Ketorolac causes the release of methionine-enkephalin in rats.

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) that is indicated for the short-term management of moderately severe, acute pain, that causes analgesia equivalent to that caused by morphine. It has been shown experimentally that the analgesia produced by ketorolac in mice can be diminished by pretreatment with naloxone. This observation suggests that ketorolac produces some of its analgesia by interacting with opioid receptors. However, ketorolac does not directly interact with opioid receptors (Lopez et al., 1987). The present experiments demonstrate that the analgesia produced by ketorolac may be caused by the release of the endogenous opioid, methionine-enkephalin.

Penile erection in the primate: induction with nitric-oxide donors.

The primate model has been used for investigations on the physiology and pharmacology of erection. Recent in vitro investigations indicate that nitric oxide acts as the mediator of penile erection, but in vivo primate studies are needed to corroborate these findings. Penile erections were induced in a primate model using intracavernosal injections of nitric oxide donors s-nitrocysteine (NO-CYS) and sodium nitroprusside (SNP), and acetylcholine (ACh) which stimulates the formation of nitric oxide. Penile length and intracavernosal pressures following agonist injection were compared with baseline (flaccid) and control erections (elicited by injection of a papaverine/phentolamine/PGE1 standard mixture). Dose-response curves for each drug were determined with respect to maximal intracavernosal pressure, duration of effect and penile length, and systemic arterial pressure was monitored. All three agents induced erections, with dose-dependent increases in cavernosal pressure and penile length. The maximal cavernosal pressure attained was similar for all three agents, but the duration of action was significantly shorter with ACh (p < .05). Injection of L-nitro-arginine-methyl-ester (L-NAME), a nitric oxide synthase inhibitor, before injection of the nitric oxide donor shortened the duration of effect but did not alter maximal cavernosal pressure or penile length attained. Although systemic hypotension was induced by each agent, digital compression at the base of the penis at the time of injection prevented such changes. These results suggest that the primate is a useful model to evaluate the action of substances that induce or inhibit penile erection. The findings provide support for the hypothesis that nitric oxide is a mediator of penile erection and that nitric oxide donors may be useful in the treatment of erectile dysfunction.

Nitric oxide mediates penile erection in cats.

The present study was undertaken to investigate the in vivo effects of nitric oxide (NO) mediating agents injected intracavernosally on penile erection in cats. All NO donors increased the cavernosal pressure and penile length in a dose-dependent manner. The maximal effects on cavernosal pressure and penile length induced by s-nitrosocysteine (NO-CYS) and s-nitroso-n-acetylpenicillamine (SNAP), respectively, were 8-fold and 5-fold increases in pressure, and 45% and 34% increases in length when compared with baseline values. These changes were comparable to that caused by the control drug combination (papaverine, phentolamine and prostaglandin E1). The effects of acetylcholine (ACh) and substance P on cavernosal pressure and penile length were less than those obtained with the control drug combination, NO-CYS (p < 0.01), or SNAP (p < 0.05). N omega-nitro-l-arginine-methyl-ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, significantly decreased the effects of NO-CYS, ACh and substance P on penile erection. This in vivo study with NO donors and an NOS inhibitor suggests that NO is a mediator of penile erection in cats.

Effect of changes in rate of vascular perfusion on release of substances into the effluent from the brain of the rabbit.

The cerebral vasculature of five anaesthetised rabbits was perfused with a perfluorocarbon emulsion via the internal carotid arteries, and the effluent from the jugular veins analysed for ATP, substance P (SP), endothelin (ET) and arginine vasopressin (AVP). Viability of the preparation was monitored periodically by the electrocorticogram, oxygen uptake, carbon dioxide release and perfusion pressure. The basal rate of infusion of 7.8 +/- 1.26 ml.min-1 resulted in an infusion pressure of 114.0 +/- 22.1 mmHg and when increased first to 10.5 +/- 1.53 ml.min-1 and then to 15.0 +/- 1.87 ml.min-1, rose to 163.0 +/- 33.1 mmHg and to 170.0 +/- 33.2 mmHg, respectively. Between each 3-min period of increased flow the rate was returned to the basal rate for 6 min. Of the four vasoactive substances, ET was released at the largest rate during the initial period of basal flow, 65.3 +/- 10.7 pmol.min-1. This increased further when the infusion rate rose to 10.5 ml.min-1, but was significant only when the infusion rate was increased to 15.0 ml.min-1. ATP was released at 41.5 +/- 11.5 pmol.min-1 during the initial period of basal flow. Its release significantly increased with flow and peaked at 15.0 ml.min-1. SP was released at a rate of 13.3 +/- 8.2 pmol.min-1 during the initial period of basal flow. Its rate of release was increased significantly the second time the flow was increased to 10.5 ml.min-1 and increased even further when the flow was increased to 15.0 ml.min-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Electron-immunocytochemistry of peptides in endothelial cells of rabbit cerebral vessels following perfusion with a perfluorocarbon emulsion.

