Role of adenosine in the maintenance of coronary vasodilation distal to a severe coronary artery stenosis. Observations in conscious domestic swine.

Abstract

SUMMARY. The purpose of this study was to test the hypothesis that adenosine is required to maintain arteriolar vasodilation distal to a severe coronary stenosis. Eight closed-chest conscious pigs were prepared by placing a 7.5-mm long stenosis (82% lumenal diameter reduction) in the proximal left anterior descending coronary artery. Regional myocardial blood flow (microsphere technique) was measured at control 1, after 10 minutes of intracoronary infusion of adenosine deaminase (7-10 U/kg per min) distal to the stenosis, and 20-30 minutes after stopping adenosine deaminase infusion. Studies with 125 I-labeled adenosine deaminase were conducted in six additional pigs to document the extent to which infused adenosine deaminase penetrated the interstitial space. I-labeled adenosine deaminase was infused for 10 minutes (10-11 U/kg per min) into the left anterior discending coronary artery. Calculated interstitial fluid concentrations of adenosine deaminase ranged between 71 and 272 U/ml and were at least one order of magnitude greater than that required to deaminate all the adenosine which would be released into the interstitium in response to 15-30 seconds of coronary occlusion. In the primary group of animals (n = 8), endocardial flow (ml/min per g) distal to stenosis at control 1 (1.15 ± 0.33) was reduced vs. endocardial flow in the nonobstructed circumflex zone (1.59 ± 0.38, P < 0.05). Flows in epicardial layers were comparable at control 1 (distal zone = 1.40 ± 0.36 vs. circumflex zone = 1.45 ± 0.41). Distal zone endocardial and epicardial flows did not change vs. control 1 in response to infusion of adenosine deaminase. However, the distakcircumflex epicardial flow ratio declined vs. control 1 (0.98 ± 0.14) during adenosine deaminase infusion (0.87 ± 0.17, P < 0.05). The distakcircumflex endocardial flow ratio during adenosine deaminase (0.72 ± 0.20) was unchanged vs. control 1 (0.76 ± 0.22) but was less than control 2 (0.80 ± 0.18, P < 0.05). Thus, destruction of all or most interstitial adenosine caused only slight relative reduction in regional myocardial blood flow distal to a severe coronary artery stenosis. Accordingly, adenosine contributes only modestly to maintenance of arteriolar vasodilation in this setting or else its absence is almost fully compensated for by another mechanism(s). (Circ Res 53: 42-51, 1983) ADENOSINE is widely regarded as the primary physiological mediator of both reactive hyperemia and autoregulation of the coronary vascular bed (Beme and Rubio, 1979). Although several recent studies (Hester et al., 1982;Jones et al., 1982;Manfredi and Sparks, 1982;Saito et al., 1981) have undertaken tests of the adenosine hypothesis as it applies to reactive hyperemia or autoregulation in response to increased myocardial oxygen demand, none have addressed the role of adenosine in the maintenance of normal or only modestly reduced levels of myocardial blood flow distal to a severe coronary artery stenosis. Accordingly, the present investigation was performed to test the hypothesis that adenos...

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.…”

Tissue acidosis: role in sustained arteriolar dilatation distal to a coronary stenosis.

“…Although other mediators may substitute for low pH or elevated Pco2, results of earlier studies conducted in our laboratory indicate that sustained elevation of interstitial fluid adenosine concentration19 or increased prostacyclin production32 also are not essential for long-term maintenance of reduced arteriolar tone distal to a severe coronary arterial stenosis. Thus, the results of the present investigation are best understood in the context of a series of experiments, [16][17][18][19]31,32 which indicate that known mediators of acute changes in coronary arteriolar tone may not have an important role (either alone or in combination) in the long-term maintenance of reduced arteriolar tone distal to a severe coronary arterial stenosis. The mechanism(s) involved in maintenance of reduced coronary arteriolar tone in this setting is unknown but could involve alterations in one or more proteins responsible for regulation of vascular smooth muscle contraction and relaxation.…”

Adenosine, the heart, and coronary circulation.

“…69 - 70 The absence of reduction in myocardial blood flow by adenosine deaminase administered distal to a coronary stenosis also indicates that adenosine contributes only modestly to maintenance of arteriolar vasodilation in hypoperfused hearts. 70 Failure to resolve this controversy may be due to the fact that adenosine deaminase has not been clearly demonstrated to destroy all of the adenosine in the interstitial space. 71 In addition, factors other than adenosine may be involved in flow changes during ischemia and hypoxia.…”