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The effects of ranolazine (CAS 95635-55-5, KEG-1295), a novel antianginal drug, on the ST-segment changes induced by coronary ligation, epinephrine, and vasopressin were examined following oral or intraduodenal administration. In anesthetized dogs, intraduodenal administration of KEG-1295 (10, 30, or 50 mg/kg) or atenolol (10 mg/kg) significantly attenuated the ST-T wave elevation induced by 2-min coronary ligation imposed during electrical heart pacing (200 beats/min). This antianginal effect of KEG-1295 persisted for 3 h without any changes in hemodynamic parameters, while that of atenolol was accompanied by more or less maintained decreases in diastolic blood pressure, heart rate, and the maximum first derivative of left ventricular pressure. In anesthetized rats, oral administration of KEG-1295 (10, 30, or 50 mg/kg) attenuated the ST-T wave elevation induced by epinephrine (0.3 microgram/kg i.v.) in a dose-dependent manner, although KEG-1295 (10 or 30 mg/kg p.o.) failed to attenuate the ST-segment depression induced by vasopressin (0.2 IU/kg i.v.). These findings suggest that, taken orally, KEG-1295 may exert potent protective effects against angina pectoris, except that caused by vasospasm. Further, KEG-1295 may be categorized as a new type of antianginal agent, without any primary hemodynamic effects.

We compared the effect of a beta 3-adrenoceptor (AR) agonist with that of beta 1 and beta 2-AR agonists on the urethra and bladder in the dog and rat.In an in vitro experiment we studied the relaxant effect of subtype selective beta-AR agonists in canine and rat urethral and bladder smooth muscle using an organ bath method. In addition, in urethane anesthetized rats we measured urethral pressure and bladder pressure simultaneously in the presence of the beta 3-agonist CL316243 and the beta 2-agonist procaterol in 4 or 5 animals.In the dog the relaxing effects of isoprenaline in the distal urethra were about half those seen in the detrusor and trigone. The rank order of relaxing potency was CL316243dobutamine (beta 1-agonist) = procaterol in detrusor and trigone but procateroldobutamine = CL316243 in the prostatic and distal urethra. In rat urethral smooth muscle in vitro the corresponding order was procaterolCL316243dobutamine and the maximal relaxation to each agonist was about half that seen in the bladder. In the anesthetized rat procaterol clearly decreased urethral pressure but CL316243 produced only a slight decrease at its maximal dose, although each agonists clearly reduced bladder pressure. The beta 2-antagonist ICI-118551 counteracted the decrease in urethral and bladder pressure induced by procaterol.In rats and dogs a selective beta 3-AR agonist can decrease bladder pressure without affecting urethral pressure.

A Cynomolgus monkey hemodialysis model was used to evaluate the efficacy of a new factor Xa (FXa) inhibitor as an anticoagulant for hemodialysis. We tested the selective FXa inhibitor KFA-1411, using doses of 0.15 mg/ kg/hr, 0.3 mg/kg/hr, and 0.6 mg/kg/hr by continuous infusion in combination with a single loading-dose at the start. As a reference control, dalteparin, which is a low-molecular-weight heparin, was used at a dose of 20 IU/kg/hr plus 30 IU/kg single loading. As a monitoring method for KFA-1411, clotting time was measured in blood samples obtained from the body (systemic) and from the extracorporeal circulation (in-circuit). At KFA-1411 doses of 0.3 mg/ kg/hr and 0.6 mg/kg/hr hemodialysis was maintained with essentially no change in the intra-bloodline pressure in the extracorporeal circulation. With dalteparin, the pressure increased almost to the upper limit (set at 250 mmHg). The clot-deposition score measured, after testoration of normal circulation, in the dialyzer and air-trap chamber in the extracorporeal circulation was improved in a dose‐dependent manner in the KFA-1411 groups. There were no large differences between humans and Cynomolgus monkeys in the in vitro plasma anticoagulant activities of KFA1411 and dalteparin. These results indicate that this selective FXa inhibitor could be used as an anticoagulant for hemodialysis. Both activated partial thromboplastin time (APTT) and prothrombin time (PT) can be used to monitor the anticoagulant activity in the extracorporeal circulation, and a drug dose that has sufficient anticoagulant efficacy for hemodialysis will prolong in-circuit-APTT about 2 times and in-circuit-PT about 3 times compared to normal.

