Effects of the calcium antagonist nilvadipine on focal cerebral ischemia in spontaneously hypertensive rats

We studied the efficacy of preischemic and postischemic systemic treatment with a new calcium antagonist nilvadipine in a permanent focal cerebral ischemia model of spontaneously hypertensive rats. Rats that underwent microsurgical middle cerebral artery occlusion were blindly assigned to a single intraperitoneal injection of nilvadipine (0.32 mg/kg) or the same amount of polyethylene glycol either 15 minutes before, immediately after, 1 hour after, or 3 hours after occlusion of the left middle cerebral artery. Neurologic conditions of rats were closely examined, and rats were killed 24 hours later. Removed brains were sliced coronally, stained with triphenyltetrazolium chloride, and the size of infarct was determined. Although no neurologic improvements were observed in the treated rats, the area of infarcts was significantly reduced in the groups treated before, immediately after, and 1 hour after occlusion of the middle cerebral artery. Treatment started 3 hours after occlusion was ineffective.     

Glomerular prostaglandin production in diabetic rats with renovascular hypertension

A rat model combining two-kidney, one-clip (2K1C) renovascular hypertension and streptozotocin-induced diabetes mellitus was used to assess the pathogenetic significance of vasodilator prostaglandins in diabetic glomerular injury. Glomeruli isolated from normotensive diabetic rats produced greater than normal amounts of PGE2 and 6-keto PGF1 alpha under in vitro incubation conditions. In 2K1C hypertensive-diabetic rats, glomeruli from unclipped kidneys (which are prone to accelerated diabetic glomerular injury) produced similarly elevated amounts of PGE2 and 6-keto PGF1 alpha, which significantly exceeded the levels produced by glomeruli from clipped kidneys (which are relatively protected from glomerular injury), despite exposure to a similar diabetic environment. In contrast, glomeruli from both unclipped and clipped kidneys of 2K1C hypertensive-non-diabetic rats produced normal amounts of PGE2 and 6-keto PGF1 alpha. These results suggests a correlation between vasodilator prostaglandin metabolism and susceptibility to diabetic glomerular injury, and illustrate that enhanced glomerular prostaglandin production is not an invariable metabolic consequence of hyperglycemia or insulin deficiency. The data also demonstrate that hemodynamic as well as metabolic factors may influence glomerular prostaglandin metabolism in experimental diabetes mellitus.     

Cerebral vasospasm: effects of prostaglandin synthetase inhibitors in vitro

Because previous studies suggest that prostaglandins (PGs) are involved in the contraction of cerebral arteries, the present study was undertaken to assess the direct effects of arachidonic acid, the precursor of PGs, on isolated dog basilar arteries and to ascertain the actions of three prostaglandin synthesis inhibitors, aspirin, indomethacin, and meclofenamate, on contractions induced by agonists of diverse chemical structure. Arachidonic acid induced sustained contractions and in optimal concentrations produced constriction that was 56% as great as that produced by serotonin. These responses were markedly inhibited (95%) by meclofenamate (10(-5) M), but aspirin (10(-3) M) had no such effect. Moreover, this concentration of meclofenamate reduced resting tension and inhibited by 16% the optimal responses caused by PGF2 alpha, while having no significant effect on serotonin contractions. Higher doses of meclofenamate (10(-4) M, 10(-3) M) produced increasing degrees of inhibition of contractions caused by serotonin or PGF2 alpha. Conversely, aspirin had no effect on PGF2 alpha contractions and slightly enhanced serotonin effects. The actions of indomethacin resembled those of meclofenamate. The results show clearly that different prostaglandin synthesis inhibitors have different effects on cerebral vasomotion in vitro. Aspirin, known to inhibit platelet function markedly, seems to have little effect on isolated vascular smooth muscle. On the other hand, the pharmacodynamic effects of meclofenamate and some related drugs may afford a new approach in the treatment of cerebral vasospasm.     

