nitroarginine and ramiprilat

Tissue edema is a facet of ischemia/reperfusion injury in many organs, polymorphonuclear leukocytes (PMN) presumably playing a contributory role. We studied the intracoronary adhesion of PMN and its effect on vascular permeability during reperfusion in isolated guinea-pig hearts. After a global ischemia of 15 min duration. PMN (10(7)) were infused into the coronary system during the first minute of reperfusion. PMN adhesion was measured as difference of applied PMN and those recovered in the effluent perfusate. Coronary permeability was assessed by measuring the rate of transudate formation (TF) on the epicardial surface, before as well as 5, 15 and 30 min after ischemia. Experiments were also performed in the presence of the NO-synthase inhibitor nitro-L-arginine (10 microM) and the ACE-inhibitor ramiprilat (2 microM), the latter known to enhance endogenous nitric oxide formation. Furthermore, the radical scavenger uric acid (0.5 mM) was applied either before and during ischemia or starting after PMN application. Ischemia/reperfusion increased coronary PMN adherence from 23 +/- 1% (basal) to 33 +/- 2%. Whereas ischemia alone did not influence TF (about 100 microliters/min during reperfusion), postischemic PMN infusion led to progressive TF. With nitro-L-arginine, PMN adhesion rose to 45 +/- 3%; TF increased to 212 +/- 30 microliters/min. In contrast, ramiprilat caused post-ischemic adhesion and TF to decline to basal values. In the presence of uric acid (UA) PMN adhesion declined to 26 +/- 2%, however, the subsequent increase in TF after withdrawal of UA was not markedly attenuated. On the other hand, infusion of UA after application of PMN caused a significant decrease of TF. The extracellular antioxidants SOD/catalase were without effect. As shown using luminol enhanced chemiluminescence. No was able to scavenge oxygen free radicals released by activated PMN. These findings indicate that enhanced PMN adhesion in reperfusion leads to an increase in coronary permeability. Scavenging of oxygen free radicals with NO or UA appears to mitigate both, postischemic PMN adhesion and PMN-induced vascular injury, even after adhesion.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Catalase; Cell Adhesion; Cell Membrane Permeability; Coronary Vessels; Free Radicals; Guinea Pigs; In Vitro Techniques; Luminescent Measurements; Male; Myocardial Ischemia; Myocardial Reperfusion; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Nitric Acid; Nitric Oxide Synthase; Nitroarginine; Ramipril; Superoxide Dismutase; Uric Acid

We studied whether primary cultured porcine brain capillary endothelial cells (PBCEC) respond to bradykinin with an enhanced intracellular cytosolic calcium concentration [Ca2+]i with subsequent formation of nitric oxide (NO) and prostacyclin (PGI2). In addition we examined whether these cells synthetize and release kinins that may accumulate during angiotensin-converting enzyme (ACE) inhibition. [Ca2+]i was assessed by the fluorescent dye Fura-2, NO formation by determination of intracellular cyclic GMP and PGI2 by a specific radioimmunoassay for 6-ketoprostaglandin F1 alpha. Bradykinin and the ACE inhibitor ramiprilat concentration-dependently increased the formation of cyclic GMP which was completely prevented by the stereospecific inhibitor of NO synthase, NG-nitro-L-arginine. Also the specific B2-kinin receptor antagonist icatibant (Hoe 140) abolished the increase in cyclic GMP as well as the ramiprilat-induced increase in PGI2 formation. The data demonstrate the existence of B2-kinin receptors and ACE activity in PBCEC. Moreover PBCEC are capable of producing and releasing kinins in amounts that lead via stimulation of B2-kinin receptors to an enhanced [Ca2+]i as well as NO and PGI2 synthesis and release, provided that degradation of kinins is prevented by inhibition of endothelial ACE activity.

Topics: 1-Methyl-3-isobutylxanthine; 6-Ketoprostaglandin F1 alpha; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Bradykinin; Calcium; Capillaries; Cells, Cultured; Cerebrovascular Circulation; Cyclic GMP; Cytosol; Dose-Response Relationship, Drug; Endothelium, Vascular; Epoprostenol; Fura-2; Kinetics; Nitric Oxide; Nitroarginine; Ramipril; Swine

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

The interaction of angiotensin-converting enzyme (ACE) inhibitors and bradykinin was investigated in isolated bovine and human coronary arteries. Rings with and without endothelium were mounted in organ chambers for measurement of isometric force. The effects of the ACE inhibitors lisinopril, enalaprilat, fosinoprilat, ramiprilat, and captopril were determined during submaximal stimulation with bradykinin or other vasodilators. Lisinopril and captopril alone did not affect vascular tone; however, in rings with endothelium partially relaxed with bradykinin (> or = 10(-10) M), all ACE inhibitors caused further relaxations. Lisinopril did not affect bradykinin concentrations in the incubation medium. Mechanical removal of the endothelium or incubation with nitro-L-arginine or the bradykinin2-receptor antagonist Hoe 140 prevented the relaxations to bradykinin and lisinopril. Other vasodilators including acetylcholine, adenosine diphosphate, substance P, or SIN-1 did not prime the rings to respond to ACE inhibitors. Endothelium-dependent relaxations to lisinopril were also observed in human coronary arteries treated with bradykinin (> or = 10(-7) M). Thus, ACE inhibitors potentiate endothelium-dependent relaxations to submaximal concentrations of bradykinin in bovine and human coronary arteries. This local mechanism occurs regardless of elevated bradykinin concentrations in the blood and reduced angiotensin II generation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Bradykinin; Captopril; Cattle; Coronary Vessels; Dipeptides; Enalaprilat; Endothelium, Vascular; Fosinopril; Humans; In Vitro Techniques; Lisinopril; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroarginine; Ramipril; Receptors, Bradykinin; Receptors, Neurotransmitter; Vasodilation; Vasodilator Agents

Like bradykinin the converting enzyme inhibitor ramiprilat concentration-dependently enhances the formation of nitric oxide and prostacyclin assessed by intracellular cyclic GMP accumulation and 6-keto prostaglandin F1. resp. Both ramiprilat-induced effects are completely suppressed by the specific kinin receptor antagonist Hoe 140. The ramiprilat-induced cyclic GMP increase is totally blocked by the stereospecific inhibitor of nitric oxide synthase, NG-nitro-L-arginine.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Arginine; Bradykinin; Captopril; Cattle; Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Epoprostenol; Nitric Oxide; Nitroarginine; Ramipril