Tetrahydrobiopterin ameliorates the exaggerated exercise pressor response in patients with chronic kidney disease

CKD patients have an exaggerated blood pressure (BP) response during rhythmic handgrip exercise (RHG 20%). Nitric Oxide (NO) levels increase substantially during exercise and help prevent excessive hypertension; therefore, reduced NO bioavailability may be one factor contributing to the exaggerated exercise pressor response, since CKD is characterized by decreased NO bioavailability. Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthase that has been shown to increase NO bioavailability in experimental models of CKD. Therefore, we hypothesized that BH4 may ameliorate the exaggerated increase in BP during RHG 20%. In a randomized, double-blinded, placebo-controlled trial, we tested the effects of 12 weeks of oral BH4 treatment versus placebo on BP and muscle sympathetic nerve activity (MSNA) responses during RHG 20% in CKD. At baseline, CKD patients (N=32) had significantly higher BP responses, but equicovocal MSNA responses during RHG 20% compared to Controls without CKD (N=10). The CKD patients only were then randomized to BH4 versus placebo. In contrast to patients randomized to placebo (N=14), those randomized to BH4 (N=18) had a significant reduction in the BP response during RHG 20%, but no change in MSNA response. A subset of CKD patients randomized to placebo received intravenous nitroprusside (NTP) infusion during RHG 20% to lower BP responses to equal that of BH4-treated patients; MSNA response during RHG20% was significantly lower after BH4 compared to after placebo when the BP responses were equalized with NTP. These findings suggest that BH4 ameliorates the exaggerated exercise pressor response in CKD via mechanisms both dependent and independent of sympathetic nerve response.