In the mid-1990s started the developement of a novel group of drugs: soluble guanylate cyclase (sGC) activators, which activate sGC in an NO- and heme-independent manner. Animal models showed positive effects of these drugs on diseases like arterial hypertension, pulmonary hypertension, heart failure, atherosclerosis, erectile dysfunction, renal failure und liver fibrosis.In the present work the sGC activator BAY 60-2770 was used to clarify whether the developement of nitroglycerin-induced tolerance is based on inactivation of sGC because of oxidization or loss of the prosthetic heme group, and whether an increase of intracellular tetrahydrobiopterin (BH4) levels prevents nitrate tolerance. Therefore, cultured porcine aortic endothelial cells (PAECs) and RFL-6 fibroblasts were preincubated with the quinoxaline-derivative ODQ, an heme oxidizing agent, as well as with nitroglycerin (GTN). cGMP levels were measured after incubation with the NO donor DEA/NO or BAY 60-2770. In both types of cells, preincubation with ODQ as well as with GTN led to accumulation of cGMP by BAY 60-2770, whereas the effect of DEA/NO decreased.In addition, PAECs were preincubated with GTN and sepiapterin. This led to a decreased effect of BAY 60-2770, which shows that sepiapterin protects sGC against haem oxidation.In the second part of the work, the effects of BAY 60-2770 on isolated sGC were studied. Therefore, sGC was treated with ODQ to oxidize the heme or with the surfactant TWEEN®20 to dissociate the heme. After incubation with DEA/NO or BAY 60-2770, cGMP levels were measured. The data showed that dissociation of the prosthetic heme group is essential for sGC activation by BAY 60-2770.