Effects of aminoguanidine and desferrioxamine on some vascular and biochemical changes associated with streptozotocin-induced hyperglycaemia in rats.

The effects of aminoguanidine (AG; 100 mg x kg(-1)) and desferrioxamine (DFO; 50 mg x kg(-1)) on some vascular and biochemical changes associated with streptozotocin (STZ; 65 mg x kg(-1); i.p.)-induced hyperglycaemia were investigated in rats. Both AG and DFO were administered i.p., once daily, for 14 consecutive days to normal and hyperglycaemic animals. The responsiveness of the isolated aortic rings to phenylephrine (PE) was tested. In addition, biochemical markers for oxidative stress such as plasma levels of lipid peroxides and total thiols, as well as the activities of erythrocytic superoxide dismutase (SOD) and whole blood glutathione peroxidase (GSH-Px) were assessed. Results of the present study indicated that induction of hyperglycaemia was associated with increased aortic ring responsiveness to PE, loss in body weight, increase in urine volume, elevation of plasma total thiols and lipid peroxide levels and elevated SOD and GSH-Px enzymatic activities. Treatment of normal rats with AG reduced the response of their aortae to PE. Furthermore, a profound increase in body weight without any significant change in the measured biochemical parameters was observed. In hyperglycaemic animals, AG tended to normalize the enhanced aortic response to PE and modulated STZ-induced biochemical changes without affecting the elevated plasma glucose level. Treatment of normal rats with DFO reduced the response of their aortae to PE and decreased their body weight without altering any of the chosen biochemical parameters. In hyperglycaemic animals, DFO attenuated the responsiveness of their aortae to PE and at the same time, did not affect the loss in body weight and the elevation of plasma glucose level observed in the hyperglycaemic group. Additionally, DFO normalized the elevated plasma level of total thiols and exerted a modulatory influence on the enhanced activities of SOD and GSH-Px as well as on the increased levels of lipid peroxides. Our data lend further credence for the contribution of oxidative stress in the vascular and biochemical changes associated with STZ-induced hyperglycaemia. It is also apparent that advanced glycosylation end products and nitric oxide might be involved. Until clinical studies prove the efficacy and safety of these drugs, specific agents which could scavenge free radicals and block protein glycosylation seem beneficial as a helpful adjunct to the therapy of diabetes.

Ginkgo biloba extract (EGb 761) modulates bleomycin-induced acute lung injury in rats.

The effect of Ginkgo biloba extract (EGb 761) on bleomycin (BLM)-induced acute lung injury was studied in rats. The responsiveness of isolated pulmonary arterial rings to 5-hydroxytryptamine (5-HT) as well as the levels of some relevant biochemical markers in the lung tissue were taken as evidence for the acute lung injury. BLM was given intraperitoneally at a dose of 15 mg/kg/day for five consecutive days. It was found that BLM treatment attenuated the vasoconstrictor effect of 5-HT on the isolated pulmonary arteries. In lung tissues BLM also elevated the level of lipid peroxides and enhanced the activity of glutathione peroxidase. On the other hand, the level of glutathione and the activity of alkaline phosphatase were reduced. Body weight, lung weight and tissue glutathione-S-transferase activity were, however, not altered. Oral administration of EGb 761 at a dose of 100 mg/kg/day for five consecutive days did not alter any of the chosen biochemical parameters in the lung tissue except for a slight reduction in alkaline phosphatase activity. However, treatment with EGb 761 reduced the responsiveness of the pulmonary artery to 5-HT. Administration of EGb 761 (100 mg/kg/day; po) two hours prior to BLM (15 mg/kg/day; ip), for five consecutive days blunted the occurrence of further reduction in the vasoconstrictor response of the pulmonary artery to 5-HT. Furthermore, EGb 761 tended to normalize BLM-induced alterations in the measured biochemical markers in the lung tissue. The apparent modulatory influence of EGb 761 on BLM-induced acute lung injury stems, at least in part, from its beneficial free radical scavenging properties that provide the extract with antioxidant activity.

Thymoquinone-induced relaxation of guinea-pig isolated trachea.

