The long-term objective of this proposal is to understand the microvascular mechanisms that produce elevated peripheral resistance in hypertension. Recent evidence strongly implicates mechanisms of blood flow autoregulation as a cause of vasoconstric- tion in the development of hypertension. However, the local physiological conditions that promote the participation of autoregulation and the long-term functional consequences of altering local vasoregulation remain as key issues requiring investigation. The goal of this research program is to investigate the functional characteristics of myogenic vasoregulation in the microcirculation and to explore its role as a determinant of the abnormally elevated vascular resistance in hypertension. This proposal will examine the hypothesis that two distinct Ca+2 - entry pathways are involved in the development of the pressure- dependent myogenic response and that these pathways can inde- pendently contribute to myogenic tone under different circumstances. One pathway is viewed as a depolarization-sensitive channel (potential-dependent) and the second as a stretch-sensitive channel (potential-independent). This proposal will also address the hypothesis that the myogenic mechanism, operating through one or both of these Ca+2 - entry channels, contributes to vasoconstriction in hypertension. Microcirculatory preparations of the cremaster muscle, small intestine and mesentery will be studied using the """"""""pressure-box"""""""" technique to increase intravascular pressure independent of changes in the pressure gradient for blood flow. This approach will selectively stimulate the myogenic mechanism which will then be characterized in normotensive, renal and spontaneously (genetic) hypertensive rats by measuring diameter, intravascular pressure and red cell velocity in individual arterioles. The potential-dependent and potential independent components of the myogenic response will be investigated using calcium antagonists which interfere with calcium movement into vascular smooth muscle through depolarization- sensitive channels. The experimental aims will be to: 1) investigate whether potential-dependent or potential-independent Ca+2 - entry acts to determine either the static or the rate- sensitive properties of the myogenic response; 2) determine if hypertension results in an altered myogenic responsiveness of arterioles; and 3) determine if hypertension selectively affects either the potential-dependent or potential-independent Ca+2 - entry components of the myogenic response.
