Early protective effects of iloprost after experimental spinal cord ischemia in rabbits.

The potential role of Iloprost, a stable analogue of prostocyclin, in treating spinal cord ischemia was investigated in rabbits subjected to aortic occlusion for 15 minutes. Ten adult rabbits weighing 2-2.5 kg received an intravenous infusion of saline (SF) as a control group and 14 rabbits received an intravenous infusion of Iloprost, 25 microg/kg/h. Iloprost infusion was started immediately after clamping of the aorta and continued 60 minutes thereafter. Cortical somatosensorial evoked potentials (CSEP) were recorded during the pre-ischemic period as a baseline and post-ischemic readings were taken at 15, 30 and 60 minutes. There was no statistically significant difference between CSEP of the saline and Iloprost treated groups (p < 0.05). All animals were examined neurologically by using a modification of Tarlov scale and all subjects were then deeply anesthetized and their spinal cords were removed for light and electron microscopic examinations at 24 h after spinal cord ischemia. In order to obtain an accurate comparison of ultrastructural changes between saline treated and Iloprost treated groups, a grading scale was performed. The light microscopic and ultrastructural analysis of the Iloprost treated group revealed that there was moderate protection of the myelin and axons and edema was attenuated. Findings of this study suggest that Iloprost exerts a protective effect on spinal cord ischemia. However, further studies are needed to reveal possible mechanisms of protection provided by Iloprost.

The early protective effects of L-arginine and Ng-nitro-L-arginine methyl ester after experimental acute spinal cord injury. A light and electron microscopic study.

The purpose of this study was to investigate the early protective effects of L-arginine and Ng-nitro-L-arginine methyl ester (L-NAME) after acute spinal cord injury. Acute spinal cord injury was performed by epidural application of an aneurysm clip at thoracic (T) 7 - 11 level. L-arginine at a dose of 750 microg/kg/min was administered 10 min before acute spinal cord injury and continued for 30 min to 10 animals (Group II). L-NAME at a dose of 250 microg/kg/min was administered 10 min before acute spinal cord injury and continued for 30 min to 10 animals (Group III). No drug was administered to 10 animals after acute spinal cord injury (Group I). Light and electron microscopic analysis were performed in all of the groups. Oedema of perineural, axoplasm or white matter in the L-arginine-treated group was less than in Group I and Group III. Thickening in the walls of the arterioles and venules in the L-arginine-treated group was much milder than in Group I and Group III. Degeneration of myelinated axons in the L-arginine-treated group was milder than in the control group. But there was no different between Group II and Group III.

Nitric oxide and prostanoid-dependent relaxation induced by angiotensin II in the isolated precontracted mouse tracheal muscle and the role of potassium channels.

In this study we examined the mechanism of the concentration-dependent relaxant effect of angiotensin II (A II) on mouse isolated tracheal rings precontracted by carbachol. The contractile effect of carbachol is increased while the relaxant effect of A II decreased by pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME). This finding suggests that the L-arginine nitric oxide (NO) pathway is activated by the peptide. The relaxing effect of A II was also mediated through the release of cyclo-oxygenase products of arachidonic acid, as evidenced by the inhibition of the response by lysine acetylsalicylic acid (ASA) pretreatment. A II also caused a relaxation in the isolated tracheal rings precontracted by K(+)(>60 m m). K(+)-channel blockers partially inhibited the relaxant effect of A II in carbachol-precontracted mouse tracheal rings. A non-selective blocker of K(+)channels, tetraethylammonium, completely abolished the relaxation induced by A II. Among the other channel blockers, the inhibitory effect of apamine and glibenclamide was higher than that of iberiotoxin, indicating the involvement of K(ATP)and small conductance K(Ca)channels in the relaxing response to the octapeptide. These results suggest that the mechanisms, involved in the relaxation induced by A II in the isolated mouse tracheal rings precontracted by carbachol, were firstly l -arginine NO and cyclo-oxygenase products of arachidonic acid, secondly K(+)channels.

The contribution of nitric oxide and endothelins to angiotensin: II. Evoked responses in the rat isolated uterus smooth muscle.

