Inhibition of thromboxane synthetase potentiates the antihypertensive action of an angiotensin-converting enzyme inhibitor by a prostaglandin-dependent but kinin-independent mechanism.
Mean arterial pressure (BP) was measured in conscious, spontaneously hypertensive rats (SHR). Oral administration of the angiotensin I-converting enzyme inhibitor (ACEI) CGS 16617 significantly lowered BP. In contrast, the thromboxane synthetase inhibitor (TxSI) CGS 12970 lacked an antihypertensive action in SHR. When administered concurrently, the TxSI significantly potentiated the antihypertensive actions of the ACEI. Inhibition of thromboxane synthetase did not potentiate the antihypertensive actions of metoprolol or verapamil, indicating that a specific interaction exists between a TxSI and an ACEI. The antihypertensive actions of CGS 16617 also were potentiated by the cyclooxygenase inhibitor indomethacin, a result suggesting that CGS 12970 may enhance the action of CGS 16617 by inhibiting the action of vasoconstrictor prostaglandins produced after administration of an ACEI. The potentiation of the antihypertensive actions of CGS 16617 by CGS 12970 remained unaffected by either the kallikrein inhibitor aprotinin or a bradykinin receptor antagonist. Thus, although the interaction between an ACEI and a TxSI is a prostaglandin-dependent mechanism, it is not mediated by endogenous kinins. Inhibition of thromboxane synthetase significantly stimulated renin release and significantly attenuated the pressor response to exogenously administered angiotensin II. An increase in the dependency of BP upon the renin-angiotensin system and attenuation of the vascular actions of angiotensin II may serve to explain the potentiation of the antihypertensive action of ACEI after inhibition of thromboxane synthetase. The interaction between ACEI and TxSI was not restricted to SHR, because a TxSI potentiated the actions of an ACEI in both normotensive and deoxycorticosterone acetate/Na hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmaceuticals Division, CIBA-GEIGY Corporation, Summit, New Jersey.
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D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004357:Drug Synergism; D007213:Indomethacin / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D012083:Renin / Q000097:blood; D013045:Species Specificity; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014700:Verapamil / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D011725:Pyridines; C049113:3-methyl-2-(3-pyridyl)-1-indoleoctanoic acid; D014700:Verapamil; D012083:Renin; D013930:Thromboxane-A Synthase; C052134:libenzapril; D007213:Indomethacin