The effect of thymoquinone (TQ), the main constituent of the volatile oil of black seed (Nigella sativa), on the guinea-pig isolated tracheal zig-zag preparation was investigated. TQ caused a concentration-dependent decrease in the tension of the tracheal smooth muscle precontracted by carbachol. The effects of TQ were significantly potentiated by pretreatment of the tracheal preparations with quinacrine, a phospholipase A2 inhibitor, nordihydroguiaretic acid, a lipoxygenase inhibitor and by pretreatment with methylene blue, an inhibitor of soluble guanylyl cyclase. On the other hand, the effects of TQ were not influenced by pretreatment of the tracheal preparations with indomethacin, a cyclooxygenase inhibitor, propranolol, a non-selective beta-adrenoceptor blocker or by the pretreatment with theophylline, an adenosine receptors antagonist TQ totally abolished the pressor effects of histamine and serotonin on the guinea-pig isolated tracheal and ileum smooth muscles. The results of the present study suggest that TQ induced relaxation of precontracted tracheal preparation is probably mediated, at least in part, by inhibition of lipoxygenase products of arachidonic acid metabolism and possibly by non-selective blocking of the histamine and serotonin receptors. This relaxant effect of TQ, further support the traditional use of black seeds either alone or in combination with honey to treat bronchial asthma.

Effect of streptozotocin-induced hyperglycaemia on intravenous pharmacokinetics and acute cardiotoxicity of doxorubicin in rats.

The present study was designed to investigate the pharmacokinetics and acute cardiotoxicity of doxorubicin (DOX) after intravenous (i.v.) administration (15 mg kg(-1)) to streptozotocin (STZ)-induced hyperglycaemic and normoglycaemic male Wistar albino rats. In STZ diabetic rats the area under the serum DOX time-concentration curve (AUC(0-24 h)) increased (13.35+/-1.33 compared with 7.13+/-0.71 microg h(-1) ml(-1); P<0.0001) and plasma and renal DOX clearance decreased. The DOX accumulation in STZ-induced diabetic rat heart (12.7+/-1.2 microg g(-1)) was increased (P<0.05) compared with non-diabetic hearts (11.0+/-0.9 microg/g), 24 h after DOX administration. Serum creatine phosphokinase (CPK) activity showed 25% increase in peak level in STZ diabetic rats compared to non-diabetic rats. DOX produced a reduction in heart rate of anaesthetized non-diabetic (20%) and diabetic (14%) rats 1 and 2 h after its administration, respectively. Isolated atria of diabetic rats were more sensitive to the negative chronotropic effect of DOX (150 microm). These preliminary results indicate that hyperglycaemia may alter the pharmacokinetics and acute cardiotoxicity of DOX and suggest that i.v. doses of DOX in diabetic patients may need to be modified if the present data could be extrapolated to humans.

Effect of captopril on doxorubicin-induced nephrotoxicity in normal rats.

Biochemical evaluations of the effects of the sulfhydryl-containing angiotensin-converting enzyme inhibitor (captopril) on the nephrotoxicity induced by doxorubicin in normal rats were carried out. A single dose of doxorubicin (15 mg kg-1) which caused nephrotoxicity was manifested biochemically by the elevation of serum urea after 24 and 48 h of administration. Also a severe decrease in total proteins and albumin after 4, 24 and 48 h was observed. Moreover, a decrease of non-protein sulfhydryl (-SH) concentrations in the kidney tissues after 24 h and an increase in the lipid peroxidation was observed after 4 h administration of doxorubicin. Captopril (60 mg kg-1 i.p.) injection did not induce any change in the biochemical parameters measured, however, captopril administered 1 h before doxorubicin ameliorated the biochemical toxicity induced by doxorubicin. This was evidenced by a significant reduction in serum urea and the lipid peroxidation after 4 and 24 h and a significant reduction in creatinine after 48 h. Also, the captopril amelioration was evidenced by an increase in total proteins and albumin after 4 and 24 h of doxorubicin administration. Captopril did not change non-protein sulfhydryl (-SH) concentrations or protein content in the kidney tissues. These results suggest that captopril may be beneficial as a protective agent against nephrotoxicity induced by doxorubicin.

Protective effect of aminoguanidine against cardiovascular toxicity of chronic doxorubicin treatment in rats.

