FORMATION OF A TERNARY COMPLEX WITH SERUM ALBUMIN: AN EXPLANATION FOR THE EFFECT OF α-MERCAPTO-β-(2-FURAN) ACRYLIC ACID ON RAT PLASMA ZINC CLEARANCE

1. Four, six and eight hours after gavage of rats with α-mercapto-β-(2-furan) acrylic acid (MFA) (25 mg/kg) serum zinc concentration was increased ten-fold over control levels and a mean molar ratio of 1 albumin:0.4 zinc:0.8 MFA was found for seventeen sera. 2. At pH 7.5 a maximum of 1 mole of MFA could be bound per mole of metal-free bovine serum albumin. 3. In the presence of zinc ion, albumin-zinc-MFA complexes formed, since for each mole of albumin-zinc complex an additional mole of MFA could be bound to albumin. Complexes up to a molar stoichiometry of 1 albumin:2 zinc:3 MFA were prepared. 4. MFA stabilized the albumin-zinc complex against dissociation. 5. Formation of similar complexes in vivo may account for the markedly delayed clearance of plasma zinc seen in rats administered β-aryl derivatives of α-mercaptoacrylic acid.     

EFFECT OF TRANSMUCOSAL FLUID MOVEMENT ON ZINC AND COPPER ABSORPTION FROM THE RAT SMALL INTESTINE

1. The effects of transmucosal fluid movement on zinc and copper absorption from rat small intestine were investigated using an in situ recirculating perfusion method. 2. Transmucosal fluid movement was obtained by using hypo-, iso- or hyperosmotic perfusate containing various concentrations of sodium chloride. Linear correlations were obtained between net fluid movement and absorption rate constants, which were calculated from the perfusion decline of zinc (n = 15; r= 0.77) and copper (n= 15; r = 0.75). 3. The changes in serum levels of these metals did not correlate with the increase in the absorption rate. 4. The present study indicates that zinc and copper absorption is dependent on transmucosal fluid movement.     

THE EFFECT OF PRAZOSIN ON PRE- AND POSTSYNAPTIC α-RECEPTORS IN THE PITHED RAT

1. Prazosin had a marked inhibitory effect on post-synaptic a-receptors in the pithed rat, as measured by the blood pressure response to the cumulative administration of clonidine. 2. Prazosin had no inhibitory effect, however, on the pre-synaptic a-receptor, as measured by the clonidine-induced reduction in the tachycardia produced by stimulation of the cardiac nerves. 3. These results suggest that prazosin has a selective antagonistic affinity for post-synaptic a-receptors.     

THE EFFECT OF VASOPRESSIN ON HEPATIC ARTERY FLOW IN THE RAT

The effects of vasopressin infusion on hepatic artery flow was studied in rats. Hepatic artery ligation followed by the infusion of vasopressin (0.08 microU/g body weight per min) decreases portal venous flow and liver blood flow. Vasopressin infusion results in an increase in hepatic artery flow and liver blood flow both of which are abolished by subsequent hepatic artery ligation. The increase in hepatic artery flow and the decrease in portal venous flow following the infusion of vasopressin is discussed in relation to the management of patients presenting with bleeding oesophageal varices.     

THE EFFECT OF AGING ON α-ADRENOCEPTORS AND THEIR RESPONSES IN RABBITS

The effects of age on alpha-adrenoceptor responses, sensitivity and number were studied in rabbits aged from 1 to 36 months. Three types of investigation were carried out: conscious animal studies, isolated tissue studies and radioligand binding studies. Specific [3H]-prazosin binding decreased with age in both spleen and heart suggesting that the number of alpha 1-receptors declined at least in the tissues studied. The specific binding of [3H]-clonidine to spleen membranes and [3H]-yohimbine to platelets was not affected by age. In vitro responsiveness to alpha-adrenoceptor agonists decreased with age in abdominal aorta and renal artery, while the affinity of adrenoceptors for prazosin (pA2) was not altered. The decrease may be non-specific as responses to potassium were also altered. No change in alpha 2-adrenoceptor mediated platelet aggregation was observed. No change in pressor or depressor responses to full adrenoceptor agonists or to antagonists was observed in vivo. However, responses to clonidine, which is a partial agonist at alpha 1-adrenoceptors, were decreased. While aging influenced alpha-adrenoceptor subtypes differently, there was no direct relation between functional changes and number of receptors.     

