Efficacy of BAY 60-2770, a Soluble Guanylate Cyclase Activator, for Coronary Spasm in Animal Models.

Abstract

Ischemia with non-obstructive coronary arteries (INOCA), caused by coronary artery spasm, has gained increasing attention owing to the poor quality of life of impacted patients. Therapeutic options to address INOCA remain limited, and developing new therapeutic agents is desirable. Here, we examined whether soluble guanylate cyclase (sGC) activators could be beneficial in preventing coronary spasms. In organ chamber experiments with isolated canine coronary arteries, prostaglandin F_{2 α} -induced, endothelin-1-induced, 5-hydroxytryptamine-induced, and potassium chloride-induced contractions were suppressed by the sGC activator BAY 60-2770 (0.1, 1, and 10 nM). In isolated pig coronary arteries, BAY 60-2770 (0.1, 1, and 10 nM) could prolong the cycle length of phasic contractions induced by 3,4-diaminopyridine, as well as lower the peak and bottom tension of the contraction in a concentration-dependent manner. Additionally, BAY 60-2770 (1 pM-0.1 µM) evoked a concentration-related relaxation to a greater extent in small (first diagonal branch) coronary arteries than in large (left anterior descending) coronary arteries. In vasopressin-induced angina model rats, pretreatment with BAY 60-2770 (3 µg/kg) suppressed electrocardiogram S-wave depression induced by arginine vasopressin without affecting changes in mean blood pressure and heart rate. These findings suggest that BAY 60-2770 could be valuable in preventing both large and small coronary spasms. Therefore, sGC activators could represent a novel and efficacious therapeutic option for INOCA. SIGNIFICANCE STATEMENT: The soluble guanylate cyclase (sGC) activator BAY 60-2770 exerted antispastic effects on the coronary arteries in animal vasospasm models as proof-of-concept studies. These data can help to support potential clinical development with sGC activators, suitable for human use in patients with vasospastic angina.