Kampo medicine, Stephania tetrandra Radix (Stephania) in Boi-ogi-to increases the blood insulin level and falls the blood glucose level in streptozotocin (STZ)-diabetic ddY mice. These actions of Stephania are potentiated by Astragalus membranaceus Bunge Radix (Astragali) in Boi-ogi-to (Liu et al., J. Traditional Med., 17, 253-260, 2000). In the present study, actions of bis-benzylisoquinoline alkaloids isolated from Stephania were investigated in the hyperglycemia of STZ-diabetic mice. A main bis-benzylisoquinoline alkaloid, fangchinoline (0.3-3 mg/kg) significantly fell the blood glucose level of the diabetic mice in a dose-dependent manner. The effect of fangchinoline was 3.9-fold greater than that of water extract of Stephania. However, another main compound, tetrandrine (1-100 mg/kg) did not have any effect. The water extract of Astragali did not affect singly but potentiated the anti-hyperglycemic action of fangchinoline (0.3 mg/kg). Out of used compounds (1 mg/kg) isolated from Stephania, fangchinoline, fangchinoline 2'-N-alpha-oxide and 2'-N-norfangchinoline, which are substituted with 7-hydroxy side chain for 7-O-methyl side chain, decreased to near 50% of high blood glucose level. In addition, tetrandrine 2'-N-beta-oxide, tetrandrine 2'-N-alpha-oxide, tetrandrine 2-N-beta-oxide, fangchinoline 2'-N-alpha-oxide, which are added to 2- or 2'-N-oxide side chain, also decreased to near 50% of the high blood glucose level. In conclusion, fangchinoline but not tetrandrine from Stephania shows the anti-hyperglycemic action in the STZ-diabetic mice. The demethylation of 7-O-position and/or addition of 2- or 2'-N-oxide side chain in bis-benzylisoquinoline compounds in Stephania have a role for the induction of the anti-hyperglycemic actions.
Angiogenesis of cultured choroids was quantitatively assayed in spontaneously diabetic GK and a bolus-treated streptozotocin (STZ)-diabetic Wistar rats. The number and total length of microvessels budded from cultured choroidal explants were measured to use as angiogenic indices. Both indices in 10-week-old Wistar rats were increased in parallel by 5% fetal bovine serum (FBS) from days 2 to 7 in culture. These indices in STZ-rats (10 weeks of age) were increased by 5% FBS to a greater extent than those in age-matched normal rats. These enhanced actions of FBS were concentration-dependent. The explants of 16-week-old GK rats also increased these indices to a greater extent than those of age-matched Wistar rats. Aging to 18 weeks of age also increased choroidal angiogenesis in the normal rats. In conclusion, the assay model of choroidal angiogenesis was established by determining the number and length of microvessels in cultured choroidal explants. The diabetic states of STZ-Wistar and GK rats enhanced FBS-induced choroidal angiogenesis. This assay model is useful for determining angiogenic activity of growth factors and effective drugs in diabetic choroidopathy and retinopathy.
Structure-activity relationships of tetrandrine, isolated from a Kampo medicine, Stephania tetrandrae S. MOORE (root), and related synthetic compounds, were investigated in in vitro fetal bovine serum (FBS)-stimulated angiogenesis of cultured choroids in streptozotocin-diabetic Wistar rats, and air-pouch granuloma angiogenesis in vivo in diabetic mice. Tetrandrine, KS-1-1 (6,7-dimethoxy-1-[[4-[5-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroiso quinolinyl)methyl-2-methoxy]phenoxy]benzyl]-2-methyl-1,2,3,4-tetrahyd roisoquinoline), and KS-1-4 (6,7-dimethoxy-1-[[4-[4-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroiso quinolinyl)methyl]phenoxy]benzyl]-2-methyl-1,2,3,4-tetrahydroisoquino line), potently inhibited choroidal angiogenesis and air-pouch granuloma angiogenesis in the diabetic state. Their inhibitory effects on diabetic choroids were greater than those on normal choroids. Among these compounds, KS-1-4 inhibited only diabetic angiogenesis. These compounds significantly inhibited FBS-stimulated tube formation in vascular endothelial cells from normal rats. Tetrandrine and KS-1-4, but not KS-1-1, inhibited vascular endothelial growth factor- and platelet-derived growth factor-BB-stimulated angiogenesis in normal choroids. The bis[tetrahydroisoquinoline] moiety, connected by oxy-bis[phenylenemethylene] and 2,2'-dimethyl groups in tetrandrine, contributes to the inhibition of diabetic choroidal angiogenesis. KS-1-4 may be a candidate for anti-choroidopathy and retinopathy drugs in the diabetic state.
