局灶性脑缺血再灌注致血脑屏障破坏与zileuton的保护作用

目的： 探讨局灶性脑缺血再灌注损伤（CIRI）致血脑屏障(BBB) 通透性破坏的影响因素,观察高选择性5-脂氧合酶（5-LO）抑制剂zileuton的保护作用并分析其机制。方法: 线栓法制备大鼠大脑中动脉闭塞2 h/再灌注24 h模型（MCAO2 h/R24 h）,于缺血前2 h、再灌注0、5、10 h,分别灌胃给予zileuton10、50 mg·kg-1。伊文氏蓝示踪剂检测BBB;AutoCAD图像分析软件计算脑水肿程度;RT-PCR法检测脑组织白三烯受体1mRNA（CysLTR1 mRNA）;ELISA法检测血清白三烯B4（LTB4）;免疫组化法检测脑组织水通道蛋白4（AQP4）、基质金属蛋白酶9（MMP-9）蛋白。结果: MCAO2 h/R24 h后,BBB通透性明显增高,出现脑水肿,血清LTB4含量升高,梗塞侧脑组织CysLTR1mRNA表达增强,缺血区与梗塞灶周边缺血半暗带（IP）区AQP4与MMP-9蛋白表达上调; zileuton10、50 mg·kg-1均能有效控制CIRI所致的BBB破坏,改善脑水肿,降低血清LTB4含量,下调脑组织CysLTR1mRNA、AQP4与MMP-9表达。结论: CIRI后BBB通透性明显破坏,zileuton的保护作用与抑制脑组织和循环血液中的5-LO通路活化、下调脑组织缺血区与IP区的AQP4与MMP-9蛋白表达有关。     

The effect of a selective 5-lipoxygenase inhibitor,zileuton, on tissue damage in acute colonic inflammation in rats

Though the mechanism of tissue damage induced by colonic inflammation in ulcerative colitis is unknown, it has been established that the inflammatory mediator and potent neutrophil (PMN) chemotaxin, leukotriene B4(LTB₄), is present in elevated amounts in the inflamed mucosa. The unique role of 5-lipoxygenase in the production of leukotrienes has made it a target for inhibition. This study used a rat model of acute colonic inflammation induced by a single IP injection of Mitomycin-C to test the efficacy of a specific and potent 5-lipoxygenase inhibitor zileuton in the treatment of colonic inflammation. We hypothesized that after inducing colitis in rats with mitomycin-C, the administration of oral zileuton would inhibit leukotriene production, thus preventing PMN infiltration and subsequent tissue damage. Zileuton decreased colonic tissue damage as measured by Histological score. However, zileuton did not significantly decrease neutrophil infiltration measured by mucosal PMN or myeloperoxidase (MPO) levels. Although zileuton was successful in significantly decreasing the frequency of severe colitis in our model, the fact that the decrease in PMN count and MPO level was not statistically significant suggests that another mechanism may be involved in its anti-inflammatory effect.     

The discovery and development of zileuton: an orally active 5-lipoxygenase inhibitor.

The enzyme 5-lipoxygenase is a key target in the effort to discover drugs which inhibit the pathophysiology associated with the formation of leukotrienes. The research efforts of these laboratories have focused on the discovery of direct enzyme inhibitors of 5-lipoxygenase. In particular, compounds with hydroxamate or N-hydroxyurea functionalities have proven to be potent inhibitors of leukotriene biosynthesis in vitro and more importantly in vivo. One of these compounds, zileuton (N-(1-benzo-[b]-thien-2-ylethyl)-N-hydroxyurea) has been shown recently to be an effective leukotriene inhibitor in man. The critical approaches and breakthroughs in the discovery and development of zileuton are described. In addition, some recent results with zileuton in animals and man are detailed.     

