Role of adenosine in coronary blood flow regulation after reductions in perfusion pressure.

Abstract

SUMMARY. We employed intracoronary infusion of adenosine deaminase to test the hypothesis that endogenous adenosine contributes to regulation of coronary blood flow following acute reductions in coronary artery pressure. In 16 closed-chest anesthetized dogs, we perfused the left circumflex coronary artery from a pressurized arterial reservoir and measured coronary blood flow following changes in perfusion pressure before and 10 minutes after the start of intracoronary adenosine deaminase, 5 U/min per kg body weight. Parallel studies showed that this dose of enzyme resulted in cardiac lymph adenosine deaminase concentrations of 3.2 ± 0.4 U/ml. Adenosine deaminase abolished the vasodilator response to intracoronary adenosine, 4 and 8 /tg, but had no effect on the vasodilator response to intracoronary papaverine, 200 and 300 ^g, demonstrating enzyme efficacy and specificity. Additional experiments demonstrated that adenosine deaminase reversibly attenuated myocardial reactive hyperemia following 5-and 10-second coronary occlusions by 30% (P < 0.05), evidence that the infused enzyme effectively degraded endogenous adenosine. However, adenosine deaminase did not alter the time course for coronary autoregulation or the steady state autoregulatory flow response over the pressure range between 125 and 75 mm Hg. Further, adenosine deaminase did not alter steady state coronary flow when perfusion pressure was reduced below the range for effective autoregulation (60-40 mm Hg). Such results show that adenosine is not essential for either coronary autoregulation or for the maintenance of coronary vasodilation when autoregulatory vasodilator reserve is expended. (CircRes 56: 517-524, 1985) CORONARY autoregulation is the intrinsic ability of the heart to maintain its blood supply relatively constant in the face of fluctuations in perfusion pressure (Mosher et al., 1964;Cross, 1964). The mechanism underlying this fundamental adaptive flow response is unknown. According to the metabolic hypothesis, coronary autoregulation is initiated by flow-dependent changes in tissue levels of a metabolic substrate or a metabolite (Johnson, 1964;Rubio and Berne, 1975;Belloni, 1979;Feigl, 1983). Several studies have demonstrated increased adenosine production and release during conditions in which oxygen supply is reduced (Katori and Berne, 1966;Rubio and Berne, 1969;Rubio et al., 1974;. In one of these studies , tissue adenosine content and adenosine release increased when perfusion pressure was lowered over the autoregulation range in isolated buffer-perfused guinea pig hearts. As the investigators point out, such a correlation only suggests, but does not prove, that adenosine is the primary determinant of changes in coronary resistance during autoregulation.This study tests the hypothesis that endogenous adenosine is an essential mediator of coronary autoregulation. The hypothesis predicts that destroying interstitial adenosine should abolish autoregulation. Extending this inquiry to pressures below the autoregulation range tests a secon...

Autoregulation of blood flow.

“…Schrader et al 36 found that coronary venous levels of adenosine and inosine in the saline-perfused guinea pig heart increased at reduced arterial pressures. On the other hand, Dole et al 37 found that adenosine deaminase infused into the blood-perfused dog myocardium moderately reduced the magnitude of reactive hyperemia but did not significantly affect autoregulation. Hanley et al 38 also found that adenosine deaminase did not attenuate autoregulation the blood-perfused dog heart.…”

“…56 and causes arteriolar constriction in the rat mesoappendix, 37 rat cremaster, 23 and cat mesentery. 58 In the rat mesoappendix and rat cremaster the constriction to venous pressure elevation is greatest in the terminal region of the arteriolar network where the pressure rise would presumably also be greatest.…”

Adenosine, the heart, and coronary circulation.

“…When coronary perfusion pressure is reduced, adenosine is reported to increase to maintain coronary blood flow, 27 suggesting the role of adenosine in coronary autoregulation. However, adenosine deaminase does not affect vascular resistance during graded reduction in perfusion pressure, 45 indicating that adenosine does not play a role in autoregulation of coronary blood flow. Similar results were obtained by blocking the adenosine receptors with theophylline.…”

“…Similar results were obtained by blocking the adenosine receptors with theophylline. In fact, since intra-arterially administered adenosine deaminase was detected in cardiac lymph, 45 it is probable that infused adenosine deaminase is distributed in the interstitial space. 46 Other observations suggest that the interstitial adenosine concentration may be too low to elicit vasodilation 47 and that the concentration does not change during autoregulation.…”

Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts

“…We [20,44] and others [10,11,45] previously demonstrated that adenosine also plays a physiological role in regulating coronary resting flow in human [11], swine [10], dogs [45], guinea pigs [46], and mice [20,44], while some other groups failed to observe an endogenous role of adenosine [3,47,48], which leaves this scientific topic controversial. This discrepancy may be due to different animal models, differences in species, and/or different agonists and antagonists applied in these studies [19].…”