Ph.D. - Biomedical Sciences (Pharmacology)

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Effects of adrenergic agonists and antagonists in potassium intoxication

([Honolulu], 1973) Lockwood, Raymond H.

Studies were performed to assess the role of the sympathetic nervous system in regulating the metabolism of an administered load of potassium in anesthetized cats. A nonlethal intravenous infusion of KCl (10 mg/Kg/min for 10 minutes) produced effects indicative of a sympatho-adrenal discharge; these effects included an increase in heart rate, a rise in blood pressure and an increase in blood glucose. The increases in heart rate and blood pressure were abolished by acute adrenalectomy and by pretreatment with reserpine. Propranolol pretreatment antagonized the heart rate but not the blood pressure response associated' with the KCl infusion. Acute adrenalectomy as well as pretreatment with reserpine, propranolol and 1-(4'methylphenyl)-2- isopropylamino-propanol (H35/25) increased the susceptibility of the animals to KCl intoxication; thus, a significant number of fatalities occurred in these animals when they received a rate of KCl infusion (10 mg/Kg/min) which produced no deaths in intact, non-pretreated controls. The fatalities were correlated with higher plasma K+ values than in the controls. Butoxamine pretreatment did not significantly increase the susceptibility to KCl intoxication from a mortality standpoint but did significantly increase the hyperkalemic response to the KCl infusion. The above suggested that the sympatho-adrenal system has an important attenuating effect on the rise in plasma K+ produced by infusion of the ion. Chlorisondamine and bretylium pretreatment failed to increase the susceptibility of the animals to KCl intoxication. Evidence is presented which suggests that these latter two agents may not effectively antagonize the sympatho-adrenal discharge elicited by KCl infusion. The i.v. infusion of epinephrine completely protected animals against an infusion of KCl (12 mg/Kg/min for 10 minutes) which was lethal to most control animals. Plasma K+ data showed that the protection was related to an ability of epinephrine to attenuate the hyperkalemia produced by infusion of the ion. Similar effects on mortality and plasma K+ were produced by isoproterenol (a beta adrenergic stimulant) but not by phenylephrine (an alpha adrenergic stimulant). The epinephrine-induced protection against death due to KCl infusion as well as the plasma K+ lowering effect were abolished by propranolol and sotalol (beta blocking agents) but not by phenoxybenzamine (an alpha blocking agent). Acute nephrectomy or pancreatectomy did not affect the protective action of epinephrine. An infusion of glucose (which produced blood glucose levels higher than those in the epinephrine series) did not protect against KGI intoxication. The K+ content of skeletal and cardiac muscle in animals given an infusion of KCl was significantly greater in animals infused with epinephrine than in controls infused with saline. The foregoing suggests that epinephrine protected against KCl intoxication in these experiments by virtue of a direct beta stimulant action which promoted the entry of K+ into cells and thus prevented plasma K+ from reaching a lethal level. Studies were also performed to determine the "subtype" of beta receptor subserving the above effect on K+. Butoxamine and H35/25 were very effective in antagonizing the effects of epinephrine in potassium intoxication. Practolol, which blocked the cardiostimulant effect of epinephrine, did not block the protective effect or attenuation of hyperkalemia during KCI infusion by this catecholamine. Salbutamol and soterenol had effects similar to epinephrine, but l-isopropylamino-3-(2-thiazoloxy)2-propanol (ITP) failed to protect against KCl intoxication. The above spectrum of agonism and antagonism would be consistent with a beta-2 type of adrenergic receptor according to the Lands classification, although the adequacy of this classification in delineating the beta receptors found in different tissues has been questioned.
The chemistry and pharmacology of a central nervous system stimulant from the sea anemone, Stoichactis kenti

([Honolulu], 1971) Turlapaty, Prasad D.M.V.