Reduction of the multiple organ injury and dysfunction caused by endotoxemia in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton

The role of 5-lipoxygenase (5-LOX) in the pathophysiology of the organ injury/dysfunction caused by endotoxin is not known. Here, we investigate the effects of treatment with 5-LOX inhibitor zileuton in rats and targeted disruption of the 5-LOX gene in mice (5-LOX(-/-)) on multiple organ injury/dysfunction caused by severe endotoxemia. We also investigate the expression of beta2-integrins CD11a/CD18 and CD11b/CD18 on rat leukocytes by flow cytometry. Zileuton [3 mg/kg intravenously (i.v.)] or vehicle (10% dimethyl sulfoxide) was administered to rats 15 min prior to lipopolysaccharide (LPS; Escherichia coli, 6 mg/kg i.v.) or vehicle (saline). 5-LOX(-/-) mice and wild-type littermate controls were treated with LPS (E. coli, 20 mg/kg intraperitoneally) or vehicle (saline). Endotoxemia for 6 h in rats or 16 h in mice resulted in liver injury/dysfunction (increase in the serum levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, bilirubin), renal dysfunction (creatinine), and pancreatic injury (lipase, amylase). Absence of functional 5-LOX (zileuton treatment or targeted disruption of the 5-LOX gene) reduced the multiple organ injury/dysfunction caused by endotoxemia. Polymorphonuclear leukocyte infiltration (myeloperoxidase activity) in the lung and ileum as well as pulmonary injury (histology) were markedly reduced in 5-LOX(-/-) mice. Zileuton also reduced the LPS-induced expression of CD11b/CD18 on rat leukocytes. We propose that endogenous 5-LOX metabolites enhance the degree of multiple organ injury/dysfunction caused by severe endotoxemia by promoting the expression of the adhesion molecule CD11b/CD18 and that inhibitors of 5-LOX may be useful in the therapy of the organ injury/dysfunction associated with endotoxic shock.     

Lack of effect of the 5-lipoxygenase inhibitor zileuton in blocking oral aspirin challenges in aspirin-sensitive asthmatics.

BACKGROUND: Leukotrienes (LTs) have been implicated as major mediators of aspirin-(ASA)-induced respiratory reactions. It was therefore logical to assume that an inhibitor of 5-lipoxygenase (5-LO), such as zileuton, given before and during oral challenges with ASA, might prevent ASA-induced respiratory reactions. Indeed, in prior studies, pretreatment of ASA-sensitive respiratory disease patients with leukotriene modifiers eliminated or attenuated respiratory reactions upon re-challenge with the previously established provoking dose of ASA. However, doses higher than the provoking doses were not administered during these reported studies. OBJECTIVE: We wished to determine whether zileuton pretreatment could prevent ASA-induced respiratory reactions in our six volunteers with aspirin-sensitive respiratory disease when ASA challenge doses were started below the usual provoking dose of 60 mg and then increased until a respiratory reaction occurred. METHOD: Aspirin sensitivity was established previously in all six patients during a prior ASA oral challenge. In this study, pretreatment with zileuton 600 mg qid was initiated 7 days prior to, and continued during oral ASA challenges. Patients underwent single-blind oral ASA challenges with escalating doses of ASA, every 3 hours, according to our standard protocol. RESULTS: All six patients reacted to doses of ASA between 45 and 325 mg. Four patients experienced bronchospasm (FEV1 declined 19% to 53%) while receiving zileuton. All six had naso-ocular reactions. Concentrations of urine LTE4 also increased significantly (mean 334 pg/mg Cr at baseline, increasing to 1024 pg/mg Cr at respiratory reactions). CONCLUSIONS: During ASA challenges, zileuton, in standard doses of 600 mg qid was associated with increased synthesis of LTs in five of six patients and naso-ocular reactions in all six patients, as well as bronchospasm in four patients.     

The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air

BACKGROUND. The enzyme 5-lipoxygenase catalyzes the metabolism of arachidonic acid to form products that have been implicated in the airway obstruction of asthma. We hypothesized that if products of the 5-lipoxygenase pathway are important in mediating this obstruction, then prevention of their formation should decrease the severity of an induced asthmatic response. METHODS. In a randomized, double-blind, placebo-controlled, crossover study, we examined the effect of A-64077, a 5-lipoxygenase inhibitor, on the bronchoconstriction induced by hyperventilation of cold, dry air in 13 patients with asthma. The completeness of 5-lipoxygenase inhibition was confirmed by examining the profile of eicosanoids produced in whole blood ex vivo after activation with the calcium ionophore A-23187. RESULTS. A-64077 decreased the mean (+/- SEM) ionophore-induced synthesis of leukotriene B4, a 5-lipoxygenase product, by 74 percent (from 265.3 +/- 30.3 to 69.5 +/- 21.5 ng per milliliter, P less than 0.001), but it did not affect the ionophore-induced synthesis of thromboxane B2, a cyclooxygenase metabolite of arachidonic acid (80.0 +/- 17.1 ng per milliliter before A-64077 vs. 75.8 +/- 14.3 ng per milliliter after A-64077). In concert with the selective inhibition of 5-lipoxygenase by A-64077, the amount of cold, dry air (expressed as respiratory heat exchange) required to reduce the forced expiratory volume in one second by 10 percent was increased by 47 percent after A-64077 (3.0 kJ per minute for placebo vs. 4.4 kJ per minute for A-64077, P less than 0.002). Similar results were obtained when minute ventilation was used as an indicator of outcome (27.5 liters per minute for placebo vs. 39.8 liters per minute for A-64077, P less than 0.005). CONCLUSIONS. Selective inhibition of 5-lipoxygenase by A-64077 is associated with a significant amelioration of the asthmatic response to cold, dry air, suggesting that 5-lipoxygenase products are involved in this response. This approach may be useful in the treatment of asthma.     

