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Angiotensin-Converting Enzyme Inhibitors for Bevacizumab-Induced Hypertension

Clinical Fellow Department of Medical Oncology Hacettepe University Institute of Oncology Sihhiye Ankara 06100, Turkey fax 90-312-3052928 muratdincer{at}mynet.com

Kadri Altundag, MD

Associate Professor Department of Medical Oncology Hacettepe University Institute of Oncology

Published Online, November 14, 2006. www.theannals.com, DOI 10.1345/aph.1H244

Currently, there is no specific antihypertensive agent recommended for bevacizumab-induced hypertension. However, drugs used successfully for treatment of the hypertension include angiotensin-converting enzyme (ACE) inhibitors and calcium-channel blockers.²

Several studies have demonstrated a hypotensive effect of VEGF. VEGF preferentially dilates arterioles and venules without any effect on medium-sized arteries and veins. Intravenous infusions of recombinant human VEGF have produced decreases in systolic blood pressure in humans. This suggested hypotensive effect of VEGF is related to activation of protein kinase B, which stimulates the phosphorylation of endothelial type nitric oxide synthase (eNOS), resulting in augmented, calcium-independent activity and leading to enhanced nitric oxide production and hypotension.³ Furthermore, long-term inhibition of eNOS is known to induce hypertension. This inhibition also increases expression of plasminogen activator inhibitor-1 (PAI-1) in tissues.⁴ PAI-1, a member of the serpin superfamily of serine protease inhibitors, serves as the primary physiological inhibitor of tissue plasminogen activator. In other words, plasma PAI-1 is a critical determinant of endogenous fibrinolytic activity and resistance to thrombolysis.⁴ Therefore, increased plasma PAI-1 activity induced by bevacizumab may also contribute to exacerbation of existing hypertension.

ACE inhibitors block the enzyme responsible for conversion of biologically inert angiotensin I from activating angiotensin II and block degradation of kinins. Additionally, ACE inhibitors act as antihypertensive agents, preventing PAI-1 expression.⁴ Other antihypertensive agents, including calcium-channel blockers, do not have such an antihypertensive mechanism. Therefore, the use of ACE inhibitors in the treatment of bevacizumab-induced hypertension may be more rational. Moreover, VEGF maintains the glomerular and peritubular capillary network in the kidneys and may play a role in maintaining the podocyte function as well as renal vasculature, thereby protecting glomeruli and interstitium from progressive renal insults.⁵ The anti-VEGF molecule bevacizumab may distort the glomerular and peritubular capillary network, resulting in proteinuria, a rare adverse effect of bevacizumab. Besides their antihypertensive mechanism of inhibiting PAI-1 synthesis, ACE inhibitors may also decrease proteinuria induced by bevacizumab by changing the expression and distribution of the important podocyte molecules in nephrons.

In summary, through its VEGF inhibition, bevacizumab decreases eNOS activity, stimulates PAI-1 expression, and alters renal podocyte function and renal vasculature. All of these changes increase the risk of hypertension, proteinuria, hypercoagulopathy, and arterial thrombosis. In contrast, ACE inhibitors, in addition to their primary antihypertensive activity, may also prevent arterial thrombosis by lowering serum PAI-1 levels and bevacizumab-induced proteinuria. Therefore, ACE inhibitors may be the preferred antihypertensive agent in the management of bevacizumab-induced hypertension.

References

1. Fernando NH, Hurwitz HI. Targeted therapy of colorectal cancer: clinical experience with bevacizumab. Oncologist 2004;9(suppl 1):11 -8.[Abstract/Free Full Text]
2. Gordon MS, Cunningham D. Managing patients treated with bevacizumab combination therapy. Oncology 2005;69(suppl 3):25 -33.
3. Henry TD, Annex BH, McKendall GR, et al. The VIVA trial: vascular endothelial growth factor in ischemia for vascular angiogenesis.Circulation 2003;107:1359-65.
4. Katoh M, Egashira K, Mitsui T, et al. Angiotensin-converting enzyme inhibitor prevents plasminogen activator inhibitor-1 expression in a rat model with cardiovascular remodeling induced by chronic inhibition of nitric oxide synthesis. J Mol Cell Cardiol 2000;32:73-83.[CrossRef][Medline]
5. Hara A, Wada T, Furuichi K, et al. Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis. Kidney Int 2006;69:1986-95.[CrossRef][Medline]

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