Effect of 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzene-sulfonamide on calcium influx in three contraction models

Abstract

2,4,6-Trimethyl--[3-(trifluoromethyl)phenyl]benzenesulfonamide (m-3M3FBS) activates phospholipase C and stimulates apoptosis; however, in smooth muscle cells it may increase the perfusion pressure. The main aim of the present study was to evaluate the physiological effect of direct stimulation of phospholipase C on vascular smooth muscle reactivity using three contraction models. Experiments were performed on the isolated and perfused tail artery of Wistar rats. The contraction force in the present model was measured by an increased level of perfusion pressure with a constant flow. Concentration-response curves (CRCs) obtained for phenylephrine, arg-vasopressin, mastoparan-7 and Bay K8644 presented a sigmoidal association. In comparison to the control curves, CRCs in the presence of m-3M3FBS were significantly shifted to the left except for Bay K8644. Analyses of calcium influx suggest that in the presence of m-3M3FBS the calcium influx from intra- and extracellular calcium stores was significantly higher. The results of the present experiments suggest that m-3M3FBS significantly increases the reactivity of vascular smooth muscle stimulated with metabotropic receptors or G-protein by an increase in calcium influx from intra- and extracellular calcium stores. The current knowledge regarding the apoptotic pathway shows the significance of calcium ions involved in this process, thus, m-3M3FBS may induce apoptosis by an increase of cytoplasmic calcium concentration; however, simultaneously, the use of this mechanism in therapy must be preceded by a molecular modification that eliminates a possible vasoconstriction effect.

2,4,6-Trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide increases calcium influx in lipopolisaccharide-pre-treated arteries

“…m-3M3FBS is responsible for the increase in calcium influx from intra-and extracellular calcium stores that activate G-protein-coupled receptors, including α 1 -adrenoceptors and vasopressin receptors, thus stimulating vascular smooth muscle cells. In a previous study by our group, the same increase was found during extra-receptor stimulation, such as during direct stimulation of G-protein with mastoparan-7; however, the presence of m-3M3FBS did not modify the arterial muscle reactivity following direct stimulation of L-type calcium channels with the calcium agonist Bay K8644 (13).…”

“…Activation of PLC is a key event in numerous metabotropic receptors, the physiological response of which was assessed in the present study. Inhibition of PLC function leads to a reduction in the calcium ion concentration in the cytoplasm of cells activated by the stimulation of α1-adrenergic receptors (13,18,19), endothelin receptor type A (20) and angiotensin II receptor type-1 (21). Furthermore, it has been demonstrated that the increase in cytoplasmic calcium concentration induced by PLC is significant at the molecular level and able to induce a significant physiological reponse (14).…”

“…Treatment with iNOS increases receptor reserve and perfusion pressure in various experimental models, and may thus be a possible method of pharmacological intervention for early sepsis (26). Other mechanisms of increasing smooth muscle function, associated with increases in the function of various post-receptor enzymes, were analyzed in previous experimental studies (13)(14)(15). PLC is present in a number of different tissues and thus, there is no selectivity in enzyme stimulation; furthermore, in the presence of PLC activators, peripheral and central effects may occur (13).…”

“…Other mechanisms of increasing smooth muscle function, associated with increases in the function of various post-receptor enzymes, were analyzed in previous experimental studies (13)(14)(15). PLC is present in a number of different tissues and thus, there is no selectivity in enzyme stimulation; furthermore, in the presence of PLC activators, peripheral and central effects may occur (13). The potential protective effect of m-3M3FBS against sepsis has been previously suggested by Kim et al (15).…”

Anti-atherogenic properties of resveratrol: 4-week resveratrol administration associated with serum concentrations of SIRT1, adiponectin, S100A8/A9 and VSMCs contractility in a rat model

“…The maximal response of tissue (E max ) was calculated as a percent of the maximal response for PHE. Half maximal effective concentration (EC 50 ) was estimated using classical pharmacologic methods with pD2 as the negative logarithm of the EC 50 , similarly to previous studies (30). The number of CRCs and E max were used in all calculations estimating the statistical significance.…”