Cardiovascular effects of SK&F 104078, a novel alpha-adrenoceptor antagonist, in normotensive and hypertensive rats.
SK&F 104078 is a novel alpha-adrenoceptor antagonist derived from the 3-benzazepine alpha 2-adrenoceptor antagonist SK&F 86466. SK&F 104078 will block both alpha 1- and vascular postjunctional alpha 2-adrenoceptors but does not block most prejunctional alpha 2-adrenoceptors. Intravenous (i.v.) administration of SK&F 104078 decreased blood pressure (BP) in both spontaneously hypertensive and DOCA-salt hypertensive rats. SK&F 104078 potentiated the hypotensive response to tilt in anesthetized spontaneously hypertensive rats (SHR). Although SK&F 104078 had no effect on BP in normotensive rats, the tilt-induced decrease in BP in these animals was also potentiated. In this regard, SK&F 104078 resembled the selective alpha 1-adrenoceptor antagonist prazosin, rather than the alpha 2-adrenoceptor antagonists rauwolscine or SK&F 86466. Oral administration of SK&F 104078 had no significant effect on BP in SHR unless extremely high doses were administered. This was consistent with low plasma concentrations of SK&F 104078 observed after oral administration. After i.v. administration, the clearance of SK&F 104078 from plasma was 123 ml/min/kg, the steady-state volume of distribution was 17 L/kg, and the fraction excreted unchanged in urine was less than 1%. The low oral bioavailability of SK&F 104078 did not appear to be due to high first-pass oxidative metabolism, since pretreatment of SHR with the suicide substrate inhibitor of cytochrome P-450, 1-aminobenzotriazole (ABT), did not result in increased oral efficacy. SK&F 101253, a close structural analogue of SK&F 104078, was an effective antihypertensive when administered orally. Comparison of the stability of SK&F 101253 and SK&F 104078 in acid media showed SK&F 104078, but not SK&F 101253, to be rapidly degraded.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, Smith Kline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
J P
JP
Hieble
A C
AC
Sulpizio
L
L
Gutzait
C T
CT
Gombar
D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D015016:Yohimbine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D001552:Benzazepines; C054935:SK&F 104078; D015016:Yohimbine; D003900:Desoxycorticosterone; D011224:Prazosin; C039139:benalfocin