OMEPRAZOLE: EFFECTS ON OXIDATIVE DRUG METABOLISM IN THE RAT

Omeprazole, a substituted benzimidazole and a potent gastric antisecretory drug has been tested for inhibition of microsomal drug oxidative function in the rat. A single dose of 40 mg/kg prolonged pentobarbitone sleeping times from 118 (range 73-168) min to 195 (159-222) min (P less than 0.01), pentobarbitone half-lives from 89 (63-114) to 112 (54-146) min (P less than 0.05) and aminopyrine breath 14CO2 half-lives from 43 (37-51) to 56 (49-79) min (P less than 0.05). Omeprazole in doses of 20 mg/kg or less had no significant effect. In prolonging pentobarbitone sleeping times omeprazole 40 mg/kg and an equimolar (30 mg/kg) dose of cimetidine were approximately equipotent. These results contrast with studies in man in which much smaller doses of omeprazole have been shown to produce clinically significant inhibition of drug metabolism.     

THE EFFECT OF SOME CENTRALLY ACTIVE DRUGS ON CORTICOSTERONE SECRETION AND METABOLISM IN RATS

1. Male rats were treated with morphine sulphate (10 mg/kg), methadone (10 mg/kg) and chlorpromazine (8.0 mg/kg) respectively, for 2 weeks. 2. At the end of this period, the adrenal glands of treated rats had increased in weight. 3. The concentration of corticosterone in the peripheral plasma was significantly lowered in the chlorpromazine-treated rats, increased in the methadone-treated rats and was unchanged in the morphine-treated rats. 4. The metabolic clearance rate of [1,2-³H]corticosterone decreased in the chlorpromazine-treated rats, while only a slight reduction was observed with methadone treatment. 5. These results showed that chronic treatment with either morphine or methadone did not suppress the adrenal function. The possible site of action of chlorpromazine in suppressing corticosterone secretion is discussed.     

蝙蝠葛碱对血小板聚集及花生四烯酸代谢的影响

蝙蝠葛碱(Dau) 抑制AA及ADP诱导的大鼠血小板聚集,也能抑制AA,ADP及Adr诱导的人血小板聚集。这种抑制作用与Dau剂量呈依赖关系。Dau抑制大鼠洗涤血小板对[1-¹⁴C]AA经环氧酶途径的代谢,TXB₂与HHT的形成均呈剂量依赖性减少。当Dau浓度达到0.1 mmol/L时亦能抑制12-HETE的形成。Dau对AA代谢的上述影响可能是其抑制血小板聚集的机理之一。     

