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Background and purpose:Antagonists of Ca2+ channels reduce contraction of intestinal smooth muscle but also affect vascular smooth muscle. We have therefore examined the effects of AJG049, a newly synthesized antagonist for regulation of gut motility, on voltage-dependent L-type Ca2+ channels, in vascular and intestinal smooth muscle, comparing AJG049 with two other Ca2+ channel antagonists, verapamil and diltiazem.Experimental approach:Affinities of AJG049 for various types of voltage-dependent Ca2+ channels were examined by binding studies. Effects of AJG049 on voltage-dependent inward Ca2+ (or Ba2+) currents (ICa or IBa) in dispersed smooth muscle cells from guinea-pig ileum, colon and mesenteric artery were measured using conventional whole-cell configurations.Key results:In binding studies, AJG049 showed a high affinity for the diltiazem-binding site of L-type Ca2+ channels. In whole-cell configuration, AJG049 suppressed ICa in ileal myocytes, with concentration-, voltage-and use-dependencies. AJG049 shifted the steady-state inactivation curve of ICa to the left. The order of potency to inhibit ICa in ileal myocytes was AJG049>verapamil>diltiazem. AJG049 also suppressed IBa in guinea-pig mesenteric arterial myocytes, showing concentration- and voltage-dependencies and the potency order for this action was also AJG049>verapamil>diltiazem. For the relative ratio of Ki values between ileal and mesenteric arterial myocytes, the order was AJG049>diltiazem≫verapamil.Conclusions and implications:These results show that AJG049 inhibits L-type Ca2+ channels mainly through the diltiazem-binding site(s). From our results, AJG049 showed a little selectivity for these Ca2+ channels in intestinal smooth muscle.British Journal of Pharmacology (2006) 149, 155–162. doi:10.1038/sj.bjp.0706861; published online 14 August 2006 [ABSTRACT FROM AUTHOR]

1 The effects of mefenamic acid on both membrane potential and K[sup+] currents in pig urethral myocytes were investigated using patch-clamp techniques (conventional whole-cell, cell-attached, outside-out and inside-out configuration). 2 In the current-clamp mode, mefenamic acid caused a concentration-dependent hyperpolarization, which was inhibited by preapplication of 1 μM glibenclamide. In the voltage-clamp mode. mefenamic acid induced an outward current that was blocked by glibenclamide even in the presence of iberiotoxin (IbTX, 300nM) at -50mV. 3 ATP-sensitive K[sup+] channels (K[subATP] channels) could be activated in the same patch by mefenamic acid and levcromakalim, with the same unitary amplitude and the similar opening gating at -50 mV in cell-attached configuration. 4 In outside-out recording, external application of mefenamic acid activated intracellular Ca[sup2+]-activated 1bTX-sensitive large-conductance K[sup+] channels (BK[subca] channels). 5 Mefenamic acid (≤ 30 μM) activated spontaneous transient outward currents (STOCs). In contrast, mefenamic acid ( ≥ 100 μM) increased sustained outward currents, diminishing the activity of STOCs. 6 Over the whole voltage range, mefenamic acid caused opposite effects on the membrane currents in the absence and presence of 5 μM glibenclamide. In the presence of l0mM 4-aminopyridine (4-A.P). mefenamic acid only increased the outward currents. 7 These results indicate that mefenamic acid increases the channel activities of two distinct types of K[sup+] channels (i.e. BK[subCa] channels and K[subATP] channels) and decreased 4-AP-sensitive K[sup+] channels in pig urethral myocytes. [ABSTRACT FROM AUTHOR]

The urethral wall contains circular and longitudinal smooth muscle. Both layers can develop spontaneous tone, and contract further or relax in response to excitatory or inhibitory stimuli. In the pig the cells do not generate action potentials, and the membranes possess L-type calcium channels and a variety of potassium channels which may modulate the membrane potential and tone. The importance of these layers in generating the urethral pressure is not well understood in the human, but it seems likely that the circular smooth muscle is involved in generating urethral pressure in the pig. [ABSTRACT FROM AUTHOR]

