Effects of the bradykinin antagonist B4310 on smooth muscles and blood pressure in the rat, and its enzymatic degradation

British Journal of Pharmacology - Tập 96 Số 3 - Trang 531-538 - 1989
Thomas Griesbacher1, Fred Lembeck, Alois Saria
1Department of Experimental & Clinical Pharmacology, University of Graz, Austria.

Tóm tắt

Six competitive bradykinin (Bk) antagonists were tested for their agonistic properties on the rat uterus. Five of these peptides showed agonistic effects only at concentrations at least two orders of magnitude higher than those of bradykinin. The antagonistic potency of Lys‐Lys‐3‐Hyp‐5,8‐Thi‐7‐DPhe‐Bk (B4310) in the rat uterus (pA2 = 7.24) and in the rat duodenum (pA2 = 7.31) was very similar to that determined in an earlier study for the antagonism of the bradykinin‐induced stimulation of the trigeminal nerve in the rabbit iris sphincter muscle preparation (pA2 = 7.59). The fall in mean arterial blood pressure induced by i.a. injections of bradykinin was greatly reduced during an i.a. infusion of B4310, but not 10 min thereafter, which indicates a rapid inactivation of B4310 in vivo. Bacitracin possibly interferes with the enzymatic cleavage of B4310 but seems to have no effect on the degradation of bradykinin. An i.a. infusion of captopril greatly enhanced the potency of bradykinin in inducing a fall in arterial blood pressure, confirming the important role of angiotensin converting enzyme in the cleavage of bradykinin. However, the design of this experiment did not allow conclusions about the effect of captopril on the degradation of B4310. B4310 incubated with rat lung tissue disappeared from the incubation medium within a few minutes, i.e. as fast as bradykinin, which explains its short duration of action in vivo. Captopril partially inhibited the cleavage of both bradykinin and B4310. The present results show that the bradykinin antagonists available at present are useful tools for the investigation of the biological role of bradykinin. However, the susceptibility to enzymatic degradation may limit their usefulness in animal experiments or in clinical studies.

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Tài liệu tham khảo

10.1111/j.1476-5381.1972.tb08084.x

BARTON S., 1987, Synthetic competitive antagonists of bradykinin on vasodilator responses in the cat and rabbit, J. Physiol, 391, 68P

10.1161/01.HYP.8.11.971

10.1161/01.HYP.8.11.1089

10.1126/science.175444

CRECELIUS D.M., 1986, Interaction of bradykinin (Bk) with receptors on human lung fibroblasts, Fed. Proc, 45, 454

10.1161/01.RES.34.6.824

10.1042/bj1410915

10.1161/01.STR.18.4.792

10.1111/j.1476-5381.1967.tb01968.x

10.1111/j.1476-5381.1967.tb02148.x

10.1111/j.1476-5381.1987.tb11328.x

10.1007/978-3-642-46222-1_15

10.1016/0014-2999(87)90237-8

LEMBECK F., 1987, Specific antagonists for bradykinin, Br. J. Pharmacol, 91, 295P

10.1007/BF00497000

LONG J.A., 1922, The oestrous cycle in the rat and its associated phenomena, Mem. Univ. Calif, 6, 1

LONGRIDGE D.J., 1986, Synthetic competitive antagonists of bradykinin on vascular permeability in the rabbit, J. Physiol, 372, 73P

10.1139/y81-022

McCARTHY D.A., 1965, An in vivo estimation of the potencies and half‐lives of synthetic bradykinin and kallidin, J. Pharmacol. Exp. Ther, 148, 117

10.1016/0006-291X(76)90736-1

10.1007/BF00229900

10.1016/0006-291X(77)90088-2

RUBIN B., 1978, SQ 14,225 (D‐3‐mercapto‐2‐methylpropanoyl‐l‐proline), a novel orally active inhibitor of angiotensin I‐converting enzyme, J. Pharmacol. Exp. Ther, 204, 271

10.1007/978-1-4684-3198-8_32

10.1016/0040-8166(76)90025-2

10.1152/ajplegacy.1962.203.2.261

SCHILD H.O., 1957, Drug antagonism and pAx, Pharmacol. Rev, 9, 242

10.1016/0006-2952(86)90726-4

10.1016/0006-2952(86)90727-6

10.1016/0014-2999(87)90723-0

10.1007/978-1-4684-5143-6_71

STEWART J.M., 1987, Bradykinin competitive antagonists of bradykinin, Adv. Biosci, 65, 73

STEWART J.M., 1988, Kinins V.

10.1007/BF00501440

10.1016/0196-9781(85)90033-6

10.1007/BF00169123

10.1007/BF00165756

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Thông tin xuất bản

British Journal of Pharmacology

Tập 96 Số 3

531-538

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