A STUDY OF THE EFFECTS OF STEROIDS ON α-ADRENOCEPTOR-MEDIATED CONTRACTION OF THE RAT VAS DEFERENS

1. Testosterone propionate (0·5 mg/day) administered for 5 weeks to prepubertal rats increased the weight of sex accessory organs but did not alter the rate of gain of body weight. Methandienone, given in a similar dosage regimen, was without effect on these parameters. The synthetic progestagen, norgestrel, administered orally in a dose of 0·5 mg/day increased the weight of the vas deferens but was without effect on seminal vesicle and testis weights and on the growth rate. Given in combination with testosterone, norgestrel caused a marked decrease in testis weight and reversed the effects of testosterone propionate on seminal vesicle weight. Thus, in the dosage regimen used, this progestagen exhibited an endocrine profile comprising androgenic, synandro-genic and anti-androgenic effects. 2. Rats, which were castrated when they weighed 70–80 g, exhibited rates of gain of body weight which were similar to those of control animals. Testosterone propionate in the doses used reversed castration-induced atrophy of the vas deferens and seminal vesicle. 3. The contractility of the vas deferens of intact rats, determined by direct field electrical stimulation, was unaffected by treatment with the steroids used in this study. However, there was a marked impairment of the contractility of the vas deferens following castration, which was not fully restored by testosterone propionate in the dosage regimen used. 4. The efficacies and potencies of the α-adrenoceptor agonists phenylephrine and 1-metaraminol in causing contraction of the vasa deferentia from intact rats were unaffected by the steroid treatments. In contrast, these agonists did not produce sustained, dose-dependent contractions of the vasa deferentia from castrated rats; however testosterone propionate fully restored the efficacy and potency of both agonists. 5. It is concluded from this study that although adequate testosterone levels are necessary for the maintenance of contractility in the rat vas deferens, the integrity of postjunctional adrenoceptors in not modified by a variety of steroid treatments.     

抗痫灵在大鼠肝脏中代谢的研究

用离体大鼠肝脏灌流法,研究了抗痫灵在肝脏灌流过程中的代谢规律。用高效液相色谱法由灌流液中分离、制备得到了两种代谢物,经紫外吸收光谱与质谱鉴定,确定代谢物的结构为3,4-次甲基二氧桂皮酰羟基哌啶及阿魏酰哌啶,后者经化学合成得到了进一步的确证。本文还研究了肝循环过程中抗痫灵的代谢动力学,揭示了大部份抗痫灵以原形结合贮存于肝脏中。     

抗痫灵在大鼠肝脏中代谢的研究

用离体大鼠肝脏灌流法,研究了抗痫灵在肝脏灌流过程中的代谢规律。用高效液相色谱法由灌流液中分离、制备得到了两种代谢物,经紫外吸收光谱与质谱鉴定,确定代谢物的结构为3,4-次甲基二氧桂皮酰羟基哌啶及阿魏酰哌啶,后者经化学合成得到了进一步的确证。本文还研究了肝循环过程中抗痫灵的代谢动力学,揭示了大部份抗痫灵以原形结合贮存于肝脏中。     

CENTRAL α-ADRENOCEPTORS AND BLOOD PRESSURE REGULATION IN THE RAT

1. Radioligand binding studies using [³H]-prazosin (α₁) and [³H]-yohimbine (α₂) were undertaken to characterize central α-adrenoceptors in regions involved in blood pressure regulation. 2. Both α₁- and α₂-adrenoceptors were identified in the anterior and posterior hypothalamus and dorsal midline area of the caudal medulla oblongata of the rat. 3. The α₁- or α₂-adrenergic pharmacological specificity of the adrenoceptors was similar in each region, although their concentrations were different. 4. The concentration of α₂-adrenoceptors in the anterior hypothalamus was decreased following sino-aortic denervation suggesting that some hypothalamic α₂-adrenoceptors are associated with neurones of the baroreflex arc.     

ADRENALINE DEPLETION IN THE HYPOTHALAMUS OF THE RAT AFTER CHRONIC α-METHYLDOPA

1. Individual anterior hypothalamic-preoptic nuclei were dissected from the brains of control and α-methyldopa treated (2 × 40 mg/kg, 5 days) rats, and the concentrations of adrenaline and other catecholamines were estimated. 2. By a combination of radioenzymatic assay and paper chromatography the concentrations of adrenaline, noradrenaline, dopamine, α-methylnoradrenaline and α-methyldopamine were determined concurrently in the same sample. 3. α-Methyldopa reduced the adrenaline levels of the hypothalamic nuclei by 47–68% of control concentrations. 4. A differential displacement of the parent catecholamines was observed and the depletions were ranked: adrenaline < dopamine < noradrenaline. 5. α-Methylnoradrenaline and α-methyldopamine were found in all hypothalamic nuclei. 6. The depletion of hypothalamic adrenaline by α-methyldopa could represent a pharmacological mechanism contributing to the antihypertensive action of the drug.     

