Reduced sarco/endoplasmic reticulum Ca2+ uptake activity can account for the reduced response to NO, but not sodium nitroprusside, in hypercholesterolemic rabbit aorta

Background-Hypercholesterolemia (HC) impairs acetylcholine-induced relaxati on but has little effect on that caused by the NO donor sodium nitroprussid e (SNP), suggesting that acetylcholine releases less NO from the endotheliu m in HC. The relaxation to authentic NO gas, however, is also impaired in H C aortic smooth muscle, indicating an abnormal smooth muscle response. NO r elaxes arteries by both cGMP-dependent and -independent mechanisms, and the response involves calcium (Ca2+) store refilling via the, sarco/endoplasmi c reticulum calcium ATPase (SERCA). We studied the involvement of cGMP and SERCA in the smooth muscle response to NO and SNP in HC rabbit aorta. Methods and Results-A selective guanylyl cyclase inhibitor, 1H-[1,2,4]-oxad iazole-[4,3-a]quinoxalin-1-one, eliminated SNP-induced relaxation but only partially blocked NO-induced relaxation in both normal and HC aorta. The re sidual relaxation to NO was still less in HC and, in both normal and HC aor ta, was abolished by concomitant administration of the SERCA inhibitor cycl opiazonic acid (CPA). In contrast, CPA did not affect SNP-induced relaxatio n in either normal or HC aorta. SERCA activity measured by Ca-45(2+) uptake was markedly decreased in HC, although SERCA2 protein expression did not c hange significantly. Conclusions-These data suggest that NO-induced relaxation but not that to S NP is partially mediated by cGMP-independent Ca2+ uptake into sarco/endopla smic reticulum and that reduced sarco/endoplasmic reticulum Ca2+ pump funct ion can account for the impaired response to NO in HC.