Pe. Morgan et al., Chronic administration of nifedipine induces up-regulation of functional calcium channels in rat myocardium, J MOL CEL C, 31(10), 1999, pp. 1873-1883
Previous studies from our laboratory demonstrated the up-regulation of card
iac dihydropyridine (DHP) receptors in rabbits chronically treated with nif
edipine (NIFE). The goal of the present study was to further examine the fu
nctionality of this increased number of receptors by analysing different st
eps of excitation contraction coupling mechanism in adult rats chronically
treated with NIFE (a single 10-mg oral dose/kg/day for 28 days). Ca2+ chann
el density was assessed by specific binding at the DHP receptors with [meth
yl-H-3]PN 200-110 in rat ventricular membranes. Chronic NIFE treatment prod
uced up-regulation of Ca2+ channels, being the maximal binding capacities 2
22 +/-19 fmol/mg protein (n=14) and 310+/-21fmol/mg protein (n=11) in untre
ated and treated animals, respectively (P<0.05). The functional consequence
s of this up-regulation of Ca-+(2) channels were determined in isolated ven
tricular myocytes by measuring L-type Ca2+ currents (I-Ca) with the whole-c
ell configuration of patch-clamp technique and by intracellular Ca2+ (Ca-i(
2+)) transients estimated by the Indo-1/AM fluorescence ratio (410/482) sim
ultaneously monitored with cell shortening. Peak I-Ca density recorded at 0
mV was 32% greater in myocytes isolated from the treated group than in tho
se obtained from the untreated group (-10.43 +/- 0.73 pA/pF (n=13) vs - 7.1
0 +/- 0.59 pA/pF (n = 12); P<0.05). Ca-1(2+), transient amplitude and cell
shortening, explored at 1 and 2 mM extracellular calcium ([Ca](o)) were sig
nificantly higher in ventricular myocytes obtained fom NIFE-treated rats th
an in myocytes isolated from untreated animals. At 2 mM [Ca](o), the values
of Ca-1(2+) transient and shortening were 460 +/- 61 nM and 11 +/- 1% of r
esting length (L-o) in myocytes from treated rats (n = 9) and 212 +/- 22 nM
and 5.3 +/- 0.5% of L-o in myocytes from control rats (n=6, P<0.05). The r
esults demonstrate an up-regulation of functionally-active cardiac Ca2+ cha
nnels after NIFE treatment, and offer a possible explanation for a "withdra
wal effect" at myocardial level after the suppression of the treatment with
this drug. (C) 1999 Academic Press.