Moderate hypothermia reduces postischemic edema development and leukotriene production

Using the bilateral carotid artery occlusion model of cerebral ischemia in the gerbil, we studied the effect of moderate hypothermia (30 to 31 degrees C) on the postischemic production of prostanoids (cyclooxygenase pathway) and leukotrienes (lipoxygenase pathway) and accompanying changes in cerebral edema formation. Hypothermia capable of slowing central evoked potential conduction time was studied over the course of 40 minutes of cerebral ischemia and for up to 2 hours of reperfusion. The successful induction of cerebral ischemia was confirmed by somatosensory evoked potential amplitude changes. Measurements of 6-ketoprostaglandin F1 alpha (PGF1 alpha) and leukotriene B4 (LTB4) (radioimmunoassay) and cerebral edema (specific gravity) were made at early (10 minutes) and late (2 hours) reperfusion times. Although both white and gray matter showed no early significant difference in edema accumulation between normothermic and hypothermic gerbils at 10 minutes of reperfusion, hypothermic animals demonstrated significantly less white matter edema (specific gravity, 1.0397 +/- 0.0010 vs. 1.0341 +/- 0.0012, P less than 0.01) and gray matter edema (specific gravity, 1.0408 +/- 0.0009 vs. 1.0365 +/- 0.0008, P less than 0.01) by 2 hours of reperfusion. Production of PGF1 alpha was not significantly different between normothermic and hypothermic animals during the reperfusion period; however, hypothermic gerbils demonstrated significantly lower production of LTB4 at 10 minutes reperfusion time compared to normothermic animals (1.49 +/- 0.79 vs. 5.28 +/- 1.49 pg/mg of protein, P less than 0.05). This difference between the two groups in LTB4 levels was no longer detectable at 2 hours of reperfusion time.(ABSTRACT TRUNCATED AT 250 WORDS)     

Brain tolerance to middle cerebral artery occlusion during hypotension in primates

The aim of this study was to determine the duration of middle cerebral artery occlusion required to produce significant ischemic damage when the occlusion occurs during controlled systemic hypotension. In 21 anesthetized cynomolgus monkeys, an IV infusion of sodium nitroprusside was used to lower the mean arterial blood pressure to 45-50 mmHg for 90 minutes. Middle cerebral artery occlusion for 15, 30, 45, or 60 minutes was performed during the hypotensive period. Neurological function was then evaluated every 8 hours for a total of 72 hours. At the end of the observation period, the monkeys were again anesthetized, magnetic resonance imaging was performed, and the brain was perfused with 10% buffered formalin. Neurological deficits were observed after 30 minutes, but not after 15 minutes, of middle cerebral artery occlusion, and rapidly increased in incidence and severity when the duration of occlusion was increased. After 60 minutes of occlusion, all the monkeys exhibited severe deficits. Four monkeys died during the observation period--two in each of the 45- and 60-minute occlusion groups. Histopathological examination revealed that little or no ischemic damage resulted from a 15-minute occlusion during hypotension. However, severe ischemic damage began to occur after only 30 minutes of occlusion, and all monkeys subjected to middle cerebral artery occlusion for 60 minutes developed extensive regions of infarction. The size and incidence of these infarctions correlated well with the lesions observed in the magnetic resonance images. These results demonstrate that the duration of middle cerebral artery occlusion that produces cerebral infarction in primates is drastically reduced when the occlusion occurs at hypotensive levels commonly employed during neurovascular surgical procedures.     

Cold injury, blood-brain barrier changes, and leukotriene synthesis: inhibition by phenidone

Transcranial cold injury in rats and guinea pigs induced cerebral extravasation of albumin labeled with Evans blue dye or 125I, respective indicators of the area and amount of blood-brain barrier (BBB) disruption. Radioimmunoassay of brain extracts showed that cold injury induced leukotriene (LT)C4 in rat and guinea pig brains 15 min after injury. In guinea pigs, the LT synthesis inhibitor phenidone (30 mg/kg, i.p.) completely blocked cold-induced LTC4 in brain. Phenidone (30 and 100 mg/kg) also inhibited cerebral tissue accumulation of 125I-albumin and dye in rats and guinea pigs. Phenidone is reported to show antioxidant properties and selective lipoxygenase inhibition of arachidonic acid metabolism compared to cyclooxygenase inhibitors, meclofenamate sodium, and other nonsteroidal anti-inflammatory agents. Since several oxygen and hydroxyl radical scavengers and the cyclooxygenase inhibitor, meclofenamate sodium, did not inhibit protein extravasation, the findings support a role for LT as a mediator of cold-induced changes in BBB permeability in rats and guinea pigs and suggest that the inhibitory effects of phenidone on BBB permeability may be due to inhibition of LT production.     

