Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium.
Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium.
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发表时间：
1989-03
影响因子：
3.6
通讯作者：
M. Bristow;R. Hershberger;J. Port;W. Minobe;R. Rasmussen
中科院分区：
文献类型：
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作者：
M. Bristow;R. Hershberger;J. Port;W. Minobe;R. Rasmussen
普那特罗（β 1-激动剂）、地诺帕明（β 1-激动剂）和锌特罗（β 2-激动剂）是从非衰竭心腔（β 1/β 2受体亚型比约为80/20）获得的人心室肌中腺苷酸环化酶（AC）刺激的部分激动剂。在低于其低亲和力（β 2）K1的浓度下，倍他洛尔（一种高度选择性β 1-拮抗剂）抑制异丙肾上腺素（非选择性激动剂）、地诺帕明和普那特罗对AC的刺激，表明异丙肾上腺素、地诺帕明和普那特罗都能够通过β 1-受体激活来刺激AC。在低于其低亲和力（β 1）K1的浓度下，ICI 118，551（一种高选择性β 2-激动剂）抑制异丙肾上腺素和锌特罗对AC的刺激，表明异丙肾上腺素和锌特罗通过β 2-受体刺激AC。锌特罗对AC的刺激完全由β 2受体介导，因为10（-7）M倍他洛尔对锌特罗剂量-反应曲线没有影响，ICI 118，551产生一定程度的阻断（KB = 5.2 +/- 1.6 X 10（-9）M），与后者的β 2受体Kl一致（2.0 +/- .4 X 10（-9）M，p，不显著）。在非衰竭心肌中，通过非选择性激动剂异丙肾上腺素对β 1和β 2刺激的分析显示，在数字上较小（占总数的19%）的β 2部分占总腺苷酸环化酶刺激的大部分。在衰竭的心室腔中，β 1/β 2受体亚型比例从82/19（非衰竭）降至64/36（p <0.001），β 1受体密度降低61%（p <0.001），最大地诺帕胺刺激降低49%（p <0.001）。此外，在衰竭心脏的制剂中，被10（-7）M倍他洛尔（β 1组分）抑制的地诺帕胺刺激组分减少了77%（p <0.05）。最后，在来自衰竭心室肌的制剂中，β 2受体密度没有显著降低，但锌特罗对AC的刺激减少了32%（p <0.05）。我们的结论是，心力衰竭的结果在选择性β 1和β 2刺激的腺苷酸环化酶，β 1亚敏感性由于选择性β 1受体下调和β 2亚敏感性由于部分解偶联的β 2受体从随后的事件β 2-肾上腺素能通路。
Prenalterol (beta 1-agonist), denopamine (beta 1-agonist), and zinterol (beta 2-agonist) were partial agonists of adenylate cyclase (AC) stimulation in human ventricular myocardium obtained from nonfailing chambers whose beta 1/beta 2 receptor subtype ratio was approximately 80/20. At a concentration less than its low affinity (beta 2) Kl, betaxolol, a highly selective beta 1-antagonist, inhibited isoproterenol (non-selective agonist), denopamine, and prenalterol stimulation of AC, indicating that isoproterenol, denopamine, and prenalterol are all capable of stimulating AC through beta 1-receptor activation. At a concentration less than its low affinity (beta 1) Kl, ICI 118,551, a highly selective beta 2-agonist, inhibited both isoproterenol and zinterol stimulation of AC, indicating that isoproterenol and zinterol stimulate AC through beta 2-receptors. Zinterol stimulation of AC was mediated entirely by beta 2-receptors, inasmuch as 10(-7) M betaxolol had no effect on the zinterol dose-response curve and ICI 118,551 produced a degree of blockade (KB = 5.2 +/- 1.6 X 10(-9) M), consistent with the beta 2-receptor Kl of the latter (2.0 +/- .4 X 10(-9) M, p, not significant). In nonfailing myocardium, analysis of beta 1 versus beta 2 stimulation by the nonselective agonist isoproterenol revealed that the numerically small (19% of the total) beta 2 fraction accounted for the majority of the total adenylate cyclase stimulation. In failing ventricular chambers with a beta 1/beta 2 receptor subtype ratio reduced from 82/19 (nonfailing) to 64/36 (p less than 0.001) and a beta 1-receptor density reduced by 61% (p less than 0.001), maximal denopamine stimulation was reduced by 49% (p less than 0.001). Moreover, in preparations from failing heart, the component of denopamine stimulation that was inhibited by 10(-7) M betaxolol (beta 1 component) was reduced by 77% (p less than 0.05). Finally, in preparations derived from failing ventricular myocardium, beta 2-receptor density was not significantly decreased, but zinterol stimulation of AC was reduced by 32% (p less than 0.05). We conclude that heart failure results in subsensitivity to both selective beta 1 and beta 2 stimulation of adenylate cyclase, with beta 1 subsensitivity due to selective beta 1 receptor down-regulation and beta 2 subsensitivity due to partial uncoupling of beta 2 receptors from subsequent events in the beta 2-adrenergic pathway.