Characterization of the antihypertensive activity of SK&F 86466, a selective alpha-2 antagonist, in the rat.
The effects of SK&F 86466 (6-chloro-N-methyl-2,3,4,5-tetrahydro-1-H-3-benzazepine), a potent and selective alpha-2 adrenoceptor antagonist, on blood pressure and heart rate were examined in normotensive and hypertensive rats. SK&F 86466 was approximately 10-fold more potent in lowering blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertensive than in normotensive rats, when administered by i.v. infusion. A dose-related antihypertensive effect was observed in conscious DOCA-salt rats after p.o. doses of SK&F 86466 (2-15 mg/kg), with a duration of over 6 hr after the highest dose. Oral administration of SK&F 86466 was associated with tachycardia, which reached maximal levels within 15 min after dosing, followed by an interval of bradycardia. The duration of antihypertensive activity observed with SK&F 86466 was at least 6 hr, compared to less than 90 min with phentolamine, at doses which produced equal peak reductions in blood pressure in conscious DOCA-salt rats. In contrast, heart rate was still significantly elevated by phentolamine 90 min postdosing, whereas the transient tachycardia induced by SK&F 86466 had dissipated within 30 min. SK&F 86466 was also an effective antihypertensive agent in the spontaneously hypertensive rat, although lower antihypertensive efficacy was observed than in the DOCA-salt model. SK&F 86466 was even less effective in the two-kidney one-clip Goldblatt model in which hypertension is maintained by the renin-angiotensin system rather than by the sympathetic nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)
Roesler
J M
JM
McCafferty
J P
JP
DeMarinis
R M
RM
Matthews
W D
WD
Hieble
J P
JP
D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006978:Hypertension, Renovascular / Q000503:physiopathology; D008297:Male; D010646:Phentolamine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains
D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D001552:Benzazepines; D003900:Desoxycorticosterone; C039139:benalfocin; D010646:Phentolamine