THE ACTIONS OF SOME α-ADRENORECEPTOR AGONISTS AND ANTAGONISTS IN AN ANTINOCICEPTIVE TEST IN MICE

1. It has been shown that a number of sympathomimetic drugs, administered subcutaneously, have potent antinociceptive activity in the mouse abdominal constriction test. These drugs were found to be equieffective antagonists of the nociceptive action of acetic acid and acetylcholine. Of the drugs tested, clonidine was the most potent, being almost 60 times more active than morphine, whilst noradrenaline and oxymetazoline were approximately three and five times less active respectively than clonidine. Phenylephrine was without effect after doses of 2 mg/kg. 2. The regression lines relating the magnitude of the antinociceptive effect of noradrenaline and oxymetazoline to log dose were moved to the right in an approximately parallel manner after subcutaneous administration of piperoxane, 8 and 16 mg/kg. The antinociceptive action of clonidine was also antagonised by piperoxane, but to a lesser extent. Phentolamine had no antagonistic effect on any of these three a-agonists after subcutaneous doses of 16 mg/kg. 3. Oxymetazoline and clonidine, when given by intracisternal injection, were approximately eight-three and fifty times more potent respectively than by subcutaneous administration, and their antinociceptive action was not antagonized by piperoxane, 16 mg/kg subcutaneously, or 50 μg/kg intracisternally. 4. It is postulated that the antinociceptive action of the a-agonists is due to an effect on α-adrenoreceptors located on sensory nerve endings in the peritoneum, and that the affinities of these receptors for the α-agonists and antagonists is different from that shown by either pre- or postsynaptic α-adrenoreceptors. It also appears likely that the antinociceptive action of clonidine and oxymetazoline when given by intracisternal injection involves different mechanisms from their peripheral effects.     

THE EFFECT OF THE ''HYPERTENSINOGENIC STEROID, 9α-FLUORO-CORTISOL ON BLOOD PRESSURE IN SHEEP WITH ACTH-INDUCED HYPERTENSION

The effect of treatment with 9 alpha-fluorocortisol (9 alpha FF), a steroid which causes hypertension in sheep, was examined in sheep with ACTH-induced hypertension. ACTH treatment alone increased mean arterial pressure (MAP), plasma Na concentration, water intake and urine volume and decreased plasma K concentration. 9 alpha FF treatment, for 3 days during continuing ACTH administration, did not change blood pressure but increased heart rate, water intake and urine volume and decreased urinary K excretion. As 9 alpha FF did not cause a further increment in blood pressure in sheep with ACTH-induced hypertension it is possible that both ACTH and 9 alpha FF may produce hypertension by similar mechanisms.     

EFFECTS OF GOLD SODIUM THIOMALATE ON CYTOSOLIC COPPER AND ZINC IN THE RAT KIDNEY AND LIVER TISSUES

1. Male Wistar rats were given a single subcutaneous injection of gold sodium thiomalate and killed 7 days later. The binding of Au, Zn and Cu to the kidney and liver cytosolic proteins of control and gold-treated rats was determined. 2. In the renal cytosol of Au(I)- exposed rats, the binding of Cu to the low-molecular-weight (LMW) proteins increased by 62%, and to the high-molecular-weight (HMW) proteins the binding decreased by 54%. The incorporation of Cu into the liver cytosolic proteins increased, in both, the HMW and the LMW proteins. The binding of Zn into the renal cytosolic proteins was increased by 39% (HMW proteins) and 100% (LMW proteins). Au(I) had little effect on the binding of Zn to the cytosolic proteins in the liver. 3. It is suggested that the therapeutic action of gold complexes may be mediated, to some extent, by its effects on the metabolism of Cu and/or Zn.     