The urethral wall contains circular and longitudinal smooth muscle. Both layers can develop spontaneous tone, and contract further or relax in response to excitatory or inhibitory stimuli. In the pig the cells do not generate action potentials, and the membranes possess L-type calcium channels and a variety of potassium channels which may modulate the membrane potential and tone. The importance of these layers in generating the urethral pressure is not well understood in the human, but it seems likely that the circular smooth muscle is involved in generating urethral pressure in the pig. [ABSTRACT FROM AUTHOR]

Triallyl L-alanine (A3A) and triallyl L-phenylalanine (A3F) were synthesized by reactions of L-alanine and L-phenylalanine with allyl bromide in the presence of sodium hydroxide, respectively. Thiol-ene thermal polymerization of A3A or A3F with pentaerythritol-based primary tetrathiol (pS4P) or pentaerythritol-based secondary tetrathiol (S4P) at allyl/SH 1/1 in the presence of 2,2"-azobis(isobutyronitrile) produced an amino acid-incorporated polymer network (A3A-pS4P, A3A-S4P or A3F-S4P). Although the thermally cured resins were homogeneous and flat films, the corresponding thiol-ene photopolymerization did not give a successful result. Degree of swelling for each thermally cured film in N,N-dimethylformamide was much higher than that in water. The glass transition and 5% weight loss temperatures (Tg and T5) of A3F-pS4P and A3F-S4P were higher than those of A3A-pS4P and A3A-S4P, respectively. Also, A3F-pS4P and A3F-S4P exhibited much higher tensile strengths and moduli than A3A-pS4P and A3A-S4P did, respectively. Consequently, A3FpS4P displayed the highest Tg (38.7°C), T5 (282.0°C), tensile strength (9.5 MPa) and modulus (406 MPa) among all the thermally cured resins. [ABSTRACT FROM AUTHOR]

Abstract: It is acknowledged that neurotransmission in the mouse vas deferens is predominantly mediated by ATP and noradrenaline (NA) released from sympathetic nerves while cholinergic transmission in the rodent vas deferens is often overlooked despite early literature. Recently we have characterized a cholinergic component of neurogenic contraction of mouse isolated vas deferens. In the present paper, by confocal imaging of Ca2+ dynamics we detected acetylcholine (ACh) action at muscarinic cholinergic neuroeffector junctions at high-resolution. Experiments were carried out in the presence of prazosin (100 nM) and α,β methylene ATP (α,β-MeATP) (1 μM) to inhibit responses to NA and ATP respectively. Exogenous ACh (10 μM) elicited Ca2+ transients, an effect blocked by the muscarinic receptor antagonist, cyclopentolate (1 μM). Ca2+ transients were evoked by electrical stimulation of intrinsic nerves in the presence of the cholinesterase inhibitor neostigmine (10 μM). Stimulation produced a marked increase in the frequency and number of Ca2+ transients. Cyclopentolate reduced the frequency of occurrence of spontaneous and evoked events to control levels. The α2-adrenoceptor antagonist yohimbine (300 nM) did not affect the spontaneous Ca2+ transients, but increased the frequency of occurrence of evoked transients, an effect inhibited by cyclopentolate. The postjunctional effects of neuronally-released ACh are limited by the action of cholinesterase. Release of ACh appears to be tonically inhibited by NA released from sympathetic nerve terminals through action at prejunctional α2-adrenoceptors. Tetrodotoxin (TTX, 300 nM) abolished the nerve-evoked Ca2+ events, with no effect on Ca2+ transients elicited by exogenous ACh. In conclusion, the presence of spontaneous and evoked cholinergic Ca2+ transients in smooth muscle cells of the mouse isolated vas deferens has been revealed. These events are mediated by ACh acting at M3 muscarinic receptors. This action stands in marked contrast to the lack of effect of neuronally-released NA on smooth muscle Ca2+ dynamics in this tissue. [Copyright &y& Elsevier]