A central nervous system stimulant has been isolated from the sea anemone, Stoichactis kenti. A chromatographically homogeneous fraction has been obtained from the crude extract by dialysis and gel filtration on Sephadex G-50. Attempts were made to purify the active fraction further by ion exchange column chromatography, but the specific activity of the active fraction was not increased. The active substance was found to be water soluble, heat and acid labile and stable to alkali. It showed a positive color reaction with ninhydrin on paper (circular) chromatography, using n-butanol: acetic acid:water (4:1:5) system. Steroids, steroidal glycosides, nucleic acids, lipids and carbohydrates were found to be absent in the active fraction, when tested with specific reagents. The active fraction has a characteristic u.v. maximum at 277.5 nm. Determination of protein by Lowry's method and estimation of nitrogen by Kjeldahl's method indicated the active fraction was rich in protein. An acid and alkaline hydrolysis of the active fraction was carried out and hydrolysates were analyzed both by two dimensional chromatography and Technicon auto aminoacid analyzer. The following amino acids were identified by comparing with standard aminoacids: cysteine, aspartic acid (asparagine), threonine, serine, glutamic acid (glutamine), proline, glycine, alanine, valine, cystine, isoleucine, leucine, tyrosine, phenylalanine, lysine, histidine and arginine. From these results it was concluded that the active fraction was a polypeptide containing seventeen different aminoacids. Based on behavior on Sephadex G-50, the approximate molecular weight of the active fraction was estimated to be in the range of 2,500 - 3,000. Signs of central nervous system stimulatory activity produced by the active fraction in male mice included fighting episodes, increased motor activity and clonic convulsions. The ED50 of the active fraction based on fighting episodes was 6.4 mg/kg. The fighting episodes occurred at a frequency of 2-3 times/minute. After the administration of the active fraction intraperitoneally, the fighting episodes started within 4-6 minutes, peaked at 15 minutes and waned within about 30 minutes. The LD50 dose of the active fraction was 12.2 mg/kg. Toxic symptoms such as ataxia, catalepsy and tonic convulsions were observed before death. Phenobarbital sodium, chlorpromazine and methocarbamol completely blocked the fighting response of the active fraction even at the ED100 dose level but did not change the LD50. The antagonism of the active fraction induced stimulant activity (as measured by fighting episodes) by these drugs suggests that this activity was probably mediated centrally. Reserpine and tetrabenazine pretreatment markedly increased the stimulant effect of the active fraction by decreasing the ED50 of the active fraction by 50%. Such treatment increased toxicity twofold. a-methyl p-tyrosine methylester Hel (α-MPT) pretreatment did not alter the ED50, while the LD50 was significantly decreased. When α-MPT treatment was incorporated in reserpine or tetrabenazine treated animals, the stimulatory activity of the active fraction was completely blocked even at the ED100 (9.3 mg/kg) dose level. The active fraction produced a significant decrease in brain norepinephrine content at the ED50 and the ED100 doses during the stimulation period. Both the active fraction and reserpine produced a hyperthermic response in mice. DL-dopa treatment restored the active fraction induced stimulant action (fighting episodes) which was abolished after combined treatment with a-MPT and reserpine and reserpine and disulfiram. DL-dopa also increased the LD50 of the active fraction. The active fraction at the ED50 dose significantly decreased brain dopamine content. Pretreatment with p-chlorophenylalanine did not alter the ED50 and the LD50 of the active fraction. No change in brain serotonin content was observed after administration of the active fraction at the ED50 dose. The active fraction at the ED50 dose significantly inhibited the re-uptake mechanism of norepinephrine during the stimulation period. It also elevated normetanephrine levels at the ED50 dose. Propranolol but not phentolamine treatment completely blocked the stimulatory action of the active fraction, with no change in the LD50. Atropine treatment decreased the toxicity, with no change in the ED50. On the other hand physostigmine blocked the stimulatory action and increased toxicity by twofold. In conclusion, the results suggest that the active fraction causes stimulant action by releasing active norepinephrine from functional pools and inhibiting its re-uptake, thus making more norepinephrine available at adrenergic receptors.
The nature and action of a hypotensive agent from Eucalyptus robusta