Abstract-We studied the effects of the r-aminobutyric acid (GABA) receptor agonists, diazepam and muscimol, on the urinary bladder contraction induced by infusion of Tyrode's solution into the bladder in anesthetized rats. Diazepam (1 mg/kg, i.p.) completely inhibited bladder contraction, causing the bladder pressure to rise until solution leaked from the penis. The inhibitory effects of diazepam were reversed by picrotoxin (1 mg/kg, i.v., twice with an interval of 10 min), and the effects were potentiated and attenuated by pretreatment with aminooxyacetic acid (AA, 10 mg/kg, i.v.) and semicarbazide (200 mg/kg, i.v.), respectively. Only pretreatment with AA inhibited the bladder contraction induced by infusion of Tyrode's solution into the bladder in six out of eight rats. Diazepam abolished efferent discharges recorded from the left pelvic nerve, but hexamethonium facilitated the generation of efferent discharges after inhibition of bladder contraction. After complete inhibition of bladder contraction by diazepam, electrical stimulation of the left pelvic nerve at 5 Hz for 30 sec was able to induce bladder contraction, and this resulted in micturition. Intracerebroventricular injection or intrathecal injection into the sacral part of the spinal cord of 1 ug muscimol completely inhibited the bladder contraction. It was considered that the inhibitory effects of GABA receptor agonists on bladder contraction were mainly induced through the GABA receptors in the micturition center of the sacral cord, as well as the brain stem.Recently, the inhibitory effects of r aminobutyric acid (GABA) on urinary blad der motility have been widely investigated in rats, and a GABA receptor in the pontine mesencephalic region (1-3) and pelvic ganglia (4, 5) has been suggested to be involved in the modulation of urinary bladder function.However, these studies involved investigation of the central action of GABA receptor agonists on the urinary bladder hyperreactivity induced by I-dopa admin istration, and so the possibility still remained that GABA presynaptically inhibits the activation of dopaminergic neurons, thus inhibiting urinary bladder contraction (1-3). We (6) previously reported a preparation in which the urinary bladder contraction ac companying micturition was induced in a reflex manner by infusion of a solution into the bladder through the ureter in anesthetized rats. Therefore, in the present experiments, we studied the effects of GABA receptor agonists on the urinary bladder motility induced by our method and attempted to clarify the active site of GABA receptor agonists involved in the urinary bladder control mechanism. We used diazepam and muscimol as the GABA receptor agonists and used picrotoxin as a GABA receptor antago nist, since diazepam and picrotoxin bind to each of the recognition sites of the GABA receptor complex and respectively potentiate and attenuate the efficacy of GABA synaptic transmission (7), whereas muscimol is known to be as a GABA receptor agonist. Materials and MethodsThe preparations used and...
Abstract-In anesthetized rats, SKF 38393 (10 mg/kg, i.v.) did not facilitate urinary bladder motility, but bromocriptine (BR, 5 mg/kg, i.v.) alone and the combination of BR (1 mg/kg, i.v.) and SKF 38393 (1 mg/kg, i.v.) induced a hyperactive bladder response (HBR). Both HBR induced by BR alone or BR and SKF 38393 combined was suppressed by SCH 23390. sulpiride or haloperidol. These results indicate that HBR is mediated by the activation of D-2 receptors, and the effects of D-2 agonists on bladder motility are potentiated by the simultaneous stimulation of D-1 receptors.With regard to the dopaminergic neurons in rats that affect urinary bladder motility, Sillen etal. (1-3) have reported that dopamine recep tors are present in the micturition reflex center of the mesencephalic pontine region, and a hyperactive urinary response is induced upon stimulation of the receptors with dopamine agonists. Recently, we also studied the ef fects of apomorphine, a D-1 and D-2 dopa mine receptor agonist, on urinary bladder motility in rats and suggested that the hyper active bladder response was elicited via both D-1 and D-2 receptors (4). In this experiment, to clarify the roles of D-1 and D-2 receptors and their functional interactions in the genera tion of a hyperactive bladder response, we used SKF 38393 and bromocriptine as selec tive D-1 and D-2 agonists, respectively (5, 6), and we studied their effects on urinary bladder motility. As apomorphine given i.v. elicited a marked hyperactive bladder re sponse due to the combined stimulation of the micturition reflex centers in the brain stem and sacral cord (4), we studied the effects of i.v. administered drugs on bladder motility.The preparations and method used for re cording bladder contraction were described previously (4). Male Wistar rats (weighing 250-350 g) were anesthetized with urethane (1.0 g/kg, s.c.) and a-chloralose (25 mg/kg, s.c.). Bladder contraction was reflexly induced by continuous infusion of glucose-free Tyrode's solution into the bladder at a con stant rate (approximately 0.8 ml/10 min) through a cannula inserted into the bladder through the left ureter. The intravesical pres sure signals measured by a pressure trans ducer (Nihon Kohden, LPU-0
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