Abstract
Phorbol-12,13-dibutyrate (PDB) reduced concentration-dependently the contractile force of guineapig papillary muscles (EC50 1.07 μmol/l) while phorbol-12-myristate-13-acetate (PMA) was ineffective. The protein kinase C inhibitors staurosporine (0.1 μmol/l) and polymyxin B (70 μmol/l) did not antagonize the negative inotropic effect of PDB. Neither PMA nor PDB, in concentrations up to 30 μmol/l caused significant changes of the membrane resting potential, the maximum depolarization velocity, the action potential duration or the functional refractory period in intact papillary muscles. In isolated ventricular cardiomyocytes the inward calcium current was halved by either 1 μmol/l PDB or 10 μmol/l PMA. PKC inhibitors attenuated, but could not completely abolish this effect of the phorboles. It is concluded that the negative inotropic effect of PDB is caused by a reduction of the slow inward calcium current and that this inhibition is, for the greater part, not mediated by an activation of protein kinase C.
Similar content being viewed by others
References
Abrahams TP, Scholfield GG (1992) Norepinephrine-induced Ca2+ current inhibition in adult rat sympathetic neurons does not require protein kinase C activation. Eur J Pharmacol 227:189–197
Apkon M, Nerbonne JM (1988) Alpha-1 adrenergic agonists selectively suppress voltage-dependent K+ current in rat ventricular myocytes. Proc Natl Acad Sci USA 85:8756–8760
Bell RM, Burns DJ (1991) Lipid activation of protein kinase C. J Biol Chem 266:4661–4664
Benz I, Herzig JW, Kohlhardt M (1992) Opposite effects of angiotensin-II and the protein kinase-C activator OAG on cardiac Na+ channels. J Membr Biol 130:183–190
Bourinet E, Fournier F, Lory P, Charnet P, Nargeot J (1992) Protein kinase-C regulation of cardiac calcium channels expressed in Xenopus occytes. Eur J Physiol 421:247–255
Brasch H (1989) Influence of phorbol esters on stimulation-induced noradrenaline release and contractile force of isolated guinea-pig atria. Bas Res Cardiol 86:283–290
Chen H, Jassar BS, Kurenny DE, Smith PA (1994) Phorbol ester-induced M-current suppression in bull-frog sympathetic ganglion cells: insensitivity to kinase inhibitors. Br J Pharmacol 113:55–62
Clapp LH, Sims SM, Walsh JV (1992) Role of diacylglycerol in mediating the actions of ACh on M-current in gastric smooth muscle cells. Am J Physiol 321: C1274-C1281
Dirksen RT, Sheu SS (1990) Modulation of ventricular action potential by α1-adrenoceptors and protein kinase C. Am J Physiol 258:H907-H911
Dösemeci A, Dhallan, RS, Cohen NM, Lederer WJ, Rogers TB (1988) Phorbol ester increases calcium current and stimulates the effects of angiotensin II on cultured neonatal rat heart myocytes. Circ Res 62:347–357
Endoh M, Otomo J, Norota I, Takanashi M (1993) Selective inhibition by phorbol 12,13-dibutyrate of the alpha(1)-receptor-mediated positive inotropic effect. Int J Cardiol 40:191–201
Gibson IC, Logan SD (1992) The actions of phorbol esters upon isolated calcium currents of helix-aspera neurones. Comp Biochem Physiol C-Comp Pharmacol Toxicol 102:297–303
Hattori Y, Endou M, Shirota M, Kanae M (1989) Dissociation of phosphoinositide hydrolysis and positive inotropic effect of histamine mediated by H1-receptors in guinea-pig left atria. Naunyn-Schmiedeberg's Arch. Pharmacol 340:196–203
Hattori Y, Nakaya H, Nishihara J, Kanno M (1993) A dual-component positive inotropic effect of endothelin-1 in guinea pig left atria: A role of protein kinase C. J Pharmacol exp Ther 266: 1202–1212
Hochberger P, Tosselli M, Swandulla H, Lux HD (1989) A diacylglycerol analogue reduces neuronal calcium currents independently of protein kinase C activation. Nature 338:340–342
Huang K-P (1989) The mechanism of protein kinase C activation. Trends in Neurosci 12:425–432
Karmazyn M, Haist JV (1993) Calcium dependent positive inotropic effects of low phorbol ester concentrations in isolated rat hearts. Cardiovasc Res 27: 390–395
