M3, a 1,4-Dihydropyridine Derivative and Mixed L-/T-Type Calcium Channel Blocker, Attenuates Isoproterenol-Induced Toxicity in Male Wistar Rats.

Abstract

Recent evidence indicates that Ca2+ dysregulation is involved in the pathogenesis of isoproterenol (ISP)-induced biochemical toxicity and associated oxidative stress. In this study, we investigated the chemopreventive benefit of M3, a 1,4-dihydropyridine calcium channel blocker, against ISP-induced toxicity in male Wistar rats. Adult rats were divided into eight groups of six rats/group. Groups 1-5 received normal saline (control, 10mL/kg/day, p.o.), ISP (85mg/kg/day, s.c.), M3 lower dose (M3LD, 5mg/kg, p.o.), M3 upper dose (M3UD, 20mg/kg/day, p.o.), and Nifedipine (NFD, 20mg/kg/day, p.o.), respectively. Others (groups 6-8) were pretreated with either M3LD, M3UD or NFD one hour before ISP administration. All rats were sacrificed 24h after the last administration and changes in biochemical, hematological, and antioxidant parameters were assessed. Histologic examination of the heart, liver and kidney was also conducted. ISP elevated (p < 0.05) Ca2+, alanine aminotransferase, lactate dehydrogenase, triglycerides, and low-density lipoprotein levels when compared with control. Similarly, ISP increased levels of markers of renal function (p < 0.01), C-reactive protein (148.1%) and myocardial malondialdehyde (MDA, 88.7%) and tumor necrosis factor-alpha (109.2%). Platelet level was reduced (p < 0.05) in the ISP-intoxicated control rats. M3 exhibited antioxidant property, reduced levels of triglycerides, MDA and improved biochemical and hematological alterations associated with ISP toxicity. M3, however, was not effective in restoring histological changes that characterized ISP toxicity at the doses used. M3 offers chemopreventive benefits against ISP toxicity possibly through L-/T-type calcium channels blockade and modulatory actions on biochemical and antioxidant homeostasis.