Background: T1-shortening contrast media are routinely used in magnetic resonance (MR) examinations for the diagnosis of brain tumors. Although some studies show a benefit of 3 Tesla (T) compared to 1.5T in delineation of brain tumors using contrast media, it is unclear which pulse sequences are optimal. Purpose: To compare gadopentetate dimeglumine (Gd-DTPA)-induced signal enhancements in rat brain C6 glioma in the thalamus region among different pulse sequences in 3T MR imaging. Material and Methods: Five rats with a surgically implanted C6 glioma in their thalamus were examined. T1-weighted brain images of the five rats were acquired before and after Gd-DTPA administration (0.1 mmol/kg) using three clinically available pulse sequences (spin echo [SE], fast SE [FSE], fast spoiled gradient echo [FSPGR]) at 3T. Signal enhancement in the glioma (ET) was calculated as the signal intensity after Gd-DTPA administration scaled by that before administration. Pulse sequences were compared using the Tukey-Kramer test. Results: ET was 1.12±0.05 for FSE, 1.26±0.11 for FSPGR, and 1.20±0.11 for SE. FSPGR showed significantly higher signal enhancement than FSE and comparable enhancement to SE. Conclusion: FSPGR is superior to FSE and comparable to SE in its ability to delineate rat brain C6 glioma in the thalamus region. [ABSTRACT FROM AUTHOR]

Intracellular recordings were made from either sheets or isolated bundles of the circular muscle layer of guinea-pig proximal colon and the responses evoked by stimulating inhibitory nerve fibres were analysed. Inhibitory junction potentials (IJPs), evoked by single stimuli, had two components which could be separated on their pharmacological and temporal characteristics and their voltage sensitivities. The initial component, which was abolished by apamin and reduced in amplitude by pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS), had a brief time course: its amplitude was changed when the external concentration of potassium ions ([K+]o) was changed. The second component of the IJP had a slower onset than the first component, was abolished by L-nitroarginine (NOLA) and oxadiazolo quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase: its amplitude was little affected by changing [K+]o and was increased when the membrane potential of the circular layer was hyperpolarized. The observations suggest that the initial component of the IJP results from the release of ATP which triggers an increase in membrane conductance to K+ and that the second component results from the release of nitric oxide which suppresses a background inward current. [ABSTRACT FROM AUTHOR]

Background: Video-assisted thoracoscopic surgery (VATS) has become an attractive surgical procedure, but several issues remain to be resolved. Prognosis after VATS lobectomy is important to evaluate the adequacy of VATS lobectomy as a cancer operation. Interestingly, several investigators, including us, have reported that prognosis after VATS lobectomy was superior to that after open lobectomy in early non-small-cell lung cancer (NSCLC). One of the possible reasons is the low invasiveness of VATS lobectomy. But we considered that patient bias might have some influence favoring VATS lobectomy. To evaluate our hypothesis, we reviewed medical records of stage I NSCLC patients undergoing operation between 1993 and 2002. We compared and evaluated the relationship between patient characteristics and prognosis after VATS and open lobectomy. We focused particularly on histological type, classifying it into four subgroups; (1) bronchioloalveolar carcinoma (BAC), (2) mixed BAC + papillary adenocarcinoma (BAC + Pap), (3) other adenocarcinoma (Other adeno), (4) squamous cell carcinoma + others (Sq + others).Results: A total of 165 patients underwent VATS lobectomy, and 123 patients underwent open lobectomy. The 5-year survival rate of the VATS lobectomy group was 94.5% and that of the open lobectomy group was 81.5%. Univariate Cox regression of survival revealed that male, CEA > 5, Other adeno, Sq + others, open lobectomy, and tumor size > 3 cm were significant negative prognostic variables. Multivariate Cox regression of survival revealed that histological subtype and tumor size were independent prognostic factors, but surgical procedure was not an independent prognostic factor.Comments: Prognosis after VATS lobectomy was superior to that after open lobectomy, but patient bias influenced the prognosis in favor of VATS lobectomy, and the surgical procedure itself was not a prognostic factor. [ABSTRACT FROM AUTHOR]

