Regulation of coronary blood flow: effects of 2,4-dinitrophenol and theophylline

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Abstract
The relationship between cardiac energy metabolism and coronary flow was studied in isolated perfused rat hearts by infusing 2,4-dinitrophenol (DNP), an uncoupler of mitochondrial oxidative phosphorylation. Infusion at concentrations of 5.0, 7.5 and 10 .times. 10-6 M caused a dose-dependent increase in O2 consumption (up to 46%) and coronary flow (up to 30%). Concomitant changes occurred in the levels of high-energy phosphate compounds; tissue ATP and creatine phosphate (CrP) decreased, and ADP and creatine (Cr) increased, leading to decrease in the [CrP]-to-[Cr] and [ATP]free-to-[ADP]free[Pi] ratios. A rapid and sensitive method was developed for analyzing nmol levels of adenosine and its metabolites inosine and hypoxan-thine by high-pressure liquid chromatography. There was no change in the levels of these compounds in the effluent but the calculated rate of release (adenosine and inosine and hypoxine) was increased from 498 to 651 pmol .cntdot. min-1 .cntdot. g wet wt-1 because of the increase in coronary flow. Theophylline was without effect on DNP-induced vasodilation but inhibited competitively adenosine-induced vasodilation; it did not affect either the uptake or metabolism of adenosine. The results are inconsistent with adenosine having a significant role in vasodilation induced by DNP. The DNP-induced alterations in the energy state of cardiac tissue (expressed as [ATP]free/[ADP]free[Pi]) correlated with the changes in coronary flow. This correlation was the same as that observed for varied work load and during infusion of Amytal, which supports the view that tissue energy level is a major determinant of coronary flow.

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