This study describes the localization of endothelin-1-, vasopressin- and substance P-like immunoreactivity in a subpopulation of endothelial cells of the basilar and posterior communicating arteries of the (i) normal rabbit brains and (ii) rabbit brains perfused with a perfluorocarbon emulsion (PFC). Following perfusion with the PFC at increased flow the endothelial cell ultrastructure appeared normal, although there was a decrease of immunoreactivity to these peptides. This suggests that these peptides may be involved in endothelial control of blood flow in cerebral vessels.

Penile erections induced by vasoactive intestinal peptide and sodium nitroprusside.

The use of vasoactive intestinal peptide (VIP), sodium nitroprusside (SNP), and the reference combination of papaverine, prostaglandin E1, and phentolamine was studied in 22 adult cats. The maximal erectile response (intracavernous pressure, penile length, and rigidity) was produced by intracavernous injection of a combination of 1.65 mg papaverine, 0.5 micrograms PGE1, and 25 micrograms phentolamine. This combination was considered as "control" in order to compare the effect of other agents. VIP and SNP increased the intracavernous pressure and caused erection in a dose-dependent manner with a maximal response obtained with 5 micrograms VIP or 10 micrograms SNP. The duration of peak erection and the total duration of drug effect were significantly shorter with VIP and SNP than with the reference combination (P < 0.01). Epinephrine (30 micrograms) reversed the effects of SNP and significantly shortened the duration of peak action and total effect (P < 0.05). This study supports the use of an in vivo feline model for the evaluation of vasoactive agents and demonstrates that the intracavernous injection of either VIP or SNP can induce penile erection in the adult cat.

Effects of naloxone on penile erection in cats.

Male cats were anesthetized with pentobarbital. A Foley catheter was placed in the urinary bladder and physiologic saline, under a head of pressure, was allowed to flow at a constant rate through the bladder. Naloxone, 0.2 mg, caused penile erection in 5 of 11 experiments. The onset of action was 0.5 to 4 minutes, and the duration of the erection was 5 to 36 minutes. In two of three experiments a second injection of naloxone caused a second erection. The erection caused by naloxone was not changed by pre- or posttreatment with morphine or by posttreatment with propranolol. It was suggested that the erection could be due either to altered levels of hormones released from the central nervous system or to removal of reflex inhibitory tone in the spinal cord or sacral parasympathetic ganglia.

Selective alterations in cerebral metabolism within the mesocorticolimbic dopaminergic system produced by acute cocaine administration in rats.

The 2-[14C]deoxyglucose method was used to examine the effects of acute intravenous administration of cocaine on local cerebral glucose utilization in rats. These effects were correlated with the effects of cocaine on locomotor activity assessed simultaneously in the same animals. At the lowest dose of cocaine, 0.5 mg/kg (1.47 mumol/kg), alterations in glucose utilization were restricted to the medial prefrontal cortex and nucleus accumbens. Metabolic activity at 1.0 mg/kg (2.9 mumol/kg) was altered in these structures, but in the substantia nigra reticulata and lateral habenula as well. The selectivity of cocaine's effects at low doses demonstrates the particular sensitivity of these structures to cocaine's actions in the brain. In contrast, 5.0 mg/kg (14.7 mumol/kg) produced widespread changes in glucose utilization, particularly in the extrapyramidal system. Only this dose significantly increased locomotor activity above levels in vehicle-treated controls. Rates of glucose utilization were positively correlated with locomotor activity in the globus pallidus, substantia nigra reticulata, and subthalamic nucleus, and negatively correlated in the lateral habenula.

Ethanol decreases entry of vincristine into brain of rat: modification by acetylcholine or histamine.

Male Sprague-Dawley rats were anesthetized with pentobarbital sodium and a jugular vein and femoral artery cannulated. Ethanol (3%; 13.3 ml/kg) was injected intraperitoneally 5 min before the administration of 10 microCi [3H]vincristine sulfate intravenously. One minute later, saline, acetylcholine, (1 or 2 micrograms/kg) or histamine (1.25, 2.5 or 5 micrograms/kg) was given intravenously. At 15 min the thoracic cavity was opened, a cardiac sample of blood obtained, and saline infused into the left ventricle to remove blood from the brain. Samples of the cerebral cortex, midbrain, cerebellum, and plasma were subjected to liquid scintillation counting. The concentration of ethanol at 20 min after its administration was 20.3 mg/dl. This was associated with a significant decrease in radioactivity in the cerebral cortex and midbrain and a nonsignificant decrease in the cerebellum. Administration of 2 micrograms/kg of acetylcholine in the presence of ethanol decreased the blood pressure and increased the movement of radioactivity into the cerebral cortex and cerebellum while causing a significant decrease in the midbrain. Histamine (2.5 micrograms/kg) significantly increased the movement into the cerebellum and 5 micrograms/kg decreased the movement into the midbrain. The permeability of the blood-brain barrier to [3H]vincristine was decreased by ethanol and this could be modified regionally by vasoactive doses of acetylcholine and histamine. Possible therapeutic advantage might result if vincristine were given in the presence of ethanol which should diminish the potential neurotoxicity.

