The cardiovascular effects of N6-cyclopentyladenosine (CPA), a selective adenosine A1 receptor agonist and 2-[p-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21,680), a selective A2 receptor agonist have been investigated in the pithed rat with blood pressure raised to normal levels with angiotensin II. Cumulative intravenous administration of CPA, 0.3-10 micrograms/kg, induced dose-related falls in blood pressure and heart rate; over the same dose range CGS 21,680 induced hypotension but no bradycardia. Pretreatment with a maximally effective dose of the A1/A2 receptor antagonist 8-(p-sulphophenyl) theophylline (8-SPT) blocked the bradycardiac effects of CPA (92-fold) more effectively than its hypotensive activity (5.1-fold); the vasodepressor effects of CGS 21,680 were blocked 19-fold by 8-SPT. Glibenclamide, a blocker of ATP-sensitive potassium (K+ATP) channels, administered intravenously at 20 mg/kg markedly attenuated the vasodepressor effects of the potassium channel opener, (-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-cyclopent- 1-enyloxy)-2H-1-benzopyran-6-carbonitrile (SDZ PCO 400). In contrast, neither the hypotensive nor the bradycardic effects of CPA nor the fall in blood pressure following CGS 21,680 was significantly affected by pretreatment with glibenclamide. These results indicate that a significant component of the blood pressure fall induced by CPA and CGS 21,680 in the pithed rat with blood pressure supported by angiotensin II occurs by a mechanism which is insensitive to 8-SPT and unlikely, therefore, to be mediated by A1 or A2 receptors. Moreover, in contrast to the prevailing literature, the cardiovascular effects arising from adenosine receptor activation in this model are not mediated by glibenclamide-sensitive, K+ATP channels.