Heme Modulates Bladder Contractility Through the HO–CO–sGC–cGMP Pathway: Insights into Sickle Cell Disease-Associated Bladder Dysfunction

Intravascular hemolysis, a hallmark of sickle cell disease (SCD), leads to elevated plasma heme levels. Although heme is essential for physiological processes, its excess can be deleterious. Heme oxygenase (HO) degrades heme into carbon monoxide (CO), which activates the soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling cascade and can modulate smooth muscle tone. However, the direct effects of heme on bladder function remain unknown. This study investigated whether heme regulates detrusor smooth muscle contractility through the HO-CO-sGC-cGMP pathway. Detrusor strips from C57BL/6 mice were mounted on a myograph for functional analysis. Heme induced a significant, concentration-dependent relaxation of detrusor smooth muscle compared with vehicle-treated tissues. To elucidate the underlying mechanism, tissues were pre-incubated with the sGC inhibitor ODQ (10 µM) or the HO inhibitor 1J (100 µM) before heme exposure. Both inhibitors markedly attenuated heme-induced relaxation, reducing the maximal relaxation response. Moreover, pre-incubation with heme (100 µM) significantly decreased the maximal contractile responses (Emax) to carbachol, KCl, and electrical field stimulation (EFS), effects that were abolished by ODQ or 1J. In parallel, biochemical assays showed that heme markedly increased cGMP levels in detrusor tissue, an effect prevented by both inhibitors, confirming the role of the HO-CO-sGC-cGMP signaling cascade in this response. These findings demonstrate that heme modulates bladder contractility by activating the HO-CO-sGC-cGMP pathway, promoting detrusor relaxation. This mechanism suggests that excessive circulating heme, as occurs in hemolytic disorders such as SCD, may contribute to detrusor hypocontractility and voiding dysfunctions, identifying this pathway as a potential therapeutic target.