Thromboxane synthase inhibition enhances action of converting enzyme inhibitors.
Mean arterial blood pressure was measured over a 24-hour period from the femoral artery of conscious, unrestrained spontaneously hypertensive rats. Oral administration of the angiotensin converting enzyme inhibitor CGS 16617 significantly lowered mean arterial pressure. In contrast, both the thromboxane synthase inhibitor CGS 12970 and the thromboxane receptor antagonist BM 13505 lacked an antihypertensive action in the spontaneously hypertensive rat. When administered concurrently, the thromboxane synthase inhibitor CGS 12970 potentiated the antihypertensive action of the angiotensin converting enzyme inhibitor CGS 16617. This effect was not observed with the thromboxane receptor antagonist BM 13505. In addition to CGS 16617, CGS 12970 also potentiated the hypotensive effect of two structurally dissimilar angiotensin converting enzyme inhibitors, benazapril HCL and captopril. Indomethacin blocked the thromboxane synthase inhibition-induced potentiation of the antihypertensive action of angiotensin converting enzyme inhibitors. The thromboxane synthase inhibitor CGS 12970 had no effect on the hypotension induced by hydralazine, indicating that the hypotension is not a nonspecific action related to the fall in blood pressure. These results may suggest that converting enzyme inhibition augments the levels and actions of a hormone that stimulates prostaglandin formation. It is well established that thromboxane synthase inhibitors eliminate the formation of the vasoconstrictor thromboxane A2 and allow reorientation of eicosanoid production toward the formation of vasodilating prostaglandins, which could enhance the antihypertensive action of angiotensin converting enzyme inhibitors.
Levens
N R
NR
Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
Ksander
G M
GM
Zimmerman
M B
MB
Mullane
K M
KM
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004357:Drug Synergism; D006830:Hydralazine / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects; D010648:Phenylacetates / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D013449:Sulfonamides / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D010648:Phenylacetates; D011725:Pyridines; D013449:Sulfonamides; D006830:Hydralazine; C049113:3-methyl-2-(3-pyridyl)-1-indoleoctanoic acid; D013930:Thromboxane-A Synthase; C052134:libenzapril; C051762:daltroban; D007213:Indomethacin