Effect of moxisylyte on the lower urinary tracts (1). Effect on the isolated rabbit urethra and bladder]

Effect of moxisylyte on the lower urinary tracts was studied in comparison with those of prazosin and bunazosin in the isolated rabbit bladder and urethra. Moxisylyte dose-dependently inhibited the urethral contraction induced by phenylephrine. The IC50 value of moxisylyte was 1.01 x 10(-6) M. Prazosin and bunazosin inhibited the urethral contraction as well as moxisylyte. The IC50 values of prazosin and bunazosin were 2.88 x 10(-7) M and 1.44 x 10(-7) M, respectively. Moreover, moxisylyte and bunazosin inhibited the urethral contraction induced by KCl. The IC50 values of moxisylyte and bunazosin were 1.17 x 10(-5) M and 1.35 x 10(-4) M, respectively. The KCl/phenylephrine ratios of moxisylyte, bunazosin and prazosin were as follows: 17, 938 and 9201, respectively. Moxisylyte has a relaxant action on the urethra that is probably ascribable to its alpha 1-adrenoceptor antagonist and Ca++ antagonist actions. In the isolated bladder, moxisylyte inhibited the bladder contraction induced by KCl, with an IC50 value of 4.46 x 10(-5) M. However, moxisylyte did not affect the contractile response to acetylcholine. These results suggest that the relaxant effect of moxisylyte on the urethra is due to alpha 1-adrenoceptor antagonist and Ca++ antagonist actions. Therefore, moxisylyte is useful for the therapeutic treatment of micturitional disorder.     

Effect of 2-phenylaminoadenosine (CV-1808) on ischemic ST-segment elevation in anesthetized dogs

The effect of 2-phenylaminoadenosine (CV-1808) against myocardial ischemia was studied in anesthetized dogs. During intravenous infusion of CV-1808 (0.25 and 0.5 microgram/kg/min for 10 min) the ST-segment elevation in the epicardial ECG induced by a 5-min occlusion of a coronary arterial branch was occasionally enhanced in association with cardiac acceleration. In a dose of 0.5 microgram/kg/min, the agent inhibited the ST elevation 30 and 60 min after administration. The same dose did not change myocardial blood flow in the ischemic area despite significant systemic hypotension. In hearts with continuous coronary occlusion, CV-1808 (0.3 and 1.0 microgram/kg, i.v. bolus) increased the retrograde blood flow from the ischemic area immediately after administration, suggesting a collateral vasodilating action. Nifedipine (0.5 and 2.5 microgram/kg/min, i.v. for 10 min) and nitroglycerin (0.5 and 5.0 microgram/kg/min, i.v. for 10 min) had no influence on the ischemic ST-segment elevation, while a significant inhibition was seen with propranolol (0.5 mg/kg, i.v.). A moderate hypotension was induced by CV-1808, nifedipine, and nitroglycerin, while a significant reduction in cardiac function was seen after dosing with propranolol.     

硅酸钠对犬血流动力学的作用

麻醉犬8只,iv硅酸钠10～20mg/kg,观察血流动力学各参数的影响。结果表明Na_2SiO_3可使LVSP,+dp/dt max和VCE-+dp/dtmax增加,-dp/dt max增加而T值缩短,可使SBP,DBP和MAP增加,CI增加而对HR及THR影响不大。认为升压作用与CI增加,心脏作功增加有关。     

Effect of 4-ethylamino-2-butynyl(2-cyclohexyl-2-phenyl) glycolate, metabolite of oxybutynin, on intra-artery administered acetylcholine-induced urinary bladder contraction in anesthetized dogs

