The role of coronary flow and adenosine in postischemic recovery of septic rat hearts

Sepsis depresses myocardial function but prevents subsequent ischemia-reperfusion injury. Elevated coronary flow (CF) and endogenous adenosine may be important factors in the complete recovery of postischemic myocardial function observed in septic rat hearts. The purpose of this study was to determine the effects of manipulating CF and of antagonizing adenosine receptors on the postischemic recovery of left ventricular developed pressure (LVDP) in septic and control rat hearts. The relationship between CF and LVDP in septic rat hearts before ischemia was depressed compared with control. However, this relationship was unaltered by ischemia in septic hearts, whereas in control hearts it was severely depressed. Preventing the elevation of CF during reperfusion did not significantly affect the recovery of LVDP in septic rat hearts. Adenosine antagonism by 8-phenyltheophylline (0.1 and 1 nM) prevented the elevated CF during reperfusion, and the higher dose significantly depressed postischemic function. We conclude that elevated CF did not contribute to the recovery of postischemic LVDP in septic rat hearts but that endogenous adenosine may provide protection from ischemia.

Endogenous adenosine modulates alpha 2- but not alpha 1-adrenergic constriction of coronary arterioles

In the coronary circulation alpha-adrenergic constriction competes with metabolic vasodilation. Because adenosine is produced by the working myocardium and metabolic stimulation results in arteriolar dilation, we tested the hypothesis that coronary arteriolar alpha-adrenergic constriction is attenuated by the endogenous production of adenosine. To test this hypothesis, using fluorescence microscopy during stroboscopic epi-illumination of the epicardial microvasculature, we measured the diameter of coronary arterioles in anesthetized open-chest dogs. Measurements were made in the presence of beta-blockade during selective alpha 1- or alpha 2-adrenoceptor activation (phenylephrine or B-HT-933, respectively) before and in the presence of the nonselective adenosine receptor antagonist 8-p-sulfophenyltheophylline (8-pSPT) and expressed as a percent change in microvascular diameter relative to baseline. alpha 1-Activation produced constriction of coronary arterioles under control conditions, which was not augmented after adenosine antagonism (-12 +/- 2 vs. -7 +/- 3%). In contrast, alpha 2-activation did not constrict coronary arterioles under control conditions; however, blockade of adenosine receptors unmasked a significant constriction (0 +/- 2 vs. -7 +/- 2%, P < 0.05). Also adenosine antagonism did not significantly alter the baseline diameter of coronary arterioles. These results demonstrate that endogenously produced adenosine modulates alpha 2-adrenergic constriction of coronary arterioles but not alpha 1-adrenergic constriction, and therefore we speculate that the competition between alpha-adrenergic constriction and metabolic vasodilation is mediated by the alpha 1-adrenoceptor.

Myocardial adenosine, flow, and metabolism during adenosine antagonism and adrenergic stimulation

Pages H61–H70: J. P. Headrick, S. W. Ely, G. P. Matherne, and R. M. Berne. “Myocardial adenosine, flow, and metabolism during adenosine antagonism and adrenergic stimulation.” The legends to Figs. 3, 4, and 7 incorrectly state that data were collected from rat hearts. All data in the study were in fact obtained from guinea pig hearts.

Myocardial adenosine, flow, and metabolism during adenosine antagonism and adrenergic stimulation

Relationships between interstitial transudate adenosine and coronary flow and between global adenosine formation and cytosolic metabolism were examined in constant-pressure perfused guinea pig hearts during norepinephrine (NE) stimulation and adenosine antagonism with 10 microM 8-phenyltheophylline. Basal coronary flow was 5.7 ml.min-1 x g-1, and transudate and venous adenosine levels were approximately 0.26 and 0.06 microM, respectively. During 10 min of NE stimulation (15 nM), coronary flow and adenosine levels increased, the phosphocreatine-to-inorganic phosphate ratio ([PCr]/[Pi]) declined, and ATP and pH remained stable. Despite phasic release of adenosine, coronary flow correlated dose dependently with transudate adenosine, and adenosine release was inversely related to [PCr]/[Pi] under all conditions. 8-Phenyltheophylline infusion attenuated functional hyperemia by approximately 40%, enhanced the fall in [PCr]/[Pi], and potentiated elevations in transudate and venous adenosine. Similar results and correlations were obtained in hearts perfused at a constant-flow of 5.7 ml.min-1 x g-1, although stimulated adenosine levels and metabolic changes were greater and contractile responses smaller. These data indicate that: 1) endogenous adenosine plays a primary role in functional hyperemia in perfused guinea pig heart; 2) global adenosine formation appears related to phosphorylation status; and 3) adenosine receptor antagonism enhances metabolic disturbances during adrenergic stimulation and markedly potentiates adenosine release, indicating that the functional effects of antagonists may significantly underestimate the dilatory role of endogenous adenosine.

Myocardial adenosine, flow, and metabolism during adenosine antagonism and adrenergic stimulation

Pages H61–H70: J. P. Headrick, S. W. Ely, G. P. Matherne, and R. M. Berne. “Myocardial adenosine, flow, and metabolism during adenosine antagonism and adrenergic stimulation.” The legends to Figs. 3, 4, and 7 incorrectly state that data were collected from rat hearts. All data in the study were in fact obtained from guinea pig hearts.