Imatinib attenuates monocrotaline pulmonary hypertension and has potent vasodilator activity in pulmonary and systemic vascular beds in the rat

Abstract

Cardiovascular responses to the tyrosine kinase inhibitor imatinib were investigated in the rat. Intravenous injections of 0.3-30 mg/kg imatinib produced small decreases in pulmonary arterial pressure, larger dose-dependent decreases in systemic arterial pressure, and no change or small increases in cardiac output, suggesting that the systemic vasodilator response is more pronounced under baseline conditions. When pulmonary arterial pressure was increased with U-46619 or N(ω)-nitro-L-arginine methyl ester (L-NAME), intravenous injections of imatinib produced larger dose-dependent decreases in pulmonary arterial pressure. Imatinib attenuated the acute hypoxic pulmonary vasoconstrictor response. Vasodilator responses to imatinib were not inhibited by meclofenamate, glybenclamide, or rolipram, suggesting that cyclooxygenase, ATP-sensitive K(+) (KATP) channels, and cAMP were not involved in mediating the response. In a 21-day prevention study, imatinib treatment (50 mg/kg ip) attenuated the increase in pulmonary arterial pressure, right ventricular hypertrophy, and small vessel remodeling induced by monocrotaline. Imatinib reduced PDGF receptor phosphorylation and PDGF-stimulated thymidine incorporation in rat pulmonary artery smooth muscle cells. These data suggest that the beneficial effect of imatinib in pulmonary hypertension may involve inhibition of PDGF tyrosine kinase receptor-mediated effects on smooth muscle cell proliferation and on vasoconstrictor tone. These results indicate that imatinib has nonselective vasodilator activity in the pulmonary and systemic vascular beds similar to the Rho kinase inhibitor fasudil and the calcium entry antagonist isradipine. The present results are consistent with the hypothesis that imatinib may inhibit a constitutively active tyrosine kinase vasoconstrictor pathway in the pulmonary and systemic vascular beds in the rat.

Keywords: PDGF; imatinib; pulmonary vascular bed; tyrosine kinase inhibitor; vasodilation.

Fig. 1.

Changes in pulmonary and systemic arterial pressures and cardiac output in response to intravenous injections of the tyrosine kinase inhibitor imatinib in doses of 0.3–30 mg/kg under baseline tone conditions [baseline pulmonary arterial pressure (PAP) 19 ± 1 mmHg, mean arterial pressure (MAP) 114 ± 3 mmHg, and cardiac output (CO) 103 ± 10 ml/min; A], when PAP is increased with U-46619 infusion (baseline PAP 20 ± 1 mmHg, MAP 98 ± 5 mmHg, and CO 118 ± 7 ml/min; B), and after nitric oxide synthase (NOS) inhibition with N^ω-nitro-l-arginine methyl ester (l-NAME, 50 mg/kg iv) (PAP 32 ± 3 mmHg, MAP 149 ± 5 mmHg, and CO 53 ± 5 ml/min; C). n, No. of experiments. *P < 0.05. The decrease in PAP in response to intravenous injection of imatinib (3 mg/kg) was significantly less in l-NAME-treated animals compared with U-46619-infused animals (P = 0.02, unpaired t-test).

Fig. 2.

A: effect of ventilation with a 10% O₂-90% N₂ gas mixture on pulmonary arterial pressure and the effect of intravenous injection of 10 mg/kg imatinib on the hypoxia-induced increase in pulmonary arterial pressure. B: effects of cyclooxygenase inhibition with sodium meclofenamate (5 mg/kg iv), phosphodiesterase type 4 inhibition with rolipram (1.5 mg/kg iv), and inhibition of ATP-sensitive K⁺ channels with glybenclamide (5 mg/kg iv). n, No. of experiments. *P < 0.05.

Fig. 3.

Comparison of decreases in pulmonary and systemic arterial pressures and cardiac output in response to injection of imatinib (10 mg/kg iv), the Rho kinase inhibitor fasudil (300 μg/kg iv), and the calcium entry antagonist isradipine (10 μg/kg iv) when pulmonary arterial pressure is increased to ∼30 mmHg with U-46619 infusion. n, No. of experiments. *P < 0.05 compared with baseline values.

Fig. 4.

Effect of chronic imatinib (IB) treatment (50 mg/kg ip) for 21 days on the attenuation of increases in pulmonary arterial pressure, right ventricular hypertrophy, and medial wall thickness of small pulmonary arteries in monocrotaline (MCT)-induced pulmonary hypertension in a prevention trial in the rat. n, No. of experiments. RV, right ventricle; LV, left ventricle; S, septum. *P < 0.05.

Fig. 5.

Western blots showing inhibition of PDGF-α receptor (A) and PDGF-β receptor (B) phosphorylation by imatinib. Even-numbered lanes received imatinib (IB). Lanes 1 and 2, control; lanes 3 and 4, PDGF-CC; lanes 5 and 6, PDGF-AA, lanes 7 and 8, PDGF-BB; lanes 9 and 10, PDGF-AB. Black lines separate different Western blot membranes using samples from the same culture of vascular smooth muscle cells. C: comparison of effect of tyrosine kinase inhibition with imatinib on increases in thymidine incorporation (DNA synthesis) in rat PASMCs exposed to PDGF-BB, -AB, and -AA. n = 3–5 experiments. *P < 0.05.