益母草治疗痛经机制探索

目的　探讨益母草治疗痛经的药理作用及机制。方法　经十二指肠给予益母草水提液,观察豚鼠在体子宫收缩频率及幅度的变化。分别采用由缩宫素及15甲基 PGF_2α所致的子宫痉挛模型,观察小鼠口服益母草提取液后的作用。采用二甲苯致小鼠耳廓肿胀及实验性大鼠子宫炎症模型,分别观察小鼠、大鼠口服益母草提取液的抗炎作用。用放射免疫法及化学分析法分别检测大鼠口服益母草水提液后血液雌、孕激素及子宫平滑肌PGF_2α及PGE₂含量的变化。结果　益母草水提液能增强未孕正常豚鼠在体子宫的收缩。益母草能在一定程度上缓解由15M PGF_2α及缩宫素所致的小鼠子宫痉挛,能减轻二甲苯所致的小鼠耳廓肿胀的程度,改善实验性子宫炎症状况,且能降低子宫炎症时其平滑肌上PGE₂的含量,亦能降低大鼠子宫平滑肌上PGF_2α的含量。益母草水提液能升高血液孕激素的水平,而对雌激素却无明显影响。结论　益母草对子宫具有比较广泛的药理作用,可能通过抑制痉挛子宫的活动、抗炎、降低子宫平滑肌上PGF_2α,PGE₂的含量及升高体内孕激素水平等多种途径缓解痛经症状。     

阿魏酸钠对花生四烯酸代谢的影响

利用放射薄层方法测定兔血小板花生四烯酸代谢产物TXB₂,PGE₂和PGF_2α。用放射免疫法测定兔血小板TXB₂及主动脉6-keto-PGF_1α。阿魏酸钠(SF,0.1～3.2 mmol/L),抑制¹⁴C-花生四烯酸转化为TXB₂,呈剂量效应关系,IC₅₀为0.762 mmol/L。SF在较高浓度(0.8～3.2mmol/L)时亦抑制PGE₂,PGF_2α的生成。用放免法观察到,SF对血小板TXB₂和动脉壁6-keto-PGF_1α的生成均有抑制作用,对TXB₂的作用较强。结果提示,SF可抑制兔血小板和动脉壁环氧酶活性。     

天花粉对妊娠大鼠子宫中孕酮、孕酮受体和前列腺素含量的影响

天花粉对大鼠有抗早孕作用,使妊娠大鼠血浆孕酮浓度,子宫中孕酮和孕酮受体的含量下降,子宫中的PGF_2α含量增高,同时增敏子宫对15-Me-PGR_2α和催产素的反应性,消炎痛能抑制离体妊娠子宫自发收缩活动,但并不抑制天花粉增敏子宫对15-Me-PGF_2α和催产素反应性的作用,实验结果提示天花粉促进子宫PGF_2α的含量增加和增敏子宫对催产物质的反应性是它增加妊娠子宫自发收缩活动的重要机制,而天花粉的上述作用又可能与它使子宫中孕酮和孕酮受体下降有关。     

高血压大鼠和高血压患者血管平滑肌α肾上腺素受体的反应性增强作用

目的研究高血压状态下血管平滑肌α肾上腺素能受体的反应性增强作用。方法用敏感的离体血管张力描记技术记录大鼠肠系膜动脉和人大网膜动脉的张力，用实时定量的逆转录聚核酶链反应技术测定动脉平滑肌的mRNA水平，用动脉的器官培养方法研究α受体反应性增强的机制。结果自发性高血压大鼠(SHR)的肠系膜动脉环对去甲肾上腺素(NA)的反应性明显强于WKY大鼠，NA对SHR肠系膜动脉平滑肌的最大收缩(E_max)是WKY大鼠E_max的1.82倍；高血压患者大网膜动脉对NA的反应性明显高于非高血压患者，NA的量效曲线显著左移，pD₂值显著高于非高血压患者。SD大鼠肠系膜动脉的器官培养后对NA收缩反应增强，E_max增高，且培养后α₁受体的mRNA水平增高，而α₂受体的mRNA水平无明显变化。结论高血压状态下血管平滑肌α受体的反应性增强，提示α受体上调。     