The cardiotoxicity-induced by chronic treatment of doxorubicin have recently be attributed to free radical formation and/or release of nitric oxide. In the present study, an already established rat model of doxorubicin -induced cardiotoxicity was used. Doxorubicin in a total cumulative dose of 15 mgkg(-1) I.P. given in six equal injections over two week period was administered. After three weeks of doxorubicin administration, the blood pressure, serum lactate dehydrogenase, lipid peroxides, asites fluid and mortality rate were significantly increased. Doxorubicin-induced cardiotoxicity was further confirmed by examining the histopathology of heart sections. Myocardial fibres necrosis with prominent acute inflammatory cells were observed in rats hearts treated with doxorubicin. Aminoguanidine, an inhibitor of nitric oxide synthase, 100 mgkg(-1) injected every other day for two week was given concurrently with doxorubicin. Aminoguanidine given concurrently with doxorubicin return blood pressure, lactate dehydrogenase and lipid peroxides to normal control values. Furthermore, aminoguanidine reduces the mortality rate, ascites fluid formation- induced by doxorubicin and improved the histopathology of rats hearts treated with doxorubicin. In conclusion, inhibition of nitric oxide formation may be beneficial in protecting rat hearts against doxorubicin- induced cardiotoxicity.

Effects of Ehrlich ascites carcinoma cells on the responses of non-pregnant and pregnant uterine smooth muscles of mice to oxytocin and acetylcholine.

The effects of Ehrlich Ascites Carcinoma (EAC) cells on the responses of isolated uterine smooth muscles obtained from normal non-pregnant and pregnant mice to oxytocin and acetylcholine (ACh) were investigated. The contractions of normal uterine smooth muscles to oxytocin "0.1, 1 and 10 mU" and to ACh "0.1, 1 and 10 uM" were significantly reduced in the presence of EAC cells. On the other hand, induction of pregnancy in control non-tumor bearing mice significantly increases the sensitivity of the uterine smooth muscles to oxytocin as well as to ACh. In tumor bearing mice, the induction of pregnancy significantly reduced the sensitivity of the uterine smooth muscles to oxytocin and ACh when compared with the uterine muscles obtained from pregnant non-tumor bearing mice. The results of the present study indicate that the presence of tumor cells decreases the responses of the uterine smooth muscles to oxytocin and ACh, while pregnancy increases the uterine contractions induced by oxytocin and ACh. Furthermore, induction of pregnancy in tumor bearing animals reduces the responsiveness of uterine smooth muscles to oxytocin and ACh.

Synthesis and cardiotonic activity of certain imidazo[2,1-b]-1,3,4-thiadiazole derivatives.

A series of 5-imino-2-methyl-4-(4'-substituted phenacyl)-1,3, 4-thiadiazole derivatives 3-5 have been synthesized and further used to prepare a series of 2-methyl-6-(4'-substituted phenyl)imidazo[2, 1-b]-1,3,4-thiadiazoles 6-8 and 5-substituted-2-methyl-6-(4'-substituted phenyl) imidazo[2, 1-b]-1,3, 4-thiadiazoles 9-18. All of newly prepared imidazothiadiazole compounds were screened for their cardiotonic activity in isolated guinea pig atria. The detailed synthesis, spectroscopic and biological data are reported.

Fused pyrimidines. Synthesis of new derivatives of potential diuretic activity.

Certain derivatives of quinazoline and its bioisostere pyridopyrimidine carrying important structural features that contribute to diuretic activity, such as sulfonamido, morpholino and chlorophenyl, were prepared as potential diuretic agents. Likewise, some tricyclic 1,2,4-triazolo[3,4-b]quinazolines and pyrido[3,2-d][1,2,4]triazolo[4,3-alpha] pyrimidines with the same features were reported. Nine compounds were tested for the diuretic activity in rats and the results showed that the active compound is 7-chloro-2-methyl-3-phthalimido-4(3H)-quinazoline (4).

Effect of praziquantel on serum glucose and insulin levels in normal and hyperglycemic rats.