([Honolulu], 1969) Read, George Wesley

Extracts of some species of Eucalyptus have been found to be hypotensive in rats, guinea pigs, cats, and dogs. Of the 29 species of this genus available for assay, Eucalyptus robusta contained the highest concentration of the hypotensive principle. Active and inactive species were randomly distributed throughout the sections and subsections of the genus, indicating that activity is not associated with any particular group of the eucalypts. The active principle occurs in highest concentration in the leaves but is also found in the phloem, roots, and to a lesser extent in the xylem. Little or no activity is present in> the bark. The hypotensive factor is soluble in water, lower alcohols and acetone but insoluble in chloroform or ether. Addition of chloroform or ether to the alcoholic extracts precipitated a more purified fraction. Attempts to purify the active component further by adsorption, steam distillation, gel filtration, heavy metal ion precipitation, liquid-liquid extraction, and dialysis met With little success. The molecular weight of the active principle was found to be approximately 3000, using Craig's dialysis method. The active component's molecular weight, solubility characteristics, precipitability by heavy metals (especially ferric chloride), base lability, strong adsorptive tendencies especially to Sephadex), non-volatility, ease of oxidation, and ineffectiveness orally indicate that it is probably a specific tannin. Five mg/kg of the partially purified material depressed the blood pressure of rats to less than 50% of its original value for approximately 15 minutes. Larger doses lowered the blood pressure to 30% of normal and for periods greater than several hours. The active agent was effective intravenously and intraperitoneally but ineffective orally. The absence of an effect when it was given to the vascularly isolated heads of cross-circulated animals indicated that the agent's action was peripheral. Prior treatment with hexamethonium, reserpine, phenoxybenzamine, pronethalol, and atropine had little or no effect on the action of the Eucalyptus factor. The antihistaminics tripellenamine and diphenhydramine, however, did attenuate the depressor effect of the extracts. When the active principle was given first, it had little or no effect on the response to subsequently administered phenylephrine, angiotensin, isoproterenol, or methacholine. However, there was an interference with the response to histamine. These results suggest that the hypotensive agent acts on the histamine pathway. Depletion of the histamine stores With the drug 48/80 blocked the action of the hypotensive agent, as did a one-week pretreatment With the agent itself. These results, along With the blockade by antihistamines and the interference with the response to histamine, indicate that the active principle is a histamine liberator.
Chemistry and pharmacology of adrenergic blocking agents

([Honolulu], 1969) Ghouri, Mohammad Sarfraz Khan
The contractile mechanisms of sodium metavanadate in isolated vascular smooth muscle

( 1995) Zhou, Qin

The mechanism of the contractile effect of vanadate on vascular smooth muscle was investigated in the rat aorta. Sodium metavanadate (NaV03) (10-5 M - 3 x 10-3 M) induced contractile responses in a concentration-dependent manner. Removal of endothelium did not affect the response to NaV03. NaV03 has the most efficacy agent to cause contraction as compared to vanadyl sulphate and vanadium trichloride. The response to NaV03 was inhibited by nifedipine, a voltage depedent Ca2+-channel inhibitor, 2-nitro-4-carboxyphenylN, N-diphenylcarbramate (NCDC), a phospholipase C inhibitor, H-7, a protein kinase C inhibitor, indomethacin, a cyclooxygenase inhibitor, and AA861, a 5Iipoxygenase inhibitor, but not by ouabain, a Na+, K+-ATPase inhibitor, prazosin, a a1 receptor inhibitor, methysergide, a serotonin receptor inhibitor, tripelennamine, a histamine receptor inhibitor, glyburide, a KATP-channel inhibitor, -apamin, a Kca-channel inhibitor, or Mg2+-removal, a condition to inhibit Ca2+ATPase activity. The response to arachidonic acid was also inhibited by indomethacin, AA861 , nifedipine and NCDC. H-7 inhibited the response to NaV03 but not to arachidonic acid. However, in the presence of indomethacin and AA861 , H-7 did cause inhibition of the residual response to NaV03. In Ca2+-free medium with EGTA (0.02 mM), NaV03 (3 x 10-4 M) induced a phasic contraction of rat aortas. This residual response to NaV03 was partly inhibited by NCDC and indomethacin, but not by nifedipine. The subsequent addition of Ca2+ (1.2 mM) in the presence of NaV03 caused sustained contraction. In addition, the response to Ca2 + in the presence of NaV03 was completely inhibited by both NCDC and nifedipine, but only partially inhibited by indomethacin. In rat aortas, NaV03 increased the levels of inositol monophosphate (InsP) and prostaglandin F2a. Indomethacin, AA861, and NCDC inhibited the InsP increase. In addition, NCDC and indomethacin, but not AA861 , inhibited the PGF2a increase. These results suggest that the response to NaV03 may be due to the increased phosphoinositide metabolites and partly due to a subsequent increase in the metabolism of arachidonic acid.
Effects of drugs which alter blood cell deformability in circulatory shock produced by endotoxin