利多卡因对离体兔胸主动脉环收缩的影响

以维拉帕米(verapamil,Ver)作对照,在离体兔胸主动脉环上对利多卡因(lidocaine,Lid)松弛血管平滑肌的机理进行了探讨。Lid对高K+去极化主动脉环收缩和Ver一样有明显的松弛作用。对去甲肾上腺素(NA)引起主动脉环收缩的试验中,Lid和Ver都能抑制细胞内Ca²⁺的释放,但不抑制外Ca²⁺内流。Lid对KCl,NA量-效曲线产生非平行右移,最大反应压低,且对KCl的抑制作用大于NA,说明Lid对PDC通道有选择性阻滞作用,而对ROC通道相对不敏感。对CaCl₂量-效曲线也产生非平行右移且最大反应压低,呈非竞争性拮抗。初步提示Lid在一定浓度下有拮抗Ca²⁺的作用,这种作用为非特异性,是松弛血管平滑肌机理之一。     

醋酸棉酚对大鼠输卵管平滑肌收缩活动的影响

观察了醋酸棉酚水溶性制剂对离体大鼠输卵管平滑肌收缩活动的影响并对其作用机制作了初步探讨。结果表明,醋酸棉酚可提高大鼠输卵管平滑肌收缩张力,但并非为激动α兴奋性肾上腺素能受体,而与促输卵管组织前列腺素(PGs)的生物合成、释放并与促Ca²⁺内流机制有关。棉酚的这种药理作用还与性周期有密切关系,对动情期输卵管的作用明显高于间情期。结果还表明,前列腺索E₁(PGE₁)和前列腺素E₂(PGE₂)均可提高大鼠输卵管平滑肌收缩活性,以PGE₁的作用较强且较持久,此作用可为醋酸棉酚所明显增强。     

氯哌胺对15-甲基前列腺素F2α致泻和兴奋子宫作用的影响

氯哌胺(Loperamide)是一种新型止泻药,能拮抗15-M-PGF_2α引起的小鼠小肠内碳粉推进加速和腹泻,作用比吗啡和阿托品强,对离体大鼠回肠的抑制作用也比吗啡、阿托品强。氯哌胺能降低肠平滑肌张力,抑制离体大鼠回肠对15-M-PGF_2α的反应性,但却增强子宫平滑肌对15-M-PGF_2α的反应性。氯哌胺对离体大鼠子宫自发收缩活动低浓度兴奋、高浓度抑制。氯哌胺对15-M-PGF_2α促进大鼠空肠水和钠离子分泌也有拮抗作用,此作用不能被纳洛酮翻转。氯哌胺在小鼠的急性半数致死量为77.9 mg/kg。     

前列腺素F2α放射免疫分析及其应用

A specific antibody against prostaglandin F_2α (PGF_2α) was obtained from rabbits immunized with PGF_2α conjugated to bovine thyroglobulin (BTG) by N, N-Carbonyl-diimidazole (CDI). A sensitive, accurate, precise and convenient radioimmunoassay for PGF_2α has been established in our laboratory by use of this antibody, and the normal levels of PGF_2αin plasma and tissues of human and animals were measured.     

大黄素对豚鼠结肠带平滑肌细胞钾通道活性的影响

用检测平滑肌细胞电活动和张力技术,研究了大黄素对豚鼠结肠带平滑肌细胞电和收缩活动的影响并与 cromakalim, glybenclamide,四乙胺及BaCl₂的作用进行比较。结果表明,大黄素加强平滑肌细胞电和收缩活动,作用效果与剂量有关;大黄素与cromakalim的作用相互抑制。其促进平滑肌细胞电和收缩活动的作用与glybenclamide相似,而与四乙胺和BaCl₂有明显区别。提示大黄素的作用机制与抑制细胞膜K_ATP等钾通道的活性相关。     

多巴胺舒张猪冠状动脉及激活冠状动脉平滑肌细胞钾通道

采用血管环实验和膜片钳细胞贴附式技术分别在器官和细胞分子水平观察多巴胺舒张猪冠状动脉作用及对平滑肌细胞大电导型钙激活钾通道(BK_Ca)的影响. 结果表明多巴胺引起前列腺素F_2α(PGF_2α)预收缩动脉环浓度依赖性舒张反应, 而不引起高K⁺预收缩动脉环舒张反应. 表明多巴胺引起的冠状动脉血管舒张反应依赖于K⁺生理浓度梯度的存在, 结果提示钾通道参与了多巴胺的血管舒张反应. 向细胞浴液内灌流多巴胺增强冠状动脉血管平滑肌细胞膜BK_Ca通道活性. 用DA₁受体阻断剂SCH23390预处理细胞, 完全阻断多巴胺的这一作用, 而用β受体阻断剂普萘洛尔无影响. 提示多巴胺通过DA₁受体激活BK_Ca通道引起PGF_2α预收缩动脉环舒张反应.     