Effects of the new 5-lipoxygenase inhibitor E6080 on leukotriene release in vitro.

Fundamental studies were conducted to examine the release of histamine and leukotriene (LT) C4 from lung fragments of guinea pigs and the effects of E6080 on the release of LTB4 and LTC4 from lung fragments or inflammatory cells. The release of histamine and LTs showed large interindividual variations and a marked dependence on experimental conditions. Addition of 10 mM L-cysteine significantly increased LTC4 release compared with that in its absence (about 1.7 times, in terms of mean value). E6080 inhibited antigen-stimulated LTB4 and LTC4 release from passively sensitized human (IC50: LTB4 0.08 microM, LTC4 0.2 microM) and guinea-pig lung fragments (IC50: LTC4 1.1 microM). The LTB4 and LTC4 releases from healthy human polymorphonuclear leukocytes (calcium ionophore A23187) and from allergic patients' leukocytes (basophils, antigen) were inhibited by E6080 with IC50 values of below 1.0 microM. Furthermore, the LTC4 release from rat alveolar macrophages (silica particles) was inhibited by E6080 with an IC50 of 0.2 microM. The potent inhibition by E6080 might be a result of the inhibition of 5-lipoxygenase, since 5-lipoxygenase in rat basophilic leukemia cell was inhibited by E6080 with an IC50 of 0.2 microM. The results confirm the potent inhibitory effects of E6080 on the release of LTs.     

Effects of MK-886, a 5-lipoxygenase activating protein (FLAP) inhibitor, and 5-lipoxygenase deficiency on the forced swimming behavior of mice

A common biological pathway may contribute to the comorbidity of atherosclerosis and depression. Increased activity of the enzymatic 5-lipoxygenase (5-LOX, 5LO) pathway is a contributing factor in atherosclerosis and a 5-LOX inhibitor, MK-886, is beneficial in animal models of atherosclerosis. In the brain, MK-886 increases phosphorylation of the glutamate receptor subunit GluR1, and the increased phosphorylation of this receptor has been associated with antidepressant treatment. In this work, we evaluated the behavioral effects of MK-886 in an automated assay of mouse forced swimming, which identifies antidepressant activity as increased climbing behavior and/or decreased rest time. Whereas a single injection of MK-886 (3 and 10 mg/kg) did not affect forced swimming behaviors assayed 30 min later, six daily injections of 3 mg/kg MK-886 slightly increased climbing and significantly reduced rest time in wild-type mice but not in 5-LOX-deficient mice. A diet delivery of MK-886, 4 micro/(100 mg(body-weight)day), required 3 weeks to affect forced swimming; it increased climbing behavior. Climbing behavior was also increased in naive 5-LOX-deficient mice compared to naive wild-type controls. These results suggest that 5-LOX inhibition and deficiency may be associated with antidepressant activity. Increased climbing in a forced swimming assay is a typical outcome of antidepressants that increase noradrenergic and dopaminergic activity. Interestingly, 5-LOX deficiency and MK-886 treatment have been shown to be capable of increasing the behavioral effects of a noradrenaline/dopamine-potentiating drug, cocaine. Future research is needed to evaluate the clinical relevance of our findings.     