Effects of nimodipine on the production of thromboxane A2 following total global cerebral ischemia

To clarify the contribution of vasoconstrictor prostaglandins to the hypoperfusion state typically following total global cerebral ischemia, 14 mongrel dogs were subjected to 11 minutes of global cerebral ischemia. They were then randomly assigned to receive either no treatment or an intravenous bolus of the calcium channel blocker nimodipine, 10 micrograms/kg, 15 minutes after ischemia followed by a continuous infusion of nimodipine, 1.0 micrograms/kg/min. Thromboxane (Tx) A2 production, as measured by cerebral venous levels of TxB2 (the stable metabolite of TxA2) increased similarly in the two groups. In contrast to previous studies, mean postischemic cerebral blood flow did not increase sufficiently in the nimodipine-treated group to achieve statistical significance. These data suggest that the improved neurological outcome associated with nimodipine treatment following global cerebral ischemia does not relate to reduced levels of the prostaglandin precursor arachidonate.     

Post-obstruction diuresis: influence of renal prostaglandins.

The possible role of altered renal prostaglandin metabolism in the generation of post-obstruction diuresis (POD) was examined in 16 adult male Sprague-Dawley rats. Inhibition of cyclooxygenase by the administration of a combination of two nonsteroidal anti-inflammatory drugs (NSAID), meclofenamate and indomethacin in 8 of these rats exaggerated, rather than lowered the degree of natriuresis and diuresis that followed the release 24 h after bilateral ureteral ligation. Urine osmolarity was similar in the two groups of rats treated with the NSAID and vehicle. The results suggest an enhanced synthesis of renal vasoconstrictor and antidiuretic prostaglandins (thromboxane A2 or PGF2 alpha) during bilateral ureteral ligation. NSAIDs such as aspirin, indomethacin, meclofenamate and others may promote POD by blocking this prostaglandin pathway while promoting the cytochrome P450 monooxygenase pathway which may produce vasodilator, diuretic and natriuretic paracrine hormones. Additionally, inhibition of prostaglandin synthesis may have enhanced post-obstruction diuresis in the present studies by allowing a greater volume expansion during obstruction, as indicated by a reduced hematocrit in the rats that were pretreated with NSAID.     

Circadian rhythm in prostacyclin activity in gastric tissue of the fasting rat.

Gastroduodenal ulcer disease may result from the desynchronization of the circadian rhythms of gastric protective and destructive factors. The purpose of this study was to evaluate whether gastric tissue 6-keto prostaglandin F1 alpha (PGF1 alpha), a catabolic derivative of the putative protective factor prostacyclin, is produced in a circadian fashion in the rat model. Forty-eight male Sprague-Dawley rats were acclimatized in sound-attenuated, lightproof chambers for 3 weeks on a 12:12 hour light/dark entrainment schedule. After an 18-hour fast, six rats were killed at each of eight sampling times. The stomachs were exposed, removed, and assayed for total 6-keto PGF1 alpha content by radioimmunoassay. Cosinor analysis of the data showed significant (p = 0.0262) circadian rhythmicity in 6-keto PGF1 alpha content with an acrophase (peak time) value of 0503 HALO (hours after lights on) or in the middle of the lights-on inactive period for the rats. Hypothetically, the circadian rhythm in some gastric protective factors may render the gastric mucosa vulnerable to injury in a circadian fashion.     

Beneficial effect of cyclooxygenase inhibition on adverse hemodynamic responses after protamine

The hypothesis that adverse effects observed when heparin is antagonized by protamine are mediated by metabolites of the arachidonic acid cascade was tested during general anesthesia (enflurane, fentanyl) in 16 pigs classified into two groups. In the first group (n = 9), effects of intravenously administered protamine on systemic hemodynamics, blood/gas tensions, and arterial and mixed-venous prostanoid levels were studied. The second group (n = 7) was pretreated with indomethacin 10 mg/kg, and the same measurements were made. All pigs received heparin 150 units/kg. When protamine 1.1 +/- 0.1 mg/kg was administered over 3 minutes, marked hemodynamic alterations were observed in group 1: pulmonary artery pressure and pulmonary vascular resistance increased, and left ventricular end-diastolic and systemic arterial pressures decreased. Arterial and mixed-venous PO2 values deteriorated in all pigs in group 1 at the end of protamine infusion. These alterations were accompanied by significantly elevated prostanoid levels in arterial and mixed-venous plasma samples: Thromboxane A2, prostaglandin F2 alpha, KH2-PGF2 alpha (a metabolite of prostaglandin F2 alpha), and prostacyclin were maximally elevated at completion of protamine and remained significantly above control values at 5 minutes but were not significantly different from control after 10 minutes. Blocking the cyclooxygenase cascade by pretreatment of the pigs with indomethacin (group 2) prevented hemodynamic and blood gas alterations. It is concluded that in pigs the detrimental side effects associated with the use of protamine to reverse heparin are mediated by metabolites of the cyclooxygenase cascade.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sequential in vivo measurement of cerebral intracellular metabolites with phosphorus-31 magnetic resonance spectroscopy during global cerebral ischemia and reperfusion in rats

