6-ketoprostaglandin-f1-alpha and 8-phenyltheophylline

In the perfused guinea-pig heart reactive hyperaemia (RH) after occlusion of coronary flow (1-60 s) was inhibited by 100-60% with NG-nitro-L-arginine (100 microM) and to a lesser extent (by 35%) after 8-phenyltheophylline (10 microM), but not by indomethacin (5 microM). Inhibition of adenosine deaminase by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) (5 microM) not only increased the concentration of adenosine in the coronary perfusate, but also prolonged the duration of RH. RH induced cardiac generation of prostacyclin, nitric oxide and adenosine as indicated by the appearance of 6-keto-PGF1 alpha, cyclic GMP, adenosine, inosine, hypoxanthine, xanthine and urate in the perfusate. Only NO and adenosine, but not prostacyclin, were responsible for RH. RH after short-term (1-10 s) coronary occlusion was mediated by NO, whereas adenosine and NO maintained RH that followed after longer (20 s-10 min) periods of cardiac ischaemia. Prostacyclin never participated in the mediation of RH.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine; Animals; Coronary Circulation; Cyclic GMP; Cyclooxygenase Inhibitors; Electrocardiography; Endothelins; Epoprostenol; Guinea Pigs; Hyperemia; In Vitro Techniques; Indomethacin; Myocardial Ischemia; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Perfusion; Prostaglandin Antagonists; Purinergic P1 Receptor Antagonists; Purines; Theophylline

The effects of an intracoronary bolus of adenosine triphosphate (ATP), alpha, beta-methylene ATP (APCPP), beta, gamma-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. Adenine nucleotides, given by bolus injection were negatively inotropic in amounts greater than 3 X 10(-7) mol. The potency order was ATP greater than ADP greater than AMP. Adenosine (less than 1 X 10(-5)mol) had no effect on ventricular myocardial contraction. Adenine nucleotides and adenosine (1 X 10(-10)-1 X 10(-7) mol) reduced coronary tone. The potency order was ATP greater than ADP greater than 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 P2Y, which mediates vasodilation. ATP and ADP increased the concentration of prostacyclin (measured as 6-keto prostaglandin F1 alpha) in the perfusate, but only after injection of greater than 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 1 X 10(-5) mol. At a dose of 3 X 10(-9) 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 alpha,beta-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. 8 The ATP analogues APCPP (1 x 10-9_1 x 10-8 mol) and APPCP (1 x 10-8_l x 10-7mol) increased coronary tone, as did high doses (I x 10-5 mol) ofATP and ADP, indicating the presence of an additional P2-purinoceptor, subclass P2X, mediating vasoconstriction.

Topics: 6-Ketoprostaglandin F1 alpha; Adenine Nucleotides; Adenosine; Animals; Chromatography, Thin Layer; Coronary Circulation; Coronary Vessels; Male; Myocardial Contraction; Perfusion; Rats; Rats, Inbred Strains; Receptors, Purinergic; Theophylline; Vasodilation