Convergent Cardioprotection through Distinct Nitric Oxide and Carbon Monoxide Signaling Pathways after Myocardial...

Reduced nitric oxide (NO) bioavailability contributes to endothelial dysfunction and increases myocardial susceptibility to ischemic injury. In addition to NO, carbon monoxide (CO) functions as an important endogenous gasotransmitter that regulates vascular tone, mitochondrial respiration, and cellular defense mechanisms. Although NO- and CO-related interventions activate distinct proximal signaling pathways, it remains unclear whether they converge on a common anti-inflammatory and antioxidant mechanism under conditions of chronic NO deficiency. We therefore investigated cardioprotective signaling induced by the NO donor Nicorandil and the CO-releasing molecule CORM-3 in L-NAME-induced hypertensive rats subjected to myocardial infarction. Male Wistar Kyoto rats received L-NAME (20 mg/kg/day) for four weeks to induce chronic NO-deficient hypertension. Myocardial infarction was induced by left coronary artery occlusion followed by reperfusion. Before reperfusion, Nicorandil or CORM-3 was administered intramyocardially. Seven days later, blood pressure, infarct size, collagen deposition, inflammatory markers, NO synthase (NOS) activity, protein expression of eNOS, iNOS, NF-κB, Nrf2, HO-1, and antioxidant enzymes were assessed. Both Nicorandil and CORM-3 significantly reduced myocardial infarct size and attenuated fibrotic collagen deposition compared with untreated infarcted animals. Furthermore, both treatments reduced circulating TNF-α and IL-6, suppressed myocardial NF-κB activation, decreased iNOS expression, and restored antioxidant enzyme levels. However, the interventions exhibited distinct upstream molecular signatures. Nicorandil preferentially enhanced NO-related signaling, increased total NOS activity and eNOS expression, whereas CORM-3 produced stronger activation of the Nrf2/HO-1 pathway. Nicorandil and CORM-3 produce a common structural, antioxidant, and anti-inflammatory cardioprotective phenotype associated with distinct molecular signaling profiles under conditions of chronic NO deficiency.