Contractile Effects of Prostaglandin F2α on Isolated Human Peripheral Arteries and Veins

Abstract The effects of prostaglandin F_2α (PGF_2α, 2.8 × 10^-7-2.8 × 10^-5 M) on isolated segments of human peripheral arteries and veins were investigated. In both types of vessel, PGF_2α had a concentration-dependent contracting effect. The contraction developed more slowly and had a longer relaxation time after washing than responses induced by noradrenaline or potassium. In the veins, the maximum response to the prostaglandin was 128 ± 3.6% of that to potassium (P<0.01); in the arteries, the maximum amplitudes of PGF_2α and potassium induced contractions were of similar magnitude. The arterial preparations were less responsive to PGF_2α than to noradrenaline. On a molar basis, noradrenaline was approximately 10 times more potent than PGF_2α. Veins, maximally contracted by noradrenaline or potassium, increased their tension further on addition of PGF_2α. Similarly, preparations maximally contracted by PGF_2α also showed a further increase in tension after addition of noradrenaline or potassium. The PGF_2α induced contractions were not affected by α-adrenoceptor blockade (phentolamine, prazosin). The calcium antagonists verapamil and nifedipine relaxed preparations contracted by PGF_2α and reduced the responses in a concentration-dependent way when added 15 min. before the prostaglandin. Immersion for 30 min. in a calcium-free medium, reduced the PGF_2α induced response in both arteries and veins. In the veins, but not in the arteries, the responses to potassium and noradrenaline were more reduced than that to PGF_2α (P < 0.01). Contractions induced by all agents were further depressed by verapamil and nifedipine after exposing the preparations to the calcium-free medium. It is suggested that PGF_2α induces contraction both by enhancing the transmembrane flow of calcium, and by facilitating release of calcium from intracellular stores.     

The inhibitory action of pgf2α on release of [3H]noradrenaline enhanced by α2-adrenoceptor blockade,sodium-pump inhibition and 4-aminopyridine in the main pulmonary artery of the rabbit

Large concentrations of prostaglandin PGF_2α inhibited the stimulation (2 Hz) evoked release of [³H]noradrenaline from the isolated main pulmonary artery of the rabbit (the inhibition caused by 3 × 10^?5 M PGF_2α was 62%). Furthermore, PGF_2α inhibited the release evoked by stimulation when it was enhanced by different procedures. During blockade of presynaptic α₂-adrenoceptors by 3 × 10^?7 M yohimbine, which by itself enhanced the overflow of [³H]NA in response to stimulation, the inhibitory action of PGF_2α was more pronounced (78.2%). In tissue in which the Na⁺-pump was inhibited (K⁺-free treatment) where the overflow of ³H was markedly increased, PGF_2α exerted nearly equal inhibition of transmitter release to that observed in control experiments (64.3%). The inhibitory effect of PGF_2α on the stimulation-evoked release of [³H]NA was less pronounced (32.1%) in the presence of 10^?4M 4-aminopyridine (a blocker of K⁺ -channels).     

The effects of lidocaine and hexamethonium on prostaglandin F2α- and histamine-induced bronchoconstriction in normal and ASCARIS-sensitive dogs

The effects of local deposition of the topical anesthetic, lidocaine, and ganglionic blockade by hexamethonium were investigated in canine models of pharmacologic- and antigen-induced bronchoconstriction. Control bronchopulmonary provocations, i.e., increases in pulmonary resistance (R_L) and decreases in dynamic lung compliance (C_DYN), were accomplished by aerosols of prostaglandin F_2α (PGF_2α) and histamine (HIST) in normal, pentobarbital-anesthetized beagles. Pretreatment with an aerosol of lidocaine (2%, 30 breaths) significantly inhibited PGF_2α- and HIST-induced changes in R_L by 43.9 ± 6.5% and 58.0 ± 10.9%, respectively, and significantly reduced C_DYN changes due to an aerosol challenge with HIST by 43.6 ± 9.2%. An i.v. infusion of hexamethonium (10 mg/kg) significantly inhibited PGF_2α- induced changes in R_L (36.5 ± 10.4%), while inhibiting changes in both R_L and C_DYN produced by HIST (57.8 ± 7.5% and 63.1 ± 6.5%, respectively). In Ascaris-sensitive animals, neither lidocaine nor hexamethonium had any statistically significant effect on the bronchopulmonary responses to antigen challenge. These results suggest that a portion of the bronchoconstrictive response to PGF_2α and HIST in dogs may involve an indirect, vagal-mediated reflex, which is sensitive to lidocaine at the afferent cholinergic pathway and to hexamethonium at the ganglion. In antigen-induced bronchoconstriction, these reflex pathways may be of lesser importance.     