( 1991) Yao, Zhenhai

Pentoxifylline is a xanthine derivative chemically related to theophylline and caffeine. The drug is said to improve tissue oxygenation in chronic vascular occlusive disease by increasing RBC deformability and has been reported to improve survival in experimental hemorrhagic, septic and endotoxic shock. In the present investigation, the effects of pentoxifylline on endotoxin-induced mortality, disseminated intravascular coagulation (DIC), hypotension, and reduction in blood cell deformability were studied in awake rats and compared with the effects produced by two other xanthine compounds, theophylline and caffeine, and by a non-xanthine compound, buflomedil. In control rats, endotoxin (25 mg/kg, i.v.) produced a 92% mortality as well as clinical laboratory signs of DIC. The latter included increased serum fibrin(ogen) degradation products (FDP), prothrombin time. and partial thromboplastin time, and decreased plasma fibrinogen and blood platelet count as well as evidence of gross visceral hemorrhage. Pretreatment with pentoxifylline (25-50 mg/kg), caffeine sodium benzoate (25-200 mg/kg) and buflomedil hydrochloride (2.5-50 mg/kg) produced a dose-dependent reduction in the endotoxin-induced mortality and inhibited most of the manifestations of DIC produced by endotoxin. Pretreatment With theophylline (given in the form of aminophylline, 5-125 mg/kg), did not inhibit the endotoxin-induced DIC and failed to protect against death caused by the lipopolysaccharide. The effects of drugs on blood pressure and heart rate were studied in awake rats With implanted carotid catheters. All four drugs produced a dose-dependent lowering of arterial pressure when administered as a pretreatment. The administration of endotoxin (25 mg/kg) in control animals caused an immediate fall in arterial pressure, followed by a partial recovery and a later progressive decline until death of the animal. All of the control animals in this series died Within 24 hours. Pretreatment with pentoxifylline (50 mg/kg), caffeine sodium benzoate (I00-200 mg/kg) and buflomedil hydrochloride (30-50 mg/kg) significantly reduced the endotoxin-induced hypotension as well as the mortality during the 24-hour period of observation. In contrast, pretreatment With aminophylline (50-100 mg/kg) not only failed to antagonize the hypotension caused by endotoxin but actually had a deleterious effect: post-endotoxin blood pressure in the aminophylline pretreated series was significantly lower than in the saline pretreated endotoxin controls throughout the period of observation. All animals in the aminophylline series died. Vasodilator agents are known to have a protective action in circulatory shock. In the present study, the hypotensive effect produced by aminophylline was comparable to that produced by protective doses of the other agents. The difference in protective efficacy therefore was not related to a difference in vasodilator efficacy. Heart rate measurements showed that there was no correlation between cardiac stimulation produced by the xanthines and protection against endotoxic shock. All three xanthines caused a dose-dependent increase in the heart rate and antagonized the bradycardia caused by endotoxin. However, only pentoxifylline and caffeine increased survival. Buflomedil actually slowed the heart rate but nevertheless inhibited the endotoxin-induced bradycardia and decreased the mortality, Endotoxin (25 mg/kg) was found to cause a reduction in RBC deformability. The in vivo administration of pentoxifylline, caffeine and buflomedil improved the deformability of both erythrocytes and leukocytes and was found to reverse the endotoxin-induced reduction in RBC deformability. In contrast. aminophylline did not have a significant effect on blood cell deformability and did not affect the rheological effect of endotoxin. The present. investigation thus showed that prevention of endotoxin-induced DIC, circulatory shock and death by pentoxifylline, buflomedil and caffeine was positively correlated with an ability of the drugs to improve blood cell deformability. The hypothesis is advanced that a causal relationship may exist between the latter action and the protective action of the three drugs in endotoxic shock.
Studies on homocarnosinosis and on human tissue carnosinase and its inhibition by bestatin and by endogenous inhibitors

