The novel PDE5 inhibitor CPD1 attenuates pulmonary arterial hypertension through dual modulation of cGMP and TRPM8-mediated pathways
Abstract
Pulmonary arterial hypertension (PAH) remains a fatal condition with limited treatment options. While phosphodiesterase-5 (PDE5) inhibitors such as sildenafil and tadalafil are standard treatments, their therapeutic efficacy is limited by poor aqueous solubility and an incomplete understanding of the mechanisms underlying their long-term benefits on vascular remodeling. To overcome these critical limitations, we developed a novel, highly water-soluble potassium salt polymorph of a PDE5 inhibitor, designated CPD1. In a monocrotaline-induced rat model of PAH, CPD1 demonstrated superior in vivo efficacy. It dose-dependently alleviated key pathological hallmarks by significantly reducing pulmonary arterial pressure, reversing right ventricular hypertrophy, and inhibiting the remodeling of small muscular pulmonary arteries. At the vascular level, CPD1 significantly attenuated the enhanced contractile responses to endothelin-1, cyclopiazonic acid, and 1-oleoyl-2-acetyl-sn-glycerol in endothelium-denuded arteries. Mechanistically, we reveal a novel dual-pathway mechanism: in addition to elevating cyclic guanosine monophosphate (cGMP) through PDE5 inhibition, CPD1 uniquely and dose-dependently upregulates the expression of the transient receptor potential melastatin-8 (TRPM8) channel. This upregulation sensitizes the pulmonary vasculature, markedly enhancing vasodilation induced by TRPM8 activation. Our findings position CPD1 not merely as a more soluble PDE5 inhibitor but as a…
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