enalapril and imidaprilat

Imidapril, a new angiotensin-converting enzyme (ACE) inhibitor, was infused subcutaneously at the rates of 9, 30, 90, and 300 micrograms/rat/day for 4 weeks via an osmotic pump implanted under the skin in the back of male spontaneously hypertensive rats (SHRs). Plasma concentrations of imidaprilat as an active metabolite of imidapril, systolic blood pressure (SBP), and plasma ACE activity were determined periodically. These results were also compared with those of enalapril. The plasma concentrations of an active metabolite of both the imidapril and enalapril groups increased according to the doses and showed almost the same plasma concentrations at the same doses. Both groups significantly inhibited plasma ACE activity and reduced SBP, and these actions were maintained for 4 weeks. At the lowest dose studied (9 micrograms/rat/day), imidapril was more potent than enalapril in inhibiting plasma ACE (maximum 2.5-fold difference), but this difference was reduced at higher doses. In contrast, significant differences in SBP effects were observed only at the highest dose studied (300 micrograms/rat/day). Also, the imidapril group significantly decreased the relative heart weight at the rate of 300 micrograms/rat/day. Furthermore, good correlations between plasma imidaprilat concentration and plasma ACE activity or SBP were observed, suggesting that plasma concentration may be a useful marker of pharmacological effects. However, a poor relationship between plasma ACE activity and SBP for enalapril was observed, suggesting that this may not be an adequate marker of pharmacologic efficacy of ACE inhibitors in general. The clinical relevance of these findings is not known at present.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Heart; Imidazoles; Imidazolidines; Male; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR

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