Since, in the human ureter, both beta(2)- and beta(3)-adrenoceptors mediate adrenergic-stimulation-induced relaxation, selective beta(2)-/beta(3)-adrenoceptor agonists might prove clinically useful for relieving ureteral colic and promoting stone passage. We evaluated the beta-adrenoceptor subtype selectivity and ureteral-relaxing efficacy of (-)-2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amin] ethyl)phenyloxy]acetic acid (KUL-7211), a new beta-adrenoceptor agonist, in vitro. In rat isolated organs, its selectivities, for inhibition of spontaneous uterine contraction (mediated via beta(2)-adrenergic stimulation) and inhibition of colonic contraction (via beta(3)-adrenergic stimulation) versus increase in atrial rate (via beta(1)-adrenergic stimulation), were 56.3 and 242.2, respectively. KUL-7211 relaxed 80-mM-KCl-induced tonic contractions in both rabbit (pD(2) value: 5.86 +/- 0.13, whose ureteral relaxation is mediated via beta(2)-adrenergic stimulation) and canine (pD(2) value: 6.52 +/- 0.16, via beta(3)-adrenergic stimulation) isolated ureters in a concentration-dependent manner. These KUL-7211-induced relaxing effects were antagonized by ICI-118,551 (selective beta(2)-adrenoceptor antagonist, pK(B) value: 8.91 +/- 0.24) in the rabbit ureter and by bupranolol (non-selective beta-adernoceptor antagonist, pK(B) value: 6.85 +/- 0.12) in the canine ureter. KUL-7211 also reduced the spontaneous rhythmic contraction in a canine ureteral spiral preparation in a concentration-dependent manner, the pD(2) value being 6.83 +/- 0.20. These data clearly demonstrate that KUL-7211 selectively stimulates both ureteral beta(2)- and beta(3)-adrenoceptors and potently relaxes ureteral smooth muscle. KUL-7211 may be a novel and useful medication for relieving ureteral colic and promoting stone passage in urolithiasis patients.

We compared the effects of CL-316243, a selective β3-adrenoceptor agonist, and CGP-12177A, a nonconventional partial β-adrenoceptor agonist, on the KCl-induced contraction in the isolated canine ureter. CL-316243 concentration dependently relaxed the ureteral contraction, the pD2 value being 7.75 ± 0.11. This relaxation was competitively antagonized by the selective β3-adrenoceptor antagonist SR58894A and by the nonselective β-adrenoceptor antagonist bupranolol, their pA2 values being 7.08 ± 0.08 and 6.43 ± 0.09, respectively. CGP-12177A concentration dependently reduced the KCl-induced contraction, the pD2 value being 6.30 ± 0.25. Even at 1 × 10–5 mol/l, CGP-20712A (a selective β1- adrenoceptor antagonist) did not shift the concentration-response curves for CL-316243 or CGP-12177A. SR58894A did not induce a parallel rightward shift in the concentration-response curve for CGP-12177A, but bupranolol did produce such a shift, pA2 and slope values in the Schild plot being 7.15 ± 0.77 and 0.60 ± 0.15, respectively. Hence, the competition characteristics for SR58894A and bupranolol differed between the CL- 316243-induced and CGP-12177A-induced relaxations. Our results suggest that CGP-12177A produces ureteral relaxation in the dog via an atypical β-adrenoceptor (possibly, an atypical site/state of the β3-adrenoceptor) as well as via the typical β3-adrenoceptor.

Aims. To investigate the effects of selective beta(2)- and selective beta(3)-adrenoceptor (AR) agonists on prostaglandin (PG) E-2-induced bladder hyperactivity in conscious free-moving rats. Methods. Female Sprague-Dawley rats were anesthetized for implantation of bladder, intravenous, and intra-arterial catheters. The effects of a beta(3)-AR agonist (CL316,243) on cystometric and cardiovascular parameters were assessed in conscious rats. Intravesical instillation of PGE(2) (20-60 muM, 6 mL/hr) in conscious rats produced a concentration-dependent increase in voiding frequency. Results. In this model i.v. CL316,243 (beta(3)-AR agonist) reduced basal bladder pressure, increased micturition volume, and prolonged micturition interval in a dose-dependent manner, without affecting threshold pressure or micturition pressure. On the other hand, i.v. procaterol (beta(2)-AR agonist) did not counteract the bladder hyperactivity. Atropine (muscarinic antagonist) reduced micturition pressure and micturition volume, and shortened micturition interval. CL316,243 slightly decreased mean blood pressure and increased heart rate only when given at high doses (10 and 100 mug/kg, iv.). In contrast, procaterol caused a significant decrease in mean blood pressure and a significant increase in heart rate. Atropine significantly increased heart rate. Conclusions. The present results clearly demonstrated that the beta(3)-AR agonist prolonged the micturition interval without producing significant cardiovascular side effects. The human detrusor, like the rat detrusor, relaxes on beta(3)-AR stimulation. Provided that these results are valid in humans, selective beta(3)-AR agonists might be clinically useful for controlling a certain type of bladder overactivity. (Less)

