enalaprilat-anhydrous and Inflammation

To assess the effects of the angiotensin-converting enzyme inhibitor enalaprilat on endothelial cells in septic patients.. Prospective, randomized, placebo-controlled, blinded study.. Clinical investigation on a surgical intensive care unit of a university hospital.. Forty surgical septic patients (noncardiac/nonneurosurgical patients).. After inclusion in the study and after baseline data were obtained, either 0.25 mg/hr (enalaprilat group, n = 20) or saline solution as placebo (control group, n = 20) was continuously given and continued throughout the following 5 days.. Extensive hemodynamic monitoring was carried out in all patients. Plasma concentrations of endothelin-1, angiotensin II, soluble thrombomodulin, and soluble adhesion molecules (endothelial leukocyte adhesion molecule-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and granule membrane protein-140) were measured from arterial blood samples. All measurements were carried out before the start of the infusion ("baseline" values) and daily during the following 5 days. All endothelial-derived substances (thrombomodulin, endothelin-1, and all soluble adhesion molecules) were similarly increased beyond normal in both group. Endothelin-1 increased only in the untreated control patients (from 6.9 +/- 0.7 to 14.3 +/- 1.4 mg/mL). Soluble thrombomodulin increased in the untreated control patients (from 58 +/- 9 to 79 +/- 14 ng/mL [p < .05]), but significantly decreased in the enalaprilat-treated patients. Soluble adhesion molecules increased in the untreated control group (endothelial leukocyte adhesion molecule from 92 +/- 14 to 192 +/- 29 ng/mL; intercellular adhesion molecule-1 from 480 +/- 110 to 850 +/- 119 ng/ mL) and returned almost to normal values in the enalaprilat patients. The survival rate did not differ significantly between the two groups. Control patients developed severe sepsis and septic shock more often than the enalaprilat-treated group.. The complex pathogenesis of endothelial function abnormalities in sepsis may offer a large number of pharmacologic interventions. Administration of the angiotensin-converting enzyme inhibitor enalaprilat resulted in a reduced release of soluble endothelial-derived substances into the circulating blood, which may indicate an improved endothelial function. The specific actions of enalaprilat on the endothelium have to be elucidated in further studies.

Topics: Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Cell Adhesion Molecules; Critical Illness; Double-Blind Method; Enalaprilat; Endothelin-1; Endothelium, Vascular; Female; Hemodynamics; Humans; Inflammation; Male; Middle Aged; Prospective Studies; Sepsis; Survival Analysis; Thrombomodulin

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

The development of highly sensitive and specific immunoassays allowed the characterization of bradykinin and desArg9-BK metabolism in vitro. The same methods were used to study the time course evolution of the tissue content of both kinins in an carragenan inflammatory model. Quantification of T-kininogen in the same animal model allowed to show an influence of BK on the neosynthesis of this acute phase protein.

Topics: Animals; Arginine; Bradykinin; Edema; Enalaprilat; In Vitro Techniques; Inflammation; Rats; Rats, Wistar

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cilazapril; Enalaprilat; Erythema; Female; Guinea Pigs; Inflammation; Ramipril

Two non-sulfur containing ACE-inhibitors were tested concerning their local effect on experimental dermatitis in ovalbumin-sensitized guinea pigs. Enalaprilat but not cilazaprilat potentiated the ovalbumin-evoked inflammatory response. Furthermore, enalaprilat clearly enhanced the erythema evoked by substance P, whereas cilazaprilat did not. Concerning, the bradykinin-evoked erythema, enalaprilat significantly potentiated the response, whereas cilazaprilat only caused a slight increase. Our results suggest that different affinities for peptidases involved in degradation of inflammatory peptides can explain differences between the pro-inflammatory properties of enalaprilat and cilazaprilat.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cilazapril; Dermatitis; Drug Synergism; Enalaprilat; Erythema; Female; Guinea Pigs; Inflammation; Ovalbumin; Pyridazines; Substance P

Angiotensin converting enzyme (ACE) inhibitors have been demonstrated to possess proinflammatory properties. Persistent cough and increased broncho-obstruction have been reported frequently in hypertensive subjects on ACE inhibitor therapy. We have studied the effect of an alpha-2 adrenoceptor agonist, clonidine, on MK 422 (active parent diacid of enalapril)-induced hypotension and potentiated inflammatory skin responses in ovalbumin-sensitized guinea pigs. Clonidine was found to abolish dose-dependently MK 422-potentiated ovalbumin-evoked inflammatory dermal responses and it possesses additive hypotensive effects when combined with the ACE inhibitor. It would therefore be interesting to evaluate further alpha-2 adrenoceptor agonists and ACE inhibitors in a combination therapy in humans when single drug antihypertensive therapy of the drugs is insufficient.

Topics: Adrenergic alpha-Agonists; Allergens; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Clonidine; Enalapril; Enalaprilat; Female; Guinea Pigs; Inflammation; Skin Tests