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 alpha 2-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.
Hof
R P
RP
Preclinical Research Department, Sandoz Ltd., Basel, Switzerland.
Fozard
J R
JR
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D016316:Guanfacine; D006146:Guanidines / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D008863:Microspheres; D009281:Naphthalenes / Q000494:pharmacology*; D010648:Phenylacetates / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D006146:Guanidines; D009281:Naphthalenes; D010648:Phenylacetates; D010879:Piperazines; D013764:Tetrahydronaphthalenes; D016316:Guanfacine; C056895:flesinoxan; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin