Effects of in vivo treatment with Kv7.4 activator, URO-K10, on the impaired relaxation of pulmonary arteries in the monocrotaline-induced pulmonary hypertensive rats.

Pulmonary arterial hypertension (PAH) is a fatal disease marked by increased pulmonary vascular resistance and right ventricular (RV) failure. Impaired vascular relaxation and vasoconstrictive signaling, including Rho-associated kinase (ROCK2) upregulation and myosin phosphatase target subunit 1 (MYPT1) downregulation, contribute to disease progression. We investigated the therapeutic effects of URO-K10, a novel K_v7.4 channel activator, in a monocrotaline-induced rat model of PAH (PAH-MCT). In PAH-MCT rats, chronic URO-K10 administration improved body weight gain, and significantly reduced RV hypertrophy. Functional studies revealed enhanced pulmonary artery relaxation, while relaxation after high K+-induced contraction showed only partial recovery. Immunoblot analysis demonstrated that ROCK2 upregulation was reversed by URO-K10, but MYPT1 remained downregulated and MLC2 diphosphorylation persisted. Interestingly, treatment with 8-Br-cGMP restored delayed relaxation and reduced MLC2 phosphorylation in URO-K10-treated PAH-MCT while not in the untreated PAH-MCT rats, suggesting that cGMP supplementation can compensate for the recovery from impaired endogenous signaling by the URO-K10 application. These findings suggest that URO-K10 improves pulmonary hemodynamics and RV remodeling via K_v7.4 activation and downregulation of ROCK2. However, incomplete recovery of MYPT1 and MLC2 phosphorylation highlights the complexity of contractile regulation in PAH. K_v7.4 activation represents a promising therapeutic approach but may require combination strategies to fully restore vascular function in PAH.