The character of the antagonism by polyphloretin phosphate of contractions to prostaglandins E1 and F2α in guinea-pig ileum

Polyphloretin phosphate (PPP) produced a dose-dependent decrease in the tone and reduction of the spontaneous phasic contractions of the longitudinal muscle of guinea-pig isolated ileum. PPP (100 μg ml^?1) after a 2 min contact with the ileum decreased the contractile effects of PGE₁ 0·1 μM by 40·6 ± 7·4%, of PGE₁ 0·01 μM by 86·7 ± 3·3% and of PGF_2α 0·1 μM by 62·2 ± 8·6%. After 10 min contact of PPP the contractile effect of PGE₁ 0·1 μM was decreased by 47·7 ± 4·7% and that of PGF_2α0·1 μM by 89·6 ± 1·7%. When the contact was longer, PPP showed a pronounced after-effect in respect to the effects of PGE₁ and particularly of PGF_2α. PPP significantly reduced contractions to 5-HT and BaCl₂, but not to acetylcholine, histamine or substance P. The type of antagonism of PGE₁ by PPP was examined using cumulative concentration-effect curves for PGE₁ in the presence of increasing concentrations of PPP. We conclude that on guinea-pig ileum PPP acts as a non-competitive antagonist of PGE₁ and PGF_2α.     

Adrenoceptor-stimulated Endothelium-dependent Relaxation in Porcine Intrapulmonary Arteries

Summary: The responses of rings of isolated adult porcine intrapulmonary arteries to noradrenaline were observed. The effects of prazosin (α-1 adrenoceptor antagonist), yohimbine (α-2 adrenoceptor agonist) and N-ω-nitro-L-arginine methyl ester (L-NAME) on the noradrenaline responses were studied. In addition, following contraction with prostaglandin PGF_2α, the responses to noradrenaline or UK14304 (α-2 adrenoceptor agonist) were observed alone and in the presence of either prazosin or yohimbine. The effects of UK14304 were also observed following precontraction with phenylephrine. Noradrenaline produced an initial increase in vascular tone followed by a decrease and then a second increase in tone at high concentrations. The initial contractile response was inhibited by prazosin or yohimbine. L-NAME or endothelium removal enhanced the contractile responses and abolished the mid range reduction in tone. Following PGF_2α pre-contraction, UK14304 further increased the tone, with a reduction in tone at higher concentrations. The contractile effect was augmented by prazosin. Following phenylephrine pre-contraction, UK14304 only produced reduction in tone. In conclusion, in porcine intrapulmonary arteries, L-NAME inhibited noradrenaline induced endothelium dependent reduction in tone, which was also inhibited by α-1 and α-2 antagonists. UK14304 demonstrated partial α-1 agonism.     

Inhibitory effect of caffeine on pacemaker activity in the oviduct is mediated by cAMP-regulated conductances

BACKGROUND AND PURPOSE

Spontaneous electrical activity, termed slow waves, drives rhythmic, propulsive contractions in the smooth muscle of the oviduct (myosalpinx). Myosalpinx contractions cause egg transport through the oviduct. Agents that disrupt slow wave pacemaker activity will therefore disrupt myosalpinx contractions and egg transport. Caffeine is commonly used as a ryanodine receptor agonist and has been previously associated with delayed conception. Here we assessed the effects of caffeine on pacemaker activity in the murine myosalpinx.

EXPERIMENTAL APPROACH

The effects of caffeine on electrical pacemaker activity were studied using intracellular microelectrode and isometric force measurements on intact oviduct muscle preparations. Responses to caffeine were compared with responses caused by 3-isobutyl-1-methylxanthine (IBMX) and forskolin.

KEY RESULTS

Caffeine caused hyperpolarization of membrane potential and inhibited slow wave generation and myosalpinx contractions. The effects of caffeine could be mimicked by the K_ATP channel agonist pinacidil and antagonized by the K_ATP channel antagonist glibenclamide. Caffeine is known to inhibit cyclic nucleotide phosphodiesterases (PDEs), leading to an increase in cytosolic cAMP and stimulation of downstream cAMP-dependent mechanisms. The effects of caffeine were mimicked by the PDE inhibitor, IBMX, and the adenylyl cyclase activator forskolin. These effects were also reversed by glibenclamide.

