Abstract
Understanding of local metabolic control of coronary flow remains stifled by debate around data interpretation and anticipated outcomes. To address this question we performed experiments in a cannulated coronary preparation in swine to precisely control flow as myocardial oxygen consumption (MVO(2)) and contractile function were modulated by dobutamine (1-10 μg/kg/min, iv), reductions in coronary perfusion pressure (CPP), and the inhibition of voltage-gated K(+) channels with 4-aminopyridine (4-AP; 1 mM, ic). Reduction of CPP to 40 mmHg diminished coronary flow (~ 55%; P < 0.001) and systolic wall thickening (~ 35%; P < 0.001). 4-AP-mediated reductions in coronary flow (~ 35%; P = 0.01) and wall thickening (~ 40%; P < 0.05) were restored by returning coronary flow to normal baseline levels. Dobutamine increased heart rate and coronary flow ~ 65% (P < 0.001) and coronary flow remained tightly coupled with MVO(2). Inhibition of coronary responses to dobutamine was associated with an ~ 35% reduction in wall thickening and an ~ 50% increase in MVO(2). Reductions in CPP, administration of 4-AP, and diminished flow during dobutamine infusion were associated with proportional decreases in coronary flow and MVO(2). Wall thickening progressively decreased as coronary flow was reduced below ~ 5.0-7.5 μL/g/beat regardless of whether the decrease was due to diminished "supply" (CPP, 4-AP) or limitations during increased "demand" (flow clamp or restriction with dobutamine). These findings demonstrate that impairments in local metabolic control of coronary flow are reliably demonstrated by decreases in contractile function as a consequence of reductions in the volume of myocardial perfusion per beat.