Dose-dependent effect of parathyroid hormone 1-34 fragment and its influence mechanism on the functional activity of isolated heart

Anna S. Ter-Markosyan, Knarik R. Harutunyan, Rafik Sh. Sargsyan, Drastamat N. Khudaverdyan

Department of Physiology, Yerevan State Medical University after M. Heratsi, Yerevan, Armenia.
Laboratory of Integrative Biology, Physiology Institute after L. A. Orbeli of RA NAS, Yerevan, Armenia.

DOI: 10.4236/ojmip.2012.22007                

Abstract

The present investigation is the continuation of our prior clinical studies on the content of parathyroid hormone (PTH), its paracrine analog, parathyroid hormone-related protein (PTHrP) and electrolytes in blood of patients with heart failure. The results of these studies formed the basis for the nomination of the hypothesis on PTH and PTHrP compensatory-modulating effect on the contractile activity of heart. The objective of this study is to elucidate the mechanism of the compensatory-modulating effect of PTH on heart functional activity, which is realized by the study of effective doses of PTH by pharmacological analysis, using different inhibitors. The dose-dependent effect of PTH on the heart contraction rate and amplitude is studied on the frog isolated heart by the method of non-invasive registration of heart contractile activity. The method is based on the photoelectric principle of the reflected from the contractile object light ray transformation into an electric signaling. It is shown that the most effective dose that has positive chronotropic and inotropic effects on heart is 10^–10 M hormone. To clarify the mechanism of PTH physiological dose action on the contractile activity of heart PTH 1-34 is combined with Ca-channel as well as phosphodiesterase blockers. The mentioned substances are applied based on the fact that PTH effect on target cells is mediated by secondary messengers, particularly calcium ions and cAMP. Based on the data obtained by combination of hormone with Verapamil (10^–5 M) and Theophylline (10^–4 M), we concluded on the involvement of calcium ions in the realization of chronotropic and cAMP in the inotropic effects on the heart.

