Cardiovascular Effects of Modulators of Soluble Guanylyl Cyclase Activity

Abstract

Soluble guanylyl cyclase (sGC) is one of the key enzymes of the nitric-oxide (NO)/cyclic 3',5'-guanosine monophosphate (cGMP) pathway. Located in virtually all mammalian cells, it controls the vessel tone, smooth muscle cell growth, platelet aggregation, and leukocyte adhesion. In vivo sGC activity is mainly regulated by NO which in turn is released from L-arginine by nitric oxide synthases. One of the main diseases of the cardiovascular system, endothelial dysfunction, leads to a diminished NO synthesis and thus increases vessel tone as well as the risk of thrombosis. The predominant therapeutic approach to this condition is a NO replacement therapy, as exemplified by organic nitrates, molsidomin, and other NO releasing substances. Recent advances in drug discovery provided a variety of other approaches to activate sGC, which may help to circumvent both the tolerance problem and some non-specific actions associated with NO donor drugs. Substances like BAY 41-2272 stimulate sGC in a heme-dependent fashion and synergize with NO, allowing to enhance the effects both of endogenous NO and of exogenous NO donors. On the other hand, heme-independent activators like BAY 58-2667 allow to activate sGC even if it is rendered unresponsive to NO due to oxidative stress or heme loss. Furthermore, a few substances have been described as specific inhibitors of sGC that allow to alleviate the effects of excess NO production as seen in septic shock. This review discusses the cardiovascular effects of heme-dependent and heme-independent activators as well as of inhibitors of sGC. Cardiovascular Effects of sGC modulation

Chemie und Biologie der Stimulatoren und Aktivatoren der löslichen Guanylatcyclase

“…Die Pathogenese verschiedener Erkrankungen, insbesondere des Herzkreislaufsystems, geht mit einer unzureichenden sGC-Stimulation einher. [32][33][34][35][36][37][38] sGC selbst ist ein zytosolisches heterodimeres Protein, das aus einer a-und einer b-Untereinheit mit einer prosthetischen Häm-Gruppe an der b-Untereinheit (Häm-bindende Domäne) besteht. [39][40][41][42][43][44][45] NO stimuliert die sGC-Aktivität, indem es an das Fe 2+ der Häm-Gruppe bindet, was zu einer Spaltung der Fe 2+ -His105-Bindung und zu einer Konformationsänderung im Enzym führt.…”

“…Im Gegensatz zu YC-1 handelt es sich bei BAY 41-2272 um einen hochspezifischen sGC-Stimulator, der keine relevante Inhibition von Phosphodiesterasen zeigte. [27,35] [61] Diese Verbindung wurde als schwacher, aber spezifischer Stimulator der sGC charakterisiert (Stimulation von gereinigter sGC, EC 50 = 5.5 mm ; Thrombozytenaggregation, IC 50 = 2.8 mm). Bei Ratten wurde jedoch nur eine geringe orale Bioverfügbarkeit von 12 % beobachtet, und es wurde keine Weiterentwicklung dieser Serie verçffentlicht.…”

In vitro evaluation of the safe margin, antithrombotic and antiproliferative actions for the treatment of restenosis: Nitric oxide donor and polymers

“…The cGMP binding affects the activity of the target enzymes and prevents aggregation of platelets and thrombus formation. 42 Copyright Platelets can adhere to extracellular matrix containing fibrinogen and fibrinogen-coated surfaces via a IIb b 3 integrin, a membrane receptor glycoprotein Ib/IX/V 43 that interacts with von Wille-brand factor (VWF). Adherence activates the platelet, triggering intraplatelet pathways that lead to arachidonic acid metabolism and exocytosis of granules.…”

Maprotiline Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

“…Therefore, it was revealed that YC-1 has poor pharmacokinetic properties and lacks specificity ( Mulsch et al, 1997 ; Hoffmann et al, 2015 ). In contrast to YC-1, BAY 41-2272 is a highly specific sGC stimulator and has no relevant inhibition of phosphodiesterase ( Hoenicka and Schmid, 2008 ). Further studies led to the analog BAY 41-8543 displaying higher sGC stimulating potency, however, they both displayed low metabolic stability and low oral bioavailability in rats and showed a strong inhibition as well as induction of metabolizing cytochrome P450 (CYP) enzymes ( Evgenov et al, 2006 ; Mittendorf et al, 2009 ).…”