1. In the present study, we investigated the prophylactic effects of pilocarpine hydrochloride on xerostomia models induced by either single (15 Gy) or repeated (8.6 Gy x3 days) X-ray irradiation in rats. Pilocarpine hydrochloride was administered orally 90 min before each irradiation session. Then, 7 days later, salivary volume, amylase activity and protein concentration in the saliva secreted from the right parotid gland were measured before and after a subsequent administration of pilocarpine hydrochloride (intraduodenal). 2. In irradiated no-pretreatment rats, irradiation induced a significant reduction in both spontaneous and pilocarpine hydrochloride-stimulated secretion (both total salivary volume and flow rate), regardless of the protocol used for X-ray exposure. In irradiated, pilocarpine hydrochloride-pretreated rats, salivary secretion was increased after stimulation by pilocarpine hydrochloride (intraduodenal) to a degree that depended on the pretreatment dose of pilocarpine hydrochloride (p.o.) in both xerostomia models. 3. There were no differences in amylase or protein concentrations between irradiated rats pretreated with pilocarpine hydrochloride and irradiated no-pretreatment control rats. 4. A decrease in the weight of the parotid gland was observed in rats exposed to either the single dose or repeated irradiation protocols. Changes in the submandibular gland were less marked than those in the parotid gland. These changes in gland weight were not affected by pilocarpine hydrochloride pretreatment. 5. The responsiveness of the parotid gland to subsequent stimulation with pilocarpine hydrochloride was apparently preserved in both xerostomia models by pretreatment with pilocarpine hydrochloride, which itself increased salivary secretion. This suggests that pilocarpine hydrochloride may exert functional protective effects against xerostomia that occurs following irradiation therapy through a stimulation of salivary secretion.

With a novel assay using isolated ferret detrusor to estimate beta(3)-adrenoceptor agonistic activity, we found that a series of glycine derivatives of ritodrine, a beta(2)-adrenoceptor agonist, are potent beta(3)-adrenoceptor agonists, with excellent selectivity versus beta(1) and beta(2) subtypes. Substitution of halogens in the phenyl ring increased potency and selectivity for the beta(3)-adrenoceptor, and this was dependent upon the position of the halogens. The chlorine-substituted derivatives 3f-i exhibited potent beta(3)-adrenoceptor-mediated relaxation of ferret detrusor (EC(50) = 0.93, 11, 14, and 160 nM) and higher potency at beta(3)-adrenoceptors than at beta(1) or beta(2). The intravenous administration of 3h significantly reduced the urinary bladder pressure in anesthetized male rats (ED(50) = 48 microg/kg) without cardiovascular side effects. This article is the first report of structure-activity relationships (SAR) concerning beta(3)-adrenoceptor agonists as agents for the treatment of urinary frequency and incontinence.

We compared the relaxant effects of the stimulation of beta-adrenoceptors with isoproterenol and of drugs selective for beta-adrenoceptor subtypes in detrusor preparations from patients with normal and neurogenic bladder, respectively.We studied in vitro preparations of a cystometrically normal, low compliant and hyperreflexic bladder from 45, 26 and 7 patients, respectively.Isoproterenol relaxed concentration dependently and with the same potency as detrusor preparations obtained from normal and neurogenic bladders. In 37 normal detrusor, 25 low compliant and 7 hyperreflexic cases pD2 values were 6.36, 6. 25 and 6.38, respectively. Maximal relaxation did not differ significantly among the 3 groups (about 80% of 10-5 M. forskolin induced relaxation). Neither the beta1-/beta2-adrenoceptor agonist dobutamine nor the beta2-adrenoceptor agonist procaterol produced any significant relaxation of preparations from the 3 groups at a concentration of up to 10-5 M. At a concentration of 10-4 M. the preparations were relaxed but neither of these effects reached a maximum. BRL37344A and CL316243, selective beta3-adrenoceptor agonists and CGP-12177A (a selective beta3-adrenoceptor partial agonist and beta1-/beta2-adrenoceptor antagonist) relaxed detrusor preparations from the normal, low compliant and hyperreflexic groups when applied at concentrations greater than 10-6 M. For each agonist the pD2 value did not differ significantly among the 3 groups.beta-adrenoceptor stimulation is an effective way of relaxing the human detrusor and the effect is similar in normal and neurogenic bladders. A major portion of the relaxant effect of isoproterenol is mediated via beta3-adrenoceptor stimulation. Clinical trials may reveal whether this method is useful for treating bladder overactivity.

Purpose: We tried to determine the β-adrenoceptor (AR) subtypes distributed in the human ureter and to clarify their functional role in ureteral relaxation.Materials and Methods: 1) Effects of β-AR agonists on either spontaneous or KCl-induced contractions of the human ureter and the antagonism by β-AR antagonists on isoprenaline (a non-selective β-AR agonist)-induced effects were evaluated in vitro. 2) Displacement by β-AR antagonists of [3H]-dihydroalprenolol binding to a membrane preparation derived from human ureteral smooth muscle was evaluated. 3) A reverse transcription polymerase chain reaction assay was performed to determine the expression of the mRNA for β1-, β2- and β3-ARs in human ureteral smooth muscle.Results: 1) Isoprenaline and procaterol (a β2-AR agonist) concentration-dependently suppressed both spontaneous and KCl-induced contractions of the human ureter. The β3-AR agonists, CGP-12177A and CL-316243, also suppressed these ureteral contractions, but dobutamine (a β1-AR agonist) had litt...

