Effects of benzodiazepine receptor partial inverse agonists in the elevated plus maze test of anxiety in the rat

The present series of experiments examined the effects of five benzodiazepine receptor (BZR) partial inverse agonists on the behaviour of rats on an elevated plus maze. The drugs were tested in a standard plus maze with 3-cm walls added to the open arms, as this has been shown to increase the sensitivity of the plus maze to anxiogenic-like drug effects (Jones and Cole 1995). The drugs tested were FG 7142 (0–100 mg/kg),-CCE (0–30 mg/kg), ZK 132 556 (0–100 mg/kg), ZK 90 886 (0–30 mg/kg) and Ro 15–4513 (0–30 mg/kg). In addition, to allow a comparison with previous studies, the effects of three reference substances, DMCM (0–2.5 mg/kg), pentylenetetrazol (PTZ; 0–30 mg/kg) and yohimbine (0–5 mg/kg), were also examined. These three reference compounds produced a dose-dependent reduction in the duration of open arm exploration and the total number of open arm entries, indicative of anxiogenic-like effects. DMCM produced significant effects at the doses of 1.25 and 2.5 mg/kg, PTZ at 30 mg/kg, and yohimbine at 5 mg/kg. The BZR partial inverse agonist FG 7142 (10, 30 and 100 mg/kg) also reduced the duration of open arm exploration and the total number of arm entries. The minimally effective dose resulted in a receptor occupancy of approximately 80%. Ro 15–4513 also produced anxiogenic-like effects, but only at a dose (30 mg/kg) that resulted in a receptor occupancy of approximately 95%. In contrast, the other BZR partial inverse agonists, ZK 132 553 and ZK 90 886, did not significantly reduce the duration of open arm exploration, even at doses that produced greater than 95% receptor occupancies.-CCE also did not reduce open arm exploration at any dose tested (0–30 mg/kg). The GABA shift, a biochemical index of intrinsic activity, indicates that these latter three compounds are more inverse agonistic than Ro 15–4513. In summary, these results demonstrate that not all BZR receptor partial inverse agonists have anxiogenic-like activity in the rat plus maze, and that the GABA shift, a biochemical index of intrinsic efficacy, does not predict which BZR partial inverse agonists are anxiogenic.     

Contrasting effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 on performance of an operant delayed matching to position task in rats

The effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 (dizolcipine) on short term working memory in the rat were investigated. The behavioural paradigm used was discrete trial, operant delayed matching to position, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. These delays generated an orderly forgetting curve in control rats, with matching accuracy decreasing from approximately 100% at 0-s delay to approximately 75% at 30-s delay. Intraperitoneal (IP) administration of CPP (10 mg/kg) produced a markeddelay dependent impairment in performance, suggesting a specific effect on short term working memory. This effect was accