Blockers of the renin–angiotensin–aldosterone system (RAAS), that is, renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension. How exactly they exert their effect, in particular in patients with low circulating RAAS activity, also taking into consideration the so-called Ang II/aldosterone escape that often occurs after initial blockade, is still incompletely understood. Multiple studies have tried to find parameters that predict the response to RAAS blockade, allowing a personalized treatment approach. Consequently, the question should now be answered on what basis (eg, sex, ethnicity, age, salt intake, baseline renin, ACE or aldosterone, and genetic variance) a RAAS blocker can be chosen to treat an individual patient. Are all blockers equal? Does optimal blockade imply maximum RAAS blockade, for example, by combining ≥2 RAAS blockers or by simply increasing the dose of 1 blocker? Exciting recent investigations reveal a range of unanticipated extrarenal effects of aldosterone, as well as a detailed insight in the genetic causes of primary aldosteronism, and mineralocorticoid receptor blockers have now become an important treatment option for resistant hypertension. Finally, apart from the deleterious ACE-Ang II-Ang II type 1 receptor arm, animal studies support the existence of protective aminopeptidase A-Ang III-Ang II type 2 receptor and ACE2-Ang-(1 to 7)-Mas receptor arms, paving the way for multiple new treatment options. This review provides an update about all these aspects, critically discussing the many controversies and allowing the reader to obtain a full understanding of what we currently know about RAAS alterations in hypertension.

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...

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