ABSTRACT
BACKGROUND/AIMS: Tamoxifen is a widely used anticancer drug for breast cancer with frequent gastrointestinal side effects. Changes in gastrointestinal motility is associated with altered activities of membrane ion channels. Ion channels have important role in regulating membrane potential and cell excitability. This study was performed to investigate the effects of tamoxifen on the membrane ionic currents in colonic smooth muscle cells. METHODS: Murine colonic smooth muscle cells were isolated from the proximal colon using collagenase, and the membrane currents were recorded using a whole-cell patch clamp technique. RESULTS: Two types of voltage-dependent K+ currents were recorded (A-type and delayed rectifier K+ currents). Tamoxifen inhibited both types of voltage-dependent K+ currents in a dose-dependent manner. However, tamoxifen did not change the half-inactivation potential and the recovery time of voltage-dependent K+ currents. Chelerythrine, a protein kinase C inhibitor or phorbol 12, 13-dibutyrate, a protein kinase C activator did not affect the voltage-dependent K+ currents. Guanosine 5'-O-(2-thio-diphosphate) did not affect the tamoxifen-induced inhibition of voltage-dependent K+ currents. Tamoxifen inhibited voltage-dependent Ca2+ currents completely in whole-test ranges. CONCLUSIONS: These results suggest that tamoxifen can alter various membrane ionic currents in smooth muscle cells and cause some adverse effects on the gastrointestinal motility.
Subject(s)
Animals , Mice , Antineoplastic Agents, Hormonal/pharmacology , Calcium Channels/drug effects , Colon/drug effects , English Abstract , In Vitro Techniques , Membrane Potentials , Myocytes, Smooth Muscle/drug effects , Potassium Channels/drug effects , Tamoxifen/pharmacologyABSTRACT
The interstitial cells of Cajal (ICCs) are the pacemaker cells in gastrointestinal tract and generate electrical rhythmicity in gastrointestinal muscles. Therefore, ICC may be modulated by endogenous agents such as neurotransmitter, hormones, and prostaglandins (PGs). In the present study, we investigated the effects of prostaglandins, especially PGE2, on pacemaker currents in cultured ICCs from murine small intestine by using whole-cell patch clamp techniques. ICCs generated spontaneous slow waves under voltage-clamp conditions and showed a mean amplitude of -452+/-39 pA and frequency of 18+/-2 cycles/min (n=6). Treatments of the cells with PGE2 (1muM) decreased both the frequency and amplitude of the pacemaker currents and increased the resting currents in the outward direction. PGE2 had only inhibitory effects on pacemaker currents and this inhibitory effect was dose-dependent. For characterization of specific membrane EP receptor subtypes, involved in the effects of PGE2 on pacemaker currents in ICCs, EP receptor agonists were used: Butaprost (1muM), EP2 receptor agonist, reduced the spontaneous inward current frequency and amplitude in cultured ICCs (n=5). However sulprostone (1muM), a mixed EP1 and EP3 agonist, had no effects on the frequency, amplitude and resting currents of pacemaker currents (n=5). SQ-22536 (an inhibitor of adenylate cyclase; 100muM) and ODQ (an inhibitor of guanylate cyclase; 100muM) had no effects on PGE2 actions of pacemaker currents. These observations indicate that PGE2 alter directly the pacemaker currents in ICCs, and that the PGE2 receptor subtypes involved are the EP2 receptor, independent of cyclic AMP- and GMP-dependent pathway.
Subject(s)
Adenylyl Cyclases , Dinoprostone , Gastrointestinal Tract , Guanylate Cyclase , Interstitial Cells of Cajal , Intestine, Small , Membranes , Muscles , Neurotransmitter Agents , Patch-Clamp Techniques , Periodicity , ProstaglandinsABSTRACT
Although myocardial bridge is not thought to have any hemodynamic significance in most cases, some have suggested that when it produces severe systolic narrowing, ischemia or infarction may result. Myocardial bridge in adults with hypertrophic cardiomyopathy may be associated with a higher incidence of sudden death, myocardial wall-motion abnormalities, and perfusion defects on thallium-201 scintigraphy. When myocardial bridge is associated with left ventricular hypertrophy, it is known to affect longer segment and cause more severe compression during systole. We report a case of hypertrophic cardiomyopathy with myocardial bridge at the middle part of the left anterior descending coronary artery, who also showed reversible perfusion defect on the thallium scan at the same coronary territory.