The possible existence of a beta3-adrenergic receptor (beta3-AR) in the human detrusor muscle was investigated by in vitro functional studies and analysis of mRNA expression. Isoprenaline, noradrenaline and adrenaline each produced a concentration-dependent relaxation of the human detrusor. The rank order for their relaxing potencies was isoprenaline (pD2 6.37+/-0.07) > or = noradrenaline (pD2 6.07+/-0.12) > or = adrenaline (pD2 5.88 M) and its pKB value was 5.71+/-0.19. Moreover, SR58894A (10(-7) - 10(-5) M), a beta3-AR antagonist, caused a rightward shift of the concentration-relaxation curve for isoprenaline in a concentration-dependent manner. The pA2 value and slope obtained from Schild plots were 6.24+/-0.20 and 0.68+/-0.31. The beta1-, beta2- and beta3-AR mRNAs were all positively expressed in detrusor smooth muscle preparations in a reverse transcription polymerase chain reaction assay. In conclusion, the present results provide the first evidence for the existence of the beta3-AR subtype in the human detrusor. They also suggest that the relaxation induced by adrenergic stimulation of the human detrusor is mediated mainly through beta3-AR activation.

We investigated the beta-adrenoceptor subtypes mediating ureteral relaxation in rats, rabbits and dogs. The relaxing effects of beta-adrenoceptor agonists were evaluated on KCl-induced ureteral contractions. The rank order of potency of the catecholamines tested was isoprenaline > noradrenaline > adrenaline in rat ureter; isoprenaline > adrenaline > noradrenaline in rabbit ureter; only isoprenaline was effective in canine tissues. The beta1-adrenoceptor agonist, dobutamine, produced relaxation of rat ureter. The beta2-adrenoceptor agonist, procaterol, produced more significant relaxation of rabbit ureter than did dobutamine. CL-316243 [(R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethylamino]propyl]-1,3-b enzodioxole-2,2-dicarboxylate] and CGP-12177A [(+/-)[4-[3[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-+ ++benzimidazol-2-one hydrochloride], beta3-adrenoceptor agonists, were more effective in relaxing canine ureter than were dobutamine and procaterol. Isoprenaline-induced relaxation was antagonized by a beta1-adrenoceptor antagonist, CGP-20712A [2-hydroxy-5(2-((2-hydroxy-3-(4-((1-methyl-4-trifluoromethyl)1H-imidazol e-2-yl)phenoxy)propyl)amino)ethoxy)-benzamide monomethane sulphonate], in rats and by a beta2-adrenoceptor antagonist, ICI-118,551 [(+/-)-1-[(2,3-dihydro-7-methyl- 1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride], in rabbits. The non-selective beta-adrenoceptor antagonist, bupranolol, antagonized isoprenaline-induced relaxation in all species tested. In conclusion, beta-adrenoceptor agonists may relax ureter by stimulating mainly beta1-adrenoceptors in rats, beta2-adrenoceptors in rabbits and mainly beta3-adrenoceptors in dogs.

1. The beta-adrenoceptor (beta-AR) subtypes mediating relaxation of the rabbit, rat and canine detrusors were subjected to functional investigation using selective beta-AR agonists and antagonists. 2. In all three species, isoprenaline, noradrenaline and adrenaline each produced a concentration-dependent relaxation of the detrusor. The rank order for their relaxing potency was isoprenaline>adrenaline>noradrenaline in rabbits and rats, but isoprenaline>noradrenaline>adrenaline in dogs. 3. Dobutamine did not produce relaxation of the detrusors at concentrations that are selective for beta1-AR. The selective beta2-AR agonist, procaterol, had a more potent relaxing effect on rabbit and rat detrusors than on the canine detrusor. CGP-12177A, a selective beta3-AR agonist, was more effective in the rabbit than in the other two species. On the other hand, the relaxing effect of another beta3-AR agonist, CL316243, was more pronounced in dogs and rats than in rabbits. 4. CGP-20712A (10(-9) to 10(-7) M), a selective beta1-AR antagonist, caused a slight rightward shift of the concentration-relaxation response curve for isoprenaline in the canine detrusor (pA2 9.41), but not in the rabbit and rat detrusors. ICI-118,551, a selective beta2-AR antagonist, antagonized the isoprenaline-induced relaxation in rabbits (pA2 9.45) and rats (pA2 9.05), but not in dogs. Bupranolol, a non-selective beta-AR antagonist, caused a rightward shift of the concentration-relaxation curve for isoprenaline in the rabbit (pA2 9.32) and rat (pA2 8.98). However, higher concentrations (3 x 10(-8) to 10(-5) M) were needed to induce a rightward shift of the curve for isoprenaline in the dog (pA2 8.19) than in the other two species. 5. We have confirmed that the distribution of beta-AR subtypes in the detrusor muscle varies significantly from species to species and we provide here the first evidence of the presence of beta3-AR in the detrusor. It is suggested that the relaxation induced by adrenoceptor agonists in urinary bladder smooth muscle may be mediated mainly via beta2-AR in rabbits, via both beta2- and beta3-AR in rats, but mainly via beta3-AR in dogs.

