Therapeutic potential of nitric oxide donors in the prevention and treatment of angiogenesis-inhibitor-induced hypertension

Kružliak, Peter; Kováčová, Gabriela; Pecháňová, Oľga

doi:10.1007/s10456-012-9327-4

Cited by 50 publications

(35 citation statements)

References 45 publications

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“…7,24 There are sporadic reports that an exogenous NO donor can lower BP in patients who develop hypertension during angiogenesis inhibition. 29 In the current study, the phosphodiesterase 5 inhibitor sildenafil was used to increase NO responsiveness. With this agent the sunitinib-induced reduction in urinary cGMP excretion was completely prevented, but this was not associated with any BP-lowering effect.…”

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…NO donors have proven to be effective in treating anti-VEGF-induced HTN that is refractory to traditional antihypertensives. 66 These NO donors have even been suggested as possible HTN prophylaxis in certain patient populations undergoing systemic anti-VEGF therapy. 66 Intravitreal Anti-VEGF Intravitreal injections of anti-VEGF agents have become the standard of care for various ischemic and inflammatory retinal diseases.…”

Section: Anti-vegf Therapymentioning

confidence: 99%

High Intraocular Pressure Following Anti-Vascular Endothelial Growth Factor Therapy: Proposed Pathophysiology due to Altered Nitric Oxide Metabolism

RiccaAaron

Grant

WirostkoBarbara

2015

Journal of Ocular Pharmacology and Therapeutics

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The nitric oxide (NO) pathway and its physiological significance on relaxing smooth muscle and endothelial cells throughout the body is well outlined and understood. Components of this pathway have been located in the ocular anterior and posterior chambers, and they have been connected with vascular, retinal, and trabecular meshwork normal physiology. Nitric oxide has been shown to increase anterior chamber aqueous outflow via reduction in trabeculocyte size and smooth muscle contractility, and Schlemm's canal vasodilation. Anti-vascular endothelial growth factor (VEGF) therapy has been shown to disrupt the normal nitric oxide signaling pathway, producing systemic arterial hypertension following systemically administered anti-VEGF in oncology by exactly that mechanism. Intravitreal anti-VEGF therapy is now considered a standard of care in several retinal diseases. Sustained elevated intraocular pressure (IOP) has been described as a potential adverse effect of therapy that appears related to the number of injections, and it can be produced by any of the various anti-VEGF compounds. We propose a novel mechanism responsible for the increase in IOPs following prolonged intravitreal anti-VEGF therapy. This mechanism postulates a rise in IOP due to a decrease in aqueous outflow from relatively decreased levels of available nitric oxide in the anterior chamber because of anti-VEGF inhibition of nitric oxide synthase. This article outlines the novel mechanism, which provides a likely explanation for this consequence, along with offering therapeutic targets for future research and treatment.

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“…One widely held hypothesis for the mechanism of angiogenesis inhibitor-associated hypertension centers on the role of VEGF-A in nitric oxide (NO) regulation [22,23]. NO is a potent vasodilator that plays a critical role in blood pressure control.…”

Section: Introductionmentioning

confidence: 99%

Genetic markers of bevacizumab-induced hypertension

et al. 2014

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Purpose There are currently no validated biomarkers predicting bevacizumab treatment outcome or toxicity. We combined biomarker data from six phase III trials of bevacizumab to assess whether genetic variation in vascular endothelial growth factor-A (VEGF-A) pathway or hypertension-related genes are associated with bevacizumab-induced hypertension. Experimental design Germline DNA was available from 1,631 patients receiving bevacizumab-containing therapy for advanced solid tumors. Overall, 194 white patients had grade 1-4 bevacizumab-induced hypertension. In total, 236 single nucleotide polymorphisms (SNPs) located in VEGF-A, VEGF-A receptors (FLT1 and KDR), and other genes were selected using a SNP tagging approach and genotyped. A logistic regression on individual patient data was performed after adjustment for cancer type and five other covariates. Results Ten SNPs were associated with bevacizumabinduced hypertension (P B 0.05), but none surpassed the threshold adjusted for multiple testing (P \ 0.0002). The most significant VEGF-A pathway SNP was rs1680695 in EGLN3 [allelic odds ratio (OR) 1.50 [95 % confidence interval (Cl) 1.09-2.07], P = 0.012]. Two additional SNPs, rs4444903 in EGF and rs2305949 in KDR, were associated with hypertension (allelic OR 1.57 [95 % CI 1.17-2.11], P = 0.0025; allelic OR 0.62 [95 % CI 0.42-0.93], P = 0.020, respectively) and closely linked to nearby functional variants. Consistent with previous reports, rs11064560 in WNK1 was also associated with bevacizumab-induced hypertension (OR 1.41 [95 % CI 1.04-1.92], P = 0.028). Conclusions The genes described in this large genetic analysis using pooled datasets warrant further functional 123 Angiogenesis (2014) 17:685-694 DOI 10.1007 investigation regarding their role in mediating bevacizumab-induced hypertension.

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Therapeutic potential of nitric oxide donors in the prevention and treatment of angiogenesis-inhibitor-induced hypertension

Cited by 50 publications

References 45 publications

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

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

High Intraocular Pressure Following Anti-Vascular Endothelial Growth Factor Therapy: Proposed Pathophysiology due to Altered Nitric Oxide Metabolism

Genetic markers of bevacizumab-induced hypertension

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