Rho kinase inhibition mitigates sunitinib-induced rise in arterial pressure and renal vascular resistance but not increased renal sodium reabsorption

Grisk, Olaf; Koenen, Anna; Meißner, Markus; Donner, Alexander; Braun, Diana; Steinbach, Antje; Glöckl, Gunnar; Zimmermann, Uwe; Evert, Katja; Evert, Matthias; Katsari, Elpiniki; Löhn, Matthias; Plettenburg, Oliver; Rettig, Rainer

doi:10.1097/hjh.0000000000000326

Cited by 18 publications

(25 citation statements)

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“…It has recently been shown that renal cGMP excretion is reduced in rats with sunitinib‐induced hypertension,25, 26 which may be a consequence of low renal NO bioavailability 11, 16, 24. In keeping with this finding, the phosphodiesterase inhibitor sildenafil failed to attenuate the arterial pressure rise in sunitinib‐treated rats 26.…”

Section: Introductionmentioning

confidence: 75%

“…Renal NO X excretion is less in sunitinib‐treated rats than in controls,11, 16 which is indicative of reduced NO formation and availability 29. Oral nitrate supplementation has been shown to lower arterial pressure in humans30 and in rats 21, 22.…”

Section: Discussionmentioning

confidence: 94%

“…Reduced renal NO availability may contribute to sunitinib‐induced hypertension by increasing RVR and renal sodium reabsorption. This notion is supported by reduced renal nitrite and nitrate (NO X ) excretion in rats with early sunitinib‐induced hypertension 11, 16. Furthermore, a recent study in patients showed reduced renal NOx excretion in response to the VEGF receptor antagonistic RTKI pazopanib 17.…”

Section: Introductionmentioning

confidence: 95%

“…The sunitinib‐induced reduction in FE Na is not accompanied by reduced fractional lithium excretion, suggesting that proximal tubular sodium absorption is not enhanced 11. NO is part of VEGF‐dependent signaling mechanisms 1, 4.…”

Section: Introductionmentioning

confidence: 98%

“…In normotensive rats, the antiangiogenic RTKI sunitinib induces arterial hypertension accompanied by increased renal vascular resistance (RVR) and decreased renal fractional sodium excretion (FE Na ) 11, 12. The sunitinib‐induced reduction in FE Na is not accompanied by reduced fractional lithium excretion, suggesting that proximal tubular sodium absorption is not enhanced 11.…”

Section: Introductionmentioning

confidence: 99%

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Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib‐Induced Hypertension

Witte

Mühlbauer

Braun

et al. 2018

JAHA

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BackgroundThe tyrosine kinase inhibitor sunitinib causes hypertension associated with reduced nitric oxide (NO) availability, elevated renal vascular resistance, and decreased fractional sodium excretion. We tested whether (1) nitrate supplementation mitigates sunitinib‐induced hypertension and NO contributes less to renal vascular resistance as well as fractional sodium excretion regulation in sunitinib‐treated rats than in controls; and (2) renal soluble guanylate cyclase (sGC) is downregulated and sGC activation lowers arterial pressure in rats with sunitinib‐induced hypertension.Methods and ResultsArterial pressure responses to nitrate supplementation and the effects of systemic and intrarenal NO synthase (NOS) inhibition on renal hemodynamics and fractional sodium excretion were assessed in sunitinib‐treated rats and controls. Renal NOS and sGC mRNA as well as protein abundances were determined by quantitative polymerase chain reaction and Western blot. The effect of the sGC activator cinaciguat on arterial pressure was investigated in sunitinib‐treated rats. Nitrate supplementation did not mitigate sunitinib‐induced hypertension. Endothelium‐dependent reductions in renal vascular resistance were similar in control and sunitinib‐treated animals without and with systemic NOS inhibition. Selective intrarenal NOS inhibition lowered renal medullary blood flow in control but not in sunitinib‐treated rats without significant effects on fractional sodium excretion. Renal cortical sGC mRNA and sGC α1‐subunit protein abundance were less in sunitinib‐treated rats than in controls, and cinaciguat effectively lowered arterial pressure by 15‐20 mm Hg in sunitinib‐treated rats.ConclusionsRenal cortical sGC is downregulated in the presence of intact endothelium‐dependent renal vascular resistance regulation in developing sunitinib‐induced hypertension. This suggests that sGC downregulation occurs outside the renal vasculature, increases renal sodium retention, and contributes to nitrate resistance of sunitinib‐induced hypertension.

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