FPL 62064, a topically active 5-lipoxygenase/cyclooxygenase inhibitor

FLP 62064 [N-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-3-amine] is a dual inhibitor of prostaglandin synthetase and 5-lipoxygenase. The compound had anti-inflammatory activityin vivo in a number of models. It inhibited peritoneal inflammation induced by immune-complex when given locally. When applied to the skin, FPL 62064 inhibited UV irradiation-induced erythema and PGE₂ formation in the guinea pig and also oedema formation and eicosanoid production in the mouse ear produced by arachidonic acid. Co-injected with arachidonic acid in rabbit skin, FPL 62064 inhibited oedema and eicosanoid formation.     

Effects of acupuncture at GV01 on experimentally induced colitis in rats: possible involvement of the opioid system

Oriental medicine uses acupuncture at the GV01 acupoint with great success to treat diarrhea. It significantly reduced the colonic motility and inflammation in colitic rats. Naloxone pretreatment blocked these effects. The therapeutic effects of acupuncture at GV01 in colitis may involve endogenous opioid pathways.     

The effect of a selective 5-lipoxygenase inhibitor, AA-861 on airway hyperresponsiveness induced by ozone exposure in dogs

To determine whether 5-lipoxygenase products are involved in hyperresponsiveness induced by ozone exposure, we studied the effect of a selective 5-lipoxygenase inhibitor, AA-861 on ozone-induced airway hyperresponsiveness in six dogs. Airway responsiveness to methacholine was measured by modified Astograph (7 Hz oscillation method) before and after ozone exposure, and TxB2 in plasma and in BALF, 6-keto-PGF1 alpha in BALF, numbers of neutrophils in the peripheral blood and differential cell counts in BALF were measured before and after ozone exposure. Ozone exposure was carried out for 2 hr at an ozone level of 3.04 +/- 0.01 ppm (mean +/- SE). There was a significant increase in airway responsiveness to methacholine after ozone exposure in the six dogs (p less than 0.01), and the numbers of neutrophils in the peripheral blood and the neutrophil counts in BALF increased significantly after ozone exposure (P less than 0.01). A selective 5-lipoxygenase inhibitor, AA-861 significantly inhibited the increase of airway responsiveness to methacholine induced by ozone exposure (p less than 0.05), and furthermore, the increase in the numbers of neutrophils in the peripheral blood and the neutrophil counts in BALF after ozone exposure were significantly inhibited by pretreatment with AA-861 (p less than 0.05). There was no significant change in the levels of TxB2 in plasma or in BALF, and also no apparent change in the levels of histamine was observed in BALF after ozone exposure. The levels of 6-keto-PGF1 alpha in BALF decreased after ozone exposure, but the decrease was not significant. These results suggest that 5-lipoxygenase products play an important role in the development of airway hyperresponsiveness and in the infiltration of neutrophils into the airway after ozone exposure in dogs.     

一氧化氮合酶抑制剂对大鼠结肠炎损伤的影响

目的：了解一氧化氮合酶抑制剂L－精氨酸甲酯（L-NAME）对大鼠结肠炎损伤的影响。方法：将实验大鼠随机分为对照组、损伤组、NAME1、NAME2、NAME3（即N1、N2、N3）干预组。采用三硝基苯磺酸（TNB）30 mg+50%乙醇0.25 mL给大鼠灌肠复制结肠炎模型，并检测各组的溃疡指数（UI）、一氧化氮（NO）、MDA含量及GSH活性。结果：N1、N2、N3组的NO、UI、MDA值低于损伤组，GHS值高于损伤组，对照组的损伤不明显。相关分析表明，NO含量与MDA含量呈正相关，与GSH活性呈负相关。结论：在结肠炎症反应中，NO过量生成具有损伤作用，L－NAME通过抑制NOS活性，减少NO及自由基的生成，具一定的抗损伤作用。     

Effects of experimentally induced inflammation on temporomandibular joint nociceptors in rats

Response properties of nociceptors in the temporomandibular joint (TMJ) and surrounding area under experimental inflammation were investigated using an in vitro TMJ-nerve preparation in the rat. Nociceptive units (receptor and innervating nerve fiber) were classified into the following subtypes: Adelta-high-threshold mechanonociceptor (HTM), Adelta-polymodal nociceptor (POLY), C-HTM and C-POLY. In the inflamed joint, mechanical thresholds tended to be lower; however, the reaction to bradykinin was not identified as clearly as in control. Experimentally induced inflammation increased the proportion of heat-sensitive units and lowered heat threshold significantly. These results suggest that inflammation may sensitize nociceptors in the temporomandibular joint, and cause hyperalgesia and allodynia.     

