Contribution of voltage-dependent K+ and Ca2+ channels to coronary pressure-flow autoregulation

被引:39
作者
Berwick, Zachary C. [1 ]
Moberly, Steven P. [1 ]
Kohr, Meredith C. [1 ]
Morrical, Ethan B. [1 ]
Kurian, Michelle M. [1 ]
Dick, Gregory M. [2 ]
Tune, Johnathan D. [1 ]
机构
[1] Indiana Univ Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA
[2] W Virginia Univ, Dept Exercise Physiol, Ctr Cardiovasc & Resp Sci, Sch Med, Morgantown, WV 26506 USA
关键词
Autoregulation; Coronary blood flow; Potassium channel; Calcium channel; Swine; VASCULAR SMOOTH-MUSCLE; BLOOD-FLOW; PERFUSION-PRESSURE; MYOGENIC RESPONSE; NITRIC-OXIDE; MYOCARDIAL-METABOLISM; INTRACELLULAR CALCIUM; SIGNALING MECHANISMS; REACTIVE HYPEREMIA; POTASSIUM CHANNELS;
D O I
10.1007/s00395-012-0264-6
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The mechanisms responsible for coronary pressure-flow autoregulation, a critical physiologic phenomenon that maintains coronary blood flow relatively constant in the presence of changes in perfusion pressure, remain poorly understood. This investigation tested the hypothesis that voltage-sensitive K+ (KV) and Ca2+ (Ca(V)1.2) channels play a critical role in coronary pressure-flow autoregulation in vivo. Experiments were performed in open-chest, anesthetized Ossabaw swine during step changes in coronary perfusion pressure (CPP) from 40 to 140 mmHg before and during inhibition of KV channels with 4-aminopyridine (4AP, 0.3 mM, ic) or Ca(V)1.2 channels with diltiazem (10 mu g/min, ic). 4AP significantly decreased vasodilatory responses to H2O2 (0.3-10 mu M, ic) and coronary flow at CPPs = 60-140 mmHg. This decrease in coronary flow was associated with diminished ventricular contractile function (dP/dT) and myocardial oxygen consumption. However, the overall sensitivity to changes in CPP from 60 to 100 mmHg (i.e. autoregulatory gain; Gc) was unaltered by 4-AP administration (Gc = 0.46 +/- 0.11 control vs. 0.46 +/- 0.06 4-AP). In contrast, inhibition of Ca(V)1.2 channels progressively increased coronary blood flow at CPPs < 80 mmHg and substantially diminished coronary Gc to -0.20 +/- 0.11 (P < 0.01), with no effect on contractile function or oxygen consumption. Taken together, these findings demonstrate that (1) KV channels tonically contribute to the control of microvascular resistance over a wide range of CPPs, but do not contribute to coronary responses to changes in pressure; (2) progressive activation of Ca(V)1.2 channels with increases in CPP represents a critical mechanism of coronary pressure-flow autoregulation.
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页数:11
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