The present study was designed to determine the role of endogenous endothelin peptides and nitric oxide on angiotensin II (All) responses in the isolated nonpregnant rat uterine smooth muscle. AII (10, 20, or 50 ng/ml) increases rhythmic oscillations dose dependently (32.7 +/- 8.9, 55.96 +/- 10.3, and 62.78 +/- 17.7% increase, respectively). L-arginine methyl ester (L-NAME; 10(-5) M) did not affect the increase in rhythmic oscillations induced by All (10, 20, or 50 ng/ml) (17.5 +/- 12.1, 31.5 +/- 18.3, and 52.5 +/-11.8% increase, respectively, n = 6, p > 0.05). It reduced the contractile responses to AII (10 ng/ml: from 4.63 +/- 0.6 to 1.8 +/-0.7 cm2, p < 0.05: and 20 ng/ml: from 5.59 +/- 0.8 to 2.11 +/- 0.4 cm2, p < 0.05, n = 6). L-arginine (10 mM) decreased the contractile response obtained by AII (10 or 20 ng/ml) (1.93 +/- 1.05, p < 0.05 and 2.14 +/- 0.7 cm2, p < 0.05, respectively, n = 6). BQ 485 (50 ng/ml) decreased both the number of rhythmic oscillations and the contractility increased by AII. Bosentan (10(-5) M) induced an increase in the number of rhythmic oscillations but decreased the contractile responses to the higher concentrations of All. These data show that endogenous NO and endothelin peptides contribute to the motility changes induced by AII and may play an important role in the pathophysiological events of the uterine function.

Nitric oxide-mediated relaxation induced by bradykinin in the isolated mouse trachea.

We examined the nature of the relaxant effect of bradykinin on mouse isolated tracheal rings. Bradykinin produced a concentration-dependent relaxation in mouse tracheal rings contracted by carbachol. Potentiation of the contractile effect of carbachol and inhibition of the relaxant effect of bradykinin by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), L-glutamine (L-Gln) and methylene blue (MeB) suggested that the peptide activated the L-arginine nitric oxide (NO) pathway. Part of the relaxant effect of bradykinin was also mediated through the release of cyclooxygenase metabolites of arachidonic acid, as evidenced by the inhibition of this response by lysine acetylsalicylic acid (ASA) pretreatment. Bradykinin also caused a relaxant response in precontracted tracheal rings in the presence of lower but not higher concentrations of K+ (> 60 mM). NG-nitro-L-arginine methyl ester and L-Gln did not alter the contractile effect of K+. K+ channel blockers partially inhibited the relaxant effect of bradykinin in carbachol-induced precontracted tracheal rings. Tetraethylammonium, a non-selective blocker of K+ channels, completely abolished the relaxant response to the peptide. Among the other channel blockers, the inhibitory effect of glibenclamide was slightly greater than that of apamine and iberiotoxin, indicating the involvement of K(ATP) channels in the relaxant response to the peptide. These results suggest that the mechanisms of the relaxation induced by bradykinin in carbachol-induced precontracted mouse tracheal muscle primarily involve activation of L-arginine NO and arachidonic acid cyclooxygenase pathways and secondly K+ channels.

Early protective effects of Iloprost after experimental spinal cord injury.

This investigation was undertaken to study the early protective effects of Iloprost, a stable analogue of prostacyclin, after spinal cord injury in rabbit. Sixteen adult male rabbits (New Zealand Albino) were injured by application of epidural aneurysm clip. Eight rabbits received an intravenous (i.v.) infusion of 30 micrograms kg-1 Iloprost, and eight rabbits received an infusion of saline (SF). Treatment with Iloprost started immediately after spinal cord injury and continued for one hour. Evoked potentials were recorded for each rabbit at one, 15, and 60 minutes after the spinal cord injury. Twenty-four hours later, all the rabbits were deeply anesthetized and spinal cords were removed for histopathological examinations. There was no meaningful statistical difference between cortical somatosensorial evoked potentials (CSEP) of the saline and Iloprost group. However, light and electron microscopic studies showed that the Iloprost treated group had moderate protection of myelin and axons; and limited edema. These results suggest that intravenous Iloprost treatment after spinal cord injury has a highly protective effect without any side effects.

An unexpected interaction between NG-nitro-L-arginine methyl ester and L-arginine in alpha-naphthylthiourea-induced pulmonary oedema in rats.

