Mechanism of the antihypertensive effect of FCE 22716, a new ergoline derivative, in the spontaneously hypertensive rat.
Both acute and chronic oral administration (1-20 mg/kg) of FCE 22716, a new ergoline derivative, resulted in a dose-related fall of arterial blood pressure lasting for more than 6 h. Tachycardia was observed only at high dosages. Yohimbine, propranolol and indometacin did not modify its antihypertensive effect; on the other hand pretreatment with prazosin, a selective alpha 1-adrenoceptor antagonist and pithing, almost completely neutralized its antihypertensive effect. Haloperidol, a dopamine antagonist that crosses the blood-brain barrier, also antagonized FCE 22716 activity. The lack of effects of domperidone (DA2-receptor antagonist selectively acting on the periphery) together with the finding that norepinephrine and epinephrine levels were unchanged after treatment with FCE 22716, seem to rule out an involvement of peripheral DA2-receptors. Both in vitro (isolated organs) and in vivo the compound antagonized responses mediated by stimulation of alpha 1-adrenoceptors and S2-receptors. Radioligand binding studies in different cerebral regions are in line with the above reported in vitro and in vivo results. These data suggest that FCE 22716 is endowed with a multitarget mechanism of action, mainly involving blockade of alpha 1-adrenoceptors and S2-receptors.
Salvati
P
P
Farmitalia Carlo Erba, Istituto Ricerche, Nerviano, Italy.
Bondiolotti
G P
GP
Caccia
C
C
Vaghi
F
F
Bianchi
G
G
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D055598:Chemical Phenomena; D002621:Chemistry; D004873:Ergolines / Q000494:pharmacology*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006827:Hydantoins / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000097:blood; D011224:Prazosin / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D013997:Time Factors
D000959:Antihypertensive Agents; D004873:Ergolines; D006827:Hydantoins; C059913:FCE 22716; D009638:Norepinephrine; D011224:Prazosin