ETA Receptor Blockade With Atrasentan Prevents Hypertension With the Multitargeted Tyrosine Kinase Inhibitor ABT-869 in Telemetry-instrumented Rats

Banfor, Patricia N.; Franklin, Pamela A; Segreti, Jason A.; Widomski, D. L.; Davidsen, Steven K.; Albert, Daniel H.; Cox, Bryan F.; Fryer, Ryan M.; Gintant, Gary A.

doi:10.1097/fjc.0b013e3181993493

Cited by 40 publications

(22 citation statements)

References 17 publications

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“…We and others have demonstrated in rats that coadministration of an ET-1 receptor antagonist with an RTKI can largely or completely prevent the rise in MABP, suggesting that activation of the ET pathway plays an important role in the sunitinib-induced MABP rise. 11,12 These observations in rats are fully supported by the present findings in swine, because the sunitinib-induced increase in SVRi and MABP completely reversed to presunitinib values in response to acute administration of the ET A /ET B receptor blocker tezosentan.…”

Section: Discussionsupporting

confidence: 77%

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

et al. 2012

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Abstract-Angiogenesis inhibition with agents targeting tyrosine kinases of vascular endothelial growth factor receptors is an established anticancer treatment, but is, unfortunately, frequently accompanied by systemic hypertension and cardiac toxicity. Whether vascular endothelial growth factor receptor antagonism also has adverse effects on the pulmonary and coronary circulations is presently unknown. In chronically instrumented awake swine, the effects of the vascular endothelial growth factor receptor antagonist sunitinib on the systemic, pulmonary, and coronary circulation were studied. One week after sunitinib (50 mg PO daily), mean aortic blood pressure (MABP) had increased from 83Ϯ5 mm Hg at baseline to 97Ϯ6 mm Hg (PϽ0.05) because of a 57Ϯ20% increase in systemic vascular resistance as cardiac output decreased. In contrast, sunitinib had no discernible effects on pulmonary and coronary hemodynamics or cardiac function. We subsequently investigated the mechanisms underlying the sunitinib-induced systemic hypertension. Intravenous administration of NO synthase inhibitor N G -nitro-L-arginine increased MABP by 24Ϯ1 mm Hg under baseline conditions, whereas it increased MABP even further after sunitinib administration (32Ϯ3 mm Hg; PϽ0.05). Reactive oxygen species scavenging with a mixture of antioxidants lowered MABP by 13Ϯ2 mm Hg before but only by 5Ϯ2 mm Hg (PϽ0.05) after sunitinib administration. However, intravenous administration of the dual endothelin A/endothelin B receptor blocker tezosentan, which did not lower MABP at baseline, completely reversed MABP to presunitinib values. These findings indicate that sunitinib produces vasoconstriction selectively in the systemic vascular bed, without affecting pulmonary or coronary circulations. The sunitinib-mediated systemic hypertension is principally attributed to an increased vasoconstrictor influence of endothelin, with no apparent contributions of a loss of NO bioavailability or increased oxidative stress. (Hypertension. 2012;59:151-157.) Key Words: endothelin 1 Ⅲ hypertension Ⅲ oxidative stress Ⅲ pulmonary hypertension Ⅲ vascular endothelial growth factor A ngiogenesis inhibition, by targeting the tyrosine kinases of the vascular endothelial growth factor (VEGF) receptors (VEGFRs), has become an established treatment of several tumor types. This therapy is associated with adverse effects, including the development of hypertension and cardiac and renal toxicity. 1 Hypertension has been reported in Յ60% of patients treated with sunitinib, an orally active multitarget receptor tyrosine kinase inhibitor (RTKI), targeting, among others, the VEGFR-1 and -2, which is used as first-line treatment of metastatic renal cell carcinoma or imatinib-resistant gastrointestinal stromal tumors. 1 In addition, impaired cardiac function, as reflected by a decrease in left ventricular ejection fraction of 10% to 15%, has been observed in Յ28% of patients treated with sunitinib. 2 Angina pectoris and increased levels of biomarkers reflecting ischemic myocardial damage may als...

