Project Summary/Abstract Acute kidney injury and brain injury manifest as delirium each affect over 25% of the 500,000 patients undergoing cardiac surgery annually, and these organ injuries are associated with longer hospitalization, increased mortality, longer mechanical ventilation, but the underlying mechanisms are poorly understood. Vascular reactivity is a component of vascular function which enables control of tissue perfusion via smooth muscle tone. Vascular reactivity is elicited via endothelial nitric oxide synthase signaling which may be disrupted by inflammation, surgery, and oxidative stress. The endothelium is a major regulator of vascular reactivity, coagulation, and immune cell activation, and endothelial dysfunction may contribute to organ dysfunction after surgery. We have recently identified that impaired vascular reactivity is independently associated with kidney injury after surgery. Under normal circumstances, nitric oxide diffuses from the endothelium to vascular smooth muscle and binds to the heme-moiety on soluble guanylyl cyclase inducing a conformational change that allows the enzyme to catalyze the formation of cyclic guanosine monophosphate. Oxidation of the iron in this heme moiety to the ferric state, however, impairs nitric oxide binding and vascular reactivity. Impaired vascular reactivity secondary to impaired soluble guanylyl cyclase activation may be an important mechanism underlying perioperative organ injury that is not routinely addressed in clinical care. Recently, pharmacologic soluble guanylyl cyclase stimulators have been developed to enhance impaired soluble guanylyl cyclase activation and are approved for use in patients with heart failure and pulmonary arterial hypertension. These drugs stabilize the heme moiety on soluble guanylyl cyclase while binding to the enzyme at a separate site, and they directly stimulate soluble guanylyl cyclase to generate cyclic guanosine monophosphate. This project builds on our prior findings that identified impaired vascular reactivity as a potential mechanism for perioperative organ injury, and further examines the role of the soluble guanylyl cyclase stimulator vericiguat in enhancing vascular reactivity in patients undergoing cardiac surgery and at risk of organ injury. We hypothesize that administration of a soluble guanylyl cyclase stimulator prior to surgery will enhance perioperative vascular reactivity and decrease cellular markers of renal tubule and neuronal injury. We will directly assess vascular reactivity in vivo and ex vivo using gold standard techniques in patients randomized to receive vericiguat versus placebo and will compare plasma and urine biomarkers of soluble guanylyl cyclase stimulation, endothelial activation, endothelial barrier degradation, renal tubular injury, and neuronal injury.