Inhibitory effects of serotonin on transient outward potassium current in rat ventricular myocytes.
ABSTRACT To study the effects of serotonin (5-hydroxy-tryptamine, 5-HT) on transient outward potassium current (I(to)) and elucidate its mechanism in rat ventricular myocytes.
I(to) was recorded using the conventional whole cell patch-clamp techniques.
I(to) density in normal myocytes was similar to that in norepinephrine-induced hypertrophic myocytes. 5-HT depressed I(to) in a concentration-dependent manner with the half-maximal inhibitory concentration of (40+/-5) micromol/L and (38+/-7) micromol/L in normal and hypertrophic ventricular myocytes respectively. Mianserin (5-HT2 receptor antagonist), compound 48/80 (phospholipase C antagonist), and chelerythrine chloride (protein kinase C antagonist) reversed the inhibitory effects of 5-HT on I(to), while phorbol 12-myristate 13-acetate (protein kinase C agonist) enhanced the inhibitory effect of 5-HT on I(to) in normal myocytes.
5-HT markedly inhibits I(to) in rat ventricular myocytes. The putative signal pathway is that 5-HT activates phospholipase C, which causes inositol phospholipid hydrolysis. The activation of downstream signal molecule, protein kinase C, phosphorates substrate target proteins, which leads to inhibition of I(to) in ventricular myocytes.
- [Show abstract] [Hide abstract]
ABSTRACT: 1. Serotonin (5-hydroxytryptamine; 5-HT) plays important roles in the development of cardiac hypertrophy via activation of 5-HT receptors. The aim of the present study was to investigate the role of 5-HT(2B) receptors in the development of cardiomyocyte apoptosis and hypertrophy associated with noradrenaline (NA) overload. 2. Cardiac hypertrophy was induced in rats by intraperitoneal injection of 1.5 mg/kg NA for 4 weeks. Starting from Day 15, 5-HT2B receptor antagonist SB 204741 (i.p., 0.5 or 2 mg/kg) or SDZ SER 082 (i.p., 1 mg/kg) was injected twice daily for another 14 days. Whole-cell patch-clamp techniques were used to record ionic currents in freshly isolated ventricular cardiomyocytes. Western blot and terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) assays were used to assess myocardial apoptosis. 3. Expression of 5-HT(2B) receptors was enhanced in the hypertrophic left ventricle induced by NE overload in vivo. The 5-HT(2B) receptor antagonist SB 204741 partially reversed cardiac hypertrophy induced by NE overload (P < 0.05) and decreased L-type calcium currents in ventricular cardiomyocytes (P < 0.05). In addition, SB 204741 notably attenuated myocardial apoptosis, as evidenced by downregulation of Bax and caspase 3 (P < 0.05) and upregulation of the anti-apoptotic Bcl-2 protein (P < 0.05). 4. In conclusion, the data suggest an involvement of 5-HT(2B) receptors in the generation of apoptotic events associated with cardiac remodelling during increased adrenergic stimulation.Clinical and Experimental Pharmacology and Physiology 03/2010; 37(7):e145-51. · 2.41 Impact Factor