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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1995 Sep;116(2):1835–1842. doi: 10.1111/j.1476-5381.1995.tb16671.x

Beta-adrenoceptor subtypes in young and old rat ventricular myocytes: a combined patch-clamp and binding study.

E Cerbai 1, L Guerra 1, K Varani 1, M Barbieri 1, P A Borea 1, A Mugelli 1
PMCID: PMC1909098  PMID: 8528568

Abstract

1. We used electrophysiological and binding techniques to assess the presence of beta 1- and beta 2-adrenoceptors (beta 1AR and beta 2AR) in rat cardiac myocytes and to determine their ratio during aging. Experiments were performed in left ventricular myocytes enzymatically dissociated from the heart of 3-(young) or 22-month-old (old) Wistar Kyoto rats. 2. In patch-clamp experiments, myocytes from old rats showed a prolonged action potential duration (at -20 mV: 41.7 +/- 3.6 vs 26.2 +/- 3.1 ms; at -60 mV: 154.4 +/- 17.7 vs 87.1 +/- 6.9 ms, P < 0.05) and an augmented membrane capacitance (an index of cell size) (271.7 +/- 20.2 vs 164.3 +/- 14.6 pF, P < 0.05) compared to young rats. beta 2AR stimulation, achieved by superfusing myocytes with the selective beta 2AR agonist, zinterol (10 microM) or with (-)-isoprenaline (1 microM) in the presence of the selective beta 1AR antagonist, CGP 20712A (0.1 microM), significantly increased L-type calcium current (ICa,L) in rat ventricular myocytes. The percentage increase was similar in both young and old rats, either with zinterol (26.9 +/- 3.6% and 24.2 +/- 2.8%, respectively) or isoprenaline plus CGP 20712A (30.4 +/- 3.7% and 22.4 +/- 4.1%, respectively). Isoprenaline alone (beta 1AR and beta 2AR stimulation) caused a much smaller increase in ICa,L in old rats (58.4 +/- 12.1%) than in younger ones (95.3 +/- 8.1%) (P = 0.067).(ABSTRACT TRUNCATED AT 250 WORDS)

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  1. Abrass I. B., Davis J. L., Scarpace P. J. Isoproterenol responsiveness and myocardial beta-adrenergic receptors in young and old rats. J Gerontol. 1982 Mar;37(2):156–160. doi: 10.1093/geronj/37.2.156. [DOI] [PubMed] [Google Scholar]
  2. Amerini S., Fusi F., Piazzesi G., Mantelli L., Ledda F., Mugelli A. Influences of age on the positive inotropic effect mediated by alpha- and beta-adrenoceptors in rat ventricular strips. Dev Pharmacol Ther. 1985;8(1):34–42. doi: 10.1159/000457019. [DOI] [PubMed] [Google Scholar]
  3. Anversa P., Hiler B., Ricci R., Guideri G., Olivetti G. Myocyte cell loss and myocyte hypertrophy in the aging rat heart. J Am Coll Cardiol. 1986 Dec;8(6):1441–1448. doi: 10.1016/s0735-1097(86)80321-7. [DOI] [PubMed] [Google Scholar]
  4. Anversa P., Puntillo E., Nikitin P., Olivetti G., Capasso J. M., Sonnenblick E. H. Effects of age on mechanical and structural properties of myocardium of Fischer 344 rats. Am J Physiol. 1989 May;256(5 Pt 2):H1440–H1449. doi: 10.1152/ajpheart.1989.256.5.H1440. [DOI] [PubMed] [Google Scholar]
  5. Barbieri M., Varani K., Cerbai E., Guerra L., Li Q., Borea P. A., Mugelli A. Electrophysiological basis for the enhanced cardiac arrhythmogenic effect of isoprenaline in aged spontaneously hypertensive rats. J Mol Cell Cardiol. 1994 Jul;26(7):849–860. doi: 10.1006/jmcc.1994.1102. [DOI] [PubMed] [Google Scholar]
  6. Bilski A. J., Halliday S. E., Fitzgerald J. D., Wale J. L. The pharmacology of a beta 2-selective adrenoceptor antagonist (ICI 118,551). J Cardiovasc Pharmacol. 1983 May-Jun;5(3):430–437. doi: 10.1097/00005344-198305000-00013. [DOI] [PubMed] [Google Scholar]
