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Abstract: SA-OR31

Small Molecule Inhibitor of TMEM16A Chloride Channel Blocks Vascular Smooth Muscle Contraction and Lowers Blood Pressure in Spontaneously Hypertensive Rats

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Cil, Onur, University of California San Francisco, San Francisco, California, United States
  • Chen, Xiaolan, University of California San Francisco, San Francisco, California, United States
  • Askew Page, Henry, St George's University of London, London, United Kingdom
  • Jordan, Maria C., University of California Los Angeles, Los Angeles, California, United States
  • Myat Thwe, Pyone, San Francisco State University, San Francisco, California, United States
  • Baldwin, Samuel Neil, St George's University of London, London, United Kingdom
  • Anderson, Marc O., San Francisco State University, San Francisco, California, United States
  • Greenwood, Iain A., St George's University of London, London, United Kingdom
  • Roos, Kenneth P., University of California Los Angeles, Los Angeles, California, United States
  • Verkman, Alan S., University of California San Francisco, San Francisco, California, United States
Background

Hypertension is a major cause of cardiovascular morbidity and mortality, despite the availability of antihypertensive drugs with different targets and mechanisms of action. There is an unmet need for antihypertensive drugs with novel mechanisms of action for better BP control. TMEM16A (transmembrane member 16A or anoctamin-1) is a Ca2+-activated Cl- channel expressed in vascular smooth muscle. TMEM16A activation produces membrane depolarization that results in secondary activation of voltage-dependent ion channels that modulate vasoconstriction. TMEM16A is a potential target for hypertension treatment.

Methods

We recently identified by high-throughput screening and subsequent medicinal chemistry, small molecule TMEM16A inhibitor TMinh-23 that inhibits TMEM16A current fully, with IC50 ~ 30 nM. Here we tested TMinh-23 pharmacokinetics in rodents and its effects on vascular smooth muscle contraction (via wire myograph) and BP in spontaneously hypertensive rats (SHR) and wild type rodents.

Results

TMinh-23 pretreatment blocked maximum in vitro vascular smooth muscle contractions induced by a thromboxane mimetic (U46619) in rat mesenteric arteries by 90%. Intraperitoneal (ip) administration of TMinh-23 to rodents at 10 mg/kg produced sustained serum concentrations of >10 µM for >4 hours. BP measurements by tail-cuff and telemetry showed a maximum ~45 mmHg reduction in SBP in spontaneously hypertensive rats (SHR) after a single dose TMinh-23 (10 mg/kg, ip) compared to vehicle administration, with BP gradually returning to baseline values within 6-8 hours after TMinh-23 treatment. Minimal effect on BP (less than 10 mmHg decrease in SBP) was seen in wild-type rats and mice with TMinh-23 treatment (10 mg/kg, ip). Chronic 5-day treatment of SHR with TMinh-23 (10 mg/kg, ip, twice daily) caused sustained decreases (~25 mmHg) in daily average SBP, DBP and MAP during the treatment period. TMinh-23 action was reversible, with BP returning to baseline (~170/115 mmHg) by 3 days after discontinuation of treatment.

Conclusion

These studies provide validation for TMEM16A as a target for hypertension therapy, and demonstrate the proof-of-concept for efficacy of TMinh-23 as an antihypertensive with a novel mechanism of action.

Funding

  • NIDDK Support