Abstract
Background In the vasculature, nitric oxide (NO) binds and activates smooth muscle soluble guanylate cyclase (sGC), leading to increased intracellular cGMP, which triggers smooth muscle relaxation and vasodilation. sGC stimulators are a class of small molecule allosteric modulators, which stimulate cGMP production independently of NO but also act in synergy with NO. Evidence to date suggests that sGC stimulators may be balanced vasodilators, meaning that they elicit vasorelaxation in both the arterial and venous vasculature; however, there have been conflicting reports [1,2]. Our approach to developing a better understanding of the
Highlights
In the vasculature, nitric oxide (NO) binds and activates smooth muscle soluble guanylate cyclase, leading to increased intracellular cGMP, which triggers smooth muscle relaxation and vasodilation. sGC stimulators are a class of small molecule allosteric modulators, which stimulate cGMP production independently of NO and act in synergy with NO
Arterio/venoselectivity of sGC stimulators was to measure cGMP concentrations in arteries, veins, plasma, and other tissues of rats orally administered with one of our sGC stimulators (MM-46446 or MM-46805) at a pharmacologically active dose
Results were treated with either vehicle or an sGC stimulator and cyclic GMP levels were measured utilizing an extraction method paired with a sensitive LC/MS-MS detection method (LLOQ = 0.3 nmol)
Summary
Nitric oxide (NO) binds and activates smooth muscle soluble guanylate cyclase (sGC), leading to increased intracellular cGMP, which triggers smooth muscle relaxation and vasodilation. sGC stimulators are a class of small molecule allosteric modulators, which stimulate cGMP production independently of NO and act in synergy with NO. * Correspondence: nperez@ironwoodpharma.com Ironwood Pharmaceuticals, Cambridge, MA 02142, USA
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