Zhao M, Muntz K H
Department of Cell Biology and Neuroscience, University of Texas Southwestern Medical Center at Dallas 75235.
Circ Res. 1993 Nov;73(5):943-51. doi: 10.1161/01.res.73.5.943.
With agonist stimulation, cardiac beta 2-adrenergic receptors (beta 2ARs) are downregulated to a much greater extent than are beta 1ARs. It has been hypothesized that this effect is due to sympathetic innervation inhibiting the downregulation of beta 1ARs. To test this hypothesis, the technique of coverslip autoradiography was used to localize and quantify beta 1AR and beta 2AR subtypes in tissue compartments of the heart in rats subjected to sympathetic denervation by two intravenous injections of 6-hydroxydopamine (50 mg/kg per dose). After denervation, the rats were infused with L-isoproterenol (400 micrograms.kg-1 x h-1 for 7 days) or vehicle (0.001N HCI) by implantation of osmotic minipumps. Sections were incubated with 70 pmol/L of the beta AR antagonist [125I]iodocyanopindolol (ICYP) alone or in the presence of 5 mumol/L DL-propranolol or 5 x 10(-7) mol/L CGP 20712A (a beta 1AR antagonist). Binding of ICYP to sections of rat hearts was saturable and stereoselective and was displaced by beta AR agonists with the rank order of potency expected for beta ARs. There was an 89% reduction in catecholamine concentration in rat ventricles after 1 week of 6-hydroxydopamine treatment, before implantation of the minipumps. Chronic infusion of isoproterenol induced significant downregulation (63% to 74%) of beta 2ARs in atrial and ventricular myocytes, coronary arterioles, and connective tissue but no change in beta 1ARs in these regions in rats with intact sympathetic innervation. Similar changes were seen in denervated animals. There was a marked reduction in beta 2ARs but small insignificant decreases in beta 1ARs, despite the fact that in the denervated animals there was upregulation of beta 1ARs in atrial and ventricular myocytes (approximately 25%). Our study suggests that beta 1ARs in the heart are not significantly downregulated by chronic agonist exposure and that this is unrelated to sympathetic innervation. The underlying mechanism of preferential regulation of beta AR subtypes remains to be elucidated but may be related to differences in the molecular structure between beta 1ARs and beta 2ARs.
在激动剂刺激下，心脏β2 - 肾上腺素能受体（β2ARs）的下调程度比β1ARs大得多。据推测，这种效应是由于交感神经支配抑制了β1ARs的下调。为了验证这一假设，采用盖玻片放射自显影技术对经两次静脉注射6 - 羟基多巴胺（每剂量50 mg/kg）进行交感神经去支配的大鼠心脏组织区域中的β1AR和β2AR亚型进行定位和定量。去神经支配后，通过植入渗透微型泵给大鼠输注L - 异丙肾上腺素（400μg·kg-1·h-1，持续7天）或赋形剂（0.001N HCl）。切片分别与70 pmol/L的βAR拮抗剂[125I]碘氰吲哚洛尔（ICYP）单独孵育，或在5μmol/L DL - 普萘洛尔或5×10-7 mol/L CGP 20712A（一种β1AR拮抗剂）存在的情况下孵育。ICYP与大鼠心脏切片的结合具有饱和性和立体选择性，并且被βAR激动剂以βARs预期的效价顺序取代。在植入微型泵前，经6 - 羟基多巴胺处理1周后，大鼠心室中的儿茶胺浓度降低了89%。慢性输注异丙肾上腺素导致完整交感神经支配的大鼠心房和心室肌细胞、冠状动脉小动脉和结缔组织中的β2ARs显著下调（63%至74%），但这些区域中的β1ARs没有变化。去神经支配的动物也出现了类似的变化。尽管去神经支配的动物心房和心室肌细胞中的β1ARs上调（约25%），但β2ARs显著减少，而β1ARs仅有小幅度且不显著的减少。我们的研究表明，心脏中的β1ARs不会因慢性激动剂暴露而显著下调，且这与交感神经支配无关。βAR亚型优先调节的潜在机制仍有待阐明，但可能与β1ARs和β2ARs之间分子结构的差异有关。
