Key blood vessel relaxation factor identified

Prysyazhna, O., Rudyk, O., & Eaton, P. (2012). Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension. Nature medicine, 18(2), 286-90. Details

Customer study highlights

In 1987, the discovery that nitric oxide (NO) was the ‘endothelium-derived relaxing factor’ identified the major pathway involved in blood vessel relaxation. However, because blocking NO biosynthesis does not entirely abolish vasorelaxation in response to acetylcholine, many research groups have sought to identify the elusive ‘endothelium-derived hyperpolarizing factor’ (EDHF).

This study sought to identify EDHF by addressing the oxidation by hydrogen peroxide (H2O2) of a key enzyme (protein kinase G1-α, ‘PKG1-α’), which is involved in opening K+ channels that mediate hyperpolarization.

Knock-in mice expressing an ‘oxidation-dead’ version of PKGI-α were generated, and their blood pressure (BP) and vasorelaxation responses were compared to wild type (normal) mice. In vivo, arterial BP was obtained by telemetry with an intra-aortic catheter. Peak systolic BP waveforms served as heartbeat markers for HRV analysis using LabChart. Ex vivo vasorelaxation responses were also measured from the aorta, carotid, renal, femoral and mesenteric arteries using wire myography.

Arterial BP was significantly higher in knock-in mice indicating relative hypertension. Knock-in mice also showed an enhanced response to pro-hypertensive drug challenge, indicating that PKGI-α normally maintains BP homeostasis.

No significant differences in HRV parameters were found between wild-type and knock-in mice. Hence, a decrease in parasympathetic tone did not account for the hypertension.

Dose-response recordings using wire myography showed that blood vessels from knock-in mice were significantly less responsive to H2O2-induced relaxation, with smallest vessels having the lowest EC50 for H2O2-induced relaxation.

Taken together, these results provide evidence for a crucial role of PKGI-α oxidation in blood pressure regulation.

9 Mar 2012

By Matthew Goddard

Science Manager

Researcher, Dad and motorbike racer.

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