The long term objectives of this proposal are to characterize the pathways of extracellular (Calcium Ion) entry and the possible role of intracellular Calcium Ion release during endothelium-independent stretch-induced vascular tone. The blood vessel wall is stretched when transmural pressure increases. Most small arteries and some veins respond to this by contraction, a mechanism known as the myogenic response. Arterial myogenic tone makes an important contribution to the autoregulation of blood flow. Stretch-induced tone also probably participates in a major way to the intrinsic or basal tone of the circulation. In some arteries this tone is endothelium-dependent; in those proposed for study in this application, it is not. This latter type of stretch-induced tone is dependent upon extracellular Calcium Ion. The specific hypothesis being tested are that a) stretch-induced tone occurs via activation of specific Calcium Ion-entry mechanisms; b) a positive correlation exists between the extent of stretch- induced tone and Radiolabled Calcium-influx and c) stretch-induced tone has a minor requirement for intracellular stores of Calcium Ion. Since in vitro methodology will be used, segments of arteries that show endothelium- independent myogenic response and which seem to be characteristic of those responding to stretch or distension in vivo will be studied. Specifically, these are resistance arteries from the ear and kidney, the middle cerebral artery and the basilar artery. The effect of stretch on active tone and Calcium Ion -influx and release will be measured to elucidate the underlying mechanism. Tone will be produced either by stretch, membrane- depolarization or receptor activation; the susceptibility of these three types of tone to drugs which to inhibit or facilitate entry of extracellular Calcium Ion will be studied as a means of distinguishing between them. Wire-mounted arterial segments will be arranged so that Radiolabeled Calcium fluxes cannulated perfusion pressurized segments wherein changes in diameter are video-monitored. Changes in release of intracellular Calcium Ion will be studied as a function of vessel size in the renal and cerebral circulation. If there is a unique function of vessel size in the renal and cerebral circulation. If there is a unique stretch- activate Calcium Ion entry pathway and intracellular mechanism in vascular smooth muscle, it is important to characterize it since it may provide an additional site for the pharmacological manipulation of vascular tone.
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