( 1984) Peppers, Steven Carl

Carnosine (β-alanyl-L-histidine) is a major constituent of human skeletal muscle. Its function in muscle is yet undetermined, but there is evidence that carnosine may serve as a buffer, an activator of myosin ATPase, or a source of supplementary histidine or histamine. Carnosine is also highly localized in the olfactory bulb of the mouse, where it is a putative neurotransmitter for olfactory chemoreceptor neurons. Tissue carnosinase may be responsible for its degradation and consequent inactivation at the synapse. Another histidine dipeptide, homocarnosine (γ-aminobutyryl-L-histidine), is almost exclusively localized in the CNS; little is yet understood about its physiological function. Patients afflicted with homocarnosinosis have elevated concentrations of homocarnosine in brain and cerebrospinal fluid. It has been reported that they lack brain homocarnosinase. However, in the present study it was found that these patients are deficient in serum carnosinase, a dipeptidase (mol.wt. 160,000) which hydrolyzes homocarnosine in addition to carnosine. When an extract of normal human brain was chromatographed on DEAE-cellulose, all homocarnosine-hydrolyzing activity was present in one peak and had a molecular weight of 160,000. Also, homocarnosinase (Mol.wt. 57,000) was not detected in brain extracts after isoelectric focusing. Homocarnosine-hydrolyzing activities and serum carnosinase activities of human CSF samples were significantly correlated (p<0.001). In homocarnosinosis patients, both of these activities were negligible in serum samples, a CSF sample, and a brain biopsy sample when compared to corresponding controls. Thus, the ability of brain extracts and CSF to hydrolyze homocarnosine appears to be attributable solely to serum carnosinase, which is deficient in patients with homocarnosinosis. The homocarnosine-hydrolyzing activity in 12 other tissues was related to the amount of trapped blood, but brain contained 15 times the activity expected from its blood content; hence, serum carnosinase may be synthesized in the brain. Human tissue carnosinase was found to be optimally active at pH 9.5. It was inhibited by p-hydroxymercuribenzoate and activated by 2 mM dithiothreitol: indicating it to be a cysteine peptidase. By optimizing assay conditions, tissue carnosinase activities per g of tissue were 5- to 15-fold greater than those previously reported. The enzyme was present in every human tissue assayed and was entirely different from plasma carnosinase. Highly purified tissue carnosinase had a broader specificity than hog kidney carnosinase. Although tissue carnosinase was very strongly inhibited by bestatin, it did not hydrolyze tripeptides and thus appears to be a dipeptidase rather than an aminopeptidase. It was found to have a molecular weight of 90,000, an isoelectric point of 5.6, and a Km value of 10 mM carnosine under the conditions of assay. Two forms of kidney and brain carnosinase were separated by high resolution anion exchange chromatography, although only one form was detected using various electrophoretic methods. Two other enzymes, homocarnosinase and manganese-independent carnosinase, were not detected in human tissues, but were readily measured in rat and hog kidney. Crude extracts of human tissues contain endogenous tissue carnosinase inhibitors that were dialyzable and thermostable over a pH range of 1 to 11. Among 14 different tissues the amount of inhibition varied considerably, but no tissue was without inhibitor. An endogenous inhibitor from human liver was isolated and identified as L-leucine. It was found to be the most inhibitory (IC50 = 0.2 mM) of all the common amino acids, followed by cysteine and cystine. L-leucine inhibition was stereospecific, D-leucine being inactive, and was partially dependent on manganese; this indicates that it binds to the active site of tissue carnosinase. In contrast, cysteine probably inhibited carnosinase by chelating manganese; as manganese concentrations were increased above 0.02 mM, the inhibition decreased. Cystine inhibition was attributed to its reduction to cysteine by the dithiothreitol present in the digest. Since the concentrations of leucine and other amino acids in a liver extract accounted for only one fourth of its inhibitory activity, another inhibitor(s) must have been present. Inhibition by L-leu-L-leu was greater than by L-leucine, and plots of the reciprocal velocity vs. L-leucine concentration displayed upward curvature these results suggest that L-leucine binds to two sites on tissue carnosinase. L-leucine inhibition was mixed competitive and noncompetitive, being predominantly competitive at concentrations below 0.2 mM L-leucine and more noncompetitive at higher concentrations. Bestatin is a dipeptide that has potential clinical value as an immunostimulant and chemotherapeutic agent. Commonly known to inhibit leucine aminopeptidase and aminopeptidase B, bestatin was found to be an extremely potent inhibitor of human tissue carnosinase (Ki = 0.5 nM). The affinity of bestatin binding to tissue carnosinase was 18 to 40 times greater than to nonparticulate leucine aminopeptidase and 120 times greater than to aminopeptidase B. Bestatin was a competitive inhibitor and was most inhibitory at a manganese concentration close to the optimum for enzyme activity. The structures of bestatin and carnosine are similar; both contain an N-terminal β-amino connected to an a-amino acid having an R-group with a branch-point at the y-carbon. Therefore, it is proposed that bestatin binds with high affinity to tissue carnosinase because its backbone chain is identical to that of carnosine.
Effect of gender on the antidiuretic activity of vasopressin in the spontaneously hypertensive rat

(University of Hawaii at Manoa, 2003-08) Ye, Dailin ; Uyehara, Catherine FT ; Biomedical Sciences (Pharmacology)

