EFFECTS OF THE NO SYNTHASE INHIBITOR RONOPTERIN (VAS203) ON MICRO- AND MACROCIRCULATION IN HEALTHY VOLUNTEERS

Abstract

Objective: The tetrahydrobiopterin-analogue VAS203, an in vivo inhibitor of predominantly the inducible nitric oxide synthase (iNOS), was developed to reduce secondary damage in patients with severe traumatic brain injury. However, its effect on micro- and macrocirculation is less well established. The aim of the present study was to characterize in detail the pharmacological effects of VAS203 on micro- and macrocirculation in humans. Design and method: In this single-centre, double-blind, randomized, placebo-controlled cross-over phase I study 16 healthy male subjects were included. A constant infusion of VAS203 (total 10 mg/kg body weight) or placebo was administered for 6 hours. After a wash-out phase of 28 days the second course with either placebo or VAS203 was applied. Renal hemodynamics were assessed with constant-infusion input-clearance technique with para-aminohippuric acid (PAH) for renal plasma flow (RPF). In addition, we assessed retinal capillary flow, as microvascular parameter by scanning laser Doppler flowmetry (SLDF) at 670 nm and used pulse wave analysis by SphygmoCorTM device for assessment of central systolic pressure, as macrovascular parameter of systemic circulation. Results: Intravenous infusion of VAS203 resulted in a reduction of RPF, but remained unchanged with placebo (Figure), resulting in a significant decrease of RPF with VAS203 compared to placebo (p < 0.0001).In contrast, mean retinal capillary flow (mirroring cerebral circulation) remained preserved at any time-point during as well as up to 2 hours after intravenous infusion of VAS203 (all p > 0.4). Compared to placebo, there was no change of brachial blood pressure due to VAS203 infusion (p > 0.2). In addition, no significant effect of VAS203 infusion on central systolic pressure was observed, indicative of no clinical meaningful effects of VAS203 on systemic circulation (p > 0.1). Conclusions: Our phase I study in humans indicate that a dose of 10 mg/kg body weight VAS203 reduces renal perfusion within a physiological range, but has no other acute effects on assessed parameters of micro- and macrocirculation.