A small molecule inhibitor of the chloride channel TMEM16A blocks vascular smooth muscle contraction and lowers blood pressure in spontaneously hypertensive rats.

2021 ◽  
Author(s):  
Onur Cil ◽  
Xiaolan Chen ◽  
Henry R. Askew Page ◽  
Samuel N. Baldwin ◽  
Maria C. Jordan ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Small Molecule ◽  
Chloride Channel ◽  
Spontaneously Hypertensive Rats ◽  
Smooth Muscle Contraction ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Molecule Inhibitor ◽  
Vascular Smooth Muscle Contraction

Farrerol Modulates Aorta Gene Expression Profile in Spontaneously Hypertensive Rats

Planta Medica ◽  
2017 ◽  
Vol 84 (05) ◽  
pp. 296-303 ◽  
Author(s):  
Xiaojiang Qin ◽  
Xiaomin Hou ◽  
Kun Zhang ◽  
Qingshan Li
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Muscle Contraction ◽  
Signaling Pathway ◽  
Spontaneously Hypertensive Rats ◽  
Smooth Muscle Contraction ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Vascular Smooth Muscle Contraction ◽  
Wistar Kyoto

AbstractFarrerol, a typical natural flavanone and major active component in Rhododendron dauricum var. ciliatum, has been shown to possess vasoactive ability in vitro. The aim of this study was to investigate its effect on aorta gene expression in spontaneously hypertensive rats. Twelve-week-old male normotensive Wistar Kyoto rats and spontaneously hypertensive rats were treated with orally administered farrerol (50 mg/kg body weight) for 8 wk before they were sacrificed. We found that aorta samples showed 444 upregulated genes in control spontaneously hypertensive rats compared with the control Wistar Kyoto rats. Administration of farrerol in spontaneously hypertensive rats increased the expression of 2329 genes in the aorta compared with the control spontaneously hypertensive rats. Gene expression profiles performed on the aorta revealed that farrerol induced changes in vascular smooth muscle contraction, mitogen-activated protein kinase signaling pathway, regulation of actin cytoskeleton, vascular endothelial growth factor signaling pathway, calcium signaling pathway, and renin angiotensin system. Furthermore, 10 genes involved in the pathway of vascular smooth muscle contraction were verified using real-time polymerase chain reaction technique, and several novel potential target genes for the farrerol treatment of hypertension were identified. The findings of this study lend support to the potential use of farrerol as a novel therapeutic and antihypertensive candidate drug to prevent the development of hypertension.

Abstract MP30: Small Molecule Inhibitor Of Chloride Channel Tmem16a Blocks Vascular Smooth Muscle Contraction And Lowers Blood Pressure In Spontaneously Hypertensive Rats

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Onur Cil ◽  
Maria C Jordan ◽  
Henry R Askew Page ◽  
Pyone Myat Thwe ◽  
Samuel N Baldwin ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Spontaneously Hypertensive Rats ◽  
Antihypertensive Drugs ◽  
Smooth Muscle Contraction ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Cardiovascular Morbidity And Mortality ◽  
Vascular Smooth Muscle Contraction

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 to better control hypertension and reduce cardiovascular morbidity and mortality. Here, we provide evidence that pharmacological inhibition of TMEM16A (transmembrane member 16A or anoctamin-1), a Ca 2+ -activated Cl - channel expressed in vascular smooth muscle cells, reduces in vitro vascular smooth muscle contraction and decreases blood pressure in spontaneously hypertensive rats (SHR). We recently identified by high-throughput screening and subsequent medicinal chemistry, small molecule TMEM16A inhibitor TM inh -23 (2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid o-tolylamide) that inhibits TMEM16A current fully, with IC 50 ~ 30 nM. 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 (10 mg/kg, ip) TM inh -23 administration compared to vehicle treatment, 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 (~20-25 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. These studies provide validation for TMEM16A as a target for antihypertensive therapy, and demonstrate the proof-of-concept for efficacy of TM inh -23 as an antihypertensive with a novel mechanism of action.

scholarly journals Baicalin relaxes vascular smooth muscle and lowers blood pressure in spontaneously hypertensive rats

2019 ◽  
Vol 111 ◽  
pp. 325-330 ◽  
Author(s):  
Liliqiang Ding ◽  
Chenglin Jia ◽  
Yong Zhang ◽  
Wenjian Wang ◽  
Weiliang Zhu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Spontaneously Hypertensive Rats ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive

Expression of smooth muscle MyHC B in blood vessels of hypertrophied heart in experimentally hypertensive rats

2003 ◽  
Vol 284 (2) ◽  
pp. R607-R610 ◽  
Author(s):  
Katharina Wetzel ◽  
Ovidiu Baltatu ◽  
Benno Nafz ◽  
Pontus B. Persson ◽  
Hannelore Haase ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Adaptive Response ◽  
Spontaneously Hypertensive Rats ◽  
Expression Patterns ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Genetic Origin ◽  
Spontaneously Hypertensive ◽  
Muscle Myosin

We demonstrated recently a significantly lower fraction of cardiac precapillary arterioles that expressed smooth muscle myosin heavy chain (MyHC) B (SMB) in spontaneously hypertensive rats. To clarify whether this reduction of SMB expression is of genetic origin, we investigated SMB expression in cardiac precapillary arterioles of normotensive and experimentally hypertensive rats (one clip, one kidney or ANG II minipump). We observed similar SMB expression patterns in precapillary arterioles of experimentally hypertensive rats compared with normotensive controls. These observations suggest that the downregulation of SMB in spontaneously hypertensive rats is of genetic origin rather than an adaptive response to chronically enhanced blood pressure and cardiac hypertrophy.

Heparin suppresses endothelin-1 action and production in spontaneously hypertensive rats

1992 ◽  
Vol 263 (5) ◽  
pp. R1035-R1041
Author(s):  
K. Yokokawa ◽  
A. K. Mandal ◽  
M. Kohno ◽  
T. Horio ◽  
K. Murakawa ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endothelial Cells ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Spontaneously Hypertensive Rats ◽  
Antihypertensive Effect ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Endothelin 1

Previous studies have shown that chronic subcutaneous administration of heparin significantly reduces blood pressure in hypertensive rats. The intracellular mechanisms of how heparin prevents smooth muscle cell proliferation remain unclear. This study was designed to examine whether heparin affects endothelin-1 action and production, to further elucidate the mechanism of the antihypertensive effect of heparin. Four-week treatment with heparin (300 U/day sc) significantly decreased blood pressure in spontaneously hypertensive rats (SHR; 199 +/- 8 vs. 164 +/- 9 mmHg; P < 0.001) and completely blunted pressor response to endothelin-1 in SHR. Heparin treatment did not decrease blood pressure response nor did it attenuate blood pressure responses to endothelin-1 in Wistar-Kyoto rats (WKY). Heparin significantly suppressed endothelin-1-induced increase in intracellular calcium concentration and inositol 1,4,5-trisphosphate level in cultured vascular smooth muscle cells in a dose-dependent manner and endothelin-1 release from cultured endothelial cells. These inhibitions were significantly more pronounced in SHR than in WKY. In conclusion, our findings indicate that the antihypertensive effect of heparin is mediated, at least in part, by the inhibition of endothelin-1 action on vascular smooth muscle cells and endothelin-1 production from endothelial cells.

Membrane potential of vascular smooth muscle and hypertension in spontaneously hypertensive rats

1984 ◽  
Vol 62 (8) ◽  
pp. 957-960 ◽  
Author(s):  
D. W. Cheung
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Membrane Potential ◽  
Vascular Smooth Muscle ◽  
Spontaneously Hypertensive Rats ◽  
Chronic Treatment ◽  
Resting Membrane Potential ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto

The resting membrane potential of tail arteries from spontaneously hypertensive rats (SHRs) and Wistar-Kyoto controls (WKYs) was compared. At 4–5 weeks old, the blood pressure and resting membrane potential of the SHRs was not significantly different from the WKYs. The blood pressure of 8- to 10-week-old SHRs increased significantly to 183 mmHg (1 mmHg = 133.322 Pa) from 127 mmHg at 4 weeks, and the membrane potential decreased from 60 to 51 mV. At 15 weeks of age, the blood pressure of the SHRs was 193 mmHg and the membrane potential was 49 mV. In WKYs, there was no significant change in membrane potential with age. The decrease in membrane potential in the SHRs is due to a decrease in the ouabain-sensitive electrogenic pumping. Chronic treatment of the SHRs with captopril (100 mg∙kg−1∙day−1) prevented the increase in blood pressure and the decrease in membrane potential.

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