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.
Highlights
The objective of this study is to elucidate the mechanism of the compensatory-modulating effect of parathyroid hormone (PTH) on heart functional activity, which is realized by the study of effective doses of PTH by pharmacological analysis, using different inhibitors
It is not excluded that the increase in pumping capacity of the heart is associated with activation of the output of calcium from intracellular depots by IP3, which formation is enhanced via parathyroid hormone [22]
Based on the results of simultaneous action of 10–10 M 1-34-PTH with calcium channel (a) blocker Verapamil (10–5 M), which mitigated the effect of PTH on heart pacemaker activity, the assumption of calcium dependent mechanism of positive chronotropic action of PTH is put forward
Summary
Particular attention is paid to the role of calcium-regulating system of the organism (parathyroid hormone (PTH), calcitonin, parathyroid hormone-related peptide (PTHrP)) in the mechanism of pacemaker manifestation and heart contractile activity [1], blood pressure regulation [2,3,4,5,6,7], renal system functioning [8], proliferation and functioning of different structures [9], in particular, the beta cells of pancreas [10] and placental trophoblast [11], as well as the development of bone tissue, etc. [12]. In our earlier work we demonstrated that PTH is a modulator of neuron functional activity and has “early” and “late” effects [15]. It was revealed that “early” effect of the hormone is conditioned by its direct action on the calcium conductance of membrane, and the “late” one—its influence on the metabolism-dependent component, during which the activation of phosphoinositide path occupies the central place, with the involvement of diacilglycerol (DAG) and inositol triphosphate (IP3) in the realization of hormone signal [16]. A number of studies [5,7,21] indicate involvement of the major calcium-regulating factor, PTH in the regulation of heart contractile activity. Despite the research results multiplicity, some aspects of calcium-regulating system effects on the maintenance of calcium homeostasis in heart and its activity, as well as OPEN ACCESS
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