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

• 발행기관: 대한생리학회-대한약리학회
• 저자명: Seung Beom Oh Young Keul Jeon Nari Choi Hae Young Yoo Sung Joon Kim
• 간행물 정보: 『The Korean Journal of Physiology & Pharmacology』제29권 제4호, 475~485쪽, 전체 11쪽
• 주제분류: 의약학 > 의학일반
• 파일형태: PDF
• 발행일자: 2025.06.30

국문 초록

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 Kv7.4 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 Kv7.4 activation and downregulation of ROCK2. However, incomplete recovery of MYPT1 and MLC2 phosphorylation highlights the complexity of contractile regulation in PAH. Kv7.4 activation represents a promising therapeutic approach but may require combination strategies to fully restore vascular function in PAH.

목차

INTRODUCTION

METHODS

RESULTS

DISCUSSION

REFERENCES

키워드

Potassium channels voltage-gated Pulmonary arterial hypertension Pulmonary artery rho-associated kinases Smooth muscle