It is the purpose of the proposed studies to determine some of the cellular mechanisms responsible for active tone which develops as a function of increasing transmural pressure in isolated arterial segments. Toward this end, arterial segments will be cannulated and mounted in specially fabricated myographs allowing manipulation of transmural pressure. We will measure intracellular electrical and membrane biophysical parameters including membrane potential, membrane time constants, action potential characeristics, input resistance and membrane resistivity. Active tone will be measured simultaneously with electrical activity using a microscope-video camera arrangement. Emphasis will initially be placed on cerebral arteries since we know that the muscle cells in this preparation depolarize and develop spontaneous electrical and mechanical activity when transmural pressure is elevated between 0 and 150 mmHg. After characterization of this phenomenon in cerebral arteries, we will examine arteries from other vascular beds including renal and coronary. We will clarify the myogenic component of such activity by: a) using tetrodotoxin to block nerve excitation, b) destroying adrenergic nerve endings with 6-OH-dopamine, c) using specific blockers of known and putative neurotransmitters and d) study this phenomonon before and after removal of endothelium. We will examine the ionic mechanisms of pressure-induced activity via ion substitution experiments and specific blockers and ionophores of Ca2+ and Na+ permeability. Experiments will also be designed to determine the role of K+ conductance in this regard. Finally, we will determine the effect of PO2 (20 to 150 torr) and PCO2 (20 to 60 torr) on pressure mediated electrical and mechanical responses. These studies will provide information regarding: 1) the cellular mechanisms underlying pressure mediated activation (myogenic behavior) of cerebral vs. peripheral arteries, 2) the influences of neurotransmitters, endothelial factors and blood gases on myogenic behavior, and 3) some of the possible cellular mechanisms of blood flow autoregulation in the face of increasing and decreasing transmural pressures.
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