Spontaneous myometrial contraction (SMC) in pregnant uterus is greatly related with gestational age and growing in frequency and amplitude toward the end of gestation to initiate labor. But, an accurate mechanism has not been elucidated. In human and rat uterus, all TRPCs except TRPC2 are expressed in pregnant myometrium and among them, TRPC4 are predominant throughout gestation, suggesting a possible role in regulation of SMC. Therefore, we investigated whether the TRP channel may be involved SMC evoked by mechanical stretch in pregnant myometrial strips of rat using isometric tension measurement and patch-clamp technique. In the present results, hypoosmotic cell swelling activated a potent outward rectifying current in G protein-dependent manner in rat pregnant myocyte. The current was significantly potentiated by 1microM lanthanides (a potent TRPC4/5 stimulator) and suppressed by 10microM 2-APB (TRPC4-7 inhibitor). In addition, in isometric tension experiment, SMC which was evoked by passive stretch was greatly potentiated by lanthanide (1microM) and suppressed by 2-APB (10microM), suggesting a possible involvement of TRPC4/5 channel in regulation of SMC in pregnant myometrium. These results provide a possible cellular mechanism for regulation of SMC during pregnancy and provide basic information for developing a new agent for treatment of premature labor.
Animals ; Female ; Gestational Age ; Humans ; Lanthanoid Series Elements ; Mice ; Muscle Cells ; Myometrium ; Obstetric Labor, Premature ; Osmotic Pressure ; Patch-Clamp Techniques ; Pregnancy ; Rats* ; Uterine Contraction* ; Uterus

Protease-activated receptor (PAR)-2 is expressed in endothelial cells and vascular smooth muscle cells. It plays a crucial role in regulating blood pressure via the modulation of peripheral vascular tone. Although some reports have suggested involvement of a neurogenic mechanism in PAR-2-induced hypotension, the accurate mechanism remains to be elucidated. To examine this possibility, we investigated the effect of PAR-2 activation on smooth muscle contraction evoked by electrical field stimulation (EFS) in the superior mesenteric artery. In the present study, PAR-2 agonists suppressed neurogenic contractions evoked by EFS in endothelium-denuded superior mesenteric arterial strips but did not affect contraction elicited by the external application of noradrenaline (NA). However, thrombin, a potent PAR-1 agonist, had no effect on EFS-evoked contraction. Additionally, omega-conotoxin GVIA (CgTx), a selective N-type Ca2+ channel (I(Ca-N)) blocker, significantly inhibited EFS-evoked contraction, and this blockade almost completely occluded the suppression of EFS-evoked contraction by PAR-2 agonists. Finally, PAR-2 agonists suppressed the EFS-evoked overflow of NA in endothelium-denuded rat superior mesenteric arterial strips and this suppression was nearly completely occluded by omega-CgTx. These results suggest that activation of PAR-2 may suppress peripheral sympathetic outflow by modulating activity of I(Ca-N) which are located in peripheral sympathetic nerve terminals, which results in PAR-2-induced hypotension.
Animals ; Blood Pressure ; Endothelial Cells ; Hypotension* ; Mesenteric Arteries ; Mesenteric Artery, Superior ; Muscle, Smooth ; Muscle, Smooth, Vascular ; Norepinephrine ; omega-Conotoxin GVIA ; Rats ; Receptor, PAR-2 ; Thrombin

PURPOSE: Gastrointestinal stromal tumor (GIST) is the designation for c-kit signal driven mesenchymal tumor. A great majority of these tumors occur in the stomach and small intestine, and rarely in the colon, rectum and esophagus. Metastatic or recurrent GIST must be resected surgically because it is resistant to conventional cytotoxic chemotherapy. Following recent evidence for the dramatic effect of Imatinib mesylate (Glivec), Glivec has become available in our country since June 2001 without insurance coverage. Although some doubt remained, we applied Glivec to recurrent GIST patients with great expectation. METHODS: A retrospective analysis was made for 16 GIST patients who were resected during 2001. Follow up duration was 19 to 29 months. All pathologic slides were reexamined immunohistochemically by an experienced pathologist. Clinicopathologic comparison between the recurred and non-recurred groups was summarized into the tables. The therapeutic and side effects of Glivec were surveyed. CT scan files were reviewed to decided tumor regression or progression. RESULTS: Fifteen GISTs were resected in 2001. Seven cases recurred during 19 to 29 months of follow up. The recurred group was characterized by huge tumor size (mean 14 cm), serosal invasion and more than 10 mitosis in 50 HPF. A daily dose of 400 mg of Glivec was prescribed to every recurred GIST patients and CT scan was followed serially. The therapeutic effect of Glivec effect was drastic but variable; complete tumor remission (n=3), rebounded tumor growth at the same location after remission (n=1), and recurrence at another location after complete remission (n=2). CONCLUSION: Glivec drastically reduced the size of recurrent gastric GIST initially. However, it is not clear how long Glivec should be taken at a great expense in fear of rebounded growth after abstaining. It appears that reoperation is necessary without delay when tumor remission slows down.
Colon ; Drug Therapy ; Esophagus ; Follow-Up Studies ; Gastrointestinal Stromal Tumors ; Humans ; Imatinib Mesylate ; Insurance Coverage ; Intestine, Small ; Mesylates* ; Mitosis ; Rectum ; Recurrence ; Reoperation ; Retrospective Studies ; Stomach ; Tomography, X-Ray Computed