Background and purpose:Although azelnidipine is used clinically to treat hypertension its effects on its target cells, Ca2+ channels, in smooth muscle have not been elucidated. Therefore, its effects on spontaneous contractions and voltage-dependent L-type Ca2+ channels were investigated in guinea-pig portal vein.Experimental approach:The inhibitory potency of azelnidipine on spontaneous contractions in guinea-pig portal vein was compared with those of other dihydropyridine (DHP)-derived Ca antagonists (amlodipine and nifedipine) by recording tension. Also its effects on voltage-dependent nifedipine-sensitive inward Ba2+ currents (I Ba) in smooth muscle cells dispersed from guinea-pig portal vein were investigated by use of a conventional whole-cell patch-clamp technique.Key results:Spontaneous contractions in guinea-pig portal vein were reduced by all of the Ca antagonists (azelnidipine, K i=153 nM; amlodipine, K i=16 nM; nifedipine, K i=7 nM). In the whole-cell experiments, azelnidipine inhibited the peak amplitude of I Ba in a concentration- and voltage-dependent manner (-60 mV, K i=282 nM; −90 mV, K i=2 μM) and shifted the steady-state inactivation curve of I Ba to the left at −90 mV by 16 mV. The inhibitory effects of azelnidipine on I Ba persisted after 7 min washout at −60 mV. In contrast, I Ba gradually recovered after being inhibited by amlodipine, but did not return to control levels. Both azelnidipine and amlodipine caused a resting block of I Ba at -90 mV. Only nifedipine appeared to interact competitively with S(-)-Bay K 8644.Conclusions and implications:These results suggest that azelnidipine induces long-lasting vascular relaxation by inhibiting voltage-dependent L-type Ca2+ channels in vascular smooth muscle.British Journal of Pharmacology (2006) 149, 786–796. doi:10.1038/sj.bjp.0706919; published online 3 October 2006 [ABSTRACT FROM AUTHOR]

Background and purpose:ATP-sensitive K+ channels (KATP channels) play important roles in regulating the resting membrane potential of detrusor smooth muscle. Actions of ZD0947, a novel KATP channel opener, on both carbachol (CCh)-induced detrusor contractions and membrane currents in human urinary bladder myocytes were investigated.Experimental approach:Tension measurements and patch-clamp techniques were utilized to study the effects of ZD0947 in segments of human urinary bladder. Immunohistochemistry was also performed to detect the expression of the sulphonylurea receptor 1 (SUR1) and the SUR2B antigens in human detrusor muscle.Key results:ZD0947 (≥0.1 μM) caused a concentration-dependent relaxation of the CCh-induced contraction of human detrusor, which was reversed by glibenclamide. The rank order of the potency to relax the CCh-induced contraction was pinacidil>ZD0947>diazoxide. In conventional whole-cell configuration, ZD0947 (≥1 μM) caused a concentration-dependent inward K+ current which was suppressed by glibenclamide at -60 mV. When 1 mM ATP was included in the pipette solution, application of pinacidil or ZD0947 caused no inward K+ current at -60 mV. Gliclazide (≤1 μM), a selective SUR1 blocker, inhibited the ZD0947-induced currents (K i=4.0 μM) and the diazoxide-induced currents (high-affinity site, K i1=42.4 nM; low-affinity site, K i2=84.5 μM) at -60 mV. Immunohistochemical studies indicated the presence of SUR1 and SUR2B proteins, which are constituents of KATP channels, in the bundles of human detrusor smooth muscle.Conclusions and Implications:These results suggest that ZD0947 caused a glibenclamide-sensitive detrusor relaxation through activation of glibenclamide-sensitive KATP channels in human urinary bladder.British Journal of Pharmacology (2006) 149, 542–550. doi:10.1038/sj.bjp.0706893; published online 3 October 2006 [ABSTRACT FROM AUTHOR]

This chapter describes a brief overview of present advances and challenges in PET methodology from the engineering side. Topics are as follows: (1) advances in hardware design and sophisticated software development for registering PET and anatomical images, (2) higher spatial resolution approaching sub-millimeters, (3) improved temporal resolution, (4) repeat assessment of physiologic functions, (5) corrections for partial volume effect (PVE), and (6) motion correction capability. These features provide potentials of using PET in new application fields. [Copyright &y& Elsevier]