Cardiac β-Adrenoceptor Desensitization Due to Increased β-Adrenoceptor Kinase Activity in Chronic Uremia

ABSTRACT. Patients with chronic renal failure develop an autonomic dysfunction with impaired baroreflex control and attenuated cardiovascular β-adrenoceptor response to noradrenaline. In rats that underwent 5/6-nephrectomy (SNX), cardiac β-adrenoceptor responsiveness was reduced as well. Therefore, the aim of this study was to further investigate the mechanism underlying cardiac β-adrenoceptor desensitization in SNX rats. For this purpose, right and left ventricular β-adrenoceptor density, activity of the G-protein–coupled receptor kinase, and activity and density of the neuronal noradrenaline transporter (uptake 1 ) were assessed in SNX rats. Seven weeks after SNX, rats had developed left heart hypertrophy. Plasma creatinine, urea, and noradrenaline levels were significantly increased; left and right ventricular noradrenaline content was significantly decreased when compared with sham-operated control rats. In these SNX rats, left, but not right, ventricular β-adrenoceptor density was significantly reduced, and membrane-associated G-protein–coupled receptor kinase activity was significantly increased compared with sham-operated rats. Although right and left ventricular activity of uptake 1 was unchanged, the neuronal noradrenaline transporter density was significantly reduced in both ventricles of SNX versus sham-operated rats. An increase in left ventricular G-protein–coupled receptor kinase activity, possibly triggered by enhanced cardiac noradrenaline release, might be responsible for the decrease in left ventricular β-adrenoceptor responsiveness in SNX rats.