Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase activator, BAY 60–2770, are not dependent on endogenous nitric oxide or reduced heme

Abstract

4-({(4-Carboxybutyl)[2-(5-fluoro-2-{[4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}methyl)benzoic acid (BAY 60-2770) is a nitric oxide (NO)-independent activator of soluble guanylyl cyclase (sGC) that increases the catalytic activity of the heme-oxidized or heme-free form of the enzyme. In this study, responses to intravenous injections of the sGC activator BAY 60-2770 were investigated under baseline and elevated tone conditions induced by the thromboxane mimic U-46619 when NO synthesis was inhibited by N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME), when sGC activity was inhibited by 1H-[1,2,4]-oxadizaolo[4,3]quinoxaline-1-one (ODQ), an agent that oxidizes sGC, and in animals with monocrotaline-induced pulmonary hypertension. The intravenous injections of BAY 60-2770 under baseline conditions caused small decreases in pulmonary arterial pressure, larger decreases in systemic arterial pressure, and no change or small increases in cardiac output. Under elevated tone conditions during infusion of U-46619, intravenous injections of BAY 60-2770 caused larger decreases in pulmonary arterial pressure, smaller decreases in systemic arterial pressure, and increases in cardiac output. Pulmonary vasodilator responses to BAY 60-2770 were enhanced by L-NAME or by ODQ in a dose that attenuated responses to the NO donor sodium nitroprusside. ODQ had no significant effect on baseline pressures and attenuated pulmonary and systemic vasodilator responses to the sGC stimulator BAY 41-8543 2-{1-[2-(fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5(4-morpholinyl)-4,6-pyrimidinediamine. BAY 60-2770 and sodium nitroprusside decreased pulmonary and systemic arterial pressures in monocrotaline-treated rats in a nonselective manner. The present data show that BAY 60-2770 has vasodilator activity in the pulmonary and systemic vascular beds that is enhanced by ODQ and NOS inhibition, suggesting that the heme-oxidized form of sGC can be activated in vivo in an NO-independent manner to promote vasodilation. These results show that BAY 60-2770 and sodium nitroprusside decreased pulmonary and systemic arterial pressures in monocrotaline-treated rats, suggesting that BAY 60-2770 does not have selective pulmonary vasodilator activity in animals with monocrotaline-induced pulmonary hypertension.

Direct sGC Activation Bypasses NO Scavenging Reactions of Intravascular Free Oxy-Hemoglobin and Limits Vasoconstriction

“…However, the vasodilatory effects of BAY 41-8543 and BAY 60-2770 have been previously established to be mediated by the increase in cGMP in vascular smooth muscle cells. In separate studies, the in vitro efficacy of the sGC stimulator BAY 41-8543 and sGC activator BAY 60-2770 was demonstrated, which stimulates sGC directly to increase cGMP production and vasodilation (16,17,23,30,38). In addition, it was shown in other studies that this type of sGC stimulators (BAY 41-2272), indeed, directly stimulates sGC, hence enhancing renal cGMP production that results in an improved renal NO-cGMP signaling and limited progression in antiThy-1-induced chronic renal fibrosis (40).…”

“…sGC stimulators, such as BAY 41-2272 and Riociguat (BAY 63-2521), act directly on native, ferrous sGC that sensitizes sGC to low levels of bioavailable NO by stabilizing the nitrosyl-heme complex, maintaining the enzyme in its active configuration (4,34). In contrast, recently discovered sGC activators, such as BAY 60-2770 and BAY 58-2667 (cinaciguat), effectively activate sGC even when it is in an oxidized or heme-free state (16,23,29,34,37).…”

“…Furthermore, there is no risk of NO-induced formation of methemoglobin or peroxynitrite formation as observed with NO donors. sGC activators (such as BAY 60-2770 and Cinaciguat) can even activate oxidized sGC or heme-deficient sGC (23,37). Therefore, patients with cardiovascular disease who have reduced endothelial function due to oxidative stress and are expected to have more oxidized sGC might additionally benefit from the use of sGC activators along with the administration of HBOCs.…”

IRAG and novel PKG targeting in the cardiovascular system

“…Hence, the modulation of NO/cGMP signaling is an important pharmacological target pathway for the prevention of cardiovascular diseases such as angina pectoris, hypertension, heart insufficiency, and atherosclerosis (7,57,62). The knowledge of the details regarding NO/cGMP signal transduction is essential for the understanding of the physiological and pathophysiological regulation and the modulation at diverse steps in this signaling pathway (Fig.…”

Advances in the Management of Pediatric Pulmonary Hypertension

“…137 In animal models of PH, sGC expression was similarly upregulated, and direct sGC activation improved hemodynamics and vascular remodeling. [137][138][139] A proof-of-concept study was conducted that included 19 adult patients with PH (either PAH or chronic thromboembolic PH) who received the new drug riociguat (BAY 63-251). 140,141 That study suggested that riociguat was safe and found that pulmonary hemodynamics and cardiac output improved in a dose-dependent fashion.…”