Regulation of Na⁺-K⁺ pump by β₃-adrenergic receptors in aortas from noradrenaline-treated rats

G. Kayki Mutlu¹, E. Muderrisoglu¹, I. K. Karaomerlioglu¹, B. Erdogan¹, V. M. Altan², E. Arioglu Inan¹. ¹Faculty of Pharmacy Deparment of Pharmacology, Ankara University, Ankara, Turkey, ²Faculty of Pharmacy Deparment of Pharmacology, Bezmialem Vakif University, Istanbul, Turkey.

Introduction: Na⁺/K⁺-ATPase (NKA) plays an important role in the regulation of vascular tone and membrane potential. However, inactivation of NKA during sympathetic overactivation results in ionic dysregulation. Cardiac β₃-adrenoceptors (ARs) are known to mediate NKA stimulation which is likely to represent a compensatory mechanism (1). However, their effect on vascular NKA isn’t known. Therefore, we aimed to investigate the effect of β₃-AR stimulation on NKA activity under high noradrenaline concentrations.

Method: Sprague Dawley rats were divided into three groups: control, noradrenaline-treated, noradrenaline+BRL 37344 treated groups (n=5 for each group). Rats received noradrenaline (NA) (4 mg/kg/day) ± BRL (10 mg/kg/day) for 14 days via osmotic pumps. Systolic (SBP), diastolic (DBP) and mean arterial blood pressures (MAP) were investigated. Relaxation curves to KCl (0.1-10 mM) were analyzed in aortic rings with/without endothelium. NKA activity was expressed as KCl-induced relaxation in arteries incubated in K⁺-free solutions (2). All data are expressed as mean±S.E.M. Multiple comparisons were performed using one way ANOVA followed by Bonferroni test.

Results: Noradrenaline-treated rats have higher aortic weight/length ratio. They also have higher blood pressure values (Table 1). These hypertrophic and hypertensive effects were abolished after BRL treatment. Moreover, NKA activity was significantly decreased in noradrenaline-treated rats. BRL treatment abolished this decrease and stimulated NKA (Emax (%) C: 66.1±2.5; NA: 53.6±2.9; BRL: 66.3±4.3). However, this stimulating effect of BRL was lost when endothelium was removed (Emax (%) C: 34.5±4.7; NA: 23.3±2.8; BRL: 20.6±3.2) (Figure 1). On the other hand, in the presence of ouabain, KCl did not generate a relaxing effect which confirms that this effect was entirely mediated by NKA.

Table 1 Group comparison of aortic weight/10 mm length ratio and blood pressure values. (n=5)^*0.05; ^**p<0.01 vs. control; ^## p<0.01 vs. BRL-treated

Figure 1 The maximum responses to KCl. Four aortic rings were used from each rat (n=5 rats per group), two rings were used with intact endothelium and endothelium of other two were removed. ^*p<0.05

Conclusion: β₃-ARs stimulation by BRL 37344 improved hypertrophic and hypertensive effects of noradrenaline treatment. NKA activity, on the other hand, was found to be decreased under high noradrenaline concentrations whereas β₃-ARs activation stimulated pump activity in an endothelium-dependent manner.

References:

1. Bundgaard H et al. (2010). Circulation 122(25):2699-708.

2. Chen SJ et al. (2005). Shock 23(2). 179-185.