Enhanced vasoconstriction to α1 adrenoceptor autoantibody in spontaneously hypertensive rats

摘要

Autoimmune activities have been implicated in the pathogenesis of hypertension. High levels of autoantibodies against the second extracellular loop of α₁-adrenoceptor (α₁-AR autoantibody, α₁-AA) are found in patients with hypertension, and α₁-AA could exert a α₁-AR agonist-like vasoconstrictive effect. However, whether the vasoconstrictive effect of α₁-AA is enhanced in hypertension is unknown. Using aortic rings of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, we observed the vasoconstrictive responses to α₁-AA with phenylephrine (α₁-AR agonist) as a positive control drug. Aortic nitrotyrosine levels were also measured by ELISA and immunohistochemistry. The results showed that the aortic constrictive responses to α₁-AA and phenylephrine (both 1 nmol L^?1?10 μmol L^?1) were greater in SHR than in WKY rats. Endothelial denudation or L-NAME (a non-selective NOS inhibitor) (100 μmol L^?1) increased α₁-AA- or phenylephrine-induced vasoconstrictions both in SHR and WKY. However, selective iNOS inhibitor 1400W (10 μmol L^?1) enhanced the α₁-AA-induced aortic constriction in WKY, but not in SHR. The aortic nitrotyrosine level was significantly higher in SHR than WKY, as shown by both ELISA and immunohistochemistry. These results indicate that the vasoconstrictive response to α₁-AA is enhanced in SHR, and this altered responsiveness is due to endothelial dysfunction and decreased NO bioavailability. The study suggests an important role of α₁-AR autoimmunity in the pathogenesis and management of hypertension especially in those harboring high α₁-AA levels.