PHARMACOLOGY OF LR-B 081, A NEW HIGHLY POTENT, SELECTIVE AND ORALLY-ACTIVE, NONPEPTIDE ANGIOTENSIN-II AT(1) RECEPTOR ANTAGONIST/

1 The pharmacological profile of LR-B/081, (methyl 1(6H)-pyrimidinyl]m ethyl]-3-thiophenecarboxylate), a novel antagonist at the angiotensin II (AII) AT(1)-receptor, was studied in vitro and in vivo. 2 In rabbit aortic strips incubated with LR-B/081 (1-1,000 nM), the concentration -response curve to AII was displaced to the right in a nonparallel fas hion and the maximal contraction was progressively reduced, indicating that the compound is an insurmountable antagonist in this preparation (apparent pK(B) = 9.50 +/-: 0.23). However, the interaction of LR-B/0 81 with AII receptors was found to be reversible, since the maximal re sponse to AII was restored by coincubation with losartan, a surmountab le AII AT(1)-antagonist. Contractions elicited by KCl or phenylephrine were not affected by 10 mu M LR-B/081. 3 In rat isolated perfused kid ney, LR-B/081 and losartan antagonized the AII-induced vasoconstrictio n [IC50 (95% confidence limits)= 17(13-24) and 39(32-54) nM, respectiv ely]. The LR-B/081 antagonism was incompletely reversed by excess AII, while losartan was fully displaced. The IC50 values of LR-B/081 and l osartan obtained against vasoconstriction induced by endothelin-1 and noradrenaline were two orders of magnitude higher. 4 In pithed rats, t he intravenous administration of LR-B/081 (0.2-2 mu mol kg(-1)) dose-d ependently shifted to the right in a nonparallel fashion the dose-pres ser response curve to AII. The maximal presser response to AII was red uced by LR-B/081 in a dose-dependent fashion. The coadministration of losartan induced a progressive recovery of the maximal presser respons e to AII, indicating that in vivo the interaction of LR-B/081 with AII receptors is reversible. LR-B/081 at 6 mu mol kg-1, i.v. also did not affect the vasopressor response induced by noradrenaline in the pithe d rat. 5 In conscious normotensive rats, single oral administration of LR-B/081 at 6 mu mol kg(-1) markedly inhibited the AII-induced presse r response; the inhibition lasted more than 24 h. 6 In conscious renal hypertensive rats, intravenous LR-B/08I appeared as potent as losarta n (ED(40mmHg) (95% confidence limits)= 0.50(0.36-0.70) and 0.86(0.57-1 .3) mu mol kg(-1), respectively). A single intravenous (2 mu mol kg(-1 )) or oral (6 mu mol kg(-1)) administration of LR-B/081 induced a mark ed fall in blood pressure which lasted far at least 12 h. 7 In conscio us spontaneously hypertensive rats, LR-B/081 at 20 pmol kg(-1), p.o., induced a marked and sustained fall in blood pressure. The duration of the antihypertensive effect was longer than 12 h. Heart rate was not modified by LR-B/081 treatment. Repeated oral administration of 17 mu mol kg(-1) LR-B/081 for 16 days did not result in the development of t olerance. 8 These results demonstrate that LR-B/081 is a potent, selec tive and orally active antagonist of AII at the AT(1)-receptor subtype , which markedly lowers the blood-pressure in conscious renal and spon taneously hypertensive rats.