title: Contribution of voltage-dependent K+ and Ca2+ channels to coronary pressure-flow autoregulation.
abstract: 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(+) (K(V)) and Ca(2+) (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 K(V) channels with 4-aminopyridine (4AP, 0.3 mM, ic) or Ca(V)1.2 channels with diltiazem (10 μg/min, ic). 4AP significantly decreased vasodilatory responses to H(2)O(2) (0.3-10 μM, 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) K(V) 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.
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, 46202, USA.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Berwick
authors.forename: Steven P
authors.initials: SP
authors.lastname: Moberly
authors.forename: Meredith C
authors.initials: MC
authors.lastname: Kohr
authors.forename: Ethan B
authors.initials: EB
authors.lastname: Morrical
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Kurian
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Dick
authors.forename: Johnathan D
authors.initials: JD
authors.lastname: Tune
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008833:Microcirculation; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013552:Swine; D013997:Time Factors; D014655:Vascular Resistance; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology; D016276:Ventricular Function
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D014665:Vasodilator Agents