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8‐OH‐DPAT, flesinoxan and guanfacine: systemic and regional haemodynamic effects of centrally acting antihypertensive agents in anaesthetized rabbits

1 8‐Hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT) and flesinoxan, agents which show high affinity and selectivity for 5‐HT1A receptors, were administered intravenously in doses of 0.003 to 0.1 and 0.01 to 0.3 mg kg−1 respectively to 5 rabbits each. Their effects were compared with those of the centrally acting agent and α2‐adrenoceptor agonist, guanfacine, 0.01–0.3 mg kg−1, administered to a group of 5 rabbits. Five further rabbits were used as controls and treated with the vehicle of the active agents. 2 Both flesinoxan and 8‐OH‐DPAT induced similar systemic and regional haemodynamic changes. Both lowered mean arterial pressure and heart rate. The principal blood pressure lowering mechanism was vasodilatation; cardiac output changed minimally despite the falls in heart rate and myocardial contractile force. 3 With guanfacine the maximal fall of blood pressure was comparable to that obtained with the 5‐HT1A receptor ligands; however, in contrast to the latter, the dose‐response curve was U‐shaped, the highest dose eliciting a pressor effect with reversal of the vasodilatation. 4 Widespread peripheral vasodilatation was found with all the agents in the splanchnic circulation and also in the brain and skeletal muscle. A weak tendency towards vasodilatation was found in the kidneys where the dose‐response curve was bell‐shaped for guanfacine. 5 This spectrum of activity is different from that of peripheral vasodilators, such as calcium antagonists, potassium channel activating agents or hydralazine; it is, however, consistent with the putative mechanism of action of these compounds to reduce peripheral sympathetic tone by a central mechanism of action.