Cox B F, Smits G J
Department of Cardiovascular Biology, Rhône-Poulenc Rorer Central Research, Collegeville, Pennsylvania, USA.
J Pharmacol Exp Ther. 1996 Jun;277(3):1492-500.
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.
三磷酸腺苷（ATP）通过激活P2嘌呤受体产生显著的心血管效应。在本研究中，我们检测了静脉注射P2X和P2Y嘌呤能受体激动剂所产生的局部血流动力学特征。将Sprague-Dawley大鼠用氯胺酮麻醉，将导管插入股动脉和静脉，并使用多普勒血流探头对大鼠进行监测，以测量肾、肠系膜、后肢、冠状动脉和脑血流量。静脉推注剂量为1 - 1000 nmol/kg的P2X激动剂β,γ-亚甲基三磷酸腺苷（β,γ-methylene-ATP），当剂量大于100 nmol/kg时，动脉压呈剂量依赖性升高。在给予300 nmol/kg后，平均动脉压的升高是由冠状动脉、肠系膜和肾血管阻力增加介导的。仅在给予1000 nmol/kg后，脑和后肢血管阻力才显著增加。这种P2X激动剂在升高肾和肠系膜血管床阻力方面具有最大的效能。在另一组动物中，当以10分钟的间隔静脉推注激动剂时，对给予100 nmol/kg的升压反应被证明是可重复的。与P2X受体刺激相反，静脉推注剂量为1 - 1000 nmol/kg的P2Y激动剂2-甲硫基三磷酸腺苷（2-methylthio-ATP, 2MeSATP）可使平均动脉压呈剂量依赖性降低。在剂量大于30 nmol/kg时，动脉压的降低是由脑、冠状动脉和肠系膜血管阻力显著降低介导的。给予100 nmol/kg后，后肢血管阻力显著降低。P2Y激动剂2MeSATP在降低脑和后肢血管床阻力方面具有最大的效能。在任何剂量的2MeSATP下，肾血管阻力均无显著改变。给予A1/A2拮抗剂CGS15943（1 mg/kg）对这些反应的影响最小，表明这些血管收缩/舒张作用不是由腺苷A1或A2受体介导的。尽管对静脉推注的升压和降压反应强烈且可重复，但以2至200 nmol/kg·min-1的速率静脉输注这两种激动剂时，这些反应不能持续。因此，我们已经确定了在大鼠中选择性激活P2X和P2Y受体亚型的激动剂的时间进程和不同的局部血流动力学特征。
