Effects of the nitric oxide synthase inhibitor ronopterin (VAS203) on renal function in healthy volunteers

Br J Clin Pharmacol. 2019 May;85(5):900-907. doi: 10.1111/bcp.13870. Epub 2019 Feb 28.

Abstract

Aims: Reduced nitric oxide (NO) availability may adversely affect renal perfusion and glomerular filtration. The aim of the present study was to characterize in detail the pharmacological effects of VAS203, an inhibitor of NO synthase, on renal haemodynamics in humans.

Methods: This double-blind, randomized, placebo-controlled, cross-over phase-I-study comprised 18 healthy men. Renal haemodynamics were assessed with constant-infusion input-clearance technique with p-aminohippurate and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR), respectively. After baseline measurement, a constant infusion of the tetrahydrobiopterin analogue ronopterin (VAS203, total 10 mg/kg body weight) or placebo was administered at random order for 6 hours additionally. After a wash-out phase of 28 days, the second course was applied. In parallel, markers of early kidney injury and renal function were assessed repeatedly up to 48 hours after starting VAS203/placebo-infusion.

Results: VAS203-infusion resulted in a significant decrease of RPF (P < .0001) and GFR (P < .001) compared to placebo, but magnitude was within the physiological range. RPF and GFR recovered partly 2 hours after end of VAS203-infusion and was normal at beginning of the second infusion period. Compared to placebo, preglomerular resistance (P < .0001), and to lesser extent postglomerular resistance (P < .0001) increased, resulting in a decrease of intraglomerular pressure (P < .01). No treatment related effect on markers of early kidney injury, and on renal function (P for all >.20) have been observed.

Conclusions: Our phase-I-study in healthy humans indicates that VAS203 (10 mg/kg body weight) reduces renal perfusion and glomerular function within the physiological range mainly due to vasoconstriction at the preglomerular site.

Keywords: VAS203; glomerular filtration rate; nitric oxide synthase; renal haemodynamics; renal plasma flow.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / diagnosis
  • Adult
  • Biopterin / administration & dosage
  • Biopterin / adverse effects
  • Biopterin / analogs & derivatives*
  • Cross-Over Studies
  • Double-Blind Method
  • Healthy Volunteers
  • Humans
  • Infusions, Intravenous
  • Inulin / administration & dosage
  • Inulin / metabolism
  • Kidney Glomerulus / blood supply
  • Kidney Glomerulus / drug effects*
  • Kidney Glomerulus / physiology
  • Male
  • Regional Blood Flow / drug effects
  • Renal Elimination / drug effects*
  • Vasoconstriction / drug effects
  • Young Adult
  • p-Aminohippuric Acid / administration & dosage
  • p-Aminohippuric Acid / metabolism

Substances

  • 4-amino-tetrahydrobiopterin
  • Biopterin
  • Inulin
  • p-Aminohippuric Acid