Karmazyn M, Watson JE, Moffat MP (1990) Mechanisms for cardiac depression induced by phorbol myristate acetate in working rat hearts. Br J Pharmacol 100:826–830
Kushida H, Hiramoto T, Satoh H, Endoh M (1988) Phorbol ester does not mimic, but antagonizes the alpha-adrenoceptor-mediated positive inotropic effect in the rabbit papillary muscle. Naunyn-Schmiedeberg's Arch. Pharmacol 337: 169–176
Lacerda AE, Rampe D, Brown AM (1988) Effects of protein kinase C activators on cardiac Ca2+ channels. Nature 335:249–251
Leatherman GF, Kim D, Smith TW (1987) Effect of phorbol esters on contractile state and calcium flux in cultured chicken heart cells. Am J Physiol 253: H205-H209
Marquez C, Martinez C, Kroemer G, Bosca L (1992) Protein kinase-C isoenzymes display differential affinity for phorbol esters-Analysis of phorbol ester receptors in B-cell differentiation. J Immunol 149:2560–2568
Mitsui M, Karaki H (1993) Contractile and relaxant effects of phorbol ester in the intestinal smooth muscle of guineapig taenia caeci. Br J Pharmacol 109: 229–233
Musgrave IF, Foucart S, Majewski H (1989) Do phorbol myristate and phorbol dibutyrate enhance noradrenaline release by the same mechanisms? Br J Pharmacol 98: Suppl 776 P
Nishizuka Y (1984) The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308: 693–698
Northover BJ (1993) Phorbol 12,13-dibutyrate produces negative inotropism and selective antagonism of responses to adrenoceptor agonists in rat atria. Biochem Pharmacol 45: 1183–1189
Otani H, Hara M, Zeng XT, Omori K, Inagaki C (1992) Different patterns of protein kinase C redistribution mediated by alpha1-adrenoceptor stimulation and phorbol ester in rat isolated left ventricular papillary muscle. Br J Pharmacol 107:22–26
Plummer MR, Rittenhouse A, Kanaevsky M, Hess P (1991) Neurotransmitter modulation of calcium channels in rat sympathetic neurons. J Neurosci 11:2339–2348
Satoh H, Hashimoto K (1988) On electrophysiological responses to phorbol esters which stimulate protein kinase C in rabbit sino-atrial node cells. Naunyn-Schmiedeberg's Arch Pharmacol 337: 308–315
Satoh H (1992) Inhibition in L-type Ca2+ channel by stimulation of protein kinase-C in isolated guinea pig ventricular cardiac myocytes. Gen Pharmacol 23:1097–1102
Satoh H, Nakashima T, Tsuchida K (1992) The responses to phorbol esters which stimulated protein kinase-C in canine Purkinje fibers. Gen Pharmacol 23:847–852
Singerlahat D, Gershon E, Lotan I, Hullin R, Biel M, Flockerzi V, Hofmann F, Dascal N (1992) Modulation of cardiac Ca2+ channels in Xenopus oocytes by protein kinase-C. FEBS Letters 306: 113–118
Teutsch T, Weibele A, Sies M (1987) Differential inotropic and chronotropic effects of various protein kinase C activators on isolated guinea pig atria. Eur J Pharmacol 144:363–367
Those N, Kameyama M, Irisawa HI (1987) Intracellular Ca2+ and protein kinase C modulate K+ current in guinea pig heart cells. Am J Physiol 253:H1312-H1324
Toullec D, Pianetti P, Coste H, Bellevergue P, Grand-Perret T, Ajakanes M, Baudet V, Boissin P, Boursier E, Loriolle F, Duhamel L, Charon D, Kirilovsky J (1991) The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J Biol Chem 226:15771–15781
Walsh KB, Kass RS (1988) Regulation of a heart potassium channel by protein kinase A and C. Science 242:67–69
Ward CA, Moffat MP (1992) Positive and negative inotropic effects of phorbol 12-myristate 13-acetate: relationship to PKC-dependence and changes in [Ca2+]i. J Mol Cell Cardiol 24:937–948
Yuan S, Sunahara FA, Sen AK (1987) Tumor-promoting phorbol esters inhibit cardiac functions and induce redistribution of protein kinase C in perfused beating rat heart. Circ Res 61:372–378
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Siems, T., Brasch, H. Influence of phorbol esters on contractile force, action potential and calcium current of isolated guinea-pig heart tissues. Basic Res Cardiol 90, 459–466 (1995). https://doi.org/10.1007/BF00788538
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00788538