Characterization of angiotensin receptors mediating the neuromodulatory effects of angiotensin in the vas deferens of the rabbit.
The objective of the present study was to characterize receptors mediating the neuromodulatory effects of angiotensin in the prostatic vas deferens (VD) of the rabbit by using losartan (DuP 753) and PD 123177, two nonpeptide ligands interacting preferentially at the AT1 and AT2 sites, respectively. Field stimulation of the VD (3 Hz, 1 msec pulse duration, 50 V for 10 sec) resulted in a biphasic contractile response, consisting of an initial phasic component (Phase 1) and a late tonic component (Phase 2). Desensitization of purinoceptors with alpha-beta methylene ATP (3 microM) abolished completely both components of the biphasic response. Angiotensin-II (A-II) and angiotensin-III (A-III) produced a concentration-dependent potentiation of Phase 2, with A-II being approximately 10-fold more potent than A-III. Losartan (0.03, 0.3 and 3 microM) produced parallel, concentration-dependent dextral shifts of the concentration effect curve to A-II without altering the maximum response (Schild analysis: slope = 1.18, pA2 = 8.5). In a separate series of experiments, field stimulation of the VD (0.1 Hz, 1 msec pulse duration, 80 V) resulted in a monophasic twitch response (Phase 1), which was also abolished by desensitization of purinoceptors. Both A-II and A-III produced a concentration-dependent inhibition of the Phase 1, with A-III being as potent as A-II but producing a significantly greater maximum response. Losartan (0.1 and 0.01 microM) antagonized the inhibitory effects of A-II and A-III in an unsurmountable manner.(ABSTRACT TRUNCATED AT 250 WORDS)
Hegde
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Institute of Pharmacology, Syntex Research, Palo Alto, California.
Clarke
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D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D008297:Male; D009119:Muscle Contraction; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects* / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C066253:PD 123177; D019808:Losartan