Delpech N, Soustre H, Potreau D
Laboratory of General Physiology, URA CNRS 1869, Faculty of Sciences, Poitiers, France.
J Cardiovasc Pharmacol. 1997 Jan;29(1):136-43. doi: 10.1097/00005344-199701000-00021.
Endothelin-1 (ET-1) was shown to exert direct cardiac effects by complex signaling pathways and to interact with neurotransmitter regulation of cardiac activity. The effect of ET-1 was investigated on the beta-adrenergic stimulation of cardiac L-type Ca2+ current (ICaL) on isolated rat atrial myocytes by using the patch-clamp technique. ET-1 (5 x 10(-8) M) reversed the increase in ICaL induced by isoprenaline (10(-6) M) but had no effect on basal ICaL and on (-) Bay K 8644-increased ICaL (10(-6) M); so ET-1 might exert an effect only when the Ca2+ channels are phosphorylated. The antiadrenergic action of ET-1, blocked by BQ-123 (10(-6) M) and unaffected by IRL 1038 (3.5 x 10(-8) M) should be mediated by ET-A receptors. The inhibitory action of ET-1 was still observed when ICaL was previously increased by forskolin (3 x 10(-6) M), 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP; 200 microM), or cAMP (100 microM) in presence of isobutyl methyl xanthine (IBMX; 10(-6) M), suggesting that the antiadrenergic action of ET-1 on ICaL was exerted independent of the cAMP-dependent phosphorylation pathway. ET-1 is known to be an activator of phosphoinositide hydrolysis, resulting in an increased production of IP3 and diacylglycerol (DAG). A Ca(2+)-dependent inhibition of ICaL consequently to an elevation of the intracellular Ca2+ pool via IP3 might be excluded in the action of ET-1, because of the presence of EGTA in the intrapipette medium. ET-1 reversed the isoprenaline-induced increase in ICaL in the presence of protein kinase C inhibitor [PKC(19-31); 100 microM), making unlikely the involvement of a DAG-dependent activation of PKC. Therefore the antiadrenergic action of ET-1 might also be independent on the phosphoinositide pathway.
内皮素 -1（ET -1）已被证明可通过复杂的信号通路对心脏产生直接影响，并与心脏活动的神经递质调节相互作用。采用膜片钳技术，研究了ET -1对离体大鼠心房肌细胞中β - 肾上腺素能刺激的心脏L型钙电流（ICaL）的影响。ET -1（5×10⁻⁸ M）可逆转异丙肾上腺素（10⁻⁶ M）诱导的ICaL增加，但对基础ICaL以及（ - ）Bay K 8644增加的ICaL（10⁻⁶ M）无影响；因此，ET -1可能仅在钙通道磷酸化时才发挥作用。ET -1的抗肾上腺素能作用被BQ -123（10⁻⁶ M）阻断，且不受IRL 1038（3.5×10⁻⁸ M）影响，这一作用应由ET -A受体介导。当在异丁基甲基黄嘌呤（IBMX；10⁻⁶ M）存在的情况下，ICaL先前已被福斯可林（3×10⁻⁶ M）、8 - 溴环磷酸腺苷（8 - Br - cAMP；200 μM）或环磷酸腺苷（cAMP；100 μM）增加时，仍可观察到ET -1的抑制作用，这表明ET -1对ICaL的抗肾上腺素能作用独立于cAMP依赖性磷酸化途径发挥。已知ET -1是磷酸肌醇水解的激活剂，导致肌醇三磷酸（IP3）和二酰甘油（DAG）生成增加。由于在吸管内液中存在乙二醇双乙醚二胺四乙酸（EGTA），通过IP3使细胞内钙库升高从而导致的Ca²⁺依赖性ICaL抑制可能被排除在ET -1的作用机制之外。在蛋白激酶C抑制剂[PKC(19 - 31)；100 μM]存在的情况下，ET -1可逆转异丙肾上腺素诱导的ICaL增加，这使得PKC的DAG依赖性激活参与其中的可能性不大。因此，ET -1的抗肾上腺素能作用也可能独立于磷酸肌醇途径。