The effects of praziquantel (CAS 55268-74-1) on serum glucose and insulin levels in normoglycemic and hyperglycemic rats were studied. Also the combined effect of praziquantel and glibenclamide (CAS 10238-21-8) on oral glucose tolerance in rats was investigated. Praziquantel, given orally in a dose of 250 mg/kg, significantly increased serum glucose level in hyperglycemic rats without changing serum insulin level. After oral glucose load, praziquantel produced a significant increase in serum glucose level and antagonized the hypoglycemic action of glibenclamide. These results indicate that praziquantel significantly increased serum glucose level in both hyperglycemic rats and after glucose load. Since insulin levels are not significantly altered by praziquantel, the hyperglycemic effect of this drug may be attributed to inhibition of peripheral glucose utilization. Care should be taken if praziquantel is prescribed to diabetic patients.

Effect of zinc on the anti-inflammatory and ulcerogenic activities of indometacin and diclofenac.

In the present study, the potential anti-inflammatory activity of zinc sulfate (zinc) has been examined in rats with acute and chronic inflammation. Additionally, we studied the effect of the concurrent administration of zinc on the anti-inflammatory activity of indometacin and diclofenac and their gastric side effects. Oral or subcutaneous administration of zinc (25 and 15 mg/kg, respectively) significantly reduced carrageenan-induced paw edema. Subcutaneous co-administration of zinc (15 mg/kg) and indometacin (5 mg/kg) or diclofenac (10 mg/kg) resulted in a further reduction in paw edema which was more than either that produced by either agent alone. However, after oral co-administration of zinc and diclofenac the reduction in paw edema was not significantly different from that produced by either zinc or diclofenac alone. In rats with chronic inflammation, the administration of zinc (5 mg/kg s.c. for 7 days) proved as effective as either indometacin (3 mg/kg) or diclofenac (5 mg/kg). Co-administration of zinc with indometacin or diclofenac did not affect the level of activity of either drug. Co-administration of zinc did not affect the ulcerogenic effect of indometacin expressed as the ulcer index. In contrast to indometacin, administration of zinc markedly reduced the ulcerative action of diclofenac. In conclusion, zinc supplementation may contribute significantly to the treatment of inflammation. The combination of zinc with other anti-inflammatory drugs may provide beneficial additive effects and reduce their gastric hazards, particularly with diclofenac.

Effect of methylene blue on vasoreactivity in dog lung.

We examined the effect of methylene blue (MB), a putative inhibitor of guanylate cyclase (GC) activation by endothelium-derived relaxing factor (EDRF) and nitrovasodilator compounds, on vascular tone and reactivity to vasoactive substances in the isolated, blood-perfused canine lower left lung lobe. Lobar vascular resistance was partitioned into arterial and venous segments by venous outflow occlusion. Because MB did not alter vasoconstriction to either serotonin or acetylcholine (P greater than 0.05) except after cyclooxygenase inhibition (COI), we determined the effectiveness of MB as an inhibitor of GC activation by nitrovasodilators. Lobes were given graded bolus doses of nitroglycerin (GTN), sodium nitroprusside (SNP), and bradykinin (BK) at baseline vascular tone, after COI, and after vascular tone was raised by either U-46619, a thromboxane analogue, or MB infusion. GTN and BK but not SNP induced dose-dependent vasodilation when vascular tone was raised by U-46619. However, when vascular tone was increased to a similar level by 30 mg MB and 0.5 mg/min infusion, vasodilation to GTN, SNP, and BK was enhanced from U-46619 infusion. In contrast to MB, NG-nitro-L-arginine, a putative inhibitor of EDRF synthesis, diminished vasodilation to BK in cyclooxygenase-inhibited lobes with elevated vascular tone. Because MB potentiated vasodilation to GTN, SNP, and BK, it is questionable whether MB is an effective inhibitor of vasodilation to nitrovasodilators or BK in the isolated, blood-perfused canine lung.

Effects of different cyclooxygenase inhibitors on the segmental distribution of pulmonary vascular resistance in the dog.

