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Chronic administration of nifedipine induces up-regulation of functional calcium channels in rat myocardium.
J Mol Cell Cardiol. 1999 Oct; 31(10):1873-83.JM

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-(3)H]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 (I(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]0) were significantly higher in ventricular myocytes obtained fom NIFE-treated rats than in myocytes isolated from untreated animals. At 2 mM [Ca]0, the values of Ca2+(i) transient and shortening were 460+/-61 nM and 11+/-1 % of resting length (L(0)) in myocytes from treated rats (n=9) and 212+/-22 nM and 5.3+/-0.5% of L(0) 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.

Authors+Show Affiliations

Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, 1900, Argentina.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10525425

Citation

Morgan, P E., et al. "Chronic Administration of Nifedipine Induces Up-regulation of Functional Calcium Channels in Rat Myocardium." Journal of Molecular and Cellular Cardiology, vol. 31, no. 10, 1999, pp. 1873-83.
Morgan PE, Aiello EA, Chiappe de Cingolani GE, et al. Chronic administration of nifedipine induces up-regulation of functional calcium channels in rat myocardium. J Mol Cell Cardiol. 1999;31(10):1873-83.
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), 1873-83.
Morgan PE, et al. Chronic Administration of Nifedipine Induces Up-regulation of Functional Calcium Channels in Rat Myocardium. J Mol Cell Cardiol. 1999;31(10):1873-83. PubMed PMID: 10525425.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic administration of nifedipine induces up-regulation of functional calcium channels in rat myocardium. AU - Morgan,P E, AU - Aiello,E A, AU - Chiappe de Cingolani,G E, AU - Mattiazzi,A R, AU - Cingolani,H E, PY - 1999/10/20/pubmed PY - 1999/10/20/medline PY - 1999/10/20/entrez SP - 1873 EP - 83 JF - Journal of molecular and cellular cardiology JO - J Mol Cell Cardiol VL - 31 IS - 10 N2 - 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-(3)H]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 (I(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]0) were significantly higher in ventricular myocytes obtained fom NIFE-treated rats than in myocytes isolated from untreated animals. At 2 mM [Ca]0, the values of Ca2+(i) transient and shortening were 460+/-61 nM and 11+/-1 % of resting length (L(0)) in myocytes from treated rats (n=9) and 212+/-22 nM and 5.3+/-0.5% of L(0) 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. SN - 0022-2828 UR - https://www.unboundmedicine.com/medline/citation/10525425/Chronic_administration_of_nifedipine_induces_up_regulation_of_functional_calcium_channels_in_rat_myocardium_ DB - PRIME DP - Unbound Medicine ER -