The effects of postnatal maternal separation on stress responsivity and experimentally induced colitis in adult rats

In this study, we investigated the effects of three neonatal conditions on adult corticosterone (CORT) levels, acoustic startle responses (ASRs), and vulnerability to colitis induced by dextran sulfate sodium (DSS) and how these early manipulations might interact with a brief stress exposure in adulthood on the same measures. Infant animals were subjected daily to either 180-min maternal separation [prolonged maternal separation (LMS)], 10-min maternal separation [brief maternal separation (BMS)], or nonhandling (NH) conditions during postnatal days 1-14. As adults, half of the animals were exposed to a series of 10 uncontrollable foot shocks. Animals were tested for CORT levels prior to and 10 days following shock/nonshock procedures before being tested for ASRs. Finally, all animals were exposed to 4% DSS in their drinking water for 6 days. LMS animals showed enhanced vulnerability to DSS-induced colitis when previously exposed to shock and enhanced stress reactivity responses as shown by elevated startle and CORT levels. Among the nonshocked animals, NH animals showed most colonic damage. Taken together, the results support previous findings suggesting that BMS has a protective effect on adult stress exposure. Additionally, BMS protects the animals from chemically induced colitis. The NH condition has clearly an effect on sensitizing mucosal response to DSS exposure.     

Effects of SK&F 93479 on experimentally induced ventricular arrhythmias in dogs,rats and mice

The effects of SK&F 93479, a potent histamine H₂-receptor antagonist, on ventricular arrhythmias induced by coronary artery ligation in dogs and rats, and by aconitine infusion in mice were investigated. It was found that SK&F 93479 in large doses, significantly prevented the occurrence of spontaneous ventricular fibrillation and the changes in ventricular fibrillation threshold following coronary artery ligation in dogs. In rats subjected to ligation of the main left coronary artery, it significantly reduced the incidence of ventricular fibrillation, and significantly prolonged the time of onset of ventricular tachycardia and ventricular fibrillation. On the contrary, SK&F 93479 did not significantly alter the incidence or the time of onset of cardiac dysrhythmias caused by aconitine infusion in mice. These findings suggest that SK&F 93479 lacks non-specific antiarrhythmic activity and that its protective effects against coronary artery ligation may be mediated by its histamine H₂-receptor antagonizing action. They also support the hypothesis that histamine may contribute to the genesis of ventricular arrhythmias resulting from acute myocardial ischaemia.     

BI-L-239, a 5-lipoxygenase inhibitor,blocks inhaled antigen-induced airway hyperresponsiveness in conscious guinea pigs

Male Hartley guinea pigs were actively sensitized to ovalbumin (OA). Respiratory system resistance (Rrs) was measured by forced oscillations superimposed on tidal breathing. Airway responsiveness (inhaled methacholine PC₁₀₀) was determined three days prior and three days after (day 10) three alternate day inhalations of OA. Airway cell composition was assessed on day 10 by lung lavage. Three groups (n=5–6) were studied: A) vehicle challenged, B) OA challenged/placebo treated, C) OA challenged/BI-L-239 (2,6-dimethyl-4-[2-(4-fluorophenyl)ethenyl]phenol) treated (10×0.75 mg/actuation, 10 minutes prior to each OA challenge). Animals were treated with pyrilamine and indomethacin (10 mg/kg i.p.) 30 minutes prior to each OA challenge. OA induced acute increases in Rrs of 143±29%, 238±73% and 102±43% in placebo and 86±34%, 45±35% (p, 0.05 vs. placebo) and 102±31% in BI-L-239 treated. OA induced a significant (p<0.05) increase in airway leukocytes in placebo (487±36 to 1615±421×10³/ml) but not BI-L-239 treated (to 881±155×10³/ml) and decrease in methacholine PC₁₀₀ in placebo (1.487±0.49 to 0.39±0.18 mg/ml) but not BI-L-239 treated (0.99±34 to 1.04±0.39 mg/ml). We conclude that BI-L-239 attenuates the airway constriction, inflammation and hyperresponsiveness induced by repeated antigen inhalations in conscious guinea pigs.     

