l-158809 and Decerebrate-State

The pharmacologic profile of SK-1080, a nonpeptide AT1-selective angiotensin-receptor antagonist, was investigated by receptor-binding studies, functional in vitro assays with rabbit and rat aorta, and in vivo experiments in pithed rats. SK-1080 inhibited the specific binding of [125I]-[Sar1, Ile8]-angiotensin II to human recombinant AT1 receptor with a 12-fold greater potency than losartan [median inhibitory concentration (IC50): 1.01 and 12.3 nM, respectively], but it did not inhibit the binding of [125I]-CGP 42112A to human recombinant AT2 receptor (IC50: >10 microM for both). The Hill coefficient for the competition curve of SK-1080 against AT1 receptor was not significantly different from unity (0.96). Scatchard analysis showed that SK-1080 interacted with human recombinant AT1 receptor in a competitive manner, as with losartan. In functional studies with rat and rabbit aorta, SK-1080 competitively inhibited the contractile response to angiotensin II (pKB values: 9.97 and 9.51, respectively) with 15-25% decrease in the maximal contractile responses, unlike losartan, which showed competitive antagonism without any change in the maximal contractile responses to angiotensin II (pA2 values, 8.02 and 7.59, respectively). In pithed rats, SK-1080 (i.v.) induced a nonparallel right shift in the dose-pressor response curve to angiotensin II (ID50, 0.07 mg/kg) with a dose-dependent reduction in the maximal responses; this antagonistic effect was approximately 25 times more potent than losartan (ID50, 1.74 mg/kg), which showed competitive antagonism. SK-1080 did not alter the responses induced by other agonists such as norepinephrine, KCI, and vasopressin in isolated rabbit aorta and pithed rats. These results suggest that SK-1080 is a highly potent AT1-selective angiotensin II-receptor antagonist with a mode of insurmountable antagonism.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Aorta, Thoracic; Binding, Competitive; Blood Pressure; Decerebrate State; Diastole; Dose-Response Relationship, Drug; Heart Rate; Imidazoles; In Vitro Techniques; Losartan; Male; Muscle Contraction; Pyridines; Rabbits; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Sensitivity and Specificity; Tetrazoles

UP 269-6, 5-methyl-7-propyl-8(-)[2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]-1,2,4-triazolo]1,5-c]pyrimidin-2(3H)-one is a novel nonpeptide angiotensin II receptor antagonist. In vivo studies were performed to evaluate UP 269-6 for its angiotensin II antagonistic action. In pithed rats, i.v. administration of UP 269-6 (0.03-1 mg/kg) shifted dose dependently to the right the dose-pressor response curve for angiotensin II and decreased the maximum response. The angiotensin II antagonistic effect of UP 269-6 was as potent as that of L-158,809 (5,7-dimethyl-2-ethyl-3(-)[[2'- (1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-imidazo[4,5-b]pyridine) and 10 times more potent than that of losartan. UP 269-6 antagonized the angiotensin II sympathetic-mediated tachycardiac response. UP 269-6 inhibited dose dependently the pressor response to angiotensin II with an ID50 of 4.5 micrograms/kg, i.v. in conscious normotensive dogs. Oral administration of UP 269-6 (0.1 to 30 mg/kg) resulted in a dose-dependent and long-lasting inhibition of the angiotensin II-induced pressor response in conscious normotensive rats and dogs. Compared to losartan, UP 269-6 presented a more rapid onset of action. UP 269-6 caused similar angiotensin II antagonistic effects in rats and dogs but the duration of the effect was greater in dogs than in rats. UP 269-6 did not alter the tachycardiac response to isoproterenol and the pressor response to vasopressin. UP 269-6 was demonstrated to be devoid of agonistic properties in rats and dogs. Furthermore, UP 269-6 did not induce hypotension and did not cause alteration in heart rate and ECG waveforms in dogs even at a dose 1000 times higher than the angiotensin II antagonistic effective dose. These results demonstrate that UP 269-6 is a potent and specific angiotensin II receptor antagonist and dose not possess agonistic properties.

Topics: Administration, Oral; Angiotensin II; Angiotensin III; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Decerebrate State; Dogs; Dose-Response Relationship, Drug; Heart Rate; Imidazoles; Injections, Intravenous; Losartan; Male; Pyrimidines; Rats; Rats, Sprague-Dawley; Species Specificity; Tetrazoles; Vasoconstrictor Agents