Protein kinase C (PKC) involved in enhancement of α1-adrenoceptor-mediated responses of the main pulmonary artery in rats with diabetes mellitus

I V Kizub,O S Kostiuk,О I Kharchenko,A I Soloviev,L I Ostapchenko

doi:10.15421/021745

Abstract

Diabetes mellitus (DM) causes multiple dysfunctions including circulatory disorders such as cardiomyopathy, angiopathy, atherosclerosis and arterial hypertension. Moreover, DM can strongly affect pulmonary circulation, enhancing the wall thickness of the pulmonary arteries, changing their tone and contractility, and gas exchange in the lungs. It can lead to marked loss of lung function and respiratory efficiency. It is also known that protein kinase C (PKC) activity increases in DM and that PKC is involved in the mechanisms of DM-associated vascular complications. However, the effect of DM on pulmonary artery tone has been poorly investigated and the role of PKC in this remains unknown. The aim of this study was to investigate changes in contractility of pulmonary arteries in rats with DM and to determine the possible role of PKC in this process. Experimental type 1 DM was elicited in male Wistar rats by single streptozotocin (STZ, 65 mg/kg) injection. DM was verified by the presence of hyperglycaemia. The investigation was performed on the isolated rings of the main pulmonary arteries using the method of vascular tone registration. Phenylephrine (PhE, 0.1 nM – 1 mM) caused dose-dependent constriction of the pulmonary arteries. The pD2 (negative logarithm of the agonist concentration required for half-maximum response) of this constriction increased in rats with DM, however significant changes in amplitude of PhE-induced constriction were not observed. PKC inhibition with chelerythrine and staurosporine (1 µM) significantly shifted PhE the concentration-response curve to the right in intact diabetic vessels but had no effect on sensitivity to PhE in deendothelised diabetic vessels. Our data suggest that type 1 DM leads to enhancement in pulmonary artery α1-adrenoceptor-mediated contractility and PKC activity in the endothelium rather than in vascular SMCs is involved in this process.

Highlights

Diabetes mellitus (DM) is a complex syndrome that is rapidly rising in incidence throughout the world
In control intact pulmonary artery rings isolated from non-diabetic rats, phenylephrine (PhE), a selective α1-adrenoceptor agonist, applied at ascending concentrations (0.1 nM – 1 mM) evoked concentrationdependent contractions with a maximal response (Emax) 146.76 ± 18.92 % (n = 16) of constriction evoked by 5-minute application of
In intact pulmonary arteries isolated from diabetic rats, the responsiveness to PhE was enhanced since the diabetic vessels responded to lower concentrations of the agonist. pD2 value of PhE in diabetic vessels was 8.02 ± 0.09 (n = 16, Р < 0.05) (Fig. 2)

Summary

Introduction

Diabetes mellitus (DM) is a complex syndrome that is rapidly rising in incidence throughout the world. The adverse long-term effects of DM involve many organ systems and are associated with a complex pathology leading to a large number of secondary cellular and subcellular changes. DM leads to multiple dysfunctions including cardiovascular diseases, one of the major causes of morbidity, mortality, end-stage renal disease, and blindness (Madonna and de Caterina, 2011). The macrovascular manifestations of DM include angiopathy, atherosclerosis, medial calcification, and arterial hypertension mostly located in the coronary and carotid arteries (Whiteley et al, 2005; Cosson et al, 2006), cerebral vessels, and the large peripheral arteries of the lower extremities (Funk et al, 2012). Increased blood flow and vascular tone elevation have been documented in diabetes (Madonna and de Caterina, 2011)

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