Phosphorus-31 magnetic resonance (31P MR) spectroscopy was used to obtain serial in vivo measurements of cerebral adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi), and intracellular pH levels in rats during temporary global cerebral ischemia and reperfusion. Three groups of 4 rats each that recovered from permanent bilateral vertebral artery occlusion were placed in a MR spectrometer and subjected to remotely controlled bilateral carotid artery occlusion lasting 6, 15, or 30 minutes followed by 1 hour of reperfusion. Four additional rats that developed systemic hypotension (2 during a 6-minute occlusion and 2 during a 15-minute occlusion) were also studied. 31P MR spectra were obtained in each rat before, during, and after ischemia. Rats in which MR spectra showed metabolic recovery underwent a second occlusion followed by reperfusion and sacrifice. In the 12 normotensive rats, metabolic alterations began within 3 minutes after the onset of global ischemia. By the end of the occlusion period, cerebral ATP had decreased by 20 to 100% in 10 rats and PCr had decreased by 15 to 75% in all 12; Pi increased by 25 to 240%. The mean intracellular pH decreased from 7.33 to 6.9 +/- 0.6. The degree of metabolic deterioration during ischemia was not related to the duration of occlusion. During reperfusion, ATP, PCr, Pi, and intracellular pH returned to normal in 4 rats; 5 rats had partial metabolic recovery, and 3 had minimal or transient metabolic recovery followed by progressive deterioration. All rats that developed systemic hypotension had a decrease in ATP, PCr, and intracellular pH and an increase in Pi during the initial occlusion. Each had transient partial recovery in ATP during reperfusion, and 2 had slight recovery of PCr. The onset of hypotension was followed by depletion of these metabolites, progressive increase in Pi, and progressive intracellular acidosis. All rats that deteriorated metabolically after reversal of carotid occlusion died by the end of the reperfusion period or soon after. The 8 rats that recovered from the first occlusion were subjected to a second period of ischemia, during which each rat showed severe depletion of metabolites. During the second reperfusion, only 1 rat showed significant metabolic recovery, which lasted only 30 minutes and was followed by progressive deterioration. Severe global cerebral ischemia was associated with a progressive decline in both ATP and PCr, whereas less complete ischemia seemed to be characterized by stabilization or recovery of ATP and continued depression of PCr.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pyrogenic renal hyperemia: the role of prostaglandins.

The intravenous administration of triple typhoid vaccine to anesthetized dogs resulted in a significant increase in renal blood flow accompanied by a modest decline in systemic blood pressure. This renal hyperemia was associated with elevated renal secretory rates of renin and prostaglandin E and F. Measurements of the intracortical distribution of radiolabeled microspheres revealed a progressive decrease in outer cortical blood flow rates and a progressive increase in inner cortical flow rates. When meclofenamate, an inhibitor of prostaglandin synthetase, was administered concomitantly with triple typhoid vaccine renal hyperemia did not develop. The renal renin secretory rate increased modestly and intracortical renal blood flow was not redistributed. The increased renal blood flow after triple typhoid vaccine administration to unanesthetized dogs was also reversed by meclofenamate. The marked increase in prostaglandin secretion by the kidney during renal hyperemia following triple typhoid vaccine administration (pyrogen), and the effect of meclofenamate, is consonant with a role for increased renal synthesis and release of prostaglandins.     

Human internal mammary artery produces more prostacyclin than saphenous vein

The patency rate of internal mammary artery grafts is reported to be better than that of saphenous vein grafts in myocardial revascularization operations. To identify a possible biochemical explanation for this phenomenon, we studied the production of prostacyclin by the internal mammary artery and saphenous vein in 11 patients. Segments of internal mammary artery and saphenous vein from each patient were incubated in Krebs-Henseleit buffer at 37 degrees C. After 15 minutes, the basal production of 6-keto-prostaglandin F1 alpha (prostacyclin metabolite) by the internal mammary artery was 152 +/- 39 pg/mg wet weight (mean +/- standard error of the mean), whereas the saphenous vein produced only 68 +/- 17 pg/mg (p less than 0.001). After 30 minutes, the internal mammary artery produced 179 +/- 42 pg/mg, whereas the saphenous vein produced 75 +/- 18 pg/mg (p less than 0.001). After the basal incubation period, the vessels were incubated with arachidonic acid (prostaglandin substrate) for 15 minutes. The internal mammary artery produced 49.4 +/- 9.9 pg/mg, whereas the saphenous vein produced only 22.6 +/- 9.8 pg/mg (p less than 0.01). These observations suggest that the capacity of the internal mammary artery to produce prostacyclin in both a basal and a stimulated state is greater than that of the saphenous vein. Since prostacyclin is a potent vasodilator and inhibitor of platelet function, these results provide a possible biochemical explanation for the clinically observed better patency rate of internal mammary artery grafts.     

