# The effects of soluble guanylyl cyclase stimulation on perioperative vascular reactivity and organ injury in cardiac surgery trial

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $448,407

## Abstract

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.

## Key facts

- **NIH application ID:** 10917127
- **Project number:** 5R01HL164909-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Marcos G Lopez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $448,407
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917127

## Citation

> US National Institutes of Health, RePORTER application 10917127, The effects of soluble guanylyl cyclase stimulation on perioperative vascular reactivity and organ injury in cardiac surgery trial (5R01HL164909-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10917127. Licensed CC0.

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