Chronic nifedipine treatment diminishes cardiac inotropic response to nifedifine: functional upregulation of dihydropyridine receptors
de Cingolani, G.E.; Mosca, S.M.; Moreyra, A.E.; Cingolani, H.E.
Journal of Cardiovascular Pharmacology 27(2): 240-246
1996
ISSN/ISBN: 0160-2446 PMID: 8720423 Document Number: 469270
Chronic treatment with nifedipine induces upregulation of functional active Ca-2+ channels in cardiac muscle membranes. Adult male New Zealand White rabbits (NZW) were treated with nifedipine (20 mg/day) for 25 days. In isovolumic perfused hearts at constant coronary flow and heart rate (HR) the left ventricular developed pressure (LVDP) and its first derivative (dP/dt) were monitored. Basal contractility and contractility at different end-diastolic volumes (EDV) were higher in nifedipine-treated animals, with no changes in diastolic chamber stiffness. Dose response to nifedipine in pretreated animals showed less decrease in contractility than in controls (ED-50 = 1.09 +- 0.09 times 10-7 (control) and 1.55 +- 0.17 times 10-7 M nifedipine (treated) (p lt 0.05)). Ca-2+ channel density was assessed by specific binding at the dihydropyridine receptor with (methyl-3H)PN 200-110. In cardiac membranes, maximal binding capacity (B-max) was 269 +- 38 (n = 7, control) and 429 +- 46 fmol/mg protein (n = 7, treated) (p lt 0.05), without significant changes in dissociation constant. In addition, we noted no changes in dihydropyridine (DHP) binding sites in aortic membranes. Our results offer a possible explanation for the lack of decrease in contractility despite the persistent hypotensive effect in hypertensive patients during chronic treatment with nifedipine.