Keywords

1-34 Parathyroid Hormone; Isolated Heart; Calcium; cAMP

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Hara, M., Liu, Y.M., Zhen, L., et al. (1997) Positive chronotropic actions of parathyroid hormone and parathyroid hormone-related peptide are associated with increase in the current, I(f), and the slop of the pacemaker potential. Circulation, 96, 3704-3709.
[2]	Cleemann, L. and Morad, M. (1991) Role of Ca2+ channel in cardiac excitation-contraction coupling in the rat: Evidence from Ca2+ transients and contraction. Journal of Physiology, 432, 283-312.
[3]	Levi, A.J., Brooksby, P. and Hancox, J.C. (1993) One hump or two? The triggering of calcium release from the sarcoplasmic reticulum and the voltage dependence of contraction in mammalian cardiac muscle. Cardiovascular Research, 27, 1743-1757. doi:10.1093/cvr/27.10.1743
[4]	Ogino, K., Burkhoff, D. and Bilezikian, J.P. (1995) The homodynamic basis for the cardiac effects of parathyroid hormone (PTH) and PTH-related protein. Endocrinology, 136, 3024-3030. doi:10.1210/en.136.7.3024
[5]	Khudaverdyan, D.N., Ter-Markosyan, A.S., Mkrtchyan, O.V. et al. (1999) The influence of parathyroid hormone on heart contractile activity. Journal of Theoretical and Clinical Medicine, 2, 3-6.
[6]	Wang, S.Q., Song, L.S., Lakatta, E.G. et al. (2001) Ca2+ signalling between single L-type Ca2+ channels and ryanodine receptors in heart cells. Nature, 410, 592-596. doi:10.1038/35069083
[7]	Barleta, G., De Feo, M.L., Del Bene, R., et al. (2000) Cardiovascular effects of parathyroid hormone: A study in healthy subjects and normotensive patients with mild primary hyperparathyroidism. Journal of Clinical Endocrinology & Metabolism, 85, 1815-1821. doi:10.1210/jc.85.5.1815
[8]	Lee, K., Brown, D., Urena, P., et al. (1996) Localization of parathyroid hormone/parathyroid hormone-related peptide receptor mRNA in kidney. American Journal of Physiology, 270, F186-E191.
[9]	Gordon, J. and Strewler, M.D. (2000) The physiology of parathyroid hormone-related protein. New England Journal of Medicine, 342, 177-185.
[10]	Shor, R., Halabe, A., Aberbuh, E., et al. (2006) PTHrP and insulin levels following oral glucose and calcium administration. European Journal of Internal Medicine, 17, 408-411. doi:10.1016/j.ejim.2006.02.019
[11]	Kovacs, C.S., Lannske, B., Hunzelman, J.L., et al. (1996) Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proceedings of the National Academy of Sciences of USA, 93, 15233-15238. doi:10.1073/pnas.93.26.15233
[12]	Strewler, G.J. (2000) The physiology of parathyroid hormone-related protein. New England Journal of Medicine, 342, 177-185. doi:10.1056/NEJM200001203420306
[13]	Strewler, G.J. and Nissenson, R.A. (1993) Hypercalciemia in malignancy. Western Journal of Medicine, 153, 635-640.
[14]	Ogino, K., Ogura, K., Kinugasa, Y., et al. (2002) Parathyroid hormone-related protein is produced in the myocardium and increased in patients with congestive heart failure. Journal of Clinical Endocrinology & Metabolism, 87, 4722-4727. doi:10.1210/jc.2002-020314
[15]	Kostyuk, P.G., Lukyanetz, E.A., Ter-Markosyan, A.S., et al. (1990) Stimulation of the neuronal calcium conductance by parathyroid hormone. Neurophysiology, 22, 373380.
[16]	Kostyuk, P.G., Lukyanetz, E.A. and Ter-Markosyan, A.S. (1992) Parathyroid hormone enhances calcium current in snail neurons. Stimulation of the effect by phorbol esters. Pflügers Archiv, 420, 146-152. doi:10.1007/BF00374983
[17]	Lutsenco, B.K., Ter-Markosyan, A.S., Khlebnikova, N.B., et al. (1987) Parathyroid hormone influence on 45Ca2+ and 3H-GABA transport in nervous ending, isolated from rat brain cortex. Bulletin of Experimental Biology and Medicine, 103, 146-149.
[18]	Arakelyan, K.P., Sahakyan, Y.A., Hayrapetyan, L.R., et al. (2007) Calcium regulating peptide hormones and blood electrolytic balance in chronic heart failure. Regulatory Peptides, 142, 95-100. doi:10.1016/j.regpep.2007.02.001
[19]	Halapas, A, Lembessis, P, Mourouzis, I., et al. (2008) Experimental hyperthyroidism increases expression of parathyroid hormone-related peptide and type-1 parathyroid hormone receptor in rat ventricular myocardium of the Langendorff ischaemia-reperfusion model. Experimental Physiology, 93, 237-246. doi:10.1113/expphysiol.2007.039594
[20]	Deftos, L.J., Burton, D.W. and Brandt, D.W. (1993) Parathyroid hormone-like protein is a secretory product of atrial myocytes. Journal of Clinical Investigation, 92, 727-735. doi:10.1172/JCI116643
[21]	Smogorzewski, M, Zayed, M., Zhang, Y.B., et al. (1993) Parathyroid hormone increases cytosolic calcium concentration in adult rat cardiac myocytes. American Journal of Physiology—Heart and Circulatory Physiology, 264, H1998-H2006.
[22]	Khudaverdyan, D.N., Ter-Markosyan, A.S. and Tadevosyan Y.V. (1997) Initiation of the Phosphoinositide Cycle by Parathyroid Hormone in Synaptosomes. Biochemistry, 62, 1109-1112.
[23]	Klabunde, R.E. (2011) Cardiovascular Physiology Concepts. Lippincott Williams & Wilkins, Philadelphia.
[24]	Jansen, J., Gres, P., Umschlag, C., et al. (2003) Parathyroid hormone-related peptide improves contractile function of stunned myocardium in rats and pigs. American Journal of Physiology—Heart and Circulatory Physiology, 284, H49-H55.
[25]	Lütteke, D., Ross, G., Abdallah, Y., et al. (2005) Parathyroid hormone-related peptide improves contractile responsiveness of adult rat cardiomyocytes with depressed cell function irrespectively of oxidative inhibition. Basic Research in Cardiology, 100, 320-327. doi:10.1007/s00395-005-0532-9
[26]	Zaruba, M.M., Huber, B.C., Brunner, S., et al. (2008) Parathyroid hormone treatment after myocardial infarcttion promotes cardiac repair by enhanced neovascularization and cell survival. Cardiovascular Research, 77, 722-731. doi:10.1093/cvr/cvm080