endothelin-1 and benazeprilat

Visual field defects caused by vasospasm are often encountered in ophthalmology as a feature of glaucoma with poor response to conventional treatment. Combination therapy with drugs acting via different mechanisms might be more effective. Therefore, the effects of the calcium antagonist amlodipine and the angiotensin converting enzyme (ACE) inhibitor benazeprilat at low and high dose combination on contractions to endothelin-1 and endothelium-dependent relaxations to bradykinin were examined in porcine ciliary arteries.. Segments of the arteries were suspended in myographs for isometric tension recording.. Pretreatment of the vessels with either amlodipine, the low or high dose combination significantly reduced the sensitivity to endothelin-1 as compared to control (concentration shift 18.3-fold, 14.2-fold, 23.3-fold respectively; p < 0.05), while benazeprilat was ineffective. The maximal response to endothelin-1 (10(-7) M) was most inhibited by the high dose combination which reduced the contractions by 49% as compared to control (p < 0.05). The low dose combination and amlodipine alone were less effective (reduction: 25%; p < 0.05 and 20%; n.s., respectively). On the other hand, benazeprilat enhanced the sensitivity (concentration shift 73-fold; p < 0.05) and maximal relaxation to bradykinin (by 27%; p < 0.01), whereas amlodipine or the low or high dose combination were ineffective.. These findings indicate that amlodipine and benazeprilat differently affect vascular function of ciliary arteries. A high dose combination of both substances was most effective in inhibiting contractions to endothelin-1, suggesting a potentiating effect of the two compounds. In contrast, endothelium-dependent relaxations to bradykinin were enhanced by benazeprilat alone, but not when combined with amlodipine.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Arteries; Benzazepines; Bradykinin; Calcium Channel Blockers; Ciliary Body; Endothelin-1; Glaucoma; Swine

The IC50 values of phosphoramidon, CGS 25015, CGS 26129, thiorphan and benazeprilat for inhibition of endothelin converting enzyme partially purified from porcine aortic endothelial cells were 3.5, 18, 58, > 100 and > 100 microM, respectively. A similar rank order of potency was observed for inhibition of the proendothelin-1 (proET-1) -induced pressor response in the rat where phosphoramidon, CGS 25015, CGS 26129, thiorphan and benazeprilat at 30 mg/kg i.v. produced 65, 57, 27, 12, and 0% inhibition, respectively. A slightly different rank order of potency was obtained in the proET-induced contraction of porcine coronary arteries where IC50 values of < 10, 10-30, 10-30, 30-100 and 30-100 microM were exhibited by CGS 25015, CGS 26129, phosphoramidon, thiorphan and benazeprilat, respectively. These data indicate that the endothelin converting enzymes in the three systems studied are similar, except that phosphoramidon is a slightly more potent inhibitor in the in vitro assay and the in vivo pressor test than in the smooth muscle contraction assay.

Topics: Animals; Aspartic Acid Endopeptidases; Benzazepines; Blood Pressure; Coronary Vessels; Dose-Response Relationship, Drug; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Endothelium, Vascular; Glycopeptides; In Vitro Techniques; Male; Metalloendopeptidases; Methionine; Muscle Contraction; Muscle, Smooth, Vascular; Neprilysin; Propionates; Protein Precursors; Rats; Rats, Sprague-Dawley; Swine; Thiorphan