This study was designed to investigate the possible participation of the L-arginine-nitric oxide (NO) pathway in the lung oedema induced by alpha-naphthylthiourea, which is a well-known noxious chemical agent in the lung. Lung oedema was assessed by measuring fluid accumulation in the pleural cavity and the lung weight/body weight ratio following alpha-naphthylthiourea injection. Administration of NG-nitro-L-arginine methyl ester, a NO synthase inhibitor, prior to alpha-naphthylthiourea, produced a significant inhibition of pleural effusion and lung weight/body weight ratio in a dose-dependent manner. L-Arginine, but not D-arginine, when used higher doses (above 300 mg/kg) prior to alpha-naphthylthiourea injection caused a significant inhibition of pleural effusion without altering lung weight/body weight ratio. Lower doses of L-arginine (below 100 mg/kg) did not elicit an inhibitory effect against alpha-naphthylthiourea-induced pulmonary damage. However, lower doses of L-arginine greatly potentiated the inhibitory effect of NG-nitro-L-arginine-methyl ester against alpha-naphthylthiourea-induced lung oedema when used in combination. The interesting aspect of this study is the inhibition by NG-nitro-L-arginine methyl ester, a NO synthase inhibitor, and L-arginine, an endogenous donor of NO, of the lung oedema induced by alpha-naphthylthiourea. The possible role of the L-arginine-NO pathway in lung oedema induced by alpha-naphthylthiourea and the possible underlying mechanisms are discussed.

Arrhythmogenic action of endothelin peptides in isolated perfused whole hearts from guinea pigs and rats.

The arrhythmogenic actions of endothelin peptides were studied in isolated perfused hearts from guinea pigs and rats. Digoxin-induced ectopic ventricular complexes were partially antagonized by phosphoramidon, an endothelin-converting enzyme inhibitor. On the contrary, these rhythm disturbances were potentiated by big endothelin-1 in isolated perfused whole hearts from guinea pigs. Endothelin-1, when infused through the coronary circulation at a concentration of 10(-10) mol/l, produced an increase in coronary perfusion pressure without altering the heart rate and contractility in the isolated perfused hearts of rats. However, ventricular ectopic complexes occurred when the rise in coronary perfusion pressure reached the peak value. BQ 485, an endothelin-A receptor antagonist, at a concentration of 10(-6) mol/l, completely blocked the vasoconstrictor and arrhythmogenic effects of endothelin-1. In BQ 485-pretreated rat hearts, endothelin-1 produced a fall in coronary perfusion pressure and a slight positive inotropic response which could be blocked by NG-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor. BQ 485 at the same concentration also caused a significant reduction in the duration but not the onset of ventricular ectopic complexes in the guinea pig isolated perfused heart induced by digoxin. These results were taken as evidence of the arrhythmogenic action of endothelin peptides and their possible participation in the ventricular dysrhythmia induced by digoxin.

Effect of the prostacyclin analogue, iloprost, on infarct size after permanent focal cerebral ischemia.

This investigation was undertaken to study the effect of iloprost, a stable analogue of prostacyclin, on infarct size after permanent focal cerebral ischemia in the rabbit. Forty-two adult rabbits were subjected to left middle cerebral artery occlusion via the transorbital route. Fourteen rabbits received an intravenous (i.v.) infusion of 30 micrograms/kg iloprost, 7 rabbits received an i.v. infusion of 10 micrograms/ kg, and 9 rabbits received an i.v. infusion of 20 micrograms/kg iloprost. Twelve rabbits received an intravenous infusion of saline. Treatment with iloprost started immediately after middle cerebral artery occlusion and continued for 1 h. After killing the animals, brains were removed and five coronal slices were incubated in a 2,3,5-triphenyltetrazolium chloride solution to determine the infarct size. Treatment with 30 micrograms/kg iloprost significantly reduced the infarct size compared with treatment with saline (3.49 +/- 2.79% vs. 9.03 +/- 4.26%, P < 0.001), but the lower doses of iloprost did not have a beneficial effect on the size of the infarct. These results suggest that intravenous iloprost treatment after occlusion has a highly protective effect without any side effects such as hypotension.

Comparison of responses to histamine by constant-flow and constant-pressure perfusion methods in the rabbit isolated kidney preparation.

