enalaprilat-anhydrous and cilazaprilat

Bradykinin-induced responses were studied in isolated porcine iliac arteries. Relaxation was endothelium dependent and seen at low concentrations (10(-10)-10(-8) M) of bradykinin. It was inhibited by the bradykinin B2-receptor antagonist icatibant (HOE-140) and by the nitric oxide synthase inhibitor Nomega-nitro-L-arginine. Bradykinin-induced relaxation was significantly potentiated by the kininase I carboxypeptidase inhibitor mergepta (10(-6) M). Bradykinin (>10(-7) M) elicited contraction of preparations with or without endothelium. The contraction was abolished by indomethacin but was not affected by the thromboxane A2/prostaglandin H2-receptor antagonist SQ 29,548. Icatibant and the bradykinin B1-receptor antagonist desArg9[Leu8]bradykinin significantly decreased bradykinin-induced contraction regardless of endothelial function. The contraction also was decreased by treatment with mergepta. The bradykinin B1-receptor agonist desArg9-bradykinin contracted endothelium-denuded arterial strips. This contraction was significantly decreased by desArg9[Leu8]bradykinin but not by icatibant. The desArg9-bradykinin-induced contraction also was inhibited by the protein-synthesis inhibitor cycloheximide. Neither bradykinin-induced relaxation nor contraction was affected by the ACE inhibitors enalaprilat or cilazaprilat. In conclusion, bradykinin-induced relaxation of isolated porcine iliac arteries was mediated by endothelial bradykinin B2 receptors and mainly nitric oxide. Bradykinin-induced contraction was endothelium independent, indomethacin sensitive, and probably mediated by bradykinin B1 (inducible) and B2 receptors located in the vascular smooth-muscle layer. Kininase I carboxypeptidase, and not ACE, is the main enzyme responsible for bradykinin degradation in these vessels.

Topics: 3-Mercaptopropionic Acid; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Cilazapril; Cycloheximide; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Enalaprilat; Endothelium, Vascular; Enzyme Inhibitors; Iliac Artery; In Vitro Techniques; Indomethacin; Muscle Contraction; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Protease Inhibitors; Protein Synthesis Inhibitors; Receptors, Bradykinin; Swine; Vasoconstriction; Vasodilation

Topics: Amino Acid Sequence; Aminopeptidases; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cilazapril; Enalaprilat; Kidney; Kinetics; Molecular Sequence Data; Oligopeptides; Ramipril; Substance P; Substrate Specificity; Swine

We investigated the effects of angiotensin converting enzyme inhibitors on nitric oxide (NO) synthesis in cultured rat vascular smooth muscle cells. We measured the production of nitrite, a stable metabolite of NO, and the expression of inducible NO synthase mRNA by vascular smooth muscle cells. Incubation of the culture with interleukin-1 beta (10 ng/ml) for 24 h caused a significant increase in nitrite levels. The basal and interleukin-1 beta-induced nitrite production by vascular smooth muscle cells were not affected by the presence of angiotensin converting enzyme inhibitors (0.1 approximately 10 microM), enalaprilat, cilazaprilat or captopril. Unstimulated vascular smooth muscle cells expressed no inducible NO synthase transcripts, whereas incubation with interleukin-1 beta for 24 h induced marked inducible NO synthase mRNA expression. The angiotensin converting enzyme inhibitors, however, had no effects on the interleukin-1 beta-induced inducible NO synthase mRNA expression. These results indicate that angiotensin converting enzyme inhibitors do not attenuate NO synthesis by vascular smooth muscle cells under basal and interleukin-1 beta-stimulated conditions.

Topics: Amino Acid Oxidoreductases; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Captopril; Cells, Cultured; Cilazapril; Enalaprilat; Enzyme Induction; Humans; Interleukin-1; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Rats; Rats, Sprague-Dawley; Recombinant Proteins; RNA, Messenger; Transcription, Genetic

The inflammatory effects of enalaprilat and cilazaprilat were tested in an experimental model of ovalbumin-sensitised guinea-pigs. Enalaprilat, but not cilazaprilat, enhanced the ovalbumin-induced inflammatory skin responses. The effect of enalaprilat was dose-dependent. Enalaprilat significantly increased the skin content of substance P and histamine. Cilazaprilat did not alter the level of these inflammatory mediators. Enalaprilat, applied locally, but not cilazaprilat, enhanced the inflammatory reactions caused by intradermal injections of allergen and substance P. Both angiotensin converting enzyme (ACE) inhibitors enhanced the inflammatory skin response evoked by bradykinin. Our study strongly indicates that enalaprilat has pro-inflammatory properties, whereas the new long-acting ACE inhibitor cilazaprilat does not. This might give a better safety profile of cilazaprilat.

Topics: Allergens; Angiotensin-Converting Enzyme Inhibitors; Animals; Cilazapril; Dermatitis, Contact; Enalaprilat; Female; Guinea Pigs; Histamine; Peptidyl-Dipeptidase A; Pyridazines; Skin; Substance P

ACE-inhibitors have for some time been used in the treatment of hypertension. Apart from inhibiting the conversion of angiotensin I to II, the drugs also affect the metabolism of some inflammatory agents, like bradykinin and substance P. Egg albumin (EA)-sensitized guinea pigs were pretreated with the ACE-inhibitors. Measurement of flare and wheal areas induced by an intradermal injection of EA, showed that enalaprilat significantly increased, whereas cilazaprilat slightly decreased, the reaction area. Enalaprilat also showed an enhancement in histamine and substance P (SP) contents in the skin. In vitro incubation of guinea pig biopsies with enalaprilat potentiated EA- but not SP-induced histamine release. The EA-induced effect was abolished if the animals were pretreated with capsaicin. The conclusion is that cilazaprilat, in contrast to enalaprilat, does not potentiate inflammatory reactions in the guinea pig.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antigens; Cilazapril; Dermatitis; Enalaprilat; Female; Guinea Pigs; Histamine Release; Hypersensitivity; Ovalbumin; Pyridazines

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