A small molecule inhibitor of the chloride channel TMEM16A blocks vascular smooth muscle contraction and lowers blood pressure in spontaneously hypertensive rats
| Autor: | Henry R. Askew Page, Samuel N. Baldwin, Onur Cil, Alan S. Verkman, Kenneth P. Roos, Pyone Myat Thwe, Peter M. Haggie, Iain A. Greenwood, Marc O. Anderson, Maria C. Jordan, Xiaolan Chen |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Contraction (grammar) Vascular smooth muscle Inbred SHR hypertension Thromboxane vasodilators Clinical Sciences 030232 urology & nephrology Vasodilation Blood Pressure Cardiovascular Article ANO1 03 medical and health sciences 0302 clinical medicine Chloride Channels Internal medicine Vascular medicine Humans Animals antihypertensives Antihypertensive Agents Anoctamin-1 biology business.industry Evaluation of treatments and therapeutic interventions Arteries Urology & Nephrology Rats 030104 developmental biology Blood pressure Endocrinology Nephrology Vasoconstriction 5.1 Pharmaceuticals 6.1 Pharmaceuticals biology.protein Muscle Smooth medicine.symptom Development of treatments and therapeutic interventions Vascular smooth muscle contraction business Muscle Contraction Biotechnology |
| Zdroj: | Kidney international, vol 100, iss 2 Kidney Int |
| Popis: | Hypertension is a major cause of cardiovascular morbidity and mortality, despite the availability of antihypertensive drugs with different targets and mechanisms of action. Here, we provide evidence that pharmacological inhibition of TMEM16A (ANO1), a calcium-activated chloride channel expressed in vascular smooth muscle cells, blocks calcium-activated chloride currents and contraction in vascular smooth muscle invitro and decreases blood pressure in spontaneously hypertensive rats. The acylaminocycloalkylthiophene TMinh-23 fully inhibited calcium-activated TMEM16A chloride current with nanomolar potency in Fischer rat thyroid cells expressing TMEM16A, and in primary cultures of rat vascular smooth muscle cells. TMinh-23 reduced vasoconstriction caused by the thromboxane mimetic U46619 in mesenteric resistance arteries of wild-type and spontaneously hypertensive rats, with a greater inhibition in spontaneously hypertensive rats. Blood pressure measurements by tail-cuff and telemetry showed up to a 45-mmHg reduction in systolic blood pressure lasting for four-six hours in spontaneously hypertensive rats after a single dose of TMinh-23. A minimal effect on blood pressure was seen in wild-type rats or mice treated with TMinh-23. Five-day twice daily treatment of spontaneously hypertensive rats with TMinh-23 produced sustained reductions of 20-25 mmHg in daily mean systolic and diastolic blood pressure. TMinh-23 action was reversible, with blood pressure returning to baseline in spontaneously hypertensive rats by three days after treatment discontinuation. Thus, our studies provide validation for TMEM16A as a target for antihypertensive therapy and demonstrate the efficacy of TMinh-23 as an antihypertensive with a novel mechanism of action. |
| Databáze: | OpenAIRE |
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