Exercise or increased physical activity and the resulting increase in coronary transport capacity is thought to be beneficial in reducing the risk of coronary artery disease. A significant portion of increased transport capacity is due to increased coronary blood flow resulting from adaptations in coronary vascular structure and functional control mechanisms. Project2 will extent important from our current studies of exercise training (EX) induced adaptations in functional control of porcine coronary artery, specifically responses to the relaxant adenosine (ADO) and the constrictor, endothelin (ET-1). We discovered that sensitivity to ADO was influenced by a nucleoside transporter(s) present in coronary smooth muscle (CSM). The existence of a nucleoside transporter(s) in CSM was previously unrecognized.
Aim 1 will tests the hypothesis that ADO transport and metabolism is decreased in EX and EX will reverse the depressant effects of high fat (HF) on sedentary (SED) responses.
Aim 2 will determine whether ADO transport is functionally and anatomically coupled to ADO receptors, thereby restricting activation. We also observed that EX reduced the sensitivity of coronary vessels to ET-1 in male pigs. Male pigs will be used to assess effects of HF on EX adaptations. Selective blockade of voltage dependent K-channels (but not other K-channels) reversed the sensitivity to ET-1 in vessels from EX but had little effect on SED. Thus, while Project 1 will address important issues concerning myogenic tone, Project 2 will address issues related to receptor driven events. Because ADO relaxation will be evaluated in the presence of ET-1, Aim 3 will study effects of ET- 1 on K-channel activity. Specifically, Aim 3 will test the hypothesis that K-channel responses, especially Kv, will be greatest in EX and that EX will reverse the effects of HF on SED.
Aim 4 will examine I-channel mechanisms subject to control by ADO and how these are modulated by ET-1, possibly by the inhibitory actions of protein kinase C (PKC- epsilon). Thus, Aim 4 will test the hypothesis that ADO receptor activity increases Kv and K/ATP currents with ADO transport and intracellular metabolism having an inhibitory effect on K/ATP currents.
Aim 5 will test the hypothesis that ET-1 inhibits Kv and K/ATP via PKC which in turn will inhibit DO effects on K-channels. Selected protocols will be done for several coronary sites (primary and distal branches, 0.3-3.0,, OD) to test the hypothesis that ADO is more effective in activating K- channels from distal sites. Data from these studies will provide important new information effective in activating K-channels from distal sites. Data from these studies will provide important new information regarding coronary responses to native vasoactive agents (ADO and ET-1) and their modulation by EX and HF.
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