  7. Borea P. A., Amerini S., Masini I., Cerbai E., Ledda F., Mantelli L., Varani K., Mugelli A. Beta 1- and beta 2-adrenoceptors in sheep cardiac ventricular muscle. J Mol Cell Cardiol. 1992 Jul;24(7):753–763. doi: 10.1016/0022-2828(92)93389-2. [DOI] [PubMed] [Google Scholar]
  8. Bristow M. R., Ginsburg R., Umans V., Fowler M., Minobe W., Rasmussen R., Zera P., Menlove R., Shah P., Jamieson S. Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ Res. 1986 Sep;59(3):297–309. doi: 10.1161/01.res.59.3.297. [DOI] [PubMed] [Google Scholar]
  9. Bristow M. R., Hershberger R. E., Port J. D., Minobe W., Rasmussen R. Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol Pharmacol. 1989 Mar;35(3):295–303. [PubMed] [Google Scholar]
  10. Brodde O. E., Zerkowski H. R., Borst H. G., Maier W., Michel M. C. Drug- and disease-induced changes of human cardiac beta 1- and beta 2-adrenoceptors. Eur Heart J. 1989 Jun;10 (Suppl B):38–44. doi: 10.1093/eurheartj/10.suppl_b.38. [DOI] [PubMed] [Google Scholar]
  11. Buxton I. L., Brunton L. L. Direct analysis of beta-adrenergic receptor subtypes on intact adult ventricular myocytes of the rat. Circ Res. 1985 Jan;56(1):126–132. doi: 10.1161/01.res.56.1.126. [DOI] [PubMed] [Google Scholar]
  12. Cerbai E., Barbieri M., Li Q., Mugelli A. Ionic basis of action potential prolongation of hypertrophied cardiac myocytes isolated from hypertensive rats of different ages. Cardiovasc Res. 1994 Aug;28(8):1180–1187. doi: 10.1093/cvr/28.8.1180. [DOI] [PubMed] [Google Scholar]
  13. Cerbai E., Barbieri M., Mugelli A. Characterization of the hyperpolarization-activated current, I(f), in ventricular myocytes isolated from hypertensive rats. J Physiol. 1994 Dec 15;481(Pt 3):585–591. doi: 10.1113/jphysiol.1994.sp020465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cerbai E., Masini I., Mugelli A. Electrophysiological characterization of cardiac beta 2-adrenoceptors in sheep Purkinje fibers. J Mol Cell Cardiol. 1990 Aug;22(8):859–870. doi: 10.1016/0022-2828(90)90117-k. [DOI] [PubMed] [Google Scholar]
  15. Cervoni P., Herzlinger H., Lai F. M., Tanikella T. A comparison of cardiac reactivity and beta-adrenoceptor number and affinity between aorta-coarcted hypertensive and normotensive rats. Br J Pharmacol. 1981 Nov;74(3):517–523. doi: 10.1111/j.1476-5381.1981.tb10459.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Cheng Y., Prusoff W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973 Dec 1;22(23):3099–3108. doi: 10.1016/0006-2952(73)90196-2. [DOI] [PubMed] [Google Scholar]
  17. Chevalier B., Mansier P., Callens-el Amrani F., Swynghedauw B. Beta-adrenergic system is modified in compensatory pressure cardiac overload in rats: physiological and biochemical evidence. J Cardiovasc Pharmacol. 1989 Mar;13(3):412–420. doi: 10.1097/00005344-198903000-00009. [DOI] [PubMed] [Google Scholar]
  18. Dobson J. G., Jr, Fenton R. A., Romano F. D. Increased myocardial adenosine production and reduction of beta-adrenergic contractile response in aged hearts. Circ Res. 1990 May;66(5):1381–1390. doi: 10.1161/01.res.66.5.1381. [DOI] [PubMed] [Google Scholar]
  19. Dooley D. J., Bittiger H., Reymann N. C. CGP 20712 A: a useful tool for quantitating beta 1- and beta 2-adrenoceptors. Eur J Pharmacol. 1986 Oct 14;130(1-2):137–139. doi: 10.1016/0014-2999(86)90193-7. [DOI] [PubMed] [Google Scholar]
  20. Fraticelli A., Josephson R., Danziger R., Lakatta E., Spurgeon H. Morphological and contractile characteristics of rat cardiac myocytes from maturation to senescence. Am J Physiol. 1989 Jul;257(1 Pt 2):H259–H265. doi: 10.1152/ajpheart.1989.257.1.H259. [DOI] [PubMed] [Google Scholar]
  21. Guarnieri T., Filburn C. R., Zitnik G., Roth G. S., Lakatta E. G. Contractile and biochemical correlates of beta-adrenergic stimulation of the aged heart. Am J Physiol. 1980 Oct;239(4):H501–H508. doi: 10.1152/ajpheart.1980.239.4.H501. [DOI] [PubMed] [Google Scholar]
  22. Harding S. E., Brown L. A., Wynne D. G., Davies C. H., Poole-Wilson P. A. Mechanisms of beta adrenoceptor desensitisation in the failing human heart. Cardiovasc Res. 1994 Oct;28(10):1451–1460. doi: 10.1093/cvr/28.10.1451. [DOI] [PubMed] [Google Scholar]
  23. Homcy C. J., Vatner S. F., Vatner D. E. Beta-adrenergic receptor regulation in the heart in pathophysiologic states: abnormal adrenergic responsiveness in cardiac disease. Annu Rev Physiol. 1991;53:137–159. doi: 10.1146/annurev.ph.53.030191.001033. [DOI] [PubMed] [Google Scholar]
  24. Kuznetsov V., Pak E., Robinson R. B., Steinberg S. F. Beta 2-adrenergic receptor actions in neonatal and adult rat ventricular myocytes. Circ Res. 1995 Jan;76(1):40–52. doi: 10.1161/01.res.76.1.40. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Lakatta E. G. Cardiac muscle changes in senescence. Annu Rev Physiol. 1987;49:519–531. doi: 10.1146/annurev.ph.49.030187.002511. [DOI] [PubMed] [Google Scholar]
  27. Lakatta E. G., Gerstenblith G., Angell C. S., Shock N. W., Weisfeldt M. L. Diminished inotropic response of aged myocardium to catecholamines. Circ Res. 1975 Feb;36(2):262–269. doi: 10.1161/01.res.36.2.262. [DOI] [PubMed] [Google Scholar]
  28. Lakatta E. G., Yin F. C. Myocardial aging: functional alterations and related cellular mechanisms. Am J Physiol. 1982 Jun;242(6):H927–H941. doi: 10.1152/ajpheart.1982.242.6.H927. [DOI] [PubMed] [Google Scholar]
  29. Limas C. J. Increased number of beta-adrenergic receptors in the hypertrophied myocardium. Biochim Biophys Acta. 1979 Nov 15;588(1):174–178. doi: 10.1016/0304-4165(79)90382-9. [DOI] [PubMed] [Google Scholar]
  30. Mauz A. B., Pelzer H. Beta-adrenoceptor-binding studies of the cardioselective beta blockers bisoprolol, H-I 42 BS, and HX-CH 44 BS to heart membranes and intact ventricular myocytes of adult rats: two beta 1-binding sites for bisoprolol. J Cardiovasc Pharmacol. 1990 Mar;15(3):421–427. doi: 10.1097/00005344-199003000-00012. [DOI] [PubMed] [Google Scholar]
  31. McGonigle P., Neve K. A., Molinoff P. B. A quantitative method of analyzing the interaction of slightly selective radioligands with multiple receptor subtypes. Mol Pharmacol. 1986 Oct;30(4):329–337. [PubMed] [Google Scholar]
  32. Mewes T., Dutz S., Ravens U., Jakobs K. H. Activation of calcium currents in cardiac myocytes by empty beta-adrenoceptors. Circulation. 1993 Dec;88(6):2916–2922. doi: 10.1161/01.cir.88.6.2916. [DOI] [PubMed] [Google Scholar]
  33. Minneman K. P., Hegstrand L. R., Molinoff P. B. The pharmacological specificity of beta-1 and beta-2 adrenergic receptors in rat heart and lung in vitro. Mol Pharmacol. 1979 Jul;16(1):21–33. [PubMed] [Google Scholar]
  34. Munson P. J., Rodbard D. Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem. 1980 Sep 1;107(1):220–239. doi: 10.1016/0003-2697(80)90515-1. [DOI] [PubMed] [Google Scholar]
  35. Muntz K. H., Zhao M., Miller J. C. Downregulation of myocardial beta-adrenergic receptors. Receptor subtype selectivity. Circ Res. 1994 Mar;74(3):369–375. doi: 10.1161/01.res.74.3.369. [DOI] [PubMed] [Google Scholar]
