The role of myogenic mechanisms in the control of local blood flow and vascular resistance has received a great deal of attention in recent years. However, little information exists as to the intracellular events which couple the contractile response of an arteriole to an acute rise in intravascular pressure. The overall goal of this proposal is to investigate intracellular signalling pathways which are involved in the myogenic response. Four specific hypotheses will be examined: 1. that Ca2+ sensitivity of the contractile apparatus in arterioles is a function of intravascular pressure, 2. that the maintenance of a myogenic constriction in small arterioles is dependent on the involvement of protein kinase C mediated pathways, 3. that such pathways control the intracellular Ca2+ sensitivity, and thus Ca2+ requirements, of the vascular smooth muscle contractile apparatus during the maintained phase of the contraction, and 4. that desensitization to Ca2+ following exposure to vasodilators provides a mechanism whereby the myogenic response can be partially, or completely, inhibited by appropriate metabolic stimuli. A necessary component of these studies will be the description of the relationship between intracellular calcium levels and the extent of arteriolar myogenic contraction. A combination of isolated microvessel and image analysis techniques will be used to investigate that hypotheses. The proposed investigation will complement our previous in vivo studies of the microcirculation by allowing the integration of cellular biochemical events with previously documented physiologic phenomena. Knowledge of the intracellular pathways involved in the myogenic response will enable us to more fully understand blood flow autoregulation, including the interactions between metabolic and myogenic stimuli, and will also provide insight into mechanisms which underlie basal arteriolar tone. Understanding these basic mechanisms will, in addition, assist in interpreting the role of myogenic mechanisms in the vascular pathology associated with disease states such as hypertension and diabetic microangiopathy and may identify sites for novel pharmacologic intervention.
