Area under the curve analysis of blood pressure reveals increased spontaneous locomotor activity in SPAK knock-in mice: relevance for hypotension induced by SPAK inhibition?

Abstract

SPAK (Ste20/SPS1‐related proline/alanine‐rich kinase) has been recently identified as a protein kinase which targets the electroneutral cation‐coupled chloride cotransporters and it stands out as a target for inhibition in novel anti‐hypertensive agents. From this prospective, any information about physiological consequences of SPAK inhibition would be useful to better understand the efficacy and potential adverse effects of the SPAK‐based anti‐hypertensive therapy. Radiotelemetry was employed to continuously measure the parameters of blood pressure (mean arterial blood pressure, systolic blood pressure, and diastolic blood pressure), heart rate, and physical activity in SPAK knock‐in (KI) mice and littermate controls for 24 h. For each parameter, the area under the curve (AUC) was calculated and compared between the SPAK KI mice and wild type mice. There was no statistically significant difference in the AUC of blood pressure parameters between SPAK KI and littermate mice. When mice were physically inactive, the AUCs for blood pressures were significantly lower in SPAK KI than in littermates. When physically active, blood pressures were significantly higher in SPAK KI than in littermates. The heart rate followed a similar pattern. The AUC of physical activity was significantly increased in SPAK KI mice when compared to littermates and the SPAK KI mice spent significantly less time in an inactive state and significantly more time in active states. Comparison between SPAK KI mice and unrelated wild type mice yielded similar results to the comparison between SPAK KI mice and littermates. We conclude that SPAK inhibition increases spontaneous locomotor activity, which has a significant effect on blood pressure.

Simultaneous Three-Dimensional Vascular and Tubular Imaging of Whole Mouse Kidneys With X-ray μCT

“…The increase is a consequence of the 150 mmHg of perfusion pressure employed during fixation, which was chosen to increase the reliability of the initial flushing step to remove blood. While this is well above resting blood pressure, it represents the upper end of blood pressure during physical activity (Adlam et al, 2011; Burgess et al, 2019) and is in keeping with or lower than perfusion pressures typically used in vascular casting (Chugh et al, 2009; Ghanavati et al, 2014; Epah et al, 2018).

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Regulatory control of the Na–Cl co-transporter NCC and its therapeutic potential for hypertension

“…The molecular mechanism by which WNKs regulate blood pressure was discovered when it was reported that WNKs bind and phosphorylate both Ste20-related proline–alanine-rich kinase (SPAK) and oxidative stress-responsive gene 1 (OSR1) thus inducing their activation 20 , 21 , 22 , 23 . Furthermore, mice with defected SPAK and OSR1 had reduced baseline blood pressure significantly 24 , 25 , 26 , 27 , 28 . Increased phosphorylated NCC was observed in cells overexpressing SPAK 29 .…”

Beat to Beat Continuous Blood Pressure Estimation using Transmission Coefficient of On-body Antennas

“…The built logistic model assures that any increase in area under curve leads to an increase in cardiovascular risk. Previous studies [13][14][15][16][17] rarely prove the relationship between the electromagnetic transmission coe cient waveforms and blood pressure. However, subtle variations in the morphology of transmission coe cient waveforms, presented in this study, appear correlated to the pressure imposed by blood ow on the walls of blood vessels as shown in Fig.…”