OBJECTIVE: Our purpose was to compare the effects of peptidyl and nonpeptidyl oxytocin antagonists on the pregnant rat uterus in relation to the progress of gestation. STUDY DESIGN: Pregnant rats with gestational ages of 17 and 21 days were used. A saturation binding of tritiated oxytocin to myometrial membrane preparation and its displacement by unlabeled oxytocin and the oxytocin antagonists were examined. The inhibitory effects of peptidyl and nonpeptidyl oxytocin on spontaneous, oxytocin-induced, and prostaglandin F 2α - induced uterine contractions were also evaluated in vitro and in vivo. RESULTS: The number of tritiated oxytocin binding sites in myometrial membranes of pregnant rats increased markedly at day 21 of gestation compared with day 17 of gestation, whereas the dissociation constants for tritiated oxytocin did not differ significantly. As for the binding affinities to oxytocin receptors of myometrial membranes, the inhibition constant values of nonpeptidyl oxytocin were 79 and 351 times larger than those of peptidyl oxytocin at pregnancy days 17 and 21, respectively. Both drugs remarkably inhibited oxytocin-induced uterine contractions in a dose-dependent manner. However, peptidyl oxytocin did not affect spontaneous and prostaglandin F 2α - induced contractions except for spontaneous ones of rats of pregnancy day 21 in vivo. On the other hand, nonpeptidyl oxytocin suppressed spontaneous and prostaglandin F 2α - induced contractions of the uterus both in vivo (pregnancy day 17) and in vitro (pregnancy day 21). CONCLUSION: These results suggest that peptidyl oxytocin may inhibit uterine contractions by selectively antagonizing the oxytocin action at the receptor site, whereas nonpeptidyl oxytocin at high concentrations may have the additional effect of directly suppressing the contractions. This effect of nonpeptidyl oxytocin may become therapeutically advantageous in clinical application for preterm labor. (Am J Obstet Gynecol 1996;175:1348-55.)

The effects of KSG-504 ((S)-arginium (R)-4-[N-(3-methoxypropyl)-7V-pentylcarbamoyl]-5-(2-naphthylsulfonyl) pentanoate monohydrate), a new cholecystokinin (CCK)-A-receptor antagonist, on pancreatic exocrine secretion in anesthetized rats and endocrine secretion in conscious rats were studied. Intravenous injection of KSG-504 inhibited the pancreatic amylase output stimulated by intravenous infusion of CCK-8 in a dose-dependent manner (ED50: 18 μg/kg/min). Moreover, KSG-504 significantly reduced the CCK-8-stimulated increases in pancreatic juice volume and outputs of protein, trypsin and lipase. Intraduodenal infusion of casein increased the plasma CCK concentration and the pancreatic amylase output. KSG-504 significantly inhibited the pancreatic amylase output stimulated by casein. Pancreatic juice volume and bicarbonate output were significantly stimulated by intravenous infusion of secretin, but were not changed by KSG-504. When pancreatic exocrine secretion was stimulated by secretin plus CCK-8, KSG-504 suppressed the increases in juice volume and bicarbonate output to the level stimulated by secretin alone. Basal pancreatic amylase output was decreased by KSG-504. KSG-504 decreased the level of plasma immunoreactive insulin (IRI) stimulated by glucose plus CCK-8, but had no effect on IRI stimulated by glucose alone and the basal IRI. These in vivo studies suggest that KSG-504 has significant inhibitory effects both on the pancreatic exocrine and endocrine secretion stimulated by CCK, but has no effect on the exocrine secretion stimulated by secretin.

Objective: The aims of this study were (1) to evaluate the usefulness of the new β 2 -adrenergic stimulant KUR-1246 as a tocolytic agent and (2) to clarify the mechanisms that underlie the diverse inhibitory effects of β 2 -stimulants that are seen in human myometria in vitro. Study Design: The displacement of tritiated ([ 3 H]) (−)CGP 12177 (0.4 nmol/L) by KUR-1246 and other β2-stimulants was examined with human β 1 - and β 2 -receptors present on membrane fractions. The inhibitory effects of these β 2 -stimulants on the term-pregnant human myometrium were compared with the use of isometric tension recording and microelectrode methods. Finally, the relationship between [ 3 H]dihydroaloprenolol binding and the magnitude of the tocolytic effect of isoproterenol was examined. Results: KUR-1246 was approximately 80 times and 7 times more selective for β 2 -receptors than isoproterenol and ritodrine, respectively. The inhibitory effect of KUR-1246 was as strong as the inhibitory effect of the conventional β 2 -adrenergic stimulants. A wide range of inhibitory effects was observed, even when high concentrations of isoproterenol or KUR-1246 were applied. There was a correlation between the degree to which isoproterenol suppressed contractions and the number of [ 3 H]dihydroaloprenolol binding sites on the membrane in each muscle strip. Conclusion: KUR-1246 should be a very useful β2-adrenergic stimulant for use as a tocolytic agent because of its high selectivity for the β 2 -receptor and its potent inhibitory effect. The diversity of the inhibitory effects that are induced by β 2 -stimulants is at least partly due to differences in β 2 -receptor density among term-pregnant human myometria. (Am J Obstet Gynecol 2002;186:997-1004.)

