Abstract 4926: Tyrosine Kinase Inhibitors Are Potent Pulmonary Vasodilators in Rats
Background: The pathogenesis of pulmonary arterial hypertension (PAH) includes vascular remodeling and vasoconstriction. Tyrosine kinase inhibitors have recently been reported promising for the treatment of PAH. Their therapeutic effects are postulated to be due to inhibition of cell growth-related kinases, such as platelet-derived growth factor receptor, and subsequent attenuation of vascular remodeling. Nothing, however, has been considered regarding their potential vasodilatory activity. This study examined whether tyrosine kinase inhibitors might acutely induce pulmonary vasodilation.
Methods and Results: In isolated extra-lobar pulmonary arteries from normal adult rats, imatinib, sorafenib, and nilotinib concentration-dependently reversed U46619-induced contractions (see figure⇓). Nitro-L-arginine did not reduce their relaxant potency. Imatinib (30 uM) reduced phosphorylation of MYPT-1 in U46619-treated arterial rings. Imatinib (50 mg/kg, ip) acutely and preferentially lowered high right ventricular systolic pressure (from 96 ± 11 to 67 ± 7 mmHg, a 29 % reduction) compared to systemic arterial pressure (from 98 ± 3 to 89 ± 5 mmHg, a 10 % reduction) in SUGEN 5416 (VEGF receptor inhibitor; 20 mg/kg, sc) plus chronic hypoxia-exposed severe pulmonary hypertensive rats.
Conclusion: Tyrosine kinase inhibitors have potent, Ca2+ desensitization-dependent pulmonary vasodilator activity, which could be involved in their long-term beneficial effect against PAH.