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Na+/H+ exchanger inhibitor augments hyperosmolarity-induced vasoconstriction by enhancing actin polymerization
Tomoya Sasahara1, Katsutoshi Yayama, Tsuyoshi Tahara
1Laboratory of Cardiovascular Pharmacology, Department of Biopharmaceutical Sciences, Kobe Gakuin University, Minatojima 1-1-3, Chuo-ku, Kobe 6508586, Japan.
Vascular Pharmacology
|July 23, 2013
Summary
Inhibiting the Na+/H+ exchanger (NHE) in vascular smooth muscle cells enhances force production during hyperosmotic stress by promoting actin polymerization, independent of calcium or myosin light chain phosphorylation.
Area of Science:
- Physiology
- Cell Biology
- Biochemistry
Background:
- Vascular smooth muscle cells (VSMCs) activate ion transporters like Na+/H+ exchanger isoform 1 (NHE-1) and Na+, K+, 2Cl- cotransporter (NKCC) under hyperosmotic stress.
- The precise role of these transporters in mediating hyperosmotic-induced vascular smooth muscle contraction remains unclear.
Purpose of the Study:
- To investigate the contribution of NHE and NKCC to hyperosmotic stress-induced vascular smooth muscle force.
- To elucidate the signaling pathways involved in this process.
Main Methods:
- Rat aortic rings and cultured VSMCs were used to assess contractile responses and cellular changes.
- Inhibitors of NHE (5-(N,N-dimethyl)-amiloride [DMA], cariporide) and NKCC (bumetanide) were applied.
- Measurements included isometric force, intracellular pH, cell volume, cytosolic Ca2+ concentration, and actin polymerization.
Main Results:
- NHE inhibitors significantly augmented contractile force and sensitivity to hyperosmotic stimuli.
- NHE inhibition reduced intracellular pH and enhanced cell shrinkage but did not affect Ca2+ or myosin light chain phosphorylation.
- Hyperosmotic stress increased the F-/G-actin ratio, an effect potentiated by DMA, and cytochalasin B attenuated the force response.
Conclusions:
- NHE inhibition potentiates hyperosmotic-induced VSMC contraction by promoting actin polymerization.
- This mechanism operates independently of changes in intracellular Ca2+ and myosin light chain phosphorylation.
- Targeting NHE may offer a novel approach to modulate vascular smooth muscle contractility.
Keywords:
2′,7′-bis(carboxyethyl)-5,6-carboxyfluorescein tetraacetoxymethyl ester5-(N,N-dimethyl)-amilorideBCECF-AMCell volumeCytoskeletonDMAF-actinG-actinHBSSHanks' balanced salt solutionL-NAMEMLCMYPT1N(G)-nitro-L-arginine methyl esterNHENKCCNONa(+), K(+), 2Cl(−) cotransporterNa(+)/H(+) exchangerNa(+)/K(+)/2Cl(−) cotransporterRVISmooth muscleVSMCs[Ca(2+)]icytosolic free calciumfilamentous-actinglobular-actinintracellular pHmyosin light chainmyosin phosphatase target subunit 1nitric oxidep-MLCp-MYPT1pHiphosphorylated MLC at Thr18 and Ser19phosphorylated MYPT1 at Thr853regulatory volume increasevascular smooth muscle cells
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