Hypertension Induced by the Tyrosine Kinase Inhibitor Sunitinib Is Associated With Increased Circulating Endothelin-1 Levels

Abstract

Abstract-Angiogenesis inhibition with sunitinib, a multitarget tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, is associated with hypertension and cardiac toxicity, of which the underlying pathophysiological mechanism is unknown. We investigated the effects of sunitinib on blood pressure (BP), its circadian rhythm, and potential mechanisms involved, including the endothelin-1 system, in 15 patients with metastatic renal cell carcinoma or gastrointestinal stromal tumors. In addition, we investigated in rats the effect of sunitinib on BP, serum endothelin-1 levels, coronary microvascular function, cardiac structure, and cardiac mitochondrial function. In patients, BP increased by Ϸ15 mm Hg, whereas heart rate decreased after 4 weeks of treatment. Furthermore, the nocturnal dipping of BP diminished. Plasma endothelin-1 concentration increased 2-fold (PϽ0.05) and plasma renin decreased (PϽ0.05), whereas plasma catecholamines and renal function remained unchanged. In rats, 8 days of sunitinib administration induced an Ϸ30-mm Hg rise in BP, an attenuation of the circadian BP rhythm, and a 3-fold rise in serum endothelin-1 and creatinine, of which all but the rise in creatinine reversed after sunitinib withdrawal. Coronary microvascular function studies after 8 days of sunitinib administration showed decreased responses to bradykinin, angiotensin II, and sodium nitroprusside, all normalizing after sunitinib withdrawal. Cardiac structure and cardiac mitochondrial function did not change. In conclusion, sunitinib induces a reversible rise in BP in patients and in rats associated with activation of the endothelin-1 system, suppression of the renin-angiotensin system, and generalized microvascular dysfunction. (Hypertension. 2010;56:675-681.)Key Words: endothelin Ⅲ endothelial growth factors Ⅲ hypertension Ⅲ experimental Ⅲ angiogenesis Ⅲ NO A ngiogenesis, the formation of new capillaries from an existing vasculature, is critical to tumor growth, as well as metastasis. This process is regulated by numerous growth factors and their receptors, among which vascular endothelial growth factor (VEGF) and its corresponding receptors play key roles. Angiogenesis inhibition as a therapeutic strategy against malignancies was first proposed by Folkman in 1971. 1 Meanwhile, a variety of drugs, targeting VEGF or its receptors, have been approved for the treatment of several tumor types. Unfortunately, angiogenesis inhibition is associated with adverse effects, in particular, hypertension, which has been reported in Յ60% of patients treated with sunitinib, an orally active multitarget VEGF receptor tyrosine kinase inhibitor (RTKI) and one of the most commonly used angiogenesis inhibitors. 2 Decreased NO bioavailability might underlie this phenomenon. 3,4 VEGF inhibition with sunitinib is also associated with cardiac toxicity, as evidenced by a decrease in left ventricular ejection fraction in Յ28% of patients. 5 Given the sunitinib-induced changes in cardiac mitochondrial structure, this could relate to impa...

Sunitinib-Induced Systemic Vasoconstriction in Swine Is Endothelin Mediated and Does Not Involve Nitric Oxide or Oxidative Stress

“…In the coronary microcirculation of rats exposed to sunitinib for 8 days, we found, using the Langendorff heart model, that the vasodilator responses to both bradykinin (endothelium dependent) and sodium nitroprusside (endothelium independent) were impaired. 10 Remarkably, in this model we also found an attenuated vasoconstrictor response to angiotensin II. These findings suggest generalized impairment of vascular smooth muscle function during sunitinib administration that is still unexplained.…”

“…We have shown previously that administration of sunitinib in patients and rats is associated with an increase in circulating ET-1 levels. 10 In the present study, sunitinib did not significantly alter plasma ET levels, although an increase in plasma ET was observed in 3 of 4 animals. Because ET secretion is predominantly abluminal, 28 its plasma level does not adequately reflect its effect on vascular tone.…”

A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma

“…As PT2385 inhibits VEGF-A production in tumor cells, it is of interest to examine whether it elicits hemodynamic effects in a rodent model (36). Na€ ve telemetered male Sprague-Dawley rats were treated with PT2385 or sunitinib for 5 days.…”

Endothelin Receptor Antagonists (ERA) in Hypertension and Chronic Kidney Disease: a Rose with Many Thorns

“…A reduction in NO bioavailability has been proposed as the mediating mechanism, however recent data in animals [74] and humans [75] suggests that angiogenesis inhibition results in substantial increases of ET-1 levels. Even more, a recent study reveals that hypertension is mediated by endothelin and not oxidative stress or NO [76].…”

“…Even more, a recent study reveals that hypertension is mediated by endothelin and not oxidative stress or NO [76]. Furthermore, ERAs prevented the development of hypertension during angiogenesis inhibition in rats [74,77]. Moreover, the potential anti-neoplastic properties of ERAs might be of additional benefit in these patients [78,79].…”