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BF Cox and GJ Smits
Department of Cardiovascular Biology, Rhone-Poulenc Rorer Central Research, Collegeville, Pennsylvania, USA.
ATP produces significant cardiovascular effects by activation of P2 purinoceptors. In the present study, we examined the regional hemodynamic profiles produced by intravenous administration of a P2X and a P2Y purinergic receptor agonist. Sprague-Dawley rats were anesthetized with Inactin, catheters were placed in the femoral artery and vein and the rats were instrumented to measure renal, mesenteric, hindquarter, coronary and cerebral blood flow using Doppler flow probes. Administration of bolus doses (1-1000 nmol kg-1) of the P2X agonist beta, gama-methylene-ATP dose-dependently increased arterial pressure at doses greater than 100 nmol kg-1. This increase in mean arterial pressure was mediated by increases in coronary, mesenteric and renal vascular resistance after administration of 300 nmol kg-1. Cerebral and hindquarter vascular resistances were increased significantly only after 1000 nmol kg-1. This P2X agonist had the greatest efficacy in elevating resistance in the renal and mesenteric vascular beds. In a separate group of animals, the pressor response to administration of 100 nmol kg-1 was demonstrated to be reproducible when bolus doses of the agonist were administered at 10-min intervals. In contrast to P2X receptor stimulation, administration of bolus doses (1-1000 nmol kg-1) of the P2Y agonist 2-methylthio-ATP (2MeSATP) dose- dependently reduced mean arterial pressure. This decrease in arterial pressure was mediated by significant reductions in cerebral, coronary and mesenteric vascular resistance at doses greater than 30 nmol kg-1. Hindquarter vascular resistance was decreased significantly after administration of 100 nmol kg-1. The P2Y agonist 2MeSATP had the greatest efficacy in reducing resistance in the cerebral and hindquarter vascular beds. Renal vascular resistance was not altered significantly at any dose of 2MeSATP. Administration of the A1/A2 antagonist CGS15943 (1 mg kg-1) minimally affected these responses, demonstrating that these vasoconstrictor/vasodilator effects were not mediated by adenosine A1 or A2 receptors. Although the pressor and depressor responses to bolus administration were robust and reproducible, these responses were not maintained with intravenous infusion of these two agonists at rates from 2 to 200 nmol kg-1 min-1. Thus, we have established time courses and distinct regional hemodynamic profiles for agonists selectively activating P2X and P2Y receptor subtypes in the rat.
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