THE EFFECT OF TWO NEW α-GLUCOSIDASE INHIBITORS ON METABOLIC RESPONSES TO A MIXED MEAL IN NORMAL VOLUNTEERS

1. alpha-Glucosidase inhibitors delay carbohydrate absorption and have been proposed as adjunctive therapy for diabetes mellitus. 2. To determine the effects of two new alpha-glucosidase inhibitors, Bay-m-1099 and Bay-o-1248, on meal carbohydrate and lipid tolerance, plasma glucose, insulin and triglyceride levels were measured at 15-60 min intervals over 12 h after ingestion of a standard breakfast, lunch and dinner of identical composition in 31 normal volunteers. 3. The volunteers were randomized to receive either Bay-m-1099 (50 or 25 mg) or placebo prior to each meal, or the single administration of Bay-o-1248 (20 or 10 mg) or placebo prior to breakfast. 4. Only Bay-m-1099 at the 50 mg dose reduced significantly the postprandial increase in plasma insulin levels after each meal when compared with placebo (25, 36, 54% at breakfast, lunch, and dinner, respectively; P less than 0.05). Both drugs were well tolerated, with side effects limited to complaints of flatulence. 5. Thus, with the dosage schedule employed, Bay-m-1099, but not Bay-o-1248, significantly reduced postprandial increments in plasma insulin.     

INTERACTION OF VASOPRESSIN, ANGIOTENSIN AND α-ADRENERGIC SYSTEM IN SODIUM DEPLETION IN THE RAT

1. The role of vasopressin in cardiovascular adaptation to sodium depletion was examined in rats after 6 days on a low sodium diet. Studies were performed after selective or combined blockade with d(CH2)5 Tyr(Me)AVP (AVPA), enalaprilat (CEI) and phentolamine (PHENTOL). AVPA alone had no effect on systemic haemodynamics or regional blood flow distribution. After CEI or PHENTOL pretreatment, AVPA led to significant falls in peripheral resistance and increases in cardiac output and renal blood flow. In sodium depletion, endogenous vasopressin acts as a vasoconstrictor hormone, particularly in the kidney, when either the renin-angiotensin or alpha-adrenergic system is inhibited.     

INVESTIGATIONS INTO THE NATURE OF α2-ADRENOCEPTORS IN RAT TAIL ARTERIES

In rat isolated perfused tail arteries, dose-response curves were established for the vasopressor effects of phenylephrine (alpha 1-adrenoceptor agonist), clonidine (alpha 1- and alpha 2-adrenoceptor agonist), clonidine in the presence of 10(-7) mol/l prazosin (alpha 2-agonist), and BHT-920 (alpha 2-agonist). The ED50 values were: phenylephrine 1.85 X 10(-10) mol; clonidine 6.3 X 10(-10) mol; clonidine + prazosin 3.2 X 10(-6) mol; BHT-920 6.1 X 10(-6) mol. The arterial reactivity to BHT-920 was stable only after 4-5 h of perfusion. Responses to BHT-920 were not antagonized by yohimbine (alpha 2-adrenoceptor antagonist) but were antagonized by low concentrations of prazosin (alpha 1-adrenoceptor antagonist). These data constitute conflicting evidence regarding the existence of alpha 2-adrenoceptors in rat tail arteries. The data are consistent with the proposal that there are two recognition sites on alpha 1-adrenoceptors; phenylephrine and BHT-920 may stimulate different sites on alpha 1-adrenoceptors.     

一叶萩碱的高效毛细管电泳手性分离及其大鼠体内立体选择性代谢研究

目的建立一叶萩碱(SE)的高效毛细管电泳手性分离方法。方法以羟丙基-β-环糊精(HP-β-CD)为手性选择剂,测定条件为:分离介质32 mmol·L^-1 HP-β-CD的Tris-H₃PO₄缓冲液(40 mmol·L^-1,H₃PO₄调至pH 6.0);分离电压15 kV,柱温16℃,压力进样6 s,检测波长254 nm;大鼠各生物样品碱化后乙酸乙酯萃取。结果测定条件下SE基本达到基线分离,大鼠生物样品测定不受内源及代谢物干扰。大鼠ip SE经胆汁、尿和粪排泄以D型为主,具有立体选择性。结论本法简便可靠,可适用于SE在大鼠体内立体选择性代谢研究。