Oxybutynin has been used for neurogenic bladder disorders in clinic and known to have anti-cholinergic and spasmolytic properties. Metabolite of oxybutynin, 4-ethylamino-2-butynyl(2-cyclohexyl-2-phenyl) glycolate (N-desethyloxybutynin: DEOB) has been known to have similar anti-cholinergic and spasmolytic properties. However, the effect of DEOB on the urinary bladder has not been clarified in situ. Therefore, in the present study, we studied the effect of DEOB on acetylcholine-induced urinary bladder contraction in comparison with oxybutynin in anesthetized dogs. Intravenously administered DEOB dose-dependently inhibited acetylcholine-induced contractions. Oxybutynin also showed similar efficacy. From the Schild plot, it was found that the slope of DEOB and oxybutynin were 0.78 (95% confidence limit: 0.45-1.11) and 1.49 (95% confidence limit: 0.91-2.08), respectively. The dose of DEOB or oxybutynin needed to shift the concentration-dependent curve of acetylcholine rightward to a two times higher dose was calculated. The doses of DEOB and oxybutynin were 6.4 micro g/kg (95% confidence limit: 1.7-12.8 micro g/kg) and 13.9 micro g/kg (95% confidence limit: 6.3-24.5 micro g/kg), respectively. From the above results, it was found that DEOB has the same anti-cholinergic property as oxybutynin and that its activity was almost equipotent to that of oxybutynin. Therefore, DEOB was suggested to play an important role during oxybutynin therapy for neurogenic bladder disorder.     

刺五加叶皂苷对麻醉犬血流动力学的影响

目的研究刺五加叶皂苷(ASS)对麻醉犬血流动力学的影响。方法ASS按7.5、15、30mg/kg给麻醉犬静脉输注60min,应用MF-27型电磁流量计测定外周血流量(PBF)和外周血管阻力(PVR)及其血压(SBP、DBP)和心率(HR)等指标。结果ASS15、30mg/kg于给药后30min即能明显增加PBF,同时明显降低PVR,60min达高峰,一直持续到180min,7.5mg/kg对PBF和PVR均无明显影响。此外,ASS15、30mg/kg于给药后60~180min可使HR明显减慢,30mg/kg于给药后30~180min可使SBP及DBP明显降低,15mg/kg有降低SBP及DBP的趋势,7.5mg/kg对HR、SBP及DBP则无明显影响。结论ASS对心肌缺血的保护作用可能与其明显改善血流动力学有关。     

蛇床子素对麻醉开胸犬心电图和血流动力学的影响

麻醉开胸犬，ｉｖ７．５－１５ｍｇ·ｋｇ￣（－１）蛇床子素后，收缩期血压，舒张期血压，平均血压，左室收缩压，室内压最大上升速率及心输出量，总外周阻力均降低，在１０ｍｉｎ时为作用高峰；ｉｖ７．５ｍｇ·ｋｇ￣（－１），心电困无影响，但ｉｖ１５ｍｇ·ｋｇ￣（－１），心电图的Ｐ－Ｒ间期略延长。且室内压最大下降速率也降低。提示蛇床子素有抑制心脏作用，且外周阻力降低，血压下降，故在临床应用时应引起注意。     

丹参素钠对麻醉犬心肌耗氧量的影响

目的观察丹参素钠静注对麻醉犬心肌耗氧量的影响。方法采用心导管法检测冠状静脉窦血样及动脉血氧等指标,研究丹参素钠对缺血心肌的作用。结果给药后5 min到120 min的各时间点,丹参素钠可明显增加麻醉犬心输出量、冠脉流量;降低冠脉阻力;降低总外周阻力;明显降低心肌氧摄取率,与生理盐水组比较有显著差异,作用强度与剂量有一定的量效关系。结论丹参素钠对心肌缺血损伤具有一定预防治疗作用。     

注射用红景天苷对麻醉犬血流动力学的影响

目的:观察注射用红景天苷对麻醉犬血流动力学的影响。方法:杂种犬36只,人工呼吸下开胸,给药后观察其心率(HR)、血压(MAP)、心输出量(CO)、冠脉血流量(CBF)、左室压(LVP)、左心室舒张末期压(LVEDP)、左室等容收缩期压力最大变化率(±LVdP/dtmax)等指标,计算冠脉阻力(CVR)和体循环总外周阻力(TPR)等血流动力学指标。结果:红景天苷(2,4,8 mg.kg-1)对MAP,HR和LVP无明显影响,能显著增加CBF和CO,±LVdP/dtm ax也出现不同程度的增加,同时LVEDP,CVR和TPR降低。结论:注射用红景天苷能明显改善麻醉开胸犬的血流动力学指标。     

