The hypertensive effect of sorafenib is abolished by sildenafil

Nelly Cita,Fatou Dramé,Hubert Dabiré,Bijan Ghaleh

doi:10.1186/s40959-020-00064-w

Abstract

BackgroundContrasting to the well documented tyrosine kinase inhibitor (TKI)-induced hypertension, little is known on their intrinsic vasomotor effects. We investigated the vasomotor effects of sorafenib, a widely used multikinase inhibitor in the treatment of hepatocellular and renal cell carcinoma and tested the hypothesis that sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, could represent a pharmacological strategy for the treatment of TKI-induced hypertension.MethodsConcentration-response curves of sorafenib were constructed in endothelium-intact or denuded precontracted rat aorta, in the presence or absence of several inhibitors. Acute intravenous effects of sorafenib on arterial blood pressure were also investigated in anaesthetized rats. Finally, rats were chronically treated with sorafenib during 4 weeks in the presence and absence of sildenafil.ResultsIn endothelium intact aortic ring, sorafenib induced a potent concentration-dependent relaxation of precontracted rat aorta. Removal of the endothelium shifted the concentration-response curve of sorafenib to the right and significantly reduced its maximal effects, demonstrating that sorafenib-induced vasorelaxation is endothelium-dependent and endothelium-independent. Inhibition of the different pathways implicated in the endothelium-dependent and independent vasorelaxation revealed that the endothelium-dependent effects of sorafenib result mainly from the activation of prostaglandin and the nitric oxide (NO) pathways. The endothelium-independent vasodilatory effects of sorafenib may result mainly from the activation of Na/K-ATPase and soluble guanylate cyclase. These vasodilatory effects observed in vitro were confirmed by the decrease in arterial blood pressure observed during acute administrations of sorafenib in anesthetized rats. Finally, and most importantly, we report here for the first time that chronic administration of sorafenib in rats induced an increase in SBP that was abolished by sildenafil.ConclusionThe multikinase inhibitor sorafenib induced in vitro vasorelaxation of large conductance artery, primary by activating soluble guanylate cyclase. Its chronic administration led to arterial blood hypertension that was counteracted by a PDE-5 inhibitor, sildenafil. Our results suggest that targeting the cGMP pathway including NO signalling might be an interesting pharmacological strategy for the treatment of TKI-induced hypertension.

Highlights

Contrasting to the well documented tyrosine kinase inhibitor (TKI)-induced hypertension, little is known on their intrinsic vasomotor effects
Removal of the endothelium almost abolished the vasorelaxation induced by Ach (Emax = 86 ± 4 vs 22 ± 7; P < 0.001) and did not change that of sodium nitroprusside (SNP) (Emax = 100 ± 1 vs 104 ± 2), confirming the absence of functional endothelium and preserved vascular smooth muscle function (Fig. 1c and d)
We investigated the vasomotor effects of sorafenib, a widely used multikinase inhibitor in the treatment of cancers and tested the hypothesis that sildenafil, a phosphodiesterase-5 inhibitor, could represent a pharmacological strategy for the pathway including nitric oxide (NO) signalling may represent a suitable strategy for the treatment of sorafenib-induced hypertension

Summary

Introduction

Contrasting to the well documented tyrosine kinase inhibitor (TKI)-induced hypertension, little is known on their intrinsic vasomotor effects. Tyrosine kinase inhibitors (TKIs) that inhibit growth factors are widely used as targeted therapy for cancers [1,2,3,4] One of their major current side effects is arterial hypertension [5,6,7,8,9]. Nilotinib and sorafenib induced concentration-dependent relaxation of rat pulmonary artery [24] and sunitinib blunted endothelin-1-induced vasoconstriction, reduced phenylephrine-induced maximal vasoconstriction and facilitated acetylcholine (Ach) -induced vasodilation of rat renal resistance arteries [22], showing a vasodilatory property of sunitinib on renal resistance arteries This suggests that the in vivo effects of TKIs might not be the consequences of direct vasomotor properties.

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