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. 1984 May;82(1):223–232. doi: 10.1111/j.1476-5381.1984.tb16462.x

Effects of alpha-adrenoceptor stimulation with phenylephrine in the presence of propranolol on force of contraction, slow inward current and cyclic AMP content in the bovine heart.

R Brückner, H Scholz
PMCID: PMC1987239  PMID: 6329389

Abstract

The mechanism of the cyclic AMP-independent positive inotropic effect of cardiac alpha-adrenoceptor stimulation was studied by analyzing the effects of phenylephrine on force of contraction, calcium-dependent slow action potentials and the slow inward current (Isi) in bovine ventricular trabeculae. The preparations were electrically driven at 0.3 Hz in the presence of propranolol 1 mumol 1(-1). Phenylephrine increased the force of contraction in a concentration-dependent manner (maximum about 200% of control at 30 mumol 1(-1). The effect was surmountably antagonized by phentolamine. The positive inotropic effect of phenylephrine was accompanied by a concentration-dependent increase in time to peak force and occurred without any detectable increase in cyclic adenosine 3',5'-monophosphate (cyclic AMP) levels. The positive inotropic effect of phenylephrine was accompanied by an increase in action potential duration both at 20% and 90% repolarization. Calcium-dependent slow action potentials were also prolonged by phenylephrine and there was a distinct increase in the maximal rate of depolarization (dV/dtmax) of these slow potentials. These effects were also completely reversible on washing and surmountably blocked by phentolamine. However, the increase in dV/dtmax was smaller than that of isoprenaline in concentrations producing similar inotropic effects. Voltage-clamp experiments with the single sucrose-gap method showed that the phenylephrine-induced increase in force of contraction was associated not only with an increase in peak slow calcium inward current, Isi max, but also with a delay in the inactivation of Isi. Outward currents were not detectably altered by phenylephrine. It is concluded that the alpha-adrenoceptor mediated, cyclic AMP-independent positive inotropic effects of phenylephrine in bovine cardiac muscle are associated with an increase in slow inward current. Additionally, the amount of calcium influx during excitation is probably increased by a delay in the inactivation of Isi. Both effects can explain the phenylephrine-produced prolongation of the action potential, and probably contribute to the positive inotropic effect of alpha-adrenoceptor stimulation. However, as the effect on dV/dtmax is smaller than that of isoprenaline, other (still unknown) mechanisms may also be involved.

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Selected References

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  1. Benfey B. G. Cardiac alpha adrenoceptors. Can J Physiol Pharmacol. 1980 Oct;58(10):1145–1157. doi: 10.1139/y80-174. [DOI] [PubMed] [Google Scholar]
  2. Brückner R., Hackbarth I., Meinertz T., Schmelzle B., Scholz H. The positive inotropic effect of phenylephrine in the presence of propranolol. Increase in time to peak force and in relaxation time without increase in c-AMP. Naunyn Schmiedebergs Arch Pharmacol. 1978 Jul;303(3):205–211. doi: 10.1007/BF00498045. [DOI] [PubMed] [Google Scholar]
  3. Dönges C., Heitmann M., Jungbluth H., Meinertz T., Schmelzle B., Scholz H. Effectiveness of theophylline to increase cyclic AMP levels and force of contraction in electrically paced guinea-pig auricles. Comparison with isoprenaline, calcium and ouabain. Naunyn Schmiedebergs Arch Pharmacol. 1977 Dec;301(2):87–97. doi: 10.1007/BF00501422. [DOI] [PubMed] [Google Scholar]
  4. Endoh M., Brodde O. E., Schümann H. J. Relationship between the level of cAMP and the contractile force under stimulation of alpha- and beta-adrenoceptors by phenylephrine in the isolated rabbit papillary muscle. Naunyn Schmiedebergs Arch Pharmacol. 1976 Nov;295(2):109–115. doi: 10.1007/BF00499441. [DOI] [PubMed] [Google Scholar]
  5. Fozzard H. A., Beeler G. W., Jr The voltage clamp and cardiac electrophysiology. Circ Res. 1975 Oct;37(4):403–413. doi: 10.1161/01.res.37.4.403. [DOI] [PubMed] [Google Scholar]
  6. Handa Y., Wagner J., Inui J., Averesch H., Schümann H. J. Effect of alpha- and beta-sympathomimetic agonists on calcium-dependent slow action potential and force of contraction in the rabbit papillary muscle. Naunyn Schmiedebergs Arch Pharmacol. 1982 Mar;318(4):330–335. doi: 10.1007/BF00501173. [DOI] [PubMed] [Google Scholar]
  7. Harper J. F., Brooker G. Femtomole sensitive radioimmunoassay for cyclic AMP and cyclic GMP after 2'0 acetylation by acetic anhydride in aqueous solution. J Cyclic Nucleotide Res. 1975;1(4):207–218. [PubMed] [Google Scholar]
  8. Katz A. M. Cyclic adenosine monophosphate effects on the myocardium: a man who blows hot and cold with one breath. J Am Coll Cardiol. 1983 Jul;2(1):143–149. doi: 10.1016/s0735-1097(83)80387-8. [DOI] [PubMed] [Google Scholar]
  9. Ledda F., Mantelli L., Mugelli A. alpha-Sympathomimetic amines and calcium-mediated action potentials in guinea-pig ventricular muscle. Br J Pharmacol. 1980 Aug;69(4):565–571. doi: 10.1111/j.1476-5381.1980.tb07905.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ledda F., Marchetti P., Mugelli A. Studies on the positive inotropic effect of phenylephrine: a comparison with isoprenaline. Br J Pharmacol. 1975 May;54(1):83–90. doi: 10.1111/j.1476-5381.1975.tb07413.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. McDonald T. F., Trautwein W. Membrane currents in cat myocardium: separation of inward and outward components. J Physiol. 1978 Jan;274:193–216. doi: 10.1113/jphysiol.1978.sp012143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. McGuigan J. A. Some limitations of the double sucrose gap, and its use in a study of the slow outward current in mammalian ventricular muscle. J Physiol. 1974 Aug;240(3):775–806. doi: 10.1113/jphysiol.1974.sp010634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Meinertz T., Nawrath H., Scholz H. Possible role of cyclic AMP in the relaxation process of mammalian heart: effects of dibutyryl cyclic AMP and theophylline on potassium contractures in cat papillary muscles. Naunyn Schmiedebergs Arch Pharmacol. 1976 May;293(2):129–137. doi: 10.1007/BF00499217. [DOI] [PubMed] [Google Scholar]
  14. Miura Y., Inui J., Imamura H. Alpha-adrenoceptor-mediated restoration of calcium-dependent potential in the partially depolarized rabbit papillary muscle. Naunyn Schmiedebergs Arch Pharmacol. 1978 Jan-Feb;301(3):201–205. doi: 10.1007/BF00507038. [DOI] [PubMed] [Google Scholar]
  15. Nathan D., Beeler G. W., Jr Electrophysiologic correlates of the inotropic effects of isoproterenol in canine myocardium. J Mol Cell Cardiol. 1975 Jan;7(1):1–15. doi: 10.1016/0022-2828(75)90002-4. [DOI] [PubMed] [Google Scholar]
  16. Osnes J., Oye I. Relationship between cyclic AMP metabolism and inotropic response of perfused rat hearts to phenylephrine and other adrenergic amines. Adv Cyclic Nucleotide Res. 1975;5:415–433. [PubMed] [Google Scholar]
  17. Reuter H. Calcium channel modulation by neurotransmitters, enzymes and drugs. Nature. 1983 Feb 17;301(5901):569–574. doi: 10.1038/301569a0. [DOI] [PubMed] [Google Scholar]
  18. Reuter H. Divalent cations as charge carriers in excitable membranes. Prog Biophys Mol Biol. 1973;26:1–43. doi: 10.1016/0079-6107(73)90016-3. [DOI] [PubMed] [Google Scholar]
  19. Reuter H., Scholz H. A study of the ion selectivity and the kinetic properties of the calcium dependent slow inward current in mammalian cardiac muscle. J Physiol. 1977 Jan;264(1):17–47. doi: 10.1113/jphysiol.1977.sp011656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sanchez-Chapula J. Multiple effects of putative alpha-adrenoceptor agonists on the electrical and mechanical activity of guinea-pig papillary muscle. Naunyn Schmiedebergs Arch Pharmacol. 1981 Apr;316(2):108–111. doi: 10.1007/BF00505302. [DOI] [PubMed] [Google Scholar]
  21. Skomedal T., Osnes J. B., Oye I. Differences between alpha-adrenergic and beta-adrenergic inotropic effects in rat heart papillary muscles. Acta Pharmacol Toxicol (Copenh) 1982 Jan;50(1):1–12. doi: 10.1111/j.1600-0773.1982.tb00932.x. [DOI] [PubMed] [Google Scholar]
  22. Struck C. J., Ahnert G., Glossmann H., Schaeg W. Solid phase radioimmunoassay for cyclic AMP using staphylococcal protein A-antibody adsorbent. Naunyn Schmiedebergs Arch Pharmacol. 1977 May;298(1):67–73. doi: 10.1007/BF00510989. [DOI] [PubMed] [Google Scholar]
  23. Trautwein W., McDonald T. F. Current-voltage relations in ventricular muscle preparations from different species. Pflugers Arch. 1978 Apr 25;374(1):79–89. doi: 10.1007/BF00585700. [DOI] [PubMed] [Google Scholar]
  24. Tsien R. W. Cyclic AMP and contractile activity in heart. Adv Cyclic Nucleotide Res. 1977;8:363–420. [PubMed] [Google Scholar]

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