Recently, studies have found that circulating vasopressin levels, as well as the cardiovascular and antidiuretic actions of vasopressin are greater in males than in females, but the consequences of these gender differences are unclear. Further, animal and human studies have revealed that hypertension develops more rapidly and is more prevalent in males than in females. Because vasopressin is involved with blood pressure regulation, whether vasopressin gender differences are involved in the gender difference of hypertension development should be examined. Thus, this dissertation tested the hypothesis that a gender effect on vasopressin renal action contributes to gender differences in hypertension. Renal function of male and female adult spontaneously hypertensive rats (SHR) were compared to that of normotensive (WKY) rats. Vasopressin V2 receptors were pharmacologically stimulated with a selective V2 receptor agonist, which revealed that maximal urine concentrating abilities of SHR were higher than that of WKY. While there were significant differences in concentrating abilities with hypertension, there were no significant gender differences in responses to maximal V2 stimulation in normotensive or hypertensive rats. The contribution of endogenous vasopressin on renal fluid handling to a gender difference in hypertension was also examined. Vasopressin inhibition with a selective V2 antagonist resulted in higher free water clearance in females than in males of both strains. Also, the renal response to endogenous vasopressin blockade was lower in SHR than WKY in both sexes. Expression of V2 receptors in renal inner medulla of male SHR and WKY showed that levels of V2 receptor mRNA in SHR were significantly lower than those in WKY. Thus, differences in renal fluid handling abilities between strains and gender, may be due to the differences in endogenous vasopressin levels, renal concentrating abilities, or expression of renal vasopressin receptors. In conclusion, vasopressin influence on renal fluid handling is altered in established hypertension. While there are differences in vasopressin renal action between males and females in both strains, there were no significant differences in the gender effect between normotensive and hypertensive adult rats. Thus, whether gender differences in fluid handling contribute to gender differences in hypertension development remains to be determined.
Studies on the effects of pharmacological agents on endotoxin induced pulmonary injury

(University of Hawaii at Manoa, 2003-08) Yang, Li ; Lum, Bert K B ; Biomedical Sciences (Pharmacology)

Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury, characterized by inflammation and increased capillary permeability, associated with a constellation of clinical, radiological and physiological abnormalities. The incidence of ARDS is uncertain but has been estimated to be as high as 75 cases per 100,000 hospitalized patients per year. The overall mortality of patients with ARDS remains at 40 to 60 percent. Many factors predispose to ARDS, with sepsis caused by gram negative bacteria being one of the most important. Experimentally, ARDS can be mimicked by the injection of bacterial endotoxin. Previous studies in our laboratory showed that pretreatment with pentoxifylline (a methylated xanthine), bepafant (a platelet activating factor antagonist) and nicardipine (a calcium channel blocker), 15 minutes before the administration of endotoxin, reduced the mortality and manifestations of disseminated intravascular coagulation caused by endotoxin in rats. The objective of the present study was to determine whether these drugs would also protect the rat lung against the deleterious effects of endotoxin. Anesthetized rats were given endotoxin (10 mg/kg) intravenously. One hour later, the lungs were removed and perfused with a buffered salt solution containing 4% Ficoll and aerated with air and 5% CO2 Pulmonary arterial pressure, capillary pressure, capillary permeability, and arterial and venous segmental resistances were significantly higher in lungs obtained from endotoxin-treated animals than in lungs from saline control rats. Endotoxin also caused an increase in lung weight, lung water content and the outflow of lung filtrate as compared to saline-treated controls. Pretreatment in vivo with nicardipine and bepafant, 15 minutes before the administration of endotoxin, significantly reduced the endotoxin-induced increases in capillary permeability and filtrate outflow but did not significantly affect the other parameters of measurement. Pretreatment with pentoxifylline differed from other two drugs in that the methylated xanthine significantly reduced the endotoxin-induced increases in all of the hemodynamic parameters as well as the increase in capillary permeability and filtrate outflow. Studies were also made on the effect of endotoxin on the pulmonary leukocyte count in rats. In these experiments, lungs were removed for histological examination one hour after the intravenous administration of endotoxin (10 mg/kg). Leukocyte numbers were significantly increased in the endotoxin group as compared to the saline group. Pretreatment with nicardipine and bepafant but not pentoxifylline significantly reduced the endotoxin-induced increase in pulmonary leukocyte count. The present results thus showed that the three drugs can protect against endotoxin-induced lung injury, in addition to preventing disseminated intravascular coagulation and death caused by the lipopolysaccharide. Pulmonary migration/sequestration of leucocytes and production/release of autacoids and cytokines from leucocytes are thought to play important roles in the lung injury caused by endotoxin. The results with nicardipine and bepafant suggest that these agents may act at least in part by inhibiting the pulmonary migration/sequestration of leucocytes.

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