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1 The effects of an intracoronary bolus of adenosine triphosphate (ATP), a,p-methylene ATP (APCPP), ,y-methylene ATP (APPCP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and adenosine on coronary tone and ventricular myocardial contraction were investigated in the perfused rat heart. 2 Adenine nucleotides, given by bolus injection were negatively inotropic in amounts > 3 x 10-7 mol. The potency order was ATP>ADP> AMP. Adenosine (<1 x 10-5mol) had no effect on ventricular myocardial contraction. 3 Adenine nucleotides and adenosine (1 x 10-'-1 x 10-' mol) reduced coronary tone. The potency order was ATP > ADP > AMP = adenosine. The ATP analogue APPCP was less active than ATP at reducing coronary tone, and APCPP had no vasodilator effect. This suggests the presence of a P2-purinoceptor, subclass P2w which mediates vasodilatation. 4 ATP and ADP increased the concentration of prostacyclin (measured as 6-keto prostaglandin Fa) in the perfusate, but only after injection of > 3 x 10-7 mol, suggesting that the vasodilator responses to ATP and ADP were not mediated by prostacyclin. AMP and adenosine had no effect, even at x 105mol. 5 At a dose of 3 x 10-mol, approximately 40% of ATP and 70% of ADP was converted to AMP and adenosine whilst passing through the heart. The amounts of AMP and adenosine formed, however, were insufficient to account for the vasodilator effects of ATP and ADP. 6 Vasodilatation mediated by AMP and adenosine was inhibited by an infusion of 8-phenyltheophylline (8-PT; 2 x 10-5 M) indicating interaction with a P1-purinoceptor. Vasodilatation induced by ATP (at doses at which AMP and adenosine had no action) was also depressed by 8-PT indicating either an action of ATP on PI-purinoceptors, or an effect of 8-PT on P2y receptors. 7 Vasodilatation induced by AMP was unaltered during an infusion of a,-methylene ADP (2 x 10-6 M, which inhibited breakdown of AMP to adenosine by 54.2 ± 1.5%, n = 4). This suggests that AMP acted directly, and it did not require conversion to adenosine to induce vasodilatation.

We have used the rat isolated, perfused heart to study the metabolism of adenine nucleotides on a single passage through the coronary circulation. Low doses (3-30 nmol) of ATP, ADP, or AMP injected as a bolus were extensively catabolized by ectoenzymes. Increasing doses of each nucleotide demonstrated saturability of catabolism that occurred at significantly lower doses of AMP than of ADP or ATP. The patterns of catabolites formed in each case were consistent with the major pathway of metabolism being sequential dephosphorylation of ATP----ADP----AMP----adenosine, although from experiments in which [3H]ATP was co-injected with unlabeled ADP, it appears that some direct conversion of ATP----AMP can occur. Furthermore, particularly in the presence of excess unlabeled ATP, [3H]ADP was phosphorylated to [3H]ATP, indicating that ectoenzymes capable of interconverting nucleotides are present. By evaluating recovery and metabolism in serial samples collected rapidly after bolus injection, we were able to use the integrated form of the Michaelis-Menten equation as developed by Bronikowski et al. (Math. Biosci. 61: 237-266, 1982) to derive Michaelis constant (Km) and maximum velocity times capillary plasma volume (Amax) values for adenosinetriphosphatase, adenosine diphosphatase, and 5'-nucleotidase (450, 300, and 93 microM; and 5.3, 5.9, and 1.7 mumol/min, respectively). This analysis also indicated that there is a high degree of heterogeneity of path lengths within the coronary circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

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