The aim of this study was to evaluate the effects of a β3-adrenoceptor (AR) agonist (CL-316243), an α1-AR agonist (phenylephrine), and a loop diuretic (furosemide) on the spontaneous rhythmic contractions of the isolated canine ureter and on an acute ureteral obstruction produced by inflation of a balloon catheter in anesthetized dogs. In the isolated ureter, CL-316243 concentration dependently reduced both the amplitude and frequency of the rhythmic contractions (pD2: 7.19 ± 0.33), whereas phenylephrine significantly enhanced both variables (pD2: 5.26 ± 0.09) and furosemide reduced them only slightly. In the acute ureteral obstruction model, the intraureteral pressure (IUP) gradually rose to reach a plateau of 58.9 mm Hg after inflation of a balloon catheter within the lower ureter. Intravenous administration of CL-316243 (0.3 μg/kg) significantly reduced the elevated IUP and the resumed urine flow (UF), leading to a sustained reduction in the IUP. In contrast, the IUP continued to increase above the plateau level for 10 minutes after phenylephrine administration (10 μg/kg) and for 30 minutes after furosemide administration (1,000 μg/kg). In the phenylephrine group, the UF resumed when the IUP reached 75.8 mm Hg, and thereafter the IUP gradually decreased in parallel with the increase in the UF. From these results, we conclude that in dogs, CL-316243 reduces the IUP by allowing the UF to resume as a result of a relaxation of ureter at the obstruction site, whereas with phenylephrine, the reduction in the IUP is secondary to a resumption in the UF resulting from an induced contraction of ureter that causes an increase in hydrostatic pressure above the obstruction site. Neurourol. Urodynam. 21:251–257, 2002. © 2002 Wiley-Liss, Inc.

In this study, we used a coactivator-dependent receptor-ligand interaction assay (CARLA), which is a semifunctional in vitro assay, to determine whether hypolipidemic drugs are ligands for the three peroxisome proliferator-activated receptor isotypes (PPARalpha, delta, and gamma). We also evaluated the transcriptional activities of the three PPAR isotypes by transient transfection assays. We found that bezafibrate was a ligand for PPARalpha, delta, and gamma in the CARLA and that bezafibrate induced transcriptional activation of PPARalpha/RXRalpha, PPARdelta/RXRalpha, and PPARgamma/RXRalpha. Although the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors cerivastatin, fluvastatin, and pitavastatin were not ligands for these three nuclear receptors in the CARLA, they induced transcriptional activation of PPARalpha/RXRalpha, PPARdelta/RXRalpha, and PPARgamma2/RXRalpha. Moreover, cerivastatin, fluvastatin, and pitavastatin synergistically and dose-dependently increased the transcriptional activation of PPARalpha/RXRalpha induced by bezafibrate. In addition, the cerivastatin-induced transcriptional activation of PPARalpha/RXRalpha was decreased by addition of mevalonate, farnesol, geranylgeraniol, or cholesterol and by co-transfection with sterol regulatory element-binding protein-1 (SREBP-1). Moreover, concomitant administration of statins and fibrates also decreased the transactivation of nuclear factor kappaB (NFkappaB) and the activation of NFkappaB by mitogen-activated protein kinase kinase kinase (MEKK) also decreased the transactivation of PPARalpha/RXRalpha.

In the present study, the β-adrenoceptor subtypes distributed in the detrusor of the ferret were investigated in functional experiments in vitro and in vivo using a variety of β-adrenoceptor agonists and antagonists. All the β-adrenoceptor agonists tested relaxed the isolated detrusor strip, the rank order of potency being (±)-( R *, R *)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]phenoxy]-acetic acid sodium (BRL 37344A)>(±)-4-(3- t -butylamino-2-hydroxypropoxy) benzimidazol-2-one (CGP-12177A), isoprenaline and ( R , R )-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethylamino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316,243)>dobutamine and procaterol. In antagonist experiment, 3-(2-allylphenoxy)-1-[(1 S )-1,2,3,4-tetrahydro-naphth-1-ylamino]-(2 S )-2-propanol hydrochloride (SR 58894A), but neither 2-hydroxy-5(2-((2-hydroxy-3-(4-((1-methyl-4-trifluoromethyl)1 H -imidazole-2-yl)-phenoxy)propyl)amino)ethoxy)-benzamide monomethane sulphonate (CGP-20712A) nor erythro-(±)-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol hydrochloride (ICI-118,551), caused a rightward shift of the concentration-relaxation curve for isoprenaline. In in vivo experiments, isoprenaline and CL 316,243 each reduced bladder pressure in a dose-dependent manner. CL 316,243 was the only drug that did not produce any significant influences on blood pressure and heart rate at doses that reduced bladder pressure. The present functional study provides the first evidence that relaxation of the ferret detrusor by β-adrenoceptor activation is mediated mainly via the β 3 -adrenoceptor, as in the human detrusor.