Effect of perhexiline on atrioventricular nodal function of anesthetized dogs

We investigated the effects of perhexiline, a calcium-antagonistic vasodilator, on atrioventricular (AV) conduction in anesthetized open-chest dogs and in isolated, blood-perfused AV node preparations of the dog. Perhexiline, 3 mg/kg, prolonged the AV conduction time from 103.0 +/- 4.4 to 115.3 +/- 4.0 msec (p less than 0.05) in dogs with intact cardiac nerves. In dogs on which vagotomy and stellectomy had been performed, basal AV conduction time was 119.0 +/- 5.0 msec; 3 mg/kg of perhexiline barely prolonged it (121.0 +/- 7.0 msec). Thus, the negative dromotropic effect of perhexiline was abolished by denervation. The functional refractory period of the AV node was also lengthened with 3 mg/kg of perhexiline in the nerve-intact dogs (from 246.0 +/- 15.7) to 270.0 +/- 15.5 msec), but was scarcely affected by perhexiline in the cardiac denervated dogs (from 296.7 +/- 15.7 to 303.2 +/- 13.6 msec). Verapamil, 0.1-0.3 mg/kg, exerted a negative dromotropic effect in both innervated and denervated hearts. A direct inhibitory effect of perhexiline on AV conduction was observed in isolated blood-perfused AV node preparations, but it was much weaker when compared with that of verapamil.     

Clinical study of amoxicillin used for treatment of infections of the lower urinary tracts (author's transl)]

The following results were obtained from treatment of 29 cases of lower urinary tract infections with amoxicillin. 1. Amoxicillin was remarkably effective in 13 cases of acute cystitis, in terms of effect according to dose and bacterial species. 2. The effective rate of amoxicillin in 10 cases of chronic cystitis amounted only to 30% due to complications and resistant bacteria. (The group given 1,500 mg/day was a little higher in the effective rate than the 750 mg/day group.) 3. Amoxicillin was low in effect against infections with Pseudomonas aeruginosa and hardly effective against bacteria resistant to amoxicillin. 4. So far as this study is concerned, amoxicillin produced good clinical results at a half dose of ampicillin, as in the fundamental experiment. 5. Any severe side effect was observed in no case.     

The absorption of trichloroethylene and its metabolites from the urinary bladder of anesthetized dogs

In order to examine the absorption of trichloroethylene (TRI) and its metabolites from the urinary bladder of dogs, we injected TRI and its metabolites, i.e., chloral hydrate (CH), free trichloroethanol (F-TCE), trichloroacetic acid (TCA) and conjugated trichloroethanol (Conj-TCE), into the urinary bladder of anesthetized dogs, and measured the agents and their respective metabolites in the blood or serum, urine and bile. The percentage of water absorbed from the urinary bladder was 10-20% 2 h after the administration of all substances. The percentage of agents absorbed was 60-70% for the TRI and TCA groups, and 50-60% for the CH, F-TCE and Conj-TCE groups 2 h after administration. The combined urinary and biliary excretion rates of the absorbed materials from the urinary bladder 2 h after administration were 46% for F-TCE, 30% for CH, 6% for Conj-TCE and 0.5-1.0% for TRI and TCA. Urinary re-excretion rates of the total excreted amounts were 65-70% in TRI, CH and F-TCE groups, about 50% in TCA and 99% in Conj-TCE group. It is possible that all of the substances administered, particularly F-TCE, are metabolized to Conj-TCE in the urinary bladder.     

