Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib‐Induced Hypertension

Figure 1. Twenty‐four‐hour averages of mean arterial pressure (MAP) and heart rate (HR) in vehicle or sunitinib‐treated (15 mg/[kg×d]) animals with or without nitrate (1 mmol/[kg×d]) supplementation. Nitrate supplementation was started on day 0 of the protocol. Data were analyzed by 3‐way ANOVA, the factors being sunitinib‐treatment, nitrate supplementation, and time. There were statistically significant effects of sunitinib treatment on MAP and HR (P<0.001) and statistically significant interactions between the factors sunitinib‐treatment, and time (P<0.01). *P<0.05 for MAP or HR in both groups that received sunitinib vs controls at the respective treatment days, based on post hoc between‐group comparisons by the Holm‐Sidak method. bpm indicates beats per minute.

Figure 2. Effects of acetylcholine on renal vascular resistance (RVR) under baseline conditions (upper panel) and during systemic NOS inhibition with 10 mg/kg l‐NAME (lower panel). Acetylcholine administered via the renal artery dose‐dependently decreased renal vascular resistance. There was no statistically significant effect of sunitinib on the relative acetylcholine‐induced changes in RVR. Data were analyzed by 2‐way‐ANOVA for repeated measurements. *P<0.05 vs next lower dose of acetylcholine. l‐NAME indicates N(G)‐nitro‐l‐arginine methyl ester; NOS, nitric oxide synthase.

Figure 3. Effects of l‐NAME (250 μg/kg) administration via the left renal artery on ipsilateral renal medullary blood flow (RMF, upper panel) and fractional sodium excretion (FEN a, lower panel) (n=10 per group). White bars: Control animals. Shaded bars: Sunitinib‐treated animals. Data were analyzed by 2‐way‐ANOVA for repeated measurements. Baseline data on RMF were set to 100%. *P<0.05 vs baseline conditions. FEN a indicates renal fractional sodium excretion; l‐NAME, N(G)‐nitro‐l‐arginine methyl ester.

Figure 4. Effects of sunitinib (15 mg/[kg×d] for 4 d) on renal cortical (upper panel) and medullary soluble guanylate cyclase (sGC) mRNA abundances (lower panel) (n=8 per group). White bars: Control animals. Shaded bars: Sunitinib‐treated animals. Data were analyzed by 2‐way‐ANOVA. *P<0.05 vs control animals.

Figure 5. Effects of sunitinib (15 mg/[kg×d] for 4 d) on renal cortical (left panel) and medullary soluble guanylate cyclase (sGC) protein abundances (right panel) (n=7–8 per group). sGC abundance was normalized to β‐actin. White bars: Control animals. Shaded bars: Sunitinib‐treated animals. Data were analyzed by 2‐way‐ANOVA. *P<0.05 vs control animals.

Figure 6. Twenty‐four‐hour urinary cGMP excretion rates in controls and sunitinib‐treated rats during the fourth day of respective treatments (n=8 per group). White bars: Control animals. Shaded bars: Sunitinib‐treated animals. Data were analyzed by unpaired t test. *P<0.05 vs control animals. BW indicates body weight; cGMP, cyclic GMP.

Figure 7. Twelve‐hour averages of mean arterial pressure (MAP) and heart rate (HR) in rats with sunitinib (15 mg [kg×d])‐induced hypertension. Administration of the soluble guanylate cyclase activator cinaciguat (10 mg/kg, arrow) for 1 d reduced MAP associated with reflex tachycardia. Data were analyzed by 2‐way‐ANOVA for repeated measurements. ‡ P<0.05 vs d 1–2 without sunitinib, *P<0.05 vs pair‐fed controls. bpm indicates beats per minute.