Hemodynamic Effects of a Soluble Guanylate Cyclase Stimulator, Riociguat, and an Activator, Cinaciguat, During NO-Modulation in Healthy Pigs

Abstract

Cardiovascular diseases are often characterized by dysfunctional endothelium. To compensate for the related lack of nitric oxide (NO), a class of soluble guanylate cyclase (sGC) stimulators and activators have been developed with the purpose of acting downstream of NO in the NO-sGC-cGMP cascade. These drugs have been discovered using photoaffinity labeling of sGC and high-throughput screening of a vast number of chemical compounds. Therefore, an understanding of the integrated physiological effects of these drugs in vivo is necessary on the path to clinical application. We have characterized the integrated hemodynamic impact of the sGC stimulator riociguat and the activator cinaciguat in different NO-states in healthy juvenile pigs (n = 30). We assessed the vascular effects in both systemic and pulmonary circulation, the contractile effects in the right and left ventricles, and the effects on diastolic cardiac functions. Nitric oxide-tone in these pigs were set by using the NO-blocker l-NAME and by infusion of nitroglycerine. The studies show a more pronounced vasodilatory effect in the systemic than pulmonary circulation for both drugs. Riociguat acts integrated with NO in an additive manner, while cinaciguat, in principle, completely blocks the endogenous NO effect on vascular control. Neither compound demonstrated pronounced cardiac effects but had unloading effect on both systolic and diastolic function. Thus, riociguat can potentially act in various disease states as a mean to increase NO-tone if systemic vasodilation can be balanced. Cinaciguat is a complicated drug to apply clinically due to its almost complete lack of integration in the NO-tone and balance.

The β3 Adrenergic Receptor Antagonist L-748,337 Attenuates Dobutamine-Induced Cardiac Inefficiency While Preserving Inotropy in Anesthetized Pigs

“…40 In particular since a previous study using the same strain of animals has shown high sensitivity to NOS blockade by L-NAME. 41 The changes in blood levels of FFA, glucose and lactate (Figure 3) are similar within the 2 groups with Dob infusion. This may suggest a minimal effect on blocking lipolysis at the chosen doses of L-748,337.…”

“… 40 In particular since a previous study using the same strain of animals has shown high sensitivity to NOS blockade by L-NAME. 41 …”

Effects of a Soluble Guanylate Cyclase Stimulator Riociguat on Contractility of Isolated Pulmonary Artery and Hemodynamics of U46619-Induced Pulmonary Hypertension in Dogs

“…In addition, the cGMP content in isolated canine PA was increased by the riociguat treatment ( Figure 3 ). sGC stimulators, including riociguat, induce the endothelium-independent relaxation of PA smooth muscle cells via direct activation of sGC and subsequent elevation of intracellular cGMP concentration [ 17 , 18 ]. An sGC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-1]-quinoxalin-1-one attenuated NO donor-induced relaxation of isolated canine PA through the inhibition of cGMP generation [ 25 ].…”

“…In human medicine, the sGC stimulator riociguat has been approved as a novel therapeutic agent for pulmonary arterial hypertension and chronic thromboembolic PH. sGC stimulators can induce the NO-independent activation of sGC [ 17 ], which leads to pulmonary vasorelaxation even in the presence of endothelial dysfunction [ 18 ]. Thus, it is possible that riociguat may have efficacy on refractory PH with resistance to PDE5 inhibitors in dogs.…”

The effect of Riociguat on cardiovascular function and efficiency in healthy, juvenile pigs

“…The Riociguat dose was based on a dose‐response study in four animals (Næsheim, How, & Myrmel, 2020), targeting a mean systemic blood pressure at 50 mmHg. In this study, the experiments were conducted using a repeated measures design.…”