Kidney Week

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

• Hypertension and Vascular Disease: From the Lab to Trials
  October 24, 2020 | Location: Simulive
  Abstract Time: 05:00 PM - 07:00 PM

Category: Hypertension and CVD

• 1403 Hypertension and CVD: Mechanisms

Authors

• Cil, Onur, University of California San Francisco, San Francisco, California, United States

Onur Cil, MD, PhD



Dr. Onur Cil is a pediatric nephrologist and physician-scientist with a special clinical interest in hypertension and kidney stones. His research focuses on small molecule drug discovery for epithelial ion transport modulators that can be used for treatment of renal and gastrointestinal diseases.

• Chen, Xiaolan, University of California San Francisco, San Francisco, California, United States

Xiaolan Chen,

• Askew Page, Henry, St George's University of London, London, United Kingdom

Henry Askew Page,

• Jordan, Maria C., University of California Los Angeles, Los Angeles, California, United States

Maria C. Jordan,

• Myat Thwe, Pyone, San Francisco State University, San Francisco, California, United States

Pyone Myat Thwe,

• Baldwin, Samuel Neil, St George's University of London, London, United Kingdom

Samuel Neil Baldwin,

• Anderson, Marc O., San Francisco State University, San Francisco, California, United States

Marc O. Anderson,

• Greenwood, Iain A., St George's University of London, London, United Kingdom

Iain A. Greenwood,

• Roos, Kenneth P., University of California Los Angeles, Los Angeles, California, United States

Kenneth P. Roos,

• Verkman, Alan S., University of California San Francisco, San Francisco, California, United States

Alan S. Verkman,

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 TM_inh-23 that inhibits TMEM16A current fully, with IC₅₀ ~ 30 nM. Here we tested TM_inh-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

TM_inh-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 TM_inh-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 TM_inh-23 (10 mg/kg, ip) compared to vehicle administration, with BP gradually returning to baseline values within 6-8 hours after TM_inh-23 treatment. Minimal effect on BP (less than 10 mmHg decrease in SBP) was seen in wild-type rats and mice with TM_inh-23 treatment (10 mg/kg, ip). Chronic 5-day treatment of SHR with TM_inh-23 (10 mg/kg, ip, twice daily) caused sustained decreases (~25 mmHg) in daily average SBP, DBP and MAP during the treatment period. TM_inh-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 TM_inh-23 as an antihypertensive with a novel mechanism of action.

Funding

• NIDDK Support