Ischemic preconditioning during the use of the PercuSurge occlusion balloon for carotid angioplasty and stenting

Ischemic preconditioning (IP) uses transient ischemia to render tissues tolerant to subsequent, prolonged ischemia. This study sought to evaluate factors that contributed to the development of cerebral ischemia during PercuSurge balloon (Medtronic, Santa Rosa, CA) occlusion in patients undergoing carotid angioplasty and stenting (CAS). The PercuSurge occlusion balloon was used in 43 of 165 patients treated with CAS for high-grade stenosis; 20% were symptomatic. Symptoms of cerebral hypoperfusion during temporary occlusion of the internal carotid artery occurred in 10 of 43 patients and included dysarthria, agitation, decreased level of consciousness, and focal hemispheric deficit. The development of neurologic symptoms after initial PercuSurge balloon inflation and occluded internal carotid artery flow was associated with a decrease in the mean Glasgow Coma Scale (GCS) from 15 to 10 (range 9-14); the GCS returned to normal after occlusion balloon deflation. The mean time to spontaneous recovery of full neurologic function was 8 minutes (range 4-15 minutes). The mean subsequent procedure duration was 11.9 minutes (range 6-21 minutes). No recurrence of neurologic symptoms occurred when the occlusion balloon was reinflated. All 10 patients underwent successful CAS without occlusion, dissection, cerebrovascular accident, or death. Ischemic preconditioning can be used to enable CAS with embolic protection in patients who cannot tolerate initial interruption of antegrade cerebral perfusion by PercuSurge occlusion.     

Cerebral ischemia associated with PercuSurge balloon occlusion balloon during carotid stenting: Incidence and possible mechanisms

BACKGROUND: Interruption of antegrade cerebral perfusion results in transient neurologic intolerance in some patients undergoing carotid angioplasty and stenting (CAS). This study sought to evaluate factors that contributed to the development of cerebral ischemia during PercuSurge balloon occlusion and techniques used to allow successful completion of the CAS procedure. METHODS: The PercuSurge occlusion balloon was used in 43 of 165 patients treated with CAS for high-grade stenosis (mean stenosis, 90%). All 43 patients were at increased risk for endarterectomy (7 restenosis, 3 irradiation, 3 contralateral occlusion, and 30 Goldman class II-III); 20% were symptomatic. Symptoms of cerebral hypoperfusion during temporary occlusion of the internal carotid artery occurred in 10 of 43 and included dysarthria (7/10), agitation (6/10), decreased level of consciousness (5/10), and focal hemispheric deficit (3/10). An incomplete circle of Willis or contralateral carotid artery occlusion, or both, was present in 8 of 10 patients. Symptoms resulting from PercuSurge balloon occlusion were managed by balloon deflation with or without evacuation of blood from the internal carotid artery using the Export catheter. All symptoms resolved completely without deficit after deflation of the occlusion balloon. RESULTS: The development of neurologic symptoms after initial PercuSurge balloon inflation and occluded internal carotid artery flow was associated with a decrease in the mean Glasgow Coma Scale (GCS) from 15 to 10 (range, 9 to 14); the GCS returned to normal after occlusion balloon deflation and remained normal during subsequent reinflation. The mean time to spontaneous recovery of full neurologic function was 8 minutes (range, 4 to 15 minutes). No thrombotic or embolic events were present on cerebral angiography or computed tomography scan. Balloon reinflation was performed after a mean reperfusion interval of 10 minutes after full neurologic recovery (range, 4 to 20 minutes). The mean subsequent procedure duration was 11.9 minutes (range, 6 to 21 minutes). No recurrence of neurologic symptoms occurred when the occlusion balloon was reinflated. All 10 patients underwent successful CAS without occlusion, dissection, cerebrovascular accident, or death. CONCLUSION: Several factors may contribute to the development of neurologic intolerance during CAS with balloon occlusion. Elucidation of the protective cellular mechanisms that invoke ischemic tolerance after the initial transient ischemic event may enable CAS with embolic protection in patients who cannot tolerate initial interruption of antegrade cerebral perfusion.     

