Cross-tolerance between endogenous nitric oxide and exogenous nitric oxide donors

It is still unclear whether cross-tolerance develops between endogenously produced nitric oxide and exogenous nitric oxide donors. Thus, cGMP accumulation was determined in cultured aortic smooth muscle cells exposed to a nitric oxide source. Exposure of human, rat, rabbit, porcine or bovine smooth muscle cells to sodium nitroprusside led to a time- and concentration-dependent development of tolerance. In rat aortic smooth muscle cells, cross-tolerance developed between the sodium nitroprusside and S- nitroso-N-acetylpenicillamine, but not between sodium nitroprusside and atriopeptin. In addition, when rat aortic smooth muscle cells were treated with endotoxin or interleukin-1β, they displayed lower sodium nitroprusside- induced cGMP accumulation as compared to control cells. When rat aortic smooth muscle cells were exposed to sodium nitroprusside for 12 h they displayed a decreased ability to accumulate cGMP in response to endothelium- derived nitric oxide released from bovine aortic endothelial cells. In addition, co-cultures of rat aortic smooth muscle cells with bovine aortic endothelial cells showed an L-nitroarginine methylester-sensitive decrease in sodium nitroprusside-induced cGMP accumulation compared to single rat aortic smooth muscle cell cultures. We conclude that cross-tolerance between endothelium-derived nitric oxide and exogenously applied nitric oxide donors occurs in vitro.