Antibodies against the second extracellular loop of β1-adrenergic receptors induce endothelial dysfunction in conductance and resistance arteries of the Wistar rat

Autoantibodies against beta(1)-adrenoceptors (beta(1)-ARs) have been detected in the serum of patients with various cardiac diseases; however, the pathological impact of these autoantibodies (beta(1)-AABs) has only been evaluated in cardiac tissue. The purpose of the present study was to evaluate whether beta(1)-AABs have deleterious effects on vascular reactivity in rats. An enzyme-linked immunosorbent assay was used to detect beta(1)-AABs in sera from immunized rats over a period of 1-3 months using the peptidic sequence of the second extracellular loop of human beta(1)-AR Functional studies were performed in thoracic aortic (TA) and small mesenteric artery (SMA) rings from immunized rats. Following pre-contraction with phenylephrine (0.3 mu M and 3 mu M for the TA and SMA respectively), cumulative concentration-response curves (CCRCs) to various beta-AR agonists (isoproterenol, dobutamine, salbutamol, SR 58611A), acetylcholine, A23187, and sodium nitroprusside (SNP) were then plotted. The relaxations induced by dobutamine, SR 58611A, and acetylcholine were significantly impaired, but salbutamol-induced relaxations were not affected, in both vessels from immunized rats. A significant impairment of isoproterenol-induced relaxation was only observed in SMA. CCRCs to SNP were not modified in either of the vessels. A23187-induced relaxation was impaired in immunized rats. Following pretreatment with L-arginine, vasorelaxation to acetylcholine and SR 58611A was restored in immunized rats. This study demonstrates that immunization against the second extracellular loop of beta(1)-ARs has a deleterious impact on vasorelaxations in the TA and SMA of rats, involving alterations in endothelium-dependent NO signaling pathways. (C) 2014 Elsevier B.V. All rights reserved.