An increase in pulmonary vascular resistance (PVR) after cyclooxygenase inhibition (COI) is well documented in the dog, but the site of vasoconstriction to chemically distinct cyclooxygenase inhibitors is largely unknown. The purpose of the present study was to examine and compare equimolar concentrations of three chemically unrelated cyclooxygenase inhibitors, indomethacin (INDO; n = 6), meclofenamate (MECLO; n = 6) and ibuprofen (IBU; n = 5), upon the longitudinal distribution of PVR in the isolated canine lower left lung lobe perfused at constant flow with autologous blood. At successive increases in the blood concentration of each cyclooxygenase inhibitor, PVR was partitioned into upstream (arterial, Ra), middle (Rm) and downstream (venous, Rv) resistance by arterial and venous flow occlusion with capillary pressure estimated by a double flow occlusion technique. All three cyclooxygenase inhibitors produced significant pulmonary vasoconstriction with the largest increase in PVR after INDO (104 +/- 21%) and the smallest after IBU (69 +/- 10%). The PVR increase in the INDO and MECLO group was related to an elevation in both Ra (p less than 0.01) and Rv (p less than 0.01), whereas only Rv was increased by IBU (p less than 0.01). While none of the cyclooxygenase inhibitors increased Rm (p greater than 0.05), capillary pressure was increased from pretreatment levels by each cyclooxygenase inhibitor. Although each of the three chemically distinct cyclooxygenase inhibitors raised PVR, the segmental distribution of PVR and the magnitude of the capillary pressure increase varied at equimolar blood concentration.

Multiple muscarinic receptor subtypes in the canine pulmonary circulation.

The vascular response to the muscarinic receptor agonist acetylcholine (ACh) in the presence of selected antagonists was examined in the isolated blood-perfused canine left lower lung lobe under conditions of normal (resting) and elevated vascular tone. At normal vascular tone, ACh (1-5 mumol) produced a dose-dependent increase in pulmonary arterial pressure (Ppa), total pulmonary vascular resistance (PVR), and downstream resistance (Rds) without altering upstream resistance (Rus). Pirenzepine (50 and 100 nM), the prototype M1-selective antagonist, and gallamine, an M2-selective antagonist, as well as atropine (50 nM) and secoverine (100 nM), nonselective antagonists, attenuated (P less than 0.05) the ACh-induced increase in Ppa and Rds. With elevated vascular tone induced by serotonin infusion, ACh produced a dose-dependent increase in Ppa in 19 of 25 lobes, although Rus decreased while Rds increased in all lobes. At high vascular tone, pirenzepine or gallamine attenuated the ACh-induced increase in Rds, whereas Rus was not affected. Secoverine and atropine antagonized ACh-induced increases in both Rds and Rus. The pA2 values (i.e., the negative log antagonist concentration requiring a doubling of ACh dose for an equivalent increase in Rds) for gallamine, pirenzepine, secoverine, and atropine were 6.1 +/- 0.1, 7.4 +/- 0.1, 8.3 +/- 0.2, and 10.2 +/- 0.3, respectively. These results suggest that 1) ACh increases PVR in the dog by constricting the venous segments (downstream) of the pulmonary circulation via activation of pulmonary vascular muscarinic receptors under conditions of both normal and elevated vascular tone, 2) both M1- and non-M1-muscarinic receptor subtypes appear to participate in mediating the ACh-induced increase in Rds, and 3) ACh moderately relaxes the upstream (arterial) vessels, especially under conditions of elevated tone.

Prostacyclin production with serotonin, increased flow, or elevated venous pressure in dog lung.

The lung may release prostacyclin (PGI2) in response to humoral or mechanical stimuli. We measured 6 keto-PGF1 alpha as an index of PGI2 production during serotonin (5-HT) infusion, elevated venous pressure (Pv), or increased blood flow (Q) in the isolated canine lower left lung lobe (LLL). Lobar vascular resistance (LVR) was partitioned into arterial (Ra), middle (Rm), and venous (Rv) components by arterial and venous occlusions. The infusion of 55-210 micrograms/min 5-HT (n = 9) was associated with concomitant increases in PGI2 production and dose-related increases in pulmonary arterial pressure (Pa) and LVR. 5-HT increased Ra at each infusion rate, whereas Rm was not changed and Rv was increased only at the highest infusion rate. When Pa was increased by stepwise elevations in Pv from 3.7 to 19.1 cmH2O (n = 8) or by increases in Q from 250 to 507 ml/min (n = 5) to match the Pa increase observed during 5-HT infusion, PGI2 production was not altered. Increases in Pv reduced LVR largely by decreasing Ra, whereas increases in Q reduced LVR without changing Ra, Rm, or Rv. Infusion of 5-HT when Pa was held constant by reduction in blood flow (n = 6) did not increase PGI2. Thus infusion of 5-HT at a normal blood flow rate increased PGI2 formation in the isolated blood-perfused dog lung lobe. The results also suggest that sustained mechanical effects related to increased venous pressure or elevated blood flow are not associated with a sustained elevation of PGI2 formation.

