isoalloxazine and Myocardial-Ischemia

This study was designed to elucidate the contribution of adenosine A(2A) and A(2B) receptors to coronary reactive hyperemia and downstream K(+) channels involved. Coronary blood flow was measured in open-chest anesthetized dogs. Adenosine dose-dependently increased coronary flow from 0.72 ± 0.1 to 2.6 ± 0.5 mL/minute/g under control conditions. Inhibition of A(2A) receptors with SCH58261 (1 μm) attenuated adenosine-induced dilation by ∼50%, while combined administration with the A(2B) receptor antagonist alloxazine (3 μm) produced no additional effect. SCH58261 significantly reduced reactive hyperemia in response to a transient 15 second occlusion; debt/repayment ratio decreased from 343 ± 63 to 232 ± 44%. Alloxazine alone attenuated adenosine-induced increases in coronary blood flow by ∼30% but failed to alter reactive hyperemia. A(2A) receptor agonist CGS21680 (10 μg bolus) increased coronary blood flow by 3.08 ± 0.31 mL/minute/g. This dilator response was attenuated to 0.76 ± 0.14 mL/minute/g by inhibition of K(V) channels with 4-aminopyridine (0.3mm) and to 0.11 ± 0.31 mL/minute/g by inhibition of K(ATP) channels with glibenclamide (3 mg/kg). Combined administration abolished vasodilation to CGS21680. These data indicate that A(2A) receptors contribute to coronary vasodilation in response to cardiac ischemia via activation of K(V) and K(ATP) channels.

Topics: 4-Aminopyridine; Adenosine; Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Animals; Coronary Circulation; Disease Models, Animal; Dogs; Flavins; Glyburide; Hyperemia; KATP Channels; Male; Myocardial Ischemia; Phenethylamines; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Pyrimidines; Receptor, Adenosine A2A; Receptor, Adenosine A2B; Triazoles; Vasodilation

In this study, we investigated the effect of noradrenaline depletion on contractile recovery in rat isolated heart following myocardial ischaemia. Groups tested included control tissues and hearts from reserpinised rats. Reserpine 1 mg/kg s.c. was injected into rats 18 to 24 h prior to experiments. Hearts underwent 15 min global normothermic ischaemia followed by 30 min reperfusion. Functional data (end diastolic pressure (EDP), heart rate (HR), left ventricular developed pressure (LVDP), dP/dt(max), dP/dt(min)) showed that contractile function following ischaemia-reperfusion is unaffected by reserpinisation. However, pre- and post-ischaemic coronary flow rates (CFR) were increased by 16 to 38% in hearts from reserpinised rats versus control hearts. Pre-ischaemic CFRs in control hearts (11.17+/-0.67 ml/in(-1) x g tissue(-1), n=9) were significantly lower then CFRs derived from reserpinised rat hearts (14.57+/-0.72 ml/min(-1)/g tissue(-1), n=10). Post-ischaemic reactive hyperaemia was evident in all groups. CFRs in reserpinised hearts remained elevated when compared to pre-ischaemic values through reperfusion (P<0.05). Reserpine treatment did not significantly alter pre- or post-ischaemic adenosine efflux. The A(2B) adenosine receptor antagonist alloxazine (10 microM) attenuated pre- and post-ischaemic CFRs in both control and reserpinised hearts (P<0.05) without altering the hyperaemic response while the A(2A) adenosine receptor antagonist 8-(3-chlorostyryl) caffeine (1 microM) did not alter CFRs in both groups. The A(3) adenosine receptor antagonist MRS1191 (0.1 microM) increased CFR in control and reserpinised hearts (P<0.05). Catecholamine depletion with reserpinisation enhances the responsiveness of the coronary resistance vessels to endogenous adenosine through activation of the A(2B) adenosine receptor.

Topics: Adenosine; Adenosine A2 Receptor Antagonists; Adrenergic Uptake Inhibitors; Animals; Flavins; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Myocardium; Norepinephrine; Purines; Rats; Rats, Wistar; Reperfusion; Reserpine; Time Factors; Tyramine; Vasodilator Agents