Burgess Kieran, Jovanović Sofija, Sudhir Rajni, Jovanović Aleksandar
Division of Molecular and Clinical Medicine, Medical School, University of Dundee, Dundee, UK.
University of Nicosia Medical School, Nicosia, Cyprus.
Physiol Rep. 2019 Feb;7(3):e13997. doi: 10.14814/phy2.13997.
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.
SPAK（与Ste20/SPS1相关的富含脯氨酸/丙氨酸的激酶）最近被鉴定为一种蛋白激酶，其作用靶点是电中性阳离子偶联的氯化物共转运体，并且它是新型抗高血压药物的抑制靶点。从这个角度来看，任何关于SPAK抑制的生理后果的信息都将有助于更好地理解基于SPAK的抗高血压治疗的疗效和潜在不良反应。采用无线电遥测技术连续24小时测量SPAK基因敲入（KI）小鼠和同窝对照小鼠的血压参数（平均动脉血压、收缩压和舒张压）、心率和身体活动情况。对于每个参数，计算曲线下面积（AUC）并在SPAK KI小鼠和野生型小鼠之间进行比较。SPAK KI小鼠和同窝小鼠之间血压参数的AUC没有统计学上的显著差异。当小鼠不活动时，SPAK KI小鼠的血压AUC显著低于同窝小鼠。当小鼠活动时，SPAK KI小鼠的血压显著高于同窝小鼠。心率也呈现类似的模式。与同窝小鼠相比，SPAK KI小鼠的身体活动AUC显著增加，并且SPAK KI小鼠在不活动状态下花费的时间显著减少，而在活动状态下花费的时间显著增加。SPAK KI小鼠与无关野生型小鼠之间的比较结果与SPAK KI小鼠与同窝小鼠之间的比较结果相似。我们得出结论，SPAK抑制会增加自发运动活动，这对血压有显著影响。
