Vascular-selective Effect of Lercanidipine and other 1,4-Dihydropyridines in Isolated Rabbit Tissues

Abstract

The aim of this study was to characterize the in-vitro vasoselectivity of lercanidipine (in comparison with lacidipine, amlodipine, nitrendipine and felodipine) by evaluating its functional calcium antagonistic activity on rabbit vascular (aorta) and cardiac tissues (heart ventricle). Although incubation with all the compounds tested elicited a concentration-dependent relaxant effect on vascular tissue precontracted with KCl (80 mM), 50% relaxation was reached at different times for each concentration and drug tested. At 10 nM concentration 50% relaxation was reached after 210 min with lercanidipine, 278 min with amlodipine, 135 min with lacidipine, 75 min with nitrendipine and 70 min with felodipine. The onset of the effect was, therefore, similar for lercanidipine, amlodipine and lacidipine, but faster for nitrendipine and felodipine. Similarly, all the compounds tested concentration-dependently reduced the force of cardiac contraction (negative inotropic activity). In this model, the time needed to reach 50% reduction in contractile force was also concentration-dependent, and the ranking order of the speed of onset of the effect (evaluated as the ratio of the IC50 values (the concentrations inhibiting contraction by 50%) calculated after 1 and 4 h incubation) was lacidipine (3.8) > amlodipine (9.6) > felodipine (39) > lercanidipine (68) = nitrendipine (89). The vasoselectivity, expressed as the ratio of the IC50 values obtained on cardiac and vascular tissue, were (for 4 h incubation) 730, 193, 95, 6 and 3 for lercanidipine, lacidipine, amlodipine, felodipine and nitrendipine, respectively, showing that lercanidipine is the most vasoselective of the calcium-antagonists tested. The results show that lercanidipine reduces the inotropic force of the rabbit heart to a lesser extent than do other calcium antagonists, and that this drug had the best heart/vessel selectivity index among the compounds tested at all the times tested.

Polymorphism of the methylenetetrahydrofolate reductase gene C677T and its influence on the antihypertensive and vascular protective effects of short-term lercanidipine treatment

“…It is highly selective for vascular tissue and produces smooth muscle relaxation through competitive binding to L-type calcium channels. Compared to other CCBs, lercanidipine has many advantages, such as pronounced lipophilicity, excellent tolerance, short plasma half-life, few side effects (such as ankle edema or reflex tachycardia), and pronounced vascular selectivity (Angelico et al, 1999). Due to its excellent vascular selectivity and lipophilic status, lercanidipine is considered more suitable for hypertension patients with atherosclerosis than other drugs.…”

Discovery and Development of Calcium Channel Blockers

“…Among factors responsible for heterogeneity among vessels, not only the specificity of the blocker and its voltage-dependency but also its tissue pharmacokinetics needs to be taken into account. For instance, Angelico et al (1999) have observed in isolated rabbit aorta stimulated by high KCl that 50% relaxation was reached at different times according to the CCB tested. At 10 nM concentration 50% relaxation was reached after 210 min with lercanidipine, 278 min with amlodipine, 135 min with lacidipine, 75 min with nitrendipine, and 70 min with felodipine.…”

Lercanidipine Rescues Hippocampus Pyramidal Neurons from Mild Ischemia-Induced Delayed Neuronal Death in SHRSP

“…Dihydropyridine Ca 2+ -channel blockers (CCBs) are effective at reducing blood pressure and improving cerebral vasculature (Frishman, 2002;Kuriyama et al, 1993). Lercanidipine, which is a long-acting and lipophilic dihydropyridine CCB, has been associated with desirable vasodilatory activity due to its vascular selectivity compared to other dihydropyridine derivatives (Angelico et al, 1999;Makarounas-Kirchmann et al, 2009) .…”