Verapamil inhibition of serotonin-induced vasoconstriction in dog lung.

The effect of the voltage-dependent calcium channel blocker verapamil on serotonin (5-HT)-induced vasoconstriction and segmental distribution of vascular resistance was examined in isolated, blood-perfused dog left lower lung lobe. 5-HT, 250 micrograms, increased lobar vascular resistance (LVR) by 47.3 +/- 6.5 cm H2O (n = 7), accounted for by a 30.8 +/- 4.3 and 16.4 +/- 2.8 cm H2O increase in upstream (Ra) and downstream (Rv) resistance, respectively. However, the increase in LVR, Ra, and Rv to 5-HT was significantly attenuated as verapamil concentration was increased from 1.2 to 100 microM. The verapamil concentration that inhibited 50% of LVR response (ED50) to 5-HT was 12.1 +/- 5.5 microM. The LVR response to 50, 100, and 250 micrograms 5-HT was reduced after 12.5 microM verapamil by 41 +/- 4.4, 43 +/- 3.8, and 43 +/- 5.0%, respectively. The increase in Ra to 50, 100, and 250 micrograms 5-HT was reduced by 57 +/- 6.7, 57 +/- 4.6, and 51 +/- 7.2%, respectively, by 12.5 microM verapamil, with Rv reduced by 32 +/- 3.9% only at 250 micrograms 5-HT. The alpha-adrenergic receptor antagonist, phentolamine (10 microM) reduced the pressor response to norepinephrine (NE) by 97% but reduced the Ppa increase to 250 micrograms 5-HT by only 29 +/- 10% and did not alter the pressor response to 5 mmol KCl. A verapamil concentration of 105 microM was required to inhibit 50% of the control pressor response to KCl. Our results suggest that the entry of extracellular calcium is important for 5-HT-evoked contractions of canine pulmonary vascular smooth muscle.

Reversal of tachyphylaxis to angiotensin II in dog lung.

Angiotensin II (ANG II) is a potent vasoconstrictor in most vascular beds. We studied the role of cyclooxygenase products and/or endothelium-derived relaxing factor (EDRF) in modulating the pressor response to ANG II in the isolated, blood perfused dog lung. ANG II was given as a bolus dose of 2, 4 and 8 micrograms before and after cyclooxygenase inhibition (COI) with either 40 mumol/l indometacin (INDO) or 45 mumol/l meclofenamate (MECLO), and before and after methylene blue (MB) infusion followed by MECLO or MECLO followed by MB infusion. ANG II produced an increase in lobar vascular resistance (LVR) that averaged 3.7 +/- 1.1 to 3.0 +/- 0.3 cm H2O/l/min (n = 30), but was not dose-related and exhibited marked tachyphylaxis. In contrast, after INDO, the increase in LVR to ANG II averaged 8.2 +/- 1.0 to 18.4 +/- 2.2 (n = 6) and 5.0 +/- 1.2 to 15 +/- 2.4 cm H2O/l/min after MECLO (n = 6) and both cyclooxygenase inhibitors increased (p less than 0.05) basal vascular tone. Infusion of MB did not alter baseline vascular tone, but prevented the tachyphylaxis to ANG II. Our results indicate that tachyphylaxis to ANG II-induced vasconstriction in the isolated, blood perfused dog lung lobe is not only reversed by COI, but potentiated and dose-related. Whereas MB diminished tachyphylaxis to ANG II, it failed to potentiate the pressor response to ANG II except with concurrent COI. Our findings suggest that vasodilator cyclooxygenase products are probably more important than EDRF in regulating both vascular tone and reactivity to ANG II in the dog lung.