SUMMARY 1. We examined whether KRH-594, a new angiotensin AT1 receptor antagonist, ameliorates the progression of diabetic nephropathy and hyperlipidaemia in streptozotocin (STZ)-induced diabetic unilateral nephrectomized spontaneously hypertensive rats (DM-1K-SHR) or not. 2. The oral administration of KRH-594 (3 and 10 mg/kg per day) and candesartan cilexetil (1 mg/kg per day) for 16 weeks significantly reduced systolic blood pressure, urinary albumin and urinary total protein in DM-1K-SHR. 3. In a histological study, KRH-594 (3 and 10 mg/kg per day) and candesartan cilexetil (0.3 and 1 mg/kg per day) dose-dependently improved glomerulosclerosis and the hyalin cast of tubules in DM-1K-SHR kidneys. Both KRH-594 (10 mg/kg per day) and candesartan cilexetil (0.3 and 1 mg/kg per day) dose-dependently inhibited cardiac hypertrophy. 4. KRH-594 (3 and 10 mg/kg per day), but not candesartan cilexetil, dose-dependently reduced the levels of triglyceride, total cholesterol and phospholipids in DM-1K-SHR. 5. These results suggest that KRH-594 improves diabetic complications, such as nephropathy and hyperlipidaemia, with hypertension.

Objective: Our purpose was to compare the functional roles of oxytocin in term and preterm labor in rats by both biochemical and pharmacologic means. Study Design: We determined the myometrial oxytocin receptor density and the maternal plasma concentrations of oxytocin and progesterone on gestational days 18, 20, and 22 (morning) and at the onset of delivery (day 22 afternoon) in rats with labor at term and at the onset of delivery (day 20 afternoon) in rats in preterm labor induced by the combined use of bilateral ovariectomy and estradiol injection. We also evaluated the effects of an oxytocin antagonist, L-366,509, on the initiation of both term and preterm labor. Results: The number of tritiated oxytocin binding sites in myometrial membranes rapidly increased on gestational day 22 (morning) in rats with term labor. Plasma progesterone level decreased in an inverse fashion. A rapid increase in circulating oxytocin concentration was observed at the onset of delivery in rats in labor at term. Both the plasma oxytocin concentration and the receptor density had the same values in rats with preterm labor as in rats with term labor. L-366,509 delayed the initiation of labor in rats with term and preterm labor in a dose-dependent manner. Conclusion: It is confirmed biochemically and pharmacologically that oxytocin plays an important role in the initiation of both term and preterm labor in rats. The oxytocin antagonist examined was able to delay term and preterm labor, so it might prove useful in clinical practice for the treatment of preterm labor. (Am J Obstet Gynecol 1999;180:621-7.)

The purpose of this study was to examine the placental passage of ritodrine hydrochloride in relation to the drug's effects on the fetal circulation. Studies were carried out on nine nulliparous pregnant (120-140 days) ewes with chronically implanted cannulae for measurements of maternal and fetal arterial pressures and for blood sampling. One group of animals received sequential infusions of doses ranging from 0.1 to 30 micrograms/kg per min for 30 min (group 1). A second group was given a constant infusion of the drug at a dose of 3.0 micrograms/kg per min for 4 h (group 2). The peak concentrations of ritodrine in maternal and fetal blood were determined by radioimmunoassay. In group 1 they were 313.4 +/- 24.1 ng/ml (mean +/- S.E.) and 12.6 +/- 3.7 ng/ml at the finish of 30.0 micrograms/kg per min infusion for maternal and fetal blood, respectively. In group 2, maternal drug levels were 81.3 +/- 20.4 ng/ml after 30 min and 95.9 +/- 17.1 ng/ml after 4 h of the infusion. Fetal plasma concentrations increased slowly from trace levels at 30 min to 3.3 +/- 0.7 ng/ml at 4 h. Fetal blood pressure and heart rate did not show any significant changes during and after the infusion of ritodrine in both treatment groups. Our findings demonstrate the maternal administration of ritodrine produces no significant effects on the circulatory system of the fetal lamb because of the low transplacental passage of this drug.

