Chronic nifedipine treatment diminishes cardiac inotropic response to nifedifine: functional upregulation of dihydropyridine receptors.
Chronic treatment with nifedipine induces up-regulation of functional active Ca2+ 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 [ED50 = 1.09 +/- 0.09 x 10-7 (control) and 1.55 +/- 0.17 x 10-7 M nifedipine (treated) (p < 0.05)]. Ca2+ channel density was assessed by specific binding at the dihydropyridine receptor with [methyl-3H]PN 200-110. In cardiac membranes, maximal binding capacity (Bmax) was 269 +/- 38 (n = 7, control) and 429 +/- 46 fmol/mg protein (n = 7, treated) (p < 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.
de Cingolani
G E
GE
Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Medicas, La Plata, Argentina.
Mosca
S M
SM
Moreyra
A E
AE
Cingolani
H E
HE
D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D004305:Dose-Response Relationship, Drug; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism; D009543:Nifedipine / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D013268:Stimulation, Chemical; D015854:Up-Regulation
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D009543:Nifedipine