1. Reproducibility and sensitivity of responses of isolated perfused rabbit renal vascular bed to bolus administration of histamine was compared for the conditions of constant-flow and constant-pressure perfusion by Krebs-Henseleit solution. Two other vasoactive agents (noradrenaline and angiotensin II) were also tested in the same preparation for comparison with the effect of histamine. 2. In constant-pressure mode, different hydrostatic pressures were also employed for the analysis of time-effect phenomena. 3. Drug responses were recorded by computer and were evaluated as changes of perfusion pressure or flow, to correspond to drug activities at the resistance vessels and, also, change of organ weight, as effects on exchange and capacitance functions of the circulation. Both parameters were also recorded on a Grass polygraph. 4. Reproducibility and sensitivity of responses to vasoactive agents (histamine, noradrenaline, angiotensin II) were significantly low in the constant-flow conditions, compared to constant-pressure mode. 5. Responsivity also deviated for different perfusion pressures of constant-pressure mode and 80-100 mm H2O pressure was found to be the most convenient value. 6. It is concluded that constant-flow and constant-pressure conditions provide different hydrodynamic conditions. In constant-flow methodology, when the predetermined perfusion rate is not tolerated by the vascular bed, excessive flow in the circulation would lead to depression of vasoactivity, failing pharmacodynamic equilibria and loss of responsivity. Structural deviation of the vascular bed would also be expected due to differences of organ specimen and, probably, result in the variation of responsivity of constant-flow perfusion procedure.

Acute effect of endothelin-1 on lung oedema induced by alpha-naphthylthiourea (ANTU).

Alpha-naphthylthiourea when injected intraperitoneally to rats (10 mg kg-1 i.p.) produced lung oedema as indicated by an increase in lung weight/body ratio and pleural effusion reaching a maximum within 4 hours. Prior intravenous single bolus injection of endothelin-1 elicited a significant and dose-dependent inhibition in both parameters. However, prior i.v. injection of angiotensin II using relatively higher doses did not alter the oedema-producing effect of alpha-naphthylthiourea indicating a characteristic for endothelin-1. The inhibitory effect of endothelin-1 on pleural effusion is more prominent than lung weight/body weight ratio. The resolution of lung oedema by single bolus i.v. injection of endothelin-1 is probably due to the acute long-lasting and potent vasoconstrictor effect of the peptide and its large accumulation in lung tissue. Phosphoramidon, an inhibitor of endothelin converting enzyme, did not alter the oedema producing effect of alpha-naphthylthiourea indicating the lack of the participation of endothelin-peptide cascade to this pathological event. Bosentan, a non-selective receptor blocker of endothelin-1, did not inhibit the preventive effect of the peptide against alpha-naphthylthiourea-induced lung oedema. Possible mechanisms of the acute effect of endothelin-1 on lung oedema are discussed.

Protection by Iloprost (stable analogue of prostacyclin) of endothelial damage due to chronic vasospasm in dogs: an electron microscope study.

The resolution of cerebral vasospasm and protection of endothelial damage by Iloprost was evaluated with multicisternal injections. Sixteen adult mongrel dogs (18-20 kg) were assigned to one of three experimental groups. All animals received a total amount of 15 ml fresh unheparinized arterial blood via three injections into the cisterna magna. Selective vertebral angiography was performed on day 0 and subsequently blood injections were performed on the 2nd and 3rd days after the first injection. On the 7th day angiography was reperformed to determine the chronic vasospasm. The first group (5 dogs) was the control group and received intrathecal saline which was equal to the amount of saline in which Iloprost was diluted. The second group (5 dogs) did not receive any treatment until the 7th day. The third group (6 dogs) received Iloprost intrathecally (total 10 micrograms kg-1). In the first two groups angiographic vasospasm was prominent. For the second group intraarterial Iloprost was given on the 7th day in order to evaluate its acute effect. However there was no evidence of resolution of vasospasm. In the third group, resolution of vasospasm was verified on angiograms. Electron microscope studies of basilar arteries of the first two groups revealed degenerative changes of the endothelial cells which were separated from each other and the elastic lamina was irregularly arranged. In the intrathecal Iloprost-treated group there was little thickening in the elastic lamina and the endothelial cells were almost normal in structure. These results can be considered as the evidence of the prophylactic effect of Iloprost given by the intrathecal route in the prevention of chronic cerebral vasospasm.

The effects of endothelin peptides in the rabbit isolated perfused kidney.

