IP66 (1[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxy-phenyl)piperazine) enhances beta-adrenoceptor-induced vasodilatation in rat mesenteric vascular bed.
The effect of the antihypertensive drug IP66 on dopamine-induced vasodilatation has been investigated in isolated perfused rat mesenteric bed. Experiments were carried out in phenoxybenzamine-pretreated preparations to avoid the involvement of alpha-adrenoceptors. Dopamine (1-100 microM) elicited a concentration-dependent relaxation of high-K(+)-induced vasoconstriction, which was resistant to propranolol (3 microM), but antagonized by the DA1-receptor antagonist SCH 23390 (0.1 microM). However, the dopamine-vasodilating component resistant to SCH 23390 (0.1 microM) could be abolished by simultaneous administration of propranolol. Thus, dopamine-induced vasodilatation is mainly ascribable to stimulation of DA1-receptors, although an action on beta 2-adrenoceptors might contribute as well. In presence of IP66 (10 nM), dopamine-induced vasodilatation was significantly enhanced. This amplifying activity was not observed with prazosin and it was blocked by propranolol (3 microM) but unaffected by SCH 23390 (0.1 microM) or by chemical sympathectomy. Furthermore, IP66 (10 nM) also increased, in a significant manner, the amplitude of vasodilatation elicited by the beta 2-adrenoceptor agonist terbutaline, both in rat mesenteric bed and in rat aortic strips. In rat aortic membranes, IP66 (10 nM) enhanced the stimulatory effect of terbutaline (1 microM) on adenylate cyclase activity. In conclusion, IP66 is able to enhance the vasodilatation of rat mesenteric vasculature induced by dopamine or terbutaline. It is proposed that this action might be consequent to an increase in efficiency of the coupling between beta 2-adrenoceptors and membrane adenylate cyclase.
Perretti
F
F
Istituto Farmacobiologico Malesci, Pharmacology Department, Florence, Italy.
Nediani
C
C
Manzini
S
S
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004298:Dopamine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D011954:Receptors, Dopamine; D013152:Splanchnic Circulation / Q000187:drug effects*; D013563:Sympathectomy, Chemical; D013726:Terbutaline / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D000959:Antihypertensive Agents; D001552:Benzazepines; D010879:Piperazines; D011943:Receptors, Adrenergic, beta; D011954:Receptors, Dopamine; C040940:IP 66; D011433:Propranolol; D000262:Adenylyl Cyclases; D013726:Terbutaline; D004298:Dopamine