enalaprilat-anhydrous and imidaprilat

Effects of angiotensin-converting enzyme (ACE) inhibitors, enalaprilat and imidaprilat, on bradykinin (BK) metabolizing enzymes, aminopeptidase P (APP), neutral endopeptidase (NEP) and carboxypeptidase N (CPN), were examined. APP activity in the mouse lung was inhibited by enalaprilat in a concentration-dependent manner while imidaprilat did not influence the enzyme activity. The inhibitory effects of these ACE inhibitors on the NEP activity in the mouse lung and the CPN activity in the mouse serum were negligible. These data suggested that the influence of enalaprilat on the APP activity and subsequent BK metabolism are different from those of imidaprilat.

Topics: Aminopeptidases; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Dose-Response Relationship, Drug; Enalaprilat; Enzyme Inhibitors; Imidazoles; Imidazolidines; Lysine Carboxypeptidase; Male; Mice; Mice, Inbred ICR; Neprilysin

We used a flexibly mounted microdialysis technique to the hearts of rats and examined the protective effect of imidaprilat, an angiotensin-converting enzyme (ACE) inhibitor, on the production of hydroxyl free radical (*OH) generation. A microdialysis probe was implanted into the left ventricular myocardium, and dialysate norepinephrine (NE) concentrations were measured as an index of myocardial interstitial NE levels. Sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was directly infused through a microdialysis probe to detect the generation of *OH reflected by the formation of dihydroxybenzoic acid (DHBA) in rat myocardium. When tyramine (1 mM) was directly infused through the microdialysis probe, the level of NE significantly increased in the dialysate and the level of NE increased by 128 +/- 43%. Imidaprilat (5, 25 and 50 microM) decreased the level of tyramine (1 mM)-induced NE in a concentration-dependent manner. Tyramine clearly produced an increase in *OH formation. In the presence of imidaprilat (50 microM), tyramine failed to increase both 2,3- and 2,5-dihydroxylation. Therefore, the effects of imidaprilat on the *OH generation in the sympathetic nerve blockaded hearts by reserpine treatment were not observed. Moreover, to examine the effect of imidaprilat on *OH formation by ischemia/reperfusion of the myocardium, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery. When the heart was reperfused, elevation of NE and 2,3- and 2,5-DHBA in imidaprilat (50 microM)-pretreated animals was not observed in the heart dialysate. Imidaprilat 2.5 mg/kg i.p. pretreatment at 5 h before coronary occlusion significantly blunted the rise of serum creatine phosphokinase and improved the electrocardiogram 2 h after coronary occlusion. These results suggest that imidaprilat, an ACE inhibitor, is associated with cardioprotective effect due to the suppression of NE-induced *OH generation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Electrochemistry; Enalaprilat; Hydroxyl Radical; Imidazoles; Imidazolidines; Male; Myocardium; Rats; Rats, Wistar

We examined the effect of non-SH-containing angiotensin converting enzyme (ACE) inhibitor imidaprilat on hydroxyl radical (.OH) generation using microdialysis. Salicylic acid in Ringer's solution containing sodium salicylate (0.5 n mol microL-1 min-1) was infused directly through a microdialysis probe to detect the generation of .OH as reflected by the formation of 2,3-dihydroxybenzoic acid (DHBA) in the myocardium of anesthetized rats. We compared the ability of two non-SH-containing ACE inhibitors (imidaprilat and enalaprilat) with an -SH-containing ACE inhibitor (captopril) to scavenge the .OH. When iron (II) was administered to animals pretreated with these three ACE inhibitors, a decrease in 2,3-DHBA of all three compounds was observed, as compared with the iron (II) only-treated group. All three ACE inhibitors were able to scavenge .OH generated by the action of iron (II). However, imidaprilat is a free radical scavenger more potent than enalaprilat. These results suggested that ACE inhibitors are probably not only related to the presence of the SH radical.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Enalaprilat; Free Radical Scavengers; Hydroxyl Radical; Imidazoles; Imidazolidines; Male; Microdialysis; Molecular Structure; Rats; Rats, Wistar