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Section: Discussionsupporting

confidence: 77%

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

et al. 2012

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“…Of note, in contrast to the current findings, hypertension induced by the multitarget tyrosine kinase inhibitor ABT-869 could be completely prevented by the selective ET A receptor blocker atrasentan. 18 Whether selective ET A receptor blockade could also prevent renal toxicity has not been evaluated in that study.…”

Section: Discussionmentioning

confidence: 99%

The Vascular Endothelial Growth Factor Receptor Inhibitor Sunitinib Causes a Preeclampsia-Like Syndrome With Activation of the Endothelin System

Kappers

Smedts²,

Horn³

et al. 2011

Hypertension

117

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Abstract-Angiogenesis inhibition is an established treatment for several tumor types. Unfortunately, this therapy is associated with adverse effects, including hypertension and renal toxicity, referred to as "preeclampsia." Recently, we demonstrated in patients and in rats that the multitarget tyrosine kinase inhibitor sunitinib induces a rise in blood pressure (BP), renal dysfunction, and proteinuria associated with activation of the endothelin system. In the current study we investigated the effects of sunitinib on rat renal histology, including the resemblance with preeclampsia, as well as the roles of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature of preeclampsia, which was partly reversible after sunitinib discontinuation. The histological abnormalities were accompanied by an increase in urinary excretion of endothelin 1 and diminished NO metabolite excretion. In rats on sunitinib alone, BP increased (⌬BP: 31.6Ϯ0.9 mm Hg). This rise could largely be prevented with the endothelin receptor antagonist macitentan (⌬BP: 12.3Ϯ1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (⌬BP: 25.9Ϯ2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine nitrates but decreased proteinuria and urinary endothelin 1 excretion. Our findings indicate that both the endothelin system and oxidative stress play important roles in the development of sunitinib-induced proteinuria and that the endothelin system rather than oxidative stress is important for the development of sunitinib-induced hypertension. (Hypertension. 2011;58:295-302.) • Online Data Supplement

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“…22 The knowledge that activation of the endothelin-axis is involved in the hypertension induced by angiogenesis inhibition may also favor the use of endothelin receptor blockers in angiogenesis inhibitioninduced hypertension. 6,7,36 ET A receptor stimulation has been shown to be mitogenic in cancer cells through activation of the mitogen-activated protein kinase pathway. 37 Thus, besides lowering BP, endothelin receptor antagonism may exert antitumor effects.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Hypertension and Renal Injury Induced by the Angiogenesis Inhibitor Sunitinib

et al. 2014

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Abstract-Common adverse effects of angiogenesis inhibition are hypertension and renal injury. To determine the most optimal way to prevent these adverse effects and to explore their interdependency, the following drugs were investigated in unrestrained Wistar Kyoto rats exposed to the angiogenesis inhibitor sunitinib: the dual endothelin receptor antagonist macitentan; the calcium channel blocker amlodipine; the angiotensin-converting enzyme inhibitor captopril; and the phosphodiesterase type 5 inhibitor sildenafil. Mean arterial pressure was monitored telemetrically. After 8 days, rats were euthanized and blood samples and kidneys were collected. In addition, 24-hour urine samples were collected. After sunitinib start, mean arterial pressure increased rapidly by ≈30 mm Hg. Coadministration of macitentan or amlodipine largely prevented this rise, whereas captopril or sildenafil did not. Macitentan, captopril, and sildenafil diminished the sunitinib-induced proteinuria and endothelinuria and glomerular intraepithelial protein deposition, whereas amlodipine did not. Changes in proteinuria and endothelinuria were unrelated. We conclude that in our experimental model, dual endothelin receptor antagonism and calcium channel blockade are suitable to prevent angiogenesis inhibitioninduced hypertension, whereas dual endothelin receptor antagonism, angiotensin-converting enzyme inhibitor, and phosphodiesterase type 5 inhibition can prevent angiogenesis inhibition-induced proteinuria. Moreover, the variable response of hypertension and renal injury to different antihypertensive agents suggests that these side effects are, at least

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ETA Receptor Blockade With Atrasentan Prevents Hypertension With the Multitargeted Tyrosine Kinase Inhibitor ABT-869 in Telemetry-instrumented Rats

Cited by 40 publications

References 17 publications

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

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

The Vascular Endothelial Growth Factor Receptor Inhibitor Sunitinib Causes a Preeclampsia-Like Syndrome With Activation of the Endothelin System

Treatment of Hypertension and Renal Injury Induced by the Angiogenesis Inhibitor Sunitinib

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