Chronic administration of nifedipine induces up-regulation of functional calcium channels in rat myocardium

Patricio E. Morgan, Ernesto A. Aiello, Gladys E. Chiappe De Cingolani, Alicia R. Mattiazzi, Horacio E. Cingolani

Research output: Contribution to journalArticle

Abstract

Previous studies from our laboratory demonstrated the up-regulation of cardiac dihydropyridine (DHP) receptors in rabbits chronically treated with nifedipine (NIFE). The goal of the present study was to further examine the functionality of this increased number of receptors by analysing different steps of excitation contraction coupling mechanism in adult rats chronically treated with NIFE (a single 10-mg oral dose/kg/day for 28 days). Ca2+ channel density was assessed by specific binding at the DHP receptors with [methyl-3H]PN 200-110 in rat ventricular membranes. Chronic NIFE treatment produced up-regulation of Ca2+ channels, being the maximal binding capacities 222 ± 19 fmol/mg protein (n = 14) and 310 ± 21 fmol/mg protein (n = 11) in untreated and treated animals, respectively (P < 0.05). The functional consequences of this up-regulation of Ca2+ channels were determined in isolated ventricular myocytes by measuring L-type Ca2+ currents (L(Ca)) with the whole-cell configuration of patch-clamp technique and by intracellular Ca2+ (Ca2+(i)) transients estimated by the Indo-1/AM fluorescence ratio (410/482) simultaneously monitored with cell shortening. Peak I(Ca) density recorded at 0 mV was 32% greater in myocytes isolated from the treated group than in those obtained from the untreated group (-10.43 ± 0.73 pA/pF (n = 13) vs -7.10 ± 0.59 pA/pF (n = 12); P < 0.05). Ca2+(i) transient amplitude and cell shortening, explored at 1 and 2 mM extracellular calcium ([Ca](O)) were significantly higher in ventricular myocytes obtained from NIFE-treated rats than in myocytes isolated from untreated animals. At 2 mM [Ca](O), the values of Ca2+(i) transient and shortening were 460 ± 61 nM and 11 ± 1% of testing 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 results demonstrate an up-regulation of functionally-active cardiac Ca2+ channels after NIFE treatment, and offer a possible explanation for a 'withdrawal effect' at myocardial level after the suppression of the treatment with this drug.

Original languageEnglish (US)
Pages (from-to)1873-1883
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume31
Issue number10
DOIs
StatePublished - Oct 1999

Keywords

  • Calcium channels
  • Myocytes
  • Nifedipine

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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    Morgan, P. E., Aiello, E. A., Chiappe De Cingolani, G. E., Mattiazzi, A. R., & Cingolani, H. E. (1999). Chronic administration of nifedipine induces up-regulation of functional calcium channels in rat myocardium. Journal of Molecular and Cellular Cardiology, 31(10), 1873-1883. https://doi.org/10.1006/jmcc.1999.1019