Intracoronary adenosine deaminase reduces canine myocardial reactive hyperemia.

Abstract

SUMMARY We employed intracoronary infusions of calf intenstine adenosine deaminase (ADA) to test the hypothesis that adenosine regulates coronary blood flow during myocardial reactive hyperemia (RH). Infusions of 4.5 U ADA/min per kg body weight into the left circumflex coronary artery of 10 open-chest dogs reversibly reduced repayment of flow debt by 30-39% ( P < 0.05) following 5-, 10-, 15-, 20-, and 30-second coronary occlusions, the percentage reduction being independent of occlusion length. ADA reduced peak RH flow rate (17%, P < 0.05) only after 5-second occlusions. Intracoronary infusions of ["']ADA in seven dogs produced interstitial ADA concentrations between 1.2 and 13.1 U/ ml in perfused myocardium and, In five of these dogs, '"I activity in the cardiac node was 1.8-35 times that of contiguous mediastinal tissue. Theophylline, a specific adenosine antagonist, reduced repayment of flow debt by 27-38% {P < 0.02) in eight dogs, an effect similar to that of ADA, In six other dogs, ADA plus theophylline did not reduce RH flow debt repayment below that produced by ADA alone. This experiment confirms the contribution of adenosine to myocardial RH but shows that this nucleoside accounts for but a third of volume flow. Other, as yet unidentified, factors are collectively more important. Ore Res 49: 1383Res 49: -1267 TWO lines of evidence support the hypothesis that adenosine regulates coronary blood flow during myocardial reactive hyperemia: (1) adenosine appears in coronary venous blood during reactive hyperemia in quantities paralleling the duration of the preceding ischemic interval (Rubio et al., 1969), and (2) coronary flow rate changes concordantly during reactive hyperemia with changes in myocardial adenosine content (Olsson et al., 1978).However, other evidence challenges this view. Methylxanthines strongly antagonize the coronary effects of exogenous adenoaine (Afonso, 1970), yet only modestly reduce the reactive hyperemic response (Bittar and Pauly, 1971;Juhran et al., 1971; Cumish et al., 1972;Eikens and Wilcken, 1977). Coronary occlusions of one heart beat or less have no detectable effect on myocardial metabolism, yet elicit hyperemic responses (Eikens and Wilcken, 1974; Schwartz et el, 1980). Other vasodilatory substances such as K + and CO 2 (or H + ) accumulate in ischemic hearts and also could participate in reactive hyperemia (Raberger et al., 1975;Case, 1976;Murray and Sparks, 1978).This study estimates the contribution of adenosine to canine myocardial reactive hyperemia by employing adenosine deaminase (ADA) to destroy adenosine in the cardiac interstitium. This enzyme reduces but does not abolish this response, confirming that adenosine contributes to, but is not solely responsible for, post-ischemic coronary vasodilation. MethodsHealthy mongrel dogs weighing 15.5-30 kg were anesthetized by sodium pentobarbital (30 mg/kg, iv) and artificially ventilated at rates maintaining arterial blood Poj and Pco 2 in the normal range (Feigl and D'Alecy, 1971). Catheters in the right femoral vein a...

Voltage-dependent K+ channels regulate the duration of reactive hyperemia in the canine coronary circulation

“…Importantly, however, other studies provide compelling data to indicate that adenosine plays no role in coronary reactive hyperemia (8). Our data are more like those of Bittar and Pauly (8) than those of Saito et al (46). The development of arginine analogs soon placed NO on the list of mediators of reactive hyperemia.…”

“…Additionally, exogenous adenosine (at levels comparable to ischemic production) elicits vasodilation equal to that observed in reactive hyperemia (38). Finally, adenosine deaminase reversibly reduces hyperemic flow (without any effect on peak) following an occlusion longer than 5 s (46). These data solidify the place of adenosine on the list of viable mediators of reactive hyperemia.…”

Role of K+ ATP channels and adenosine in the regulation of coronary blood flow during exercise with normal and restricted coronary blood flow.

“…Previous studies have demonstrated that endogenous adenosine is not obligatory for maintaining coronary blood flow during normal arterial inflow. Thus, studies in anesthetized open-chest dogs (15)(16)(17)(18)(19) and awake dogs (1,20) failed to demonstrate an effect of intracoronary adenosine deaminase (15)(16)(17), or adenosine receptor blockade with intravenous aminophylline (18, 19) or 8-phenyltheophylline (1, 20), on (21) examined the effect of exercise on myocardial adenosine production. They found that treadmill exercise in dogs resulted in a fivefold increase in myocardial adenosine content, with a doubling of the coronary arterio-venous adenosine content difference.…”

Adenosine, the heart, and coronary circulation.

“…43 Adenosine deaminase reduced coronary reactive hyperemia after a brief period of ischemia by 27-36%. 44 These observations support a substantial role of adenosine in mediating ischemia-induced coronary hyperemic flow. The constituents of reactive hyperemia other than adenosine remain to be determined.…”