Studies on the possible role(s) of purine nucleotides in cardiac function
Description
Four conditions which had previously been reported to be associated with increased tissue concentrations of cyclic GMP were examined in the isolated perfused rat heart. These conditions included exposure of hearts to acetylcholine (Ach), sodium nitroprusside (SNP), ischemia, or hypoxia. The effects of these treatments on contractile force, coronary flow, and purine nucleotide contents were determined. For comparative purposes, selected brominated adenine and guanine nucleotides were administered to isolated rat hearts to examine their effects on contractile force and coronary flow. These lipophilic compounds were utilized because of their reported abilities to cross biological membranes more readily than the respective parent compounds Ach produced dose-related decreases in both contractile force and coronary flow. Ach caused significant increases in the myocardial contents of cyclic GMP, GMP, and GDP. Ach also increased the myocardial content of a substance which has been identified as a selected peak (Peak-5) from a high pressure liquid chromatographic separation. Peak-5 may correspond to FMN, because FMN and Peak-5 have the same retention time following chromatographic separation. The effects of Ach on contractile force and coronary flow were mimicked by 8-Br GMP, 8-Br AMP, and imidazole. The effects of Ach on contractile force and coronary flow were blocked by atropine, a muscarinic antagonist, as well as by 1-methyl-3-isobutylxanthine (MIX), a phosphodiesterase inhibitor SNP, like Ach, also increased the myocardial concentration of cyclic GMP. However, whereas Ach decreased coronary flow, SNP produced a dose-dependent increase. The effects of SNP on contractile force were biphasic. Doses of SNP lower than 1 x 10('-6) M significantly decreased contractile force, but there was no significant effect of SNP on force of contraction at concentrations greater than 1 x 10('-6) M. SNP increased the size of Peak-5 and decreased myocardiac AMP content. With respect to the administration of exogenous nucleotides, 8-Br cyclic GMP produced effects on the heart which were qualitatively similar to the effects of SNP. For example, low doses of either agent were associated with negative inotropic effects and high doses were associated with significantly elevated coronary flow Ischemia produced a rapid decline in contractile force that was associated with elevated tissue concentrations of Peak-5, cyclic GMP, GMP, GDP, and ADP. There were significant decreases in ATP and GTP by 180 sec of ischemia Hypoxia caused a reduction in contractile force that was associated with an increase in coronary flow. Hypoxia significantly increased the tissue contents of GMP, GDP, and ADP and decreased GTP and ATP. Exogenous administration of 8-Br adenosine produced mechanical effects on the isolated rat heart which were qualitatively similar to the effects of hypoxia, i.e., decreased force of contraction and increased coronary flow. Hypoxia produced a decrease in total adenine nucleotide content, which suggests that hypoxia caused the release of adenosine. The release of adenosine by hypoxia may have contributed to the increase in coronary flow and decrease in contractile force The results of these experiments suggest the following: (1) Ach may increase the turnover of cyclic GMP and/or cyclic AMP, an event which may be associated with its negative inotropic effect, (2) high concentrations of cyclic GMP, whether produced by exogenous administration of 8-Br cyclic GMP or by SNP, are associated with increased coronary flow, (3) some of the effects of hypoxia result from the release of adenosine, and (4) the effects of Ach on contractile force and myocardial metabolism in the isolated perfused rat heart are closely associated with its coronary vasoconstrictor activity