  36. Nanoff C., Freissmuth M., Schütz W. The role of a low beta 1-adrenoceptor selectivity of [3H]CGP-12177 for resolving subtype-selectivity of competitive ligands. Naunyn Schmiedebergs Arch Pharmacol. 1987 Nov;336(5):519–525. doi: 10.1007/BF00169308. [DOI] [PubMed] [Google Scholar]
  37. O'Donnell S. R., Wanstall J. C. Evidence that ICI 118, 551 is a potent, highly Beta 2-selective adrenoceptor antagonist and can be used to characterize Beta-adrenoceptor populations in tissues. Life Sci. 1980 Aug 25;27(8):671–677. doi: 10.1016/0024-3205(80)90008-9. [DOI] [PubMed] [Google Scholar]
  38. Saito K., Kurihara M., Cruciani R., Potter W. Z., Saavedra J. M. Characterization of beta 1- and beta 2-adrenoceptor subtypes in the rat atrioventricular node by quantitative autoradiography. Circ Res. 1988 Jan;62(1):173–177. doi: 10.1161/01.res.62.1.173. [DOI] [PubMed] [Google Scholar]
  39. Sakai M., Danziger R. S., Xiao R. P., Spurgeon H. A., Lakatta E. G. Contractile response of individual cardiac myocytes to norepinephrine declines with senescence. Am J Physiol. 1992 Jan;262(1 Pt 2):H184–H189. doi: 10.1152/ajpheart.1992.262.1.H184. [DOI] [PubMed] [Google Scholar]
  40. Scarpace P. J., Abrass I. B. Beta-adrenergic agonist-mediated desensitization in senescent rats. Mech Ageing Dev. 1986 Aug;35(3):255–264. doi: 10.1016/0047-6374(86)90128-4. [DOI] [PubMed] [Google Scholar]
  41. Stratton J. R., Cerqueira M. D., Schwartz R. S., Levy W. C., Veith R. C., Kahn S. E., Abrass I. B. Differences in cardiovascular responses to isoproterenol in relation to age and exercise training in healthy men. Circulation. 1992 Aug;86(2):504–512. doi: 10.1161/01.cir.86.2.504. [DOI] [PubMed] [Google Scholar]
  42. Vestal R. E., Wood A. J., Shand D. G. Reduced beta-adrenoceptor sensitivity in the elderly. Clin Pharmacol Ther. 1979 Aug;26(2):181–186. doi: 10.1002/cpt1979262181. [DOI] [PubMed] [Google Scholar]
  43. Walker K. E., Lakatta E. G., Houser S. R. Age associated changes in membrane currents in rat ventricular myocytes. Cardiovasc Res. 1993 Nov;27(11):1968–1977. doi: 10.1093/cvr/27.11.1968. [DOI] [PubMed] [Google Scholar]
  44. White M., Roden R., Minobe W., Khan M. F., Larrabee P., Wollmering M., Port J. D., Anderson F., Campbell D., Feldman A. M. Age-related changes in beta-adrenergic neuroeffector systems in the human heart. Circulation. 1994 Sep;90(3):1225–1238. doi: 10.1161/01.cir.90.3.1225. [DOI] [PubMed] [Google Scholar]
  45. Wilson C., Lincoln C. Beta-adrenoceptor subtypes in human, rat, guinea pig, and rabbit atria. J Cardiovasc Pharmacol. 1984 Nov-Dec;6(6):1216–1221. [PubMed] [Google Scholar]
  46. Xiao R. P., Lakatta E. G. Beta 1-adrenoceptor stimulation and beta 2-adrenoceptor stimulation differ in their effects on contraction, cytosolic Ca2+, and Ca2+ current in single rat ventricular cells. Circ Res. 1993 Aug;73(2):286–300. doi: 10.1161/01.res.73.2.286. [DOI] [PubMed] [Google Scholar]
  47. Yin F. C., Spurgeon H. A., Rakusan K., Weisfeldt M. L., Lakatta E. G. Use of tibial length to quantify cardiac hypertrophy: application in the aging rat. Am J Physiol. 1982 Dec;243(6):H941–H947. doi: 10.1152/ajpheart.1982.243.6.H941. [DOI] [PubMed] [Google Scholar]
  48. Zitnik G., Roth G. S. Effects of thyroid hormones on cardiac hypertrophy and beta-adrenergic receptors during aging. Mech Ageing Dev. 1981 Jan;15(1):19–28. doi: 10.1016/0047-6374(81)90004-x. [DOI] [PubMed] [Google Scholar]

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