Effects of leukocytic pyrogen (interleukin-1) on local cerebral glucose utilization in rats with and without premedication with indomethacin or dexamethasone.

Changes in body temperature were recorded in freely moving rats given phosphate-buffered saline or leukocytic pyrogen (interleukin-1) while the animals were in an infant incubator maintained at 25.5 +/- 0.5 degrees C. The leukocytic pyrogen increased body temperature by at least 1 degree C within 1 h. This rise in temperature was prevented by premedication with indomethacin (10 mg/kg) but not dexamethasone (0.5 mg/kg) given 15 min before the leukocytic pyrogen. Local rates of glucose utilization were measured in 47 regions of the central nervous system. In none of the regions previously reported to have an increased rate of glucose utilization associated with an ambient temperature of 32.5 degrees C (McCulloch et al., 1982b) was an increase found in the present experiments. It was concluded that the intensity of the changes in local cerebral glucose utilization in response to the fever caused by the leukocytic pyrogen was insufficient to be measured. Neither indomethacin nor dexamethasone caused remarkable changes in rates of local glucose utilization.

Permeability of the blood-brain barrier is not changed by vasoactive doses of arachidonic acid or prostaglandins in rats.

Charles River, Sprague-Dawley rats of both sexes were anesthetized with pentobarbital sodium, 50 mg/kg i.p. and a jugular vein and femoral artery cannulated. Saline, arachidonic acid (1, 2, 4 or 6 mg/kg) alone or 15 minutes after administration of indomethacin (5 mg/kg), prostaglandin E2 (0.5, 1, 2 or 4 micrograms/kg) (PGE2), prostaglandin F2 alpha (20, 40, 80 or 160 micrograms/kg) (PGF2 alpha) or prostaglandin I2 (prostacyclin) (0.5, 1, 2 or 4 micrograms/kg) (PGI2) were given intravenously. Each of the drugs caused a dose-dependent decrease in blood pressure except for PGF2 alpha which caused an initial, short-lasting fall in blood pressure followed by a more sustained rise in blood pressure. The permeability of the blood-brain barrier was measured using 99mTc-sodium pertechnetate (TcO-4). None of the prostaglandins or arachidonic acid caused a significant change in the permeability of the blood-brain barrier. This provides a further example of a dissociation between drug-induced changes in systemic blood pressure and change in the permeability of the blood-brain barrier.

Cerebral phospholipid content and Na+,K+-ATPase activity during ischemia and postischemic reperfusion in the mongolian gerbil.

Using bilateral carotid artery occlusion in adult gerbils we examined the effects of ischemia and ischemia/reperfusion on cerebral phospholipid content and Na+,K+-ATPase (EC 3.6.1.3) activity. In contrast to the large changes in phospholipid content and membrane-bound enzyme activity that have been observed in liver and heart tissues, we observed relatively small changes in the cerebral content of total phospholipid, phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylethanolamine (PE) following ischemic intervals of up to 240 min. Following 15 min of ischemia the cerebral content of sphingomyelin (SM) was decreased to less than 50% of control values but returned to near-normal levels with longer ischemic periods. Significant decreases in the cerebral content of phosphatidylinositol (PI) and phosphatidic acid (PA) were observed following shorter intervals of ischemia (15-45 min). Na+,K+-ATPase activity of cerebral homogenates prepared from the brains of gerbils subjected to 30-240 min of ischemia was decreased but significantly different from control activity only after 30 min of ischemia (-29%, p less than or equal to 0.05). With the exception of PS, reperfusion for 60 min following 60 min of ischemia resulted in marked increases in cerebral phospholipid content with PC, SM, PI, and PA levels exceeding and PE levels equal to preischemic values. Longer periods of reperfusion (180 min) resulted in decreases in cerebral phospholipid content toward (PC, SM, PI, and PA) or below (PE) preischemic levels. In contrast, the cerebral content of PS significantly decreased during reperfusion (-51% at 60 min, p less than or equal to 0.05) and remained below preischemic values even after 180 min of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Blockade of the acetylcholine-and histamine-induced changes in the permeability of the blood-brain barrier of normotensive and spontaneously hypertensive rats by atropine and pyrilamine.