CONCLUSIONS AND IMPLICATIONS

These results suggest that caffeine activates K_ATP channels in oviduct myosalpinx. Since caffeine abolishes slow waves and associated contractions of the myosalpinx, it would have a negative effect on egg transport through the oviduct and may contribute to the documented delayed conception in women consuming caffeinated beverages.     

RELATIONSHIP BETWEEN NIFEDIPINE SENSITIVITY OF AORTAE AND BLOOD PRESSURE OF STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. We have previously described an increased sensitivity to inhibition by nifedipine of noradrenaline-induced contractures of blood vessels in hypertension. In this study we have investigated whether changes in blood pressure (BP) change the sensitivity to nifedipine and K⁺ of aortic rings from normotensive (Wistar-Kyoto rats, WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were treated with: hydralazine plus hydrochloro-thiazide; captopril plus hydrochlorothiazide; hydralazine plus guanethidine; or captopril alone. WKY rats were treated with deoxycorticosterone acetate (DOCA) and NaCl. Treatment commenced from 5 weeks of age and continued until 13–15 weeks. 3. The SHRSP treatments produced similar reductions in BP, and the BP of all the treated groups were significantly lower than the mean BP of untreated SHRSP (201.0 ± 7.7 mmHg). The mean BP of the treated WKY rats (134.2 ± 7.6 mmHg) was significantly higher than the mean BP of the untreated WKY rats (86.8 ± 7.4 mmHg). 4. An area-under-curve (AUC) analysis of the inhibitory effects of nifedipine on responses of aortae to noradrenaline showed no differences between treated and untreated SHRSP groups (overall mean 40.6 ± 1.9% and 43.4 ± 3.4% inhibition of control AUC, respectively), or between DOCA-salt treated WKY and untreated WKY groups (58.8 ± 5.9 and 64.8 ± 2.3, respectively). Noradrenaline-induced contractures of aortae from all SHRSP groups were significantly more sensitive to inhibition by nifedipine than aortae from both WKY groups. 5. The molar concentration of agonist required to evoke 50% of the maximum response (EC₅₀) values for potassium chloride (KCI) were significantly increased in the aortae of all treated SHRSP groups in comparison to those from untreated SHRSP (treated SHRSP groups, 15.53 ± 0.68 mmol/L vs untreated SHRSP group, 11.36 ± 1.10 mmol/L). The EC₅₀ values for KC1 for the aortae from the DOCA-treated WKY rats were significantly less than those from aortae of the untreated WKY (11.80 ± 0.80 and 17.08 ± 1.50 mmol/L, respectively). 6. We conclude that reduction (in SHRSP) or increase (in WKY) of the BP has no effect on the sensitivity of aortic smooth muscle to the inhibitory effects of nifedipine on responses to noradrenaline, suggesting that alterations in voltage-dependent Ca²⁺ mechanisms may be a primary phenomenon in the SHRSP. In contrast, the fact that sensitivity to KC1 changes in the treated SHRSP and WKY aortae suggests such sensitivity is secondary to the BP and thus a separate phenomenon from voltage-dependent Ca²⁺ mechanisms.     

(±)-Govadine and (±)-THP,Two Tetrahydroprotoberberine Alkaloids,as Selective α1-Adrenoceptor Antagonists in Vascular Smooth Muscle Cells