Effect of vasodilator drugs on coronary occlusion and reperfusion arrhythmias in anesthetized dogs

The effect of vasodilator drugs on the incidence of ventricular arrhythmias induced during 30 min of occlusion and 15 min of reperfusion of the left anterior descending coronary artery (LAD) was studied in 65 pentobarbital-anesthetized open-chest dogs. Intravenous administration of captopril (0.5 mg/kg), enalapril (0.5 mg/kg), felodipine (4 micrograms/kg), or ketanserin (0.1 mg/kg) 30 min before LAD occlusion reduced mean arterial blood pressure by 15.5 +/- 0.6% (mean +/- SEM). Nifedipine (5 micrograms/kg bolus + 1 microgram/kg min-1) infusion reduced mean arterial blood pressure by 24.8 +/- 1.8%. In none of the dogs was the diastolic blood pressure reduced below 70 mm Hg. During LAD occlusion, reduction in arterial blood pressure by these drugs was associated with a reduced incidence of ventricular premature depolarizations, ventricular tachycardia, and ventricular fibrillation (VF). During LAD reperfusion, the incidence of VF in saline-treated animals was 6/9, whereas for captopril it was 6/9, enalapril 1/9, felodipine 7/9, nifedipine 3/8, and ketanserin 3/9 animals. Thus, only enalapril significantly lowered the incidence of VF (p less than 0.05). The mechanism responsible for this antifibrillatory effect of enalapril is unknown. The muscle mass of the left ventricle supplied by the LAD distal to the site of occlusion in dogs which survived was similar to that of dogs which developed ventricular fibrillation.     

Effect of oxybutynin hydrochloride on isolated smooth muscles (ileum, urinary bladder and urethra)

Effects of oxybutynin hydrochloride on isolated smooth muscle were investigated in preparations of isolated rabbit bladder body, bladder base, collum vesicae and urethra. ACh produced a marked contraction of the preparation from the bladder body and produced no response in the collum vesicae and the urethra; however, NE caused a marked contraction of the preparations from the collum vesicae and the urethra and relaxation in the bladder body. Oxybutynin and papaverine hardly had any effect on these preparations. Effects of oxybutynin on the contractile response of the isolated ileum or urinary bladder of rabbit, guinea pig and rat in comparison with atropine, papaverine, flavoxate and other drugs were investigated. The responsibility of these preparations to ACh were approximately 100 times higher in the ileum than in the urinary bladder. Oxybutynin showed a competitive inhibition to contractile response induced by ACh in the ileum and urinary bladder, whose potency was about 1/7-1/10 that of atropine. In the ileum of rats which were treated with oxybutynin orally at a dose of 1, 10 or 100 mg/kg for 60 days, the response to ACh in the preparations of the animals treated by 100 mg/kg were decreased, but the anticholinergic action in the groups treated with oxybutynin were not significantly different compared with the nontreated or saline treated group. On the other hand, oxybutynin showed a non-competitive inhibition to contractile response induced by Ba2+, Ca2+ and histamine in the guinea pig ileum and Ba2+, high-K+, Ca2+ and ATP in the rabbit urinary bladder. These potencies of oxybutynin were equal or slightly stronger than that of papaverine or flavoxate. However, oxybutynin had no effect on the contraction induced by NE in the rabbit urethra. The above results suggest that oxybutynin has atropine-like anticholinergic action and direct muscle relaxant action evidenced by non-competitive inhibition to contractile response induced by several agonists.     

Studies on the bradycardia induced by (-)- -trans-tetrahydrocannabinol in anesthetized dogs

