated SHR vascular muscle shows an enhanced reactivity to norepinephrine and calcium, and a diminished relaxation to vasodilator drugs. Since this augmented contractile response could be caused by a genetic membrane defect resulting in an increased concentration of cytoplasmic calcium, the whole-cell voltage-clamp technique was used to compare transmembrane calcium current in cultured azygos venous cells from neonatal WKY and SHR. Early data show that SHR vascular cells have more sustained calcium current than WKY, and voltage-dependent activation and inactivation of calcium for maintenance of vascular muscle contraction, the predominance of the sustained calcium current occurs at more positive membrane potentials. Since the sustained current likely supplies extracellular calcium current in the SHR may help to explain the augmented contractile response of isolated blood vessels from the SHR, and the increased peripheral resistance in the intact animal. The rat azygos vein has only a vestigial function after the neonatal period. Thus the purpose of this proposal is to study membrane calcium current in SHR and WKY vascular muscle cells from the mesenteric circulation, which is involved in the regulation of blood pressure. The main hypothesis to be tested is that voltage- dependent calcium current is altered in the vascular muscle membrane of spontaneously hypertensive rats. In particular, the whole-cell voltage-clamp technique will be used to measure and compare membrane calcium current in isolated mesenteric arterial and portal venous cells from neontal (1-4 day old) and adult (16 week) WKY and SHR. Further comparison of calcium current between cells from neonatal and adult SHR will define whether any changes precede or are a consequence of elevated arterial pressure, and comparison between arterial and venous cells from adult SHR will confirm if any changes are related to the development of hypertension. Specifically, proposed experiments on voltage-dependent calcium currents in WKY and SHR arterial and venous cells will: (1) Define voltage-dependent activation and inactivation of calcium current, (2) Quantitate total calcium current and its transient and sustained components, (3) Estimate the density of cell calcium current, and (4) Determine the effect of calcium channel modulating drugs on the calcium current.

R29HL040474

1988-08-01

1993-07-31