We have studied the effects of premedication with either atropine or pyrilamine on the responses of the blood pressure and the permeability of the blood-brain barrier (BBB) in normotensive (WKY) or spontaneously hypertensive (SHR) rats given acetylcholine or histamine. The rats were anesthetized with pentobarbital and the permeability of the BBB evaluated by the extravasation of either 131I-labeled radioiodinated serum albumin (RISA) or 99Tc-labeled sodium pertechnetate (TcO-4). Premedication greatly diminished the hypotensive responses to both acetylcholine and histamine, especially in the SHR animals. Additionally, the premedication blocked the increased permeability of the BBB, especially in SHR rats given TcO-4. The hypotension caused by acetylcholine or histamine in these premedicated animals given RISA again emphasizes the lack of predictability of changes in blood pressure and the permeability of the BBB.

Histamine- and acetylcholine-induced changes in the permeability of the blood-brain barrier of normotensive and spontaneously hypertensive rats.

Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats were given saline, histamine (1.25, 2.5 or 5.0 micrograms/kg) or acetylcholine (1.0 or 2.0 micrograms/kg). Both agents caused a dose-dependent decrease in blood pressure which was greater in the spontaneously hypertensive animals. The permeability of the blood brain-barrier was measured with 131I-labelled serum albumin (RISA) or with 99mTc-sodium pertechnetate (TcO4-). The lowest dose of histamine caused a decrease in permeability of the blood-brain barrier to serum albumin in normotensive rats and acetylcholine caused an increase. Only the largest dose of histamine increased the permeability of the blood-brain barrier to serum albumin in spontaneously hypertensive rats. All doses of histamine and acetylcholine increased the permeability of the blood-brain barrier to sodium per technetate in nomotensive rats and the two lower doses of histamine increased the permeability in spontaneously hypertensive animals. This provides another example of the dissociation of change in the systemic blood pressure and change in the permeability of the blood-brain barrier.

Dissociation of changes in the permeability of the blood-brain barrier from catecholamine-induced changes in blood pressure of normotensive and spontaneously hypertensive rats.

We have studied the effects of the pressor catecholamine, dopamine, and the depressor catecholamine, isoproterenol, on the systemic blood pressure and the permeability of the blood-brain barrier (BBB) to albumin in normotensive (WKY) and spontaneously hypertensive (SHR) rats. The rats were anesthetized with pentobarbital. The permeability of the BBB to protein was measured by the extravasation of radioiodinated serum albumin (RISA). The permeability was decreased by both catecholamines despite the dose-dependent, yet opposite, changes in blood pressure in the WKY rats. The blood pressure response to both of the catecholamines was enhanced in the SHR rats. Isoproterenol caused a decrease in the permeability of the BBB in the SHR but dopamine did not. Results with both WKY and SHR rats are suggestive of an adrenergically-mediated decrease in movement across the BBB of compounds of large molecular weight, regardless of changes in blood pressure.

Ototoxicity of intracisternal gentamicin in cats.

The intrathecal administration of gentamicin has been used to treat bacterial meningitis. However, the influence of this route of administration on the well-known ototoxic activity of gentamicin is unknown. This route of administration should facilitate access to the inner ear and should increase the ototoxic liability. The possible ototoxic and neurotoxic effects of intrathecally administered gentamicin (0.5, 1, 2, 4, 6, 10 mg/day) in cats were evaluated. Hearing thresholds were obtained by a noninvasive technique prior to and on the 7th and 21st days after the initiation of a seven-day dosage regimen. Histological examination of the organ of Corti was routinely done. Additionally, the vestibular organs of one animal on the 4 mg/day regimen were examined. The concentrations of gentamicin in the cerebrospinal fluid were also determined. The data indicate that the 2 mg/day dose may be very close to the threshold dose for ototoxicity when gentamicin is given by intracisternal administration.

Selective effects of alpha-MSH and MIF-1 on the blood-brain barrier.

The effects of intravenously-injected alpha-MSH and MIF-1 (Pro-Leu-Gly-NH2) on the permeability of the blood-brain barrier (BBB) to a large protein and a small anion were studied using radioiodinated serum albumin (RISA) and 99mTc-labeled sodium pertechnetate. The permeability of the BBB to RISA was unaltered by either peptide. Permeability to the inorganic pertechnetate anion, however, was significantly increased by alpha-MSH but not by MIF-1 at doses known to evoke EEG and behavioral responses. The peptides did not cause a change in the systemic blood pressure. It is possible, therefore, that at least some CNS effects of peripherally administered peptides are exerted by alteration of the permeability of the BBB to other substances.