Exposure of the rat to restraint and water immersion stress enhanced a characteristic gastric movement in a 2- to 4-hr latent period. The mechanism of producing such gastric movement was studied in connection with changes in the sympatho-adrcnal activity. Acute bilateral adrenalectomy and reserpine pretreatment significantly hastened occurrence of the gastric movement and guanethidine pretreatment showed a similar tendency. Epinephrine content in the adrenals of the stressed group markedly decreased at the time of occurrence of the gastric movement. Urinary excretion of epinephrine and norepinephrine continued to increase for 3 hr and for 6 hr respectively, after the onset of stress, and both excretory rates declined thereafter. Epinephrine and norepinephrine were much more effective on depressing the stress-induced gastric movement than cortisone and ACTH. It was suggested that: 1) at the initial stage of stress, the adrenal function as well as the sympathetic nervous function was activated, and a large amount of epinephrine and norepinephrine was secreted, which brought about an inhibition of the gastric movement; 2) at the subsequent stage, the parasympathetic nervous function became more prominent than the sympathoadrenal one and initiated the gastric movement; and 3) contribution of corticosteroids and/or ACTH to the gastric movement was small, if any.

Gastric motility of stressed rats was studied to determine its role in producing stress-induced gastric lesions. Restraint and water immersion resulted in an increase in gastric motility which consisted of an increase in frequency and amplitude of contractions and a rise in gastric tone. This increase reached maximal levels 2 to 4 hr after stress, and persisted thereafter. Formation of gastric lesions was markedly accelerated after occurrence of the increased gastric motility. In contrast, restraint alone neither produced such a vigorous increase in gastric motility, nor were the gastric lesions severe. A continuous infusion of papaverine during restraint and water immersion inhibited increase in frequency and amplitude of gastric contractions and prevented formation of gastric lesions. It is concluded that increased gastric motility is closely associated with marked formation of gastric lesions under conditions of restraint and water immersion stress and is probably a main cause for their vigorous formation, although formation of lesions occurs to a small degree without involvement of gastric motility.

Seven healthy pregnant volunteers undergoing elective cesarean section at 39–40 weeks of gestation were studied for transplacental passage of ritodrine hydrochloride, which was administered by intravenous infusion at the rate of 72–149 μg/min for 161–335 min. The concentrations of ritodrine in the collected maternal and fetal blood and the amniotic fluid were radioimmunoassayed. The levels of ritodrine in maternal serum were between 22.5 and 51.0 ng/ml one hour after the initiation of infusion, 33.7–66.4 ng/ml after 2 h, 18.2–73.6 ng/ml after 4 h and 45.7–189.6 ng/ml at delivery, respectively. The umbilical blood and amniotic fluid concentrations of ritodrine at delivery were between 15.6 and 35.1 ng/ml in arterial blood, 12.5–29.6 ng/ml in venous blood and 10.0–49.1 ng/ml in amniotic fluid. The ratio of umbilical venous blood concentrations to maternal venous concentrations ( CV MV ) ranged from 0.066 to 0.544 with the mean of 0.263 ± 0.063 (M ± S.E.). The results obtained substantiate the rapid and appreciable transfer of ritodrine to the fetus and amniotic fluid.

The effects of ritodrine hydrochloride on maternal and fetal arterial blood pH and pCO2, plasma electrolytes and maternal plasma glucose and free fatty acid levels were investigated in the third-trimester pregnant sheep. Ritodrine produced a slight fall in the maternal and fetal arterial pH without changes in the arterial pC02. The pH values were, however, within a normal range. Increases in the maternal plasma glucose and free fatty acid levels were also observed. Although maternal and fetal plasma sodium and chloride concentrations did not change, the potassium decreased in a dose-dependent manner both in the ewe and in the fetus following sequential ritodrine infusion. Constant infusion of ritodrine (3 mcg/kg/min), which is a sufficient dose to inhibit uterine contractions, also resulted in a significant decrease in the maternal plasma potassium concentration. It appears to be necessary to give attention to the metabolic effects of ritodrine in long-term therapy of premature labor.

The effects of ritodrine hydrochloride on uterine activity and maternal and fetal circulations were investigated in chronically prepared pregnant sheep. Ritodrine inhibited oxytocin-induced uterine contractions in a dose-dependent manner. The inhibition of uterine activity at 3 mcg/kg/min of ritodrine was about 70%, and greater infusion rates resulted in only minimal further inhibition of the uterine activity. Maternal tachycardia but no hypotension were observed during ritodrine infusion. There were no significant changes in fetal heart rate or blood pressure. Uterine arterial blood flow decreased remarkably at higher doses of ritodrine. These changes were, however, less pronounced when ritodrine was infused at a constant dose of 3 mcg/kg/min, which was sufficient to inhibit the uterine activity. In addition, propranolol blocked the effect of ritodrine on uterine activity and maternal heart rate. This supports the view that ritodrine produces its effects through activation of adrenergic β-receptor.