RBx 7796: A novel inhibitor of 5-lipoxygenase

Objective: To evaluate the pharmacological profile of RBx 7796, a novel 5-lipoxygenase inhibitor. Materials and methods: RBx 7796 was evaluated for 5- lipoxygenase inhibitory potential using human recombinant enzyme and profiled for selectivity against 12 and 15 lipoxygenase. RBx 7796 was evaluated in cell based assay for inhibition of A23187 induced LTB₄ release from isolated neutrophils. Ex vivo activity was evaluated for inhibition of A23187 induced LTB₄ release in blood from treated rats. In vivo efficacy of RBx 7796 was profiled in LPS induced neutrophilia model in rats and also in ovalbumin induced bronchoconstriction and airway inflammation models in guinea pigs. Results: RBx 7796, a novel chemotype, showed competitive inhibition of 5-lipoxygenase enzyme with an IC₅₀ of 3.5 ± 1.1 μM. RBx 7796 offered >100 fold selectivity against other related enzymes – 12 and 15 lipoxygenase. RBx 7796 inhibited release of LTB₄ from human and rat neutrophils in vitro. Upon administration to rats, RBx 7796 inhibited A23187 induced LTB₄ release from rat neutrophils. Upon repeated administration, dosed once daily, RBx 7796 inhibited LPS induced neutrophil influx in rat airway. RBx 7796 also inhibited allergen induced bronchoconstriction and eosinophil influx in guinea pig airway in a dose dependent manner. Conclusion: The results suggest that RBx 7796, a novel chemotype, is an orally efficacious inhibitor of 5-lipoxygenase enzyme that is effective against both neutrophilic and eosinophilic airway inflammation and shows potent inhibition with once daily administration. Received 9 March 2006; returned for revision 17 May 2006; accepted by I. Ahnfelt-R?nne 19 May 2006     

Effects of sympathectomy on experimentally induced pulpal inflammation and periapical lesions in rats

The role of sympathetic nerves in bone physiology is largely unknown. Recent studies have shown a correlation between sympathectomy and bone remodeling. The present experiments were aimed to study the effects of unilateral sympathectomy on bilateral experimentally induced pulpitis and periapical lesions in the rat maxilla and mandible. Adult male Sprague-Dawley rats were used. Experimental rats (n=11) had the right superior cervical ganglion surgically removed (SCGx) and control rats (n=5) had sham surgery. Pulpal inflammation and periapical bone lesions in the maxilla and mandible were created 14 days later in both experimental and control rats by exposing the dental pulp in the first and second molars and leaving them open to the oral microflora. The rats were perfused 20 days thereafter and the jaws processed for immunohistochemistry with neuropeptide Y (NPY) and ED1 as primary antibodies. Sympathectomy resulted in an almost complete loss of NPY-immunoreactive (IR) fibers in the right SCGx jaws. In the non-sympathectomized (non-SCGx) left side and in the control rats, sprouting of NPY-IR fiber was observed in the inflamed pulp tissue adjacent to reparative dentin formation and in the apical periodontal ligament of the partially necrotic first molars. Significantly more ED1-IR osteoclasts were found in the resorptive lacunae lining the periphery of the periapical lesions on the SCGx side compared with the non-SCGx side (P<0.04) and the controls (P<0.03). The size of the periapical lesions were larger on the SCGx side compared with the non-SCGx side (P<0.03) in the mandible, but not in the maxilla. We conclude that inflammation causes sprouting of NPY-IR nerve fibers and that unilateral removal of the SCG increases both the area of the periapical lesions and the number of osteoclasts in the inflamed region.     

Effects of ranitidine and cimetidine on experimentally induced ventricular arrhythmias in anaesthetized rats

The effects of two histamine H₂-receptor antagonists, ramitidine and cimetidine, on ventricular arrhythmias induced by acute coronary artery ligation and by aconitine infusion were studied in pentobarbitone-anaesthetized rats. The changes in arterial blood pressure and heart rate were also observed. It was found that both drugs significantly reduced the incidence, and prolonged the time of onset, of ventricular tachycardia and ventricular fibrillation following acute coronary artery ligation; however, they did not significantly alter the incidence or time of onset of ventricular dysrhythmias caused by aconitine infusion. These findings further support the hypothesis that histamine release may contribute to the genesis of early ventricular arrhythmias resulting from acute myocardial ischaemia. Since the decreased blood pressure induced by coronary artery ligation was not significantly prevented by pretreatment with either histamine H₂-receptor blocker, this suggests that histamine may not be responsible for the blood pressure changes during acute myocardial ischaemia.