The overall goal of this project is to elucidate the mechanisms by which changes in 02 availability regulate active vascular smooth muscle (VSM) tone in microvessels of the rat cremaster muscle and hamster cheek pouch, and to determine whether alterations in 02 dependent local control mechanisms can contribute to an elevated microvascular resistance in hypertensive animals (SHR, 1 kidney-1 clip Goldblatt hypertensive rats and renovascular hypertensive hamsters).
The specific aims of the project are to determine: 1) whether changes in 02 availability alter VSM transmembrane potential (Em) in microvessels, and whether the electrophysiological responses to altered P02 differ in hypertensive vs. normotensive animals; 2) whether hypoxia alters Ca 2+ or K+ conductance in isolated VSM cells; 3) whether transmural pressure affects arteriolar sensitivity to increased P02; 4) whether tissue or arteriolar surface P02 differ in hypertensive vs. normotensive animals under resting conditions or following equivalent elevations of superfusate P02 or inspired fraction of 02 (FI02); and 5), if the effects of altered P02 on microvascular pressure distribution differ in normotensive and hypertensive animals The role of electrophysiological mechanisms in regulating active VSM tone during changes in 02 availability will be assessed by measuring VSM E-m with microelectrodes in, arterioles and venules during changes in superfusate P02 or FI02, and by measuring ionic currents with patch clamp techniques in isolated, dispersed VSM cells of hypertensive and normotensive animals during reduced PO2. The role of transmural pressure in determining arteriolar 02 sensitivity will be assessed by measuring arteriolar constrictor responses to increased 02 availability before and after elevation of microvascular pressure utilizing the pressurized box technique. Tissue and arteriolar surface P02 will be measured in normotensive and hypertensive animals with 02 microelectrodes during resting conditions and during elevations of superfusate PO2 or FIO2. The role of O2 dependent mechanisms in regulating microvascular resistance in hypertensive and normotensive animals will be assessed by measuring microvascular pressure distributions via the servo null method during changes in superfusate P02 or FI02. These studies should provide important insight into the mechanisms of the altered vascular response to changes in 02 availability in hypertensive animals, and the effects of altered microvascular 02 responses on the control of vascular resistance in hypertension.
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