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Endothelin‐1 Enhances Calcium Entry Through T‐Type Calcium Channels in Cu...
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Endothelin‐1 Enhances Calcium Entry Through T‐Type Calcium Channels in Cultured Neonatal Rat Ventricular Myocytes
作者:
Tetsushi Furukawa,
Hiroshi Ito,
Junichi Nitta,
Motoyoshi Tsujino,
Susumu Adachi,
Michiaki Hiroe,
Fumiaki Marumo,
Tohru Sawanobori,
Masayasu Hiraoka,
期刊:
Circulation Research
(OVID Available online 1992)
卷期:
Volume 71,
issue 5
页码: 1242-1253
ISSN:0009-7330
年代: 1992
出版商: OVID
关键词: endothelin-1;hypertrophy;phorbol ester;protein kinase C;T-type calcium current
数据来源: OVID
摘要:
Endothelin-1 (ET-1), a 21-amino acid vasoconstrictive peptide, increases intracellular Ca2+level and has hypertrophic action on ventricular myocytes. To elucidate a possible role of Ca2+entry through sarcolemmal Ca2+channels on this ET-1 action, we examined effects of ET-1 on L-type (ICa,L) and T-type (ICaT) Ca2+currents in cultured neonatal rat ventricular myocytes using the patch-clamp technique. ET-1 at a concentration of 10 nM increased the maximum current density of ICa,Tfrom −3.0±1.4 μA/cm2in the control condition to −4.4±1.6 gA/cm2(p<0.01). Although the peak amplitude of ICa,Lwas decreased during ET-1 application (from −9.7±1.9 μA/cm2in the control condition to −5.0±1.4 μA/cm2[p<0.01]), this magnitude of decrease in ICa,L(52±19%) was comparable to that of spontaneous “run-down” of ICa,L(47±26%). The enhancement of ICa,Tby ET-1 was dose dependent; it was initiated as low as 0.32 nM, and the maximal response was attained at approximately 10 nM, with a half-maximal dose of 1.26 nM. The enhancement of ICa,Tby ET-1 was antagonized by protein kinase C inhibitors staurosporine (0.2 μM) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7, 20 μM) applied to the pipette solution. Extracellular application of tumor-promoting phorbol esters, phorbol 12,13-dibutyrate (PDBu) and 4β-phorbol 12-myristate 13-acetate, augmentedCa,TPDBu (0.2 μM) increased the maximal current density of ICa,Tfrom −4.2±0.5 μA/cm2in the control condition to −5.5±1.0 μA/cm2(p<00.01). In the presence of H-7 (20 μM) in the pipette solution, PDBu failed to enhance ICa,T, and an inactive isomer of PDBu (4α-phorbol 12, 13-dibutyrate, 0.2 μM) did not augment ICa,T. Thus, ET-1 enhances Ca2+entry through the sarcolemmal T-type Ca2+channel, possibly through a pathway involving activation of protein kinase C. This ET-1 action may be involved in the rise of the intracellular Ca2+level and may contribute to the induction of cardiac hypertrophy by ET-1.
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