1. Endothelin-1 (21-amino acids) and pre-pro endothelin-1 (39-amino acids) produced a concentration-dependent increase in perfusion pressure when infused through the renal artery of rabbit isolated perfused kidney. Addition of phosphoramidon to the medium caused a potentiation in the vasoconstrictor response to endothelin-1 and greatly, but not completely, inhibited vasoconstriction induced by pre-pro-endothelin-1. 2. Addition of indomethacin to the medium did not alter the vasoconstrictor effects of the peptides. 3. Methylene blue in the medium caused a highly significant potentiation in the vasoconstrictor response to endothelin-1. 4. A short-term infusion of endothelin-1 through the renal artery elicited a decrease in urine flow which returned to control levels after perfusing the kidney with Krebs buffer, but prolonged infusion of the peptide produced an irreversible increase in urine flow. 5. Phosphoramidon, methylene blue and indomethacin failed to alter the effect of endothelin-1 on urine flow. 6. From these results it was concluded that phosphoramidon-sensitive endothelin-converting enzyme, probably localized in microvasculature of the kidney, can convert pre-pro-endothelin-1 to endothelin-1 which is responsible for the vasoconstrictor effect of pre-pro-endothelin-1 in addition to its possible direct vasoconstrictor effect on kidney vasculature. Moreover, the endothelin-1 degradating enzyme in kidney should be a phosphoramidon-sensitive metalloproteinase(s). The results also indicated the release of EDRF but not prostanoids by endothelin-peptides in the rabbit isolated perfused kidney.

Inhibitory effect of allopurinol on adjuvant arthritis in rats.

The effect of Allopurinol (ALLO), on adjuvant arthritis was studied in rats and compared with the effect of indomethacin (IND). Drugs were given by intraperitoneal injection for each day beginning from the day of adjuvant injection (day 0) and continued until the 16th day. Paw swelling was measured on days 4, 17 and 29, and secondary lesions were assessed on days 17 and 29. Polymorphonuclear leukocyte (PMNs) count was also evaluated on day 17. ALLO, at relatively high doses (25-50 mg/kg), reduced paw swelling of the adjuvant-injected extremity on day 4; lower doses (6.25-12.5 mg/kg), however, elicited the same inhibitory effect on day 17. IND (0.25 mg/kg) also prevented paw swelling on days 4 and 17. Both ALLO and IND reduced the secondary lesions on days 17 and 29 and prevented the increase in polymorphonuclear leukocytes during the development of adjuvant arthritis. Possible mechanisms of the antiinflammatory effect of ALLO in adjuvant arthritis are discussed.

Possible involvement of endothelin peptides and L-arginine-nitric oxide pathway on the effect of endotoxin in the rabbit isolated perfused kidney.

Escherichia coli endotoxin (LPS) when infused through the renal artery of the rabbit isolated perfused kidney prepared as constant pressure mode, caused a decrease in flow rate and kidney weight indicating its primary vasoconstrictor effect. This effect was predominant in kidneys from rabbits pretreated with LPS. Endothelin-1 at a concentration of 10(-10) M and big endothelin-1 at a concentration of 10(-8) M produced equal vasoconstrictor effects in kidney. Addition of endotheHn converting enzyme inhibitor, phosphoramidon, to the perfusion medium at a concentration of 10(-6) M caused a reduction in the effects of both LPS and big ET-1 without altering the vasoconstrictor effect of ETol. However, addition of methylene blue (10(-5) M), a soluble guanylate cyclase inhibitor and N(G)-nitro-L-arginine-methyl ester (10(-6) M) to the perfusion medium caused a potentiation in the vasoconstrictor effect of LPS. Indomethacin at a concentration of 10(-6) M did not alter the effect of LPS. These results were taken as evidence for the participation of endothelin peptides and the L-arginine-nitric oxide pathway in the effect ofLPS in rabbit isolated perfused kidney.

The effect of intrathecal sodium nitroprusside on severe chronic vasospasm.

The efficacy of sodium nitroprusside in resolving cerebral vasospasm was evaluated with multicisternal injections. Twelve animals received fresh, unheparinized arterial blood via three injections (15 ml total) into the cisterna magna. Selective vertebral arteriography was performed on Day 0, and blood injections were performed on the second and third days after the first injection. On the seventh day selective arteriography was performed to evaluate the diameter of the basilar artery. In the sodium nitroprusside group, intrathecal injections of the drug were started on Day 4 and continued for two days (25 micrograms/kg/day). The diameter of the basilar artery was reduced 72.98 +/- 11.07% in control experiments. For the animals treated with intrathecal sodium nitroprusside, the mean diameter of the basilar artery was reduced 29.25 +/- 4.54%. The effect of intrathecal sodium nitroprusside on intracranial pressure (ICP), blood pressure (BP) and electrocardiogram (ECG) was also evaluated in 14 animals. There were no prominent changes in ICP, BP, or ECG when sodium nitroprusside was given intrathecally, but BP decreased and ICP and heart rate increased with intravenous doses of sodium nitroprusside. These results support the hypothesis that sodium nitroprusside administered intrathecally is an effective treatment for cerebral vasospasm.

