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Renal vasoconstrictor responses to the adenosine A1 agonist N6-cyclopentyladenosine (CPA) were compared in the in situ autoperfused rat kidney to responses evoked by angiotensin II (ANG II), endothelin-1 (ET-1), arginine vasopressin (AVP), carbocyclic thromboxane A2 (CTxA2), phenylephrine (PE), and 5-hydroxytryptamine (5-HT). On the basis of their ED50 values (dose of agonist, in mass units, that produced 50% of maximal response to that agonist), the order of vasoconstrictor potency was ANG II > or = AVP > ET-1 > CPA > 5-HT > or = PE > CTxA2. Dose-response curves to CPA were shallower and maximal responses were weaker than those produced by the other agonists. Maximal responses, the log ED50, and the slope of the dose-response curve to CPA were markedly potentiated in the presence of the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). Selective antagonism of A1 receptors increased renal blood flow and markedly attenuated CPA-induced renal vasoconstriction in the absence or presence of L-NAME but had no effect on the maximal responses to ANG II. Conversely, AT1 receptor antagonism attenuated renal vasoconstriction produced by ANG II but had little effect on the produced by CPA. These results suggest that endogenous NO modulates renal vasoconstriction produced by A1 receptor stimulation and provide evidence against an interaction between renovascular adenosine A1 and angiotensin AT1 receptors.

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2‐[(cyclohexylmethylene)hydrazino]adenosine (MRE‐0470) is an A2A‐adenosine receptor agonist that is a potent and selective coronary vasodilator. As part of a preclinical program, the pharmacology and toxicology of MRE‐0470 have been studied in the rat. In isolated vas deferens, MRE‐0470 activated A2A receptors (EC50 = 6.3 nM) and at higher concentrations activated A2B receptors (EC50 = 13 μM). In atrial tissues, MRE‐0470 produced negative inotropic and chronotropic actions through activation of A1 receptors (EC50 ˜ 9 μM). MRE‐0470 produced no positive inotropic or chronotropic actions in atrial or ventricular tissues. In anesthetized, reflex‐blocked rats, MRE‐0470 produced a decrease in hindquarter perfusion pressure (A2: ED50 = 0.31 μg) and a decrease in heart rate (A1: ED50 = 620 μg). In conscious rats, MRE‐0470 (0.04–117 μg/kg bolus or 0.03–150 μg/kg/min infusion) produced dose‐dependent hypotension and reflex tachycardia. MRE‐0470 was rapidly eliminated from rat plasma with an elimination half‐life of 10 min. In toxicology studies, once per day 10‐minute i.v. infusions of 3, 30, or 150 μg/kg/min MRE‐0470 for 14 consecutive days resulted in no deaths and no changes in blood chemistry, but resulted in decreased motor activity and dose‐related cardiomyopathy. Cardiomyopathy did not occur following single doses of MRE‐0470. The incidence of this lesion is related to the duration of the repeated reflex tachycardia. These studies show that MRE‐0470 is a potent and selective A2A receptor agonist in the rat. The observed toxicology of MRE‐0470 is consistent with the exaggerated pharmacology due to high‐dose drug administration. Drug Dev. Res. 42:76–85, 1997. © 1997 Wiley‐Liss, Inc.

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