Therapeutic effects of hyperbaric oxygenation on acute focal cerebral ischemia in rats

The effects of hyperbaric oxygenation on acute focal cerebral ischemia in rats were investigated. All rats suffered 4-hour middle cerebral artery occlusion. Nontreated controls had a 27.9% +/- 5.5% infarct volume, and a left/right hemispheric volume ratio of 109% +/- 3%. Animals treated between 2.5 and 3.5 hours following occlusion had an 18.1% +/- 9.7% infarct volume (p less than 0.01), and a 105% +/- 3% left/right hemispheric volume ratio (p less than 0.001). In conclusion, at least until 4 hours following an ischemic insult, hyperbaric oxygenation reduces ischemic neuronal injury and brain edema following middle cerebral artery occlusion in rats treated between 2.5 and 3.5 hours following occlusion.     

Indomethacin and dexamethasone treatment in experimental neoplastic spinal cord compression: Part 2. Effect on edema and prostaglandin synthesis

Edema formation and prostanoid production (prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were studied in a model of neoplastic epidural cord compression (NSCC) in rats harboring a thoracolumbar tumor. Tumor-free and tumor-bearing animals were randomized for three treatments at 12-hour intervals with saline, dexamethasone (10 mg/kg i.p.), or indomethacin (10 mg/kg i.p.). Increase in water content was observed only in the compressed lumbar cord segments of paralyzed rats; the cervical and thoracic segments did not differ from controls. The rate of release of prostaglandins was evenly distributed along the spinal segments in tumor-free rats. In tumor-bearing rats, a consistent significant increase in PGE2 production was found in the compressed lumbar segment in the presence of neurological dysfunction: early (limp tail), P less than 0.05; paraplegia, P less than 0.001. A significantly elevated PGE2 synthesis preceded the increase in water content by 2 to 3 days. A 2-fold increase in TXB2 was detected in only one of three experiments, and synthesis of 6-keto-PGF1 alpha was elevated to 4 times the normal value (P less than 0.005) in two of three experiments. Dexamethasone failed to inhibit prostaglandin synthesis in the spinal cord of normal controls or paralyzed rats, whereas in nonneural tissues (liver, uterus) it reduced synthesis of the three metabolites by at least 50%, thus demonstrating a differential effect on central nervous system (CNS) vs. non-CNS tissues. Dexamethasone also failed to reduce the increased water content of the compressed segments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological action of FPL 55712 on canine cerebral arterial segments

The pharmacological action of a leukotriene antagonist FPL 55712 was studied on canine cerebral arterial segments. FPL 55712 at concentrations of 10(-6)M and 10)-5)M showed dose-dependent inhibition of the constrictor responses of the artery to prostaglandin F2 alpha. The constrictor responses of the artery to either serotonin or haemoglobin were suppressed by 10(-5)M FPL 55712, while 10(-6)M FPL 55712 failed to alter the responses. The KCL-induced constriction was not affected by treatment with either 10(-6)M or 10(-5)M FPL 55712. The present results suggest that FPL 55712 has vasodilator properties other than those related to the inhibition of leukotrienes.     

Effects of adenosine triphosphate dependent potassium channel opener on bladder overactivity in rats with cerebral infarction

PURPOSE: We evaluated the effect of the adenosine triphosphate dependent K channel opener KRN2391 (N-cyano-N' -(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonate) (Kirin Brewery Co., Gunma, Japan) on bladder overactivity induced by middle cerebral artery occlusion. MATERIALS AND METHODS: At 7 days after implantation of a bladder catheter in male Sprague-Dawley rats a cannula for intracerebroventricular administration was implanted and the left middle cerebral artery was occluded with 4-zero monofilament nylon thread. At 22 hours after the induction of cerebral ischemia saline was infused into the bladder at a constant rate (200 microl. per minute) and a cystometrogram was obtained with the rat in the conscious state. KRN2391 (5 microl.) was administered in intracerebroventricular fashion at graded doses (0.15 to 15 microg.). RESULTS: Bladder capacity in conscious rats was significantly reduced after left middle cerebral artery occlusion. Intracerebroventricular administration of KRN2391 significantly increased bladder capacity in cerebral infarcted but not in sham operated rats. CONCLUSIONS: These results show that a adenosine triphosphate dependent K channel opener may be useful for neurogenic bladder overactivity after cerebral infarction via action on the central nervous system.