Proceedings of The Physiological Society

Physiology 2015 (Cardiff, UK) (2015) Proc Physiol Soc 34, PC267

Poster Communications

Pulse waveform analysis reveals vascular contributions to Gordon Syndrome and Gitelman Syndrome blood pressure homeostasis

K. Siew1, J. Zhang2, F. Schumacher2, D. R. Alessi2, T. Kurtz2, K. M. O'Shaughnessy1

1. Experimental Medicine & Immunotherapeutics Division, Department of Medicine, University of Cambridge, Cambridge, - Non US -, United Kingdom. 2. MRC Protein Phosphorylation & Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, United Kingdom.


  • Figure1. Pulse waveform analysis. Abbreviations: SBP (Systolic Blood Pressure), DBP (Diastolic Blood Pressure), AN (Anacrotic Notch), DN (Dicrotic Notch), T (Diastolic Presure Decay Time Constant)

The intense study of the rare monogentic diseases Gordon and Gitelman syndrome, which mirror each other phenotypically, has been instrumental to further our understanding of the WNK pathway's role in renal control of blood pressure by natriuresis. Deletion of exon-9 in Cullin-3 (CUL3Δex9) causes a severe form of familial salt-sensitive hypertension known as Gordon Syndrome, which causes renal WNK4 accumulation leading to overactivation of the thiazide-sensitive Na-Cl Cotransporters (NCC) via the WNK4 downstream effector SPAK. Conversely the salt-wasting hypotensive Gitelman syndrome is caused by mutations affecting the NCC phosphorylation sites or can modelled by mutating SPAK to reduce NCC activation. However recent evidence has suggested that the WNK pathway may have additional roles in maintaining vascular smooth muscle tone. Ex vivo aortic ring myography of SPAK knockout mice has shown reductions in vascular contractility suggesting the changes in blood pressure may not be solely due to changes in renal salt homeostasis. To investigate the vascular contribution of the WNK pathway to blood pressure in mouse models of Gordon Syndrome (CUL3Δex9 heterozygotes) and Gitelman Syndrome (SPAKL502A homozygotes) by pulse waveform analysis. Systemic blood pressure traces were generated by catheterisation of the right carotid artery with a SPR-1000 pressure transducer under terminal anaesthesia (isoflurane). Pulse waveforms were then analysed and compared to wildtype littermates (WT) using macros scripted in Lab Chart Pro 8 to extract augmentation index (AIx), a measure of arterial stiffness, and the diastolic pressure decay time constant (τ), a surrogate marker of vascular resistance. All data are mean±SEM, statistical significance was determined by two-tail t-test, **P<0.01, ***P<0.001. As expected mean arterial pressure was elevated in CUL3Δex9 vs WT (93.9±1.2 vs 81.0±0.7 mmHg***) and decreased in SPAKL502A vs WT (54.0±1.6 vs 73.7±1.8 mmHg***). Pulse waveform analysis revealed an increase in arterial stiffness in CUL3Δex9 (AIx; 50.2±1.6 vs 42.6±1.6 %**) and vascular resistance (τ; 0.65±0.01 vs 0.59±0.01 s**) [Fig1A]. Whereas SPAKL502A exhibited signs of vascular relaxation compared to WT indicated by decreased AIx (21.1±1.0 vs 35.0±2.1 %***) and τ (0.44±0.01 vs 0.56±0.02 s***). In conclusion, perturbation of the WNK pathway results in changes in vascular tone compounding the hypertension of Gordon Syndrome and hypotension of Gitelman Syndrome. These findings have implications for clinical treatment of patients to reduce long term cardiovascular risk and suggest that the WNK pathway is an attractive antihypertensive therapeutic target.

Where applicable, experiments conform with Society ethical requirements