Possible involvement of eicosanoids in alpha-naphthylthiourea-induced pulmonary oedema and alteration of angiotensin-converting enzyme activity.

alpha-Naphthylthiourea (ANTU) when injected intraperitoneally to rats at a dose of 10 mg/kg elicited lung oedema indicated by an increase in lung weight/body weight (LW/BW) ratio and pleural effusion. The injection of acetylsalicylic acid, which is a cyclo-oxygenase inhibitor, and BW 755C, a cyclo-oxygenase and lipoxygenase inhibitor, prior to ANTU produced a significant inhibition in pleural fluid accumulation without changing the LW/BW ratio. BW A4C, a selective 5-lipoxygenase inhibitor, however, caused a highly significant inhibition in pleural effusion and a slight but significant decrease in LW/BW ratio. Thromboxane A2 synthetase inhibitor, UK 38485, caused a slight but significant inhibition in pleural fluid accumulation without altering the LW/BW ratio. Iloprost, however, produced a slight but significant inhibition in the LW/BW ratio without reducing the pleural effusion rate. A significant decrease in angiotensin-converting enzyme (ACE) activity in the isolated perfused lungs of ANTU-treated rats was noted. This observation was thought to be an evidence of a functional alteration of the lung vascular endothelium. The possible role of eicosanoids in lung oedema induced by ANTU and the related mechanisms of decreased ACE activity are discussed.

Endothelin-1-induced oedema in rat and guinea-pig isolated perfused lungs.

Endothelin-1 caused an increase in perfusion pressure, bronchial resistance, lung weight and tracheal effusion when infused through the pulmonary artery of rat and guinea-pig isolated lungs. In contrast to vasoconstriction, the effects of endothelin-1 on bronchial resistance, lung weight and tracheal effusion were not concentration-dependent. Recovery from vasoconstriction occurred within 15-30 min when the lung was further perfused with Krebs buffer. Increases in lung weight, bronchial resistance and tracheal effusion induced by endothelin-1 were irreversible when infused at concentrations above 10(-10) M. UK 38,485, a thromboxane A2 synthesis inhibitor, partly prevented the increase in lung weight and tracheal effusion without altering the vasoconstriction induced by endothelin-1. Such an antagonism was not seen in guinea-pig lung at the concentration used. Iloprost, a stable analogue of prostacyclin, antagonized the effects of endothelin-1 on perfusion pressure and lung weight without reducing tracheal effusion in both rat and guinea-pig lungs. Pretreatment with allopurinol did not alter the effects of endothelin-1. These results were taken as evidence for the potent lung oedema-producing effect of the peptide which seems to be partially mediated by the secondary release of thromboxane A2.

The effect of Iloprost on chronic cerebral vasospasm.

1. Experimental chronic cerebral vasospasm induced by subarachnoid haemorrhage (SAH) in rabbits was studied in order to evaluate the efficacy of repeated i.v. infusion of Iloprost (ILO). 2. The mean diameter of the basilar artery of intact animals was calculated as 737.5 +/- 52.8 microns while this value was reduced to 237.5 +/- 22.96 microns after SAH. 3. In the ILO treated group the mean diameter of the basilar artery was significantly increased and found to be 593.75 +/- 64.0 microns. 4. No change was observed in intracranial pressure (ICP) except a slight decrease in mean arterial pressure when relatively higher doses of ILO were used. 5. These results were taken as evidence of the high therapeutic value and low side effects of ILO in the treatment of persisting cerebral vasospasm due to SAH.

Superoxide dismutase and allopurinol prevent the pressor effects of angiotensin II and histamine in the guinea-pig isolated perfused lung exposed to hypoxia.

1. In the guinea-pig isolated perfused lung exposed to hypoxia by infusing N2-gassed Krebs solution, angiotensin II and histamine produced a reduced vasoconstrictor response when compared with the responses obtained in nonhypoxic lung. 2. These reduced vasoconstrictor responses were prevented by prior addition of superoxide dismutase or allopurinol to the medium. 3. These results were taken as evidence for the initiation of the cascade free radical formation in the guinea-pig lung during hypoxia and the primary role of the released intracellular xanthine oxidase. 4. Possible mechanisms of the reduced responses to angiotensin II and histamine and tissue protective activities of allopurinol and superoxide dismutase are discussed.