cyclic-gmp and moexiprilat

The effects of angiotensin-converting enzyme (ACE) inhibitors on endothelial autacoid formation were determined in human cultured endothelial cells and in endothelium-intact bovine coronary arteries under resting conditions and after stimulation with bradykinin. Incubation of cultured human endothelial cells with moexiprilat or ramiprilat (0.3 microM) caused a maintained increase in resting intracellular calcium [Ca2+]i, which was prevented by the selective B2-receptor antagonist Hoe 140 (0.1 microM). Both ACE inhibitors also significantly enhanced the increase in [Ca2+]i elicited by bradykinin (3 nM). In parallel with their effect on resting [Ca2+]i, moexiprilat and ramiprilat both induced an increase in intracellular cyclic GMP (cGMP). This increase was prevented by Hoe 140 (0.1 microM) and was abolished by NG-nitro-L-arginine (30 microM), indicating a kinin-induced nitric oxide (NO) formation in this response. The elevation in [Ca2+]i also led to an enhanced production of prostacyclin (PGI2), as indicated by an increase in the concentration of 6-keto prostaglandin F1 alpha (PGF1 alpha) in the cell supernatant. Similar effects of the ACE inhibitors on endothelial autacoid production were observed in endothelium-intact bovine coronary arteries. Like bradykinin (30 nM), moexiprilat (0.3 microM) elicited a nearly twofold increase in the cGMP content of these arteries, which was abolished by both NG-nitro-L-arginine and removal of the endothelium. The functional consequences of this ACE inhibitor-induced increase in vascular cGMP were reflected by a distinct relaxation of arteries preconstricted with PGF2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Bradykinin; Calcium; Cattle; Cells, Cultured; Coronary Vessels; Cyclic GMP; Endothelium, Vascular; Epoprostenol; Humans; Isoquinolines; Nitric Oxide; Nitroarginine; Ramipril; Tetrahydroisoquinolines; Umbilical Veins; Vasodilation

The angiotensin converting enzyme (ACE) inhibitors, moexiprilat and ramiprilat, relaxed preconstricted endothelium-intact bovine coronary artery rings and enhanced the relaxant response to bradykinin. The relaxation was observed in the presence of a cyclooxygenase inhibitor and without previous exposure to bradykinin. ACE inhibitor-dependent relaxation was attenuated by the selective B2-kinin receptor antagonist, Hoe 140, and completely abolished by removal of the endothelium. Bradykinin or moexiprilat also significantly increased the cyclic guanosine monophosphate (cGMP) content of these coronary segments, an effect which was abolished by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (NNA), or by removal of the endothelium. NNA also diminished the relaxant response to moexiprilat, but only partially inhibited that to bradykinin, suggesting that the ACE inhibitor-induced relaxation was predominantly mediated by endothelial NO release, whereas bradykinin acted in part by another endothelium-dependent mechanism. These findings indicate that ACE inhibitors can elicit endothelium-dependent relaxations presumably by facilitating the accumulation of endothelium-derived kinins in or at the vessel wall. This local mechanism may significantly contribute to the antihypertensive action of these compounds in vivo.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Bradykinin; Cattle; Coronary Vessels; Cyclic GMP; Endothelium, Vascular; In Vitro Techniques; Isoquinolines; Nitric Oxide; Nitroarginine; Ramipril; Tetrahydroisoquinolines; Vasodilation

We have investigated the effects of angiotensin-converting enzyme (ACE) inhibitors on intracellular Ca2+ levels in human cultured endothelial cells and on endothelial autacoid formation in endothelium-intact bovine coronary arteries and in isolated perfused rabbit and rat hearts. Incubation of cultured endothelial cells with ramiprilat (0.3 microM) caused a maintained increase in resting intracellular Ca2+. This effect was long-lasting, accompanied by an increased formation of both nitric oxide (NO) and prostacyclin (PGI2), and was abolished by the specific B2-kinin receptor antagonist Hoe 140. Ramiprilat also significantly enhanced the increase in intracellular Ca2+ elicited by bradykinin (3 nM). In endothelium-intact bovine coronary arteries, moexiprilat (0.3 microM), like bradykinin (30 nM), caused a nearly twofold increase in the vascular cGMP content which was abolished by both NG-nitro-L-arginine (30 microM) and removal of the endothelium. The functional consequences of this ACE inhibitor-induced increase in vascular cGMP content were reflected by a distinct relaxation of the coronary segments preconstricted with prostaglandin F2 alpha. In the isolated perfused rabbit heart, ramiprilat (0.3 microM) affected neither resting vascular tone nor endothelial autacoid release; however, the vasodilation and release of PGI2 in response to exogenously applied bradykinin (10 nM) were significantly enhanced by ramiprilat. This effect was also seen using moexiprilat (0.1 microM) in the isolated perfused rat heart. Although these findings suggest that endothelium-derived bradykinin is not involved in the control of resting vascular tone in the coronary microcirculation of the rabbit and the rat, there appears to be significant ACE activity to modulate bradykinin-induced endothelial autacoid formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Calcium; Cells, Cultured; Coronary Vessels; Cyclic GMP; Endothelium, Vascular; Epoprostenol; Female; Humans; Isoquinolines; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide; Rabbits; Ramipril; Rats; Rats, Wistar; Tetrahydroisoquinolines; Vasodilation