Abstract
Myocardial ischemia elicits an enhanced responsivity to alpha 1-adrenergic stimulation and a reversible increase in alpha 1-adrenergic receptor number. In adult cardiac myocytes, alpha 1-adrenergic receptor number increases two- to threefold after 10 min of hypoxia, an increase similar to that seen during ischemia in vivo. To determine whether this increase in alpha 1-adrenergic receptor number leads to an enhanced synthesis of inositol trisphosphate, the intracellular second messenger for the alpha 1-adrenergic receptor, the mass of inositol trisphosphate was quantified by a novel procedure developed in our laboratory that circumvents problems associated with using labeled precursors. The peak increases in inositol trisphosphate levels of three- to fourfold were measured after 30 s of norepinephrine stimulation and exhibited a 50% effective concentration (EC50) of 7.9 x 10(-8) M. Hypoxia produced a marked leftward shift in the dose-response curve for the production of inositol trisphosphate in response to norepinephrine stimulation (EC50 = 1.2 x 10(-8) M). Hypoxia also induced a 100-fold reduction in the concentration of norepinephrine required to elicit a threshold increase in inositol trisphosphate (10(-9) M), compared with control normoxic myocytes (10(-7) M). Thus, hypoxia, which increases alpha 1-adrenergic receptor density, also leads to an enhanced production of inositol trisphosphate and could account for the enhanced alpha 1-adrenergic responsivity in the ischemic heart in vivo, which is known to facilitate arrhythmogenesis.
Full text
PDF




Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Berridge M. J., Irvine R. F. Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature. 1984 Nov 22;312(5992):315–321. doi: 10.1038/312315a0. [DOI] [PubMed] [Google Scholar]
- Brown J. H., Buxton I. L., Brunton L. L. Alpha 1-adrenergic and muscarinic cholinergic stimulation of phosphoinositide hydrolysis in adult rat cardiomyocytes. Circ Res. 1985 Oct;57(4):532–537. doi: 10.1161/01.res.57.4.532. [DOI] [PubMed] [Google Scholar]
- Corr P. B., Shayman J. A., Kramer J. B., Kipnis R. J. Increased alpha-adrenergic receptors in ischemic cat myocardium. A potential mediator of electrophysiological derangements. J Clin Invest. 1981 Apr;67(4):1232–1236. doi: 10.1172/JCI110139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heathers G. P., Juehne T., Rubin L. J., Corr P. B., Evers A. S. Anion exchange chromatographic separation of inositol phosphates and their quantification by gas chromatography. Anal Biochem. 1989 Jan;176(1):109–116. doi: 10.1016/0003-2697(89)90280-7. [DOI] [PubMed] [Google Scholar]
- Heathers G. P., Yamada K. A., Kanter E. M., Corr P. B. Long-chain acylcarnitines mediate the hypoxia-induced increase in alpha 1-adrenergic receptors on adult canine myocytes. Circ Res. 1987 Nov;61(5):735–746. doi: 10.1161/01.res.61.5.735. [DOI] [PubMed] [Google Scholar]
- Irvine R. F., Anggård E. E., Letcher A. J., Downes C. P. Metabolism of inositol 1,4,5-trisphosphate and inositol 1,3,4-trisphosphate in rat parotid glands. Biochem J. 1985 Jul 15;229(2):505–511. doi: 10.1042/bj2290505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Irvine R. F., Brown K. D., Berridge M. J. Specificity of inositol trisphosphate-induced calcium release from permeabilized Swiss-mouse 3T3 cells. Biochem J. 1984 Aug 15;222(1):269–272. doi: 10.1042/bj2220269. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Knabb M. T., Saffitz J. E., Corr P. B., Sobel B. E. The dependence of electrophysiological derangements on accumulation of endogenous long-chain acyl carnitine in hypoxic neonatal rat myocytes. Circ Res. 1986 Feb;58(2):230–240. doi: 10.1161/01.res.58.2.230. [DOI] [PubMed] [Google Scholar]
- LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
- Lindemann J. P. Alpha-adrenergic stimulation of sarcolemmal protein phosphorylation and slow responses in intact myocardium. J Biol Chem. 1986 Apr 15;261(11):4860–4867. [PubMed] [Google Scholar]
- Pogwizd S. M., Corr P. B. Electrophysiologic mechanisms underlying arrhythmias due to reperfusion of ischemic myocardium. Circulation. 1987 Aug;76(2):404–426. doi: 10.1161/01.cir.76.2.404. [DOI] [PubMed] [Google Scholar]
- Pogwizd S. M., Corr P. B. Reentrant and nonreentrant mechanisms contribute to arrhythmogenesis during early myocardial ischemia: results using three-dimensional mapping. Circ Res. 1987 Sep;61(3):352–371. doi: 10.1161/01.res.61.3.352. [DOI] [PubMed] [Google Scholar]
- Presti C. F., Jones L. R., Lindemann J. P. Isoproterenol-induced phosphorylation of a 15-kilodalton sarcolemmal protein in intact myocardium. J Biol Chem. 1985 Mar 25;260(6):3860–3867. [PubMed] [Google Scholar]
- Rittenhouse S. E., Sasson J. P. Mass changes in myoinositol trisphosphate in human platelets stimulated by thrombin. Inhibitory effects of phorbol ester. J Biol Chem. 1985 Jul 25;260(15):8657–8660. [PubMed] [Google Scholar]
- Sharma A. D., Saffitz J. E., Lee B. I., Sobel B. E., Corr P. B. Alpha adrenergic-mediated accumulation of calcium in reperfused myocardium. J Clin Invest. 1983 Sep;72(3):802–818. doi: 10.1172/JCI111051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sheridan D. J., Penkoske P. A., Sobel B. E., Corr P. B. Alpha adrenergic contributions to dysrhythmia during myocardial ischemia and reperfusion in cats. J Clin Invest. 1980 Jan;65(1):161–171. doi: 10.1172/JCI109647. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takai Y., Kishimoto A., Iwasa Y., Kawahara Y., Mori T., Nishizuka Y. Calcium-dependent activation of a multifunctional protein kinase by membrane phospholipids. J Biol Chem. 1979 May 25;254(10):3692–3695. [PubMed] [Google Scholar]
- Woodcock E. A., White L. B., Smith A. I., McLeod J. K. Stimulation of phosphatidylinositol metabolism in the isolated, perfused rat heart. Circ Res. 1987 Nov;61(5):625–631. doi: 10.1161/01.res.61.5.625. [DOI] [PubMed] [Google Scholar]