Cyclooxygenase inhibition potentiates the pulmonary vascular responses to ethanol in dogs.

The effects of ethanol on pulmonary hemodynamics and the role of arachidonic acid metabolites in mediating these responses were studied in the isolated, blood-perfused canine lung lobe. Ethanol added directly to the venous reservoir at a concentration of 0.01 or 0.1% did not alter the pulmonary vascular resistance, however, 1.0% ethanol increased (p less than 0.05) the pulmonary resistance. Indometacin, a cyclooxygenase inhibitor, significantly increased baseline pulmonary vascular resistance and markedly potentiated the pulmonary vascular responses to the three concentrations of ethanol. Addition of nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, followed by indometacin, did not diminish the indometacin-induced increases in basal tone or enhancement of the responses to ethanol indicating that leukotrienes are not involved in mediating the responses to ethanol. These results suggest that in isolated, blood-perfused dog lung lobe, a high concentration of ethanol increases the pulmonary vascular resistance and that cyclooxygenase inhibition markedly potentiated the responses to ethanol by reducing the production of vasodilator prostaglandin, most probably prostacyclin.

Effects of arachidonic acid in the rabbit pulmonary and systemic vascular beds in vivo.

We studied the effects of arachidonic acid (AA) in the pulmonary and systemic circulations of rabbit under constant blood flow conditions in vivo, using a total heart bypass model. AA (100-150 micrograms/kg) injected into the pulmonary artery produced a dose-dependent increase in pulmonary arterial pressure (Ppa), without altering systemic arterial pressure (Psa). Conversely, injection of AA into the aorta reduced Psa in a dose-dependent fashion, but did not significantly alter Ppa. FPL55712, a leukotriene receptor antagonist, did not affect any of these responses to AA. Indomethacin, a cyclo-oxygenase inhibitor, totally prevented the pulmonary pressor response to intravenously administered AA and reduced the systemic depressor response to intra-arterially administered AA. The thromboxane A2 synthetase inhibitor, 7-(1-imidazolyl)heptanoic acid, totally abolished the increase in Ppa in response to intravenously administered AA, but did not alter the dose-dependent decrease in Psa in response to intra-arterially administered AA. These results suggest that in rabbits (1) AA produces pulmonary vasoconstriction and systemic vasodilation, (2) blood metabolites of AA mediate these effects and are then rapidly deactivated, and (3) AA-induced pulmonary vasoconstriction appears to be largely dependent on thromboxane A2.

Effect of a lipoxygenase inhibitor on vasoconstriction in dog lung.

The effects of lipoxygenase inhibition and cyclooxygenase plus lipoxygenase inhibition on the pressor responses to serotonin (5-HT), acetylcholine (ACh), and norepinephrine (NE) were studied in the isolated, blood-perfused dog lung. Bolus doses of 50-250 micrograms 5-HT, 1-5 mumol ACh, and 10-50 micrograms NE were given before and after the lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), or the cyclooxygenase inhibitor, meclofenemate (Meclo), followed by NDGA. Lobar vascular resistance (LVR) was partitioned into upstream (Ra) and downstream (Rv) segments by venous occlusion. 50 microM NDGA did not change base-line LVR, Ra, or Rv; however, 100 microM NDGA increased base-line LVR (P less than 0.05) without increasing Ra or Rv (P greater than 0.05). Neither 50 or 100 microM NDGA affected the pressor response to 5-HT, ACh, or NE; however, the response to 50 micrograms 5-HT was slightly enhanced. Meclo increased base-line LVR (P less than 0.05) and subsequent addition of 50 microM NDGA did not change LVR (P greater than 0.05) from post-Meclo values. The LVR increase to both 5-HT and ACh was potentiated after Meclo (P less than 0.05) and 50 microM NDGA after Meclo did not change the LVR increase to either 5-HT or ACh. In contrast, Meclo did not enhance the pressor response to NE, and addition of 50 microM NDGA after Meclo diminished the increase to 20 and 50 micrograms NE (P less than 0.05). Our results suggest that unlike cyclooxygenase inhibition, lipoxygenase inhibition does not increase base-line LVR or the pressor response to either 5-HT or ACh.(ABSTRACT TRUNCATED AT 250 WORDS)