Angiotensin-converting enzyme (ACE) inhibitors are one of the first drugs of choice for the treatment of hypertension. However, there have been many reports of persistent chronic dry cough and inflammatory skin reactions (rash and/or angioedema, etc.) induced by ACE inhibitors. In this study, in order to evaluate the cough and inflammatory reaction, we measured the number of citric acid-induced coughs and the intradermal inflammation with ovalbumin in guinea pigs consecutively treated with ACE inhibitors (lisinopril, enalaprilat and imidapril) for 3 days. The number of citric acid-induced coughs and the inflammatory responses were significantly enhanced by treatment with lisinopril and enalaprilat, whereas imidapril produced no change in either response. These results correspond to the frequency of adverse effects in clinical practice, which suggests that imidapril has the least ability to induce the inflammatory skin response and cough. Furthermore, the enhancement produced by the ACE inhibitors in the number of coughs and the inflammatory responses were significantly reduced by pretreatment with indomethacin (prostaglandin synthesis inhibitor). This finding suggests that PGs at least participate in the mechanism for ACE inhibitor-induced cough and inflammatory skin response.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cough; Cyclooxygenase Inhibitors; Enalaprilat; Female; Guinea Pigs; Imidazoles; Imidazolidines; Indomethacin; Inflammation; Lisinopril

To investigate the involvement of the sympathoinhibitory effect of imidapril and enalapril in their antihypertensive effect at a clinically reasonable dose, we studied whether some responses induced by the stimulation of the sympathetic nervous system (SNS) were affected by intravenous administration of imidaprilat and enalaprilat in curarized pithed spontaneously hypertensive rats. Imidaprilat and enalaprilat (both at 100 micrograms/kg, i.v.), which are active metabolites of imidapril and enalapril, respectively, suppressed the pressor responses to electrical stimulation (ES) of the spinal cord (T1-L7) and exogenous noradrenaline (NA). The pressor responses to NA were significantly suppressed after either alpha 1- or alpha 2-adrenoceptors were blocked. Furthermore, imidaprilat (100 micrograms/kg, i.v.) suppressed these reduced responses. When the reduced basal blood pressure was restored by vasopressin infusion, imidaprilat and enalaprilat (both at 100 micrograms/kg, i.v.) did not suppress the responses to ES and exogenous alpha-adrenoceptor agonists. They affected neither basal plasma concentrations of NA and adrenaline nor ES-induced increase of these catecholamines. These results suggest that the suppressive effects of imidaprilat and enalaprilat on the pressor responses to ES and alpha-adrenoceptors agonists are apparently observed in pithed SHR because of a reduction of vascular tone and that imidapril and enalapril do not lower the blood pressure through suppressing SNS.

Topics: Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Chromatography, High Pressure Liquid; Decerebrate State; Electric Stimulation; Enalapril; Enalaprilat; Epinephrine; Hypertension; Imidazoles; Imidazolidines; Male; Norepinephrine; Rats; Rats, Inbred SHR; Spinal Cord; Sympathetic Nervous System; Vasopressins

The hemodynamic effects of imidapril, a novel nonsulfhydryl angiotensin-converting enzyme inhibitor, were examined in anesthetized dogs by the intravenous injection of its active metabolite 6366A ((4S)-3-((2S)-2-[N-((1S)-1-carboxy-3- phenylpropyl)amino]propionyl)-1-methyl-2-oxoimidazolidine-4-carboxylic acid, CAS 89371-44-8) and were compared to those of enalaprilat. 6366A (1-100 micrograms/kg) reduced the blood pressure and total peripheral resistance in a dose-dependent manner, while causing no marked changes in heart rate, LV dp/dtmax, and pulmonary arterial pressure. The cardiac output and stroke volume were slightly increased. Blood flow in the common carotid artery, the vertebral artery, and the femoral artery was reduced or tended to decrease, while the superior mesenteric arterial blood flow was increased. These effects were similar to those of enalaprilat. 6366A did not inhibit the pressor response of angiotensin II, but markedly inhibited that of angiotensin I, and the effects of 6366A on regional blood flow were opposite to those of angiotensin II. Thus, 6366A appears to produce its hemodynamic effects by angiotensin converting enzyme inhibition, as does enalaprilat. 6366A also tended to decrease myocardial oxygen consumption. These results suggested that the hemodynamic effects of imidapril on the heart and on regional blood flow are similar to those of enalapril.

Topics: Anesthesia; Angiotensin-Converting Enzyme Inhibitors; Animals; Dogs; Enalaprilat; Female; Heart; Hemodynamics; Imidazoles; Imidazolidines; Male; Myocardium; Oxygen Consumption; Regional Blood Flow; Vascular Resistance