(±)-Govadine and (±)-THP ((±)-2,3,10,11-tetrahydroxytetrahydroprotoberberine HBr) have been shown to inhibit noradrenaline-induced contraction of rat thoracic aortae. The pharmacological activity of the compounds was determined in thoracic aortae and cardiac tissue isolated from the rat and in trachea isolated from the guinea-pig to determine the selectivity of the compounds towards different types of receptor. (±)-Govadine and (±)-THP were found to be α₁-adrenoceptor blocking agents in rat thoracic aorta as revealed by their competitive antagonism of vasoconstriction induced by noradrenaline (pA₂ = 6.57 ± 0.07 and 5.93 ± 0.06, respectively) or phenylephrine (pA₂ = 6.74 ± 0.08 and 6.06 ± 0.10, respectively). Removal of endothelium did not affect the antagonistic potencies of (±)-govadine (pA₂ = 6.83 ± 0.09) and (±)-THP (pA₂ = 6.25 ± 0.06) on phenylephrine-induced vasoconstriction. They were more potent than yohimbine (pA₂ = 6.05 ± 0.05), but less so than phentolamine (pA₂ = 7.54 ± 0.11) and prazosin (pA₂ = 9.27 ± 0.12). (±)-Govadine and (±)-THP, furthermore, inhibited [³H]inositol monophosphate formation caused by noradrenaline (3 μm ) in rat thoracic aorta. (±)-Govadine and (±)-THP were also α₂-adrenoceptor blocking agents with pA₂ values 5.50 ± 0.13 and 5.41 ± 0.11, respectively. A high concentration of (±)-govadine (30 μm ) or (±)-THP (30 μm ) did not, however, affect the contraction induced by the thromboxane receptor agonist U46619, prostaglandin F_2α (PGF_2α), 5-hydroxytryptamine (5-HT), angiotensin II, endothelin or high K⁺ in rat aorta denuded of endothelium. Neither the cyclic AMP nor cyclic GMP content of rat thoracic aorta was, furthermore, changed by (±)-govadine or (±)-THP. Contraction of guinea-pig trachea caused by carbachol, histamine, leukotriene C₄ or neurokinin A was not affected by (±)-govadine or (±)-THP. (±)-Govadine or (±)-THP also did not block β₁- or β₂-adrenoceptor-mediated responses induced by isoprenaline in rat right atria and guinea-pig trachea. It is concluded that (±)-govadine and (±)-THP are selective α₁-adrenoceptor antagonists in vascular smooth muscle.     

吸烟、硝酸甘油对动脉粥样硬化家兔血管平滑肌细胞钙浓度的影响

目的研究吸烟、硝酸甘油对动脉粥样硬化血管平滑肌细胞胞内游离钙浓度([Ca2+]i)的影响,探讨吸烟对动脉粥样硬化形成及硝酸甘油的生物效应的作用。方法复制家兔动脉粥样硬化模型,分离血管平滑肌细胞。Fluo-3/AM负载细胞,应用流式细胞仪检测血管平滑肌细胞[Ca2+]i,激光扫描共聚焦显微系统测定单个血管平滑肌细胞内Ca2+的时空变化。结果各组动物主动脉壁均见到程度不同的动脉粥样硬化斑块形成。动脉粥样硬化家兔血管平滑肌细胞[Ca2+]i明显升高(48.45±5.31,与生理盐水对照组38.09±2.57比较,P<0.01);吸烟能增加动脉粥样硬化家兔血管平滑肌细胞[Ca2+]i(56.48±2.99,与单纯动脉粥样硬化组48.45±5.31比较,P<0.01);硝酸甘油则能明显降低动脉粥样硬化家兔血管平滑肌细胞[Ca2+]i(41.91±3.16,与单纯动脉粥样硬化组48.45±5.31比较,P<0.05);吸烟能明显抑制硝酸甘油降低血管平滑肌细胞[Ca2+]i的作用(47.99±5.10,与硝酸甘油组41.91±3.16比较,P<0.05)。结论吸烟能明显增加动脉粥样硬化血管平滑肌细胞[Ca2+]i,硝酸甘油则能明显降低动脉粥样硬化血管平滑肌细胞[Ca2+]i,吸烟能抑制硝酸甘油的生物学效应。     

Indomethacin and diclofenac sodium increase sodium and water excretion after extracellular volume expansion in the rabbit

The renal effects of an acute extracellular fluid volume expansion (50 ml Ringer/kg body weight/60 min) were studied in aldosterone-treated (100 μg/kg), anesthetized rabbits with and without pretreatment with either indomethacin (3.0 mg/kg) or diclofenac sodium (3.0 mg/kg), two different inhibitors of renal prostaglandin (PG) biosynthesis. In controls (n = 7), the volume expansion increased urine flow from 1.5 ± 0.24 to 6.1 ± 0.5 (S.E.) ml/min/100 g kidney weight and sodium excretion from 0.15 ± 0.03 to 0.99 ± 0.10 mmol/min/100 g. PAH and insulin clearance increased by 42 and 58%, respectively, while plasma renin activity and urinary excretion of PGF_2α-like immunoreactivity were reduced (P < 0.05). In aninals pretreated with indomethacin (n = 6) or diclofenac sodium (n = 6), the diuresis and the natriuresis following volume expansion were significantly increased about two-fold over controls, whereas PAH and inulin clearance, plasma renin activity and hematocrit did not differ from controls. Both drugs were found to reduce urinary excretion of PGF_2α-like immunoreactivity by 75–95% throughout the experiment. The results indicate that diclofenac sodium, indomethacin and extracellular volume expansion enhance sodium and water excretion partly by suppression of a PG sensitive reabsorption process in the kidney.