Antihypertensive Activity of Lercanidipine and Its Enantiomers in Animal Models

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Abstract
This report describes the antihypertensive properties of lercanidipine and its enantiomers in comparison with several reference compounds. In chronically catheterized conscious spontaneously hypertensive rats (SHR) after i.v. and p.o. administration, lercanidipine and its(S)-enantiomer showed a dose-related, long-lasting antihypertensive activity. The (R)-enantiomer was practically inactive. After i.v. administration, on the basis of the ED25 values calculated at peak time on diastolic blood pressure (DBP) reduction, lercanidipine appeared as potent as felodipine and more potent than nicardipine, nitrendipine. nifedipine, and amlodipine. The onset of antihypertensive action of lercanidipine and (S)-lercanidipine was significantly delayed compared to that observed for the reference calcium-entry blockers (CEBs), with the exception of amlodipine. The hypotensive effects of lercanidipine and its enantiomers in anesthesized normotensive rats after i.v. administration showed that the ED25 value obtained for the (R)-enantiomer was 84-fold higher than the effective dosecalculated for the (S)-enantiomer, in agreement with the difference in affinity for the calcium channel observed in radioligand binding studies. In chronically catheterized. renal hypertensive conscious dogs, p.o. (S)-lercanidipine was about twice as active as lercanidipine, whereas the (R)-enantiomer was practically inactive up to 30 mg/kg, inducing no more than a 10% decrease in DBP. Lercanidipine and nitrendipine were equipotent in reducing blood pressure. In normotensive, anesthetized open-chest dogs, lercanidipine and its (S)-enantiomer induced a strong dose-dependent decrease in blood pressure and total peripheral resistance, confirming that lercanidipine exerts its antihypertensive activity through peripheral vasodilator activity. Nifedipine and nitrendipine proved less potent than lercanidipine as a peripheral vasodilator in anesthetized dogs, their increase in femoral blood flow being lower than that induced by lercanidipine. In conclusion, lercanidipine showed a profile of a vascular selective CEB with a gradual onset and a long duration of antihypertensive effect.