nitroarginine and perindoprilat

1. The present study was undertaken to investigate the interaction of the renin-angiotensin system (RAS), bradykinin and the sympathetic nervous system with cholinergic transmission in the rat airways. Experiments were performed on epithelium-intact and epithelium-denuded preparations of rat isolated trachea which had been incubated with [3H]-choline to incorporate [3H]-acetylcholine into the cholinergic transmitter stores. Tracheal preparations were subjected to electrical field stimulation (trains of 1 ms pulses, 5 Hz, 15 V) and the stimulation-induced (S-I) efflux taken as an index of transmitter acetylcholine release. 2. In both epithelium-intact and epithelium-denuded tracheal preparations, the alpha 2-adrenoceptor agonist UK14304 (0.1 and 1 microM) inhibited the S-I efflux, in a concentration-dependent manner. The inhibition of S-I efflux produced by UK14304 (1 microM) was antagonized by the selective alpha 2-adrenoceptor antagonist idazoxan (0.3 microM). Idazoxan (0.3 microM) alone had no effect on the S-I efflux. 3. Angiotensin II (0.1 and 1 microM) was without effect on the S-I efflux in either epithelium-intact or epithelium-denuded tracheal preparations. When angiotensin-converting enzyme was inhibited by perindoprilat (10 microM), angiotensin II (1 microM) was also without effect on the S-I efflux. Similarly, in the presence of idazoxan (0.3 microM), to block prejunctional alpha 2-adrenoceptors, angiotensin II (0.1 and 1 microM) did not alter the S-I efflux. When added alone, perindoprilat (10 microM) did not alter the S-I efflux. 4. In epithelium-denuded preparations, bradykinin (0.01-1 microM) inhibited the S-I efflux. In epithelium-intact preparations, there was also a tendency for bradykinin (0.1 and 1 microM) to inhibit the S-I efflux but this was not statistically significant. However, when angiotensin-converting enzyme and neutral endopeptidase were inhibited by perindoprilat (10 microM) and phosphoramidon (1 microM), respectively, bradykinin (1 microM) significantly inhibited the S-I efflux in epithelium-intact preparations as well as in epithelium-denuded preparations. The inhibition of the S-I efflux produced by bradykinin, in the combined presence of perindoprilat (10 microM) and phosphoramidon (1 microM), was unaffected by the additional presence of the cyclo-oxygenase inhibitor indomethacin (10 microM) and/or the nitric oxide synthase inhibitor NG-nitro-L-arginine (100 microM), in either epithelium-intact or epithelium-denuded pre

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Brimonidine Tartrate; Epithelium; Female; Idazoxan; In Vitro Techniques; Indoles; Indomethacin; Male; Neprilysin; Nitroarginine; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Cholinergic; Renin-Angiotensin System; Sympathetic Nervous System; Trachea

To examine whether the bradykinin-nitric oxide (NO) pathway directly participates in the antihypertrophic property of angiotensin-converting enzyme (ACE) inhibitors in congestive heart failure, the effects of bradykinin were studied in rat cultured heart cells. Bradykinin (0.1, 1 nM) prevented the phenylephrine-induced increase in protein/DNA content, an index of hypertrophy of heart cells, and amplified the nitrite/nitrate content in the medium. Perindoprilat (1 microM), an ACE inhibitor, also restrained the progression of cardiac hypertrophy and augmented NO release. These effects of perindoprilat were abolished by HOE-140 (kinin B2 antagonist), N omega-nitro-L-arginine (NO synthase inhibitor), and methylene blue (guanylate cyclase inhibitor). Furthermore, there was a significant correlation between protein/DNA content and nitrite/nitrate content. These results indicate that bradykinin inhibits the progression of cardiac hypertrophy due to the increase in NO release and that perindoprilat produces beneficial effects on cardiac hypertrophy by stimulating the bradykinin-NO pathway.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Bradykinin; Bradykinin Receptor Antagonists; Cardiomegaly; Cells, Cultured; Heart; Indoles; Myocardium; Nitrates; Nitric Oxide; Nitrites; Nitroarginine; Phenylephrine; Rats; Rats, Sprague-Dawley; Receptors, Bradykinin; Regression Analysis

The present study was designed to determine whether bradykinin induces endothelium-dependent hyperpolarization of vascular smooth muscle in human coronary arteries, and if so, to define the contribution of this hyperpolarization to endothelium-dependent relaxations. The membrane potential of arterial smooth muscle cells (measured by glass microelectrodes) and changes in isometric force were recorded in tissues from six patients undergoing heart transplantation. In the presence of indomethacin and NG-nitro-L-arginine (NLA), the membrane potential was -48.3 +/- 0.6 and -46.9 +/- 0.6 mV, in preparations with and without endothelium, respectively, and was not affected by treatment with perindoprilat, an angiotensin-converting enzyme inhibitor. In the presence of both indomethacin and NLA, bradykinin evoked transient and concentration-dependent hyperpolarizations only in tissues with endothelium, which were augmented by perindoprilat and mimicked by the calcium ionophore A23187. Glibenclamide did not inhibit membrane hyperpolarization to bradykinin. In rings contracted with prostaglandin F2 alpha, the cumulative addition of bradykinin caused a concentration-dependent relaxation during contractions evoked by prostaglandin F2 alpha, which was not abolished by NLA and indomethacin. The present findings demonstrate the occurrence of endothelium-dependent hyperpolarization, and its contribution to endothelium-dependent relaxations, in the human coronary artery.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Arginine; Benzopyrans; Bradykinin; Calcimycin; Child; Coronary Vessels; Cromakalim; Dinoprost; Endothelium, Vascular; Glyburide; Humans; In Vitro Techniques; Indoles; Indomethacin; Infant; Male; Membrane Potentials; Middle Aged; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroarginine; Pyrroles; Vasodilator Agents

The angiotensin converting enzyme (ACE) inhibitor perindoprilat evokes endothelium-dependent relaxations in perfused isolated canine arteries. Kininogens, the precursors of bradykinin, elicit endothelium-dependent relaxations which are potentiated by perindoprilat, inhibited by B2-kinin antagonists and partially impaired after inhibition of NO synthase. These observations suggest that locally produced kinins may stimulate the production of NO and endothelium-derived hyperpolarizing factor, and that this action is potentiated by ACE inhibitors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Bradykinin; Carotid Arteries; Dogs; Endothelium, Vascular; In Vitro Techniques; Indoles; Indomethacin; Kininogens; Kinins; Muscle, Smooth, Vascular; Nitroarginine; Nitroprusside; Vasodilation