(?)-Δ⁹-trans-tetrahydrocannabinol (Δ⁹-THC) (39 μg-5 mg/kg, i.v.) decreased heart rate in a dose related manner in dogs under pentobarbital anesthesia. This cardiac effect of Δ⁹-THC was neither due to an impairment of transmission across the sympathetic ganglia nor to a specific stimulation of parasympathetic ganglia. Selective blockade of either parasympathetic (atropine, bilateral vagotomy) or sympathetic (propranolol, spinal section at C₂C₄ neurogenic activity to the heart partially prevented the negative chronotropic effect of Δ⁹-THC. However the bradycardic effect of Δ⁹-THC was completely abolished in animals in which the autonomic pathways to the heart were pharmacologically or surgically inactivated.Administration of Δ⁹-THC into the vascularly isolated, neurally intact cross-perfused head of dogs significantly slowed the heart rate in intact as well as debuffered recipients. This bradycardia was reduced in recipients in which the trunk was atropinized prior to cerebral administration of Δ⁹-THC into the femoral vein of the recipient in the dog cross circulation preparation also caused a significant decrease in heart rate which was essentially abolished either by bilateral vagotomy or by atropinization of the recipients.These results are compatible with the hypothesis that the negative chronotropic effects of Δ⁹-THC in dogs under pentobarbital anesthesia is of central origin and involves both a direct and reflexogenic alteration of central autonomic outflow regulating the heart rate.     

Endothelin stimulates the renal production of prostaglandin E2 and I2 in anesthetized dogs

The infusion of endothelin into the renal artery of anesthetized dogs (5 ng/kg per min) decreased the renal blood flow without changing the blood pressure, indicating that endothelin caused renal vasoconstriction. The renal secretion rate of prostaglandin E2 and I2 markedly increased and these increases were abolished by pretreatment with aspirin. Furthermore, the renal vasoconstrictor effect of endothelin was potentiated by aspirin, suggesting a role of prostaglandins in the renal action of endothelin.     

Effects of clonidine on baroreceptor function in anesthetized dogs

The effects of clonidine (15–30 μg/kg i.v.) on carotid sinus and other baroreceptors were investigated in anesthetized dogs. In 14 control dogs, right carotid sinus pressure was controlled by retrograde perfusion through the common carotid artery at constant flow with femoral arterial blood. Graded reductions in heart rate and blood pressure induced by graded increases in carotid sinus pressure were prevented, whereas reflex bradycardias associated with norepinephrine pressor activity were potentiated by clonidine. Norepinephrine-induced bradycardia, although reduced, still persisted after chronic bilateral sinusectomy and these responses were also potentiated by clonidine. In contrast, clonidine did not potentiate reflex bradycardia in dogs 20 days after aortic stripping. In intact dogs, clonidine inhibited the response to bilateral carotid artery occlusion and to carotid sinus nerve stimulation. These studies suggest that clonidine can inhibit carotid sinus baroreceptor function and simultaneously potentiate other, presumably aortic, baroreceptor activity.     

Effects of encainide (MJ9067) on the ventricular fibrillation threshold in anesthetized dogs

The right ventricular epicardial ventricular fibrillation threshold (VFT) was determined during paced supraventricular rhythm using 100 Hz trains of stimuli at 15 min intervals in dogs before and during the intravenous administration of encainide, a new antiarrhythmic drug. With each VFT determination, simultaneous blood samples were obtained for determination of drug concentration. In 6 control dogs, VFT determined every 15 min during a 210 administered as a 90 min intravenous infusion at three successive rates (0.01, 0.02 and 0.04 mg/kg/min) for 30 min each. VFT measured at 5 and 20 min of each infusion increased from a mean control of 11.5 +/- 1.5 (+/-SE) to 20.2 +/- 2.2 mA (p less than 0.01) after 20 min of the third infusion. The maximal effect occurred during the second infusion with plasma concentration of 594 +/- 46 ng/ml and then reached a plateau. In group II (n = 6), encainide was administered in four successive sequences, each one including a bolus loading intravenous dose followed by a 45 min intravenous infusion. VFT measured at 30 and 45 min of each infusion when the encainide plasma concentration was close to a steady state increased significantly (p less than 0.01) after the second infusion from 11.8 +/- 2 to 27.3 +/- 4 mA. Two dogs in group II developed transient complete atrioventricular block at an encainide plasma concentration of greater than 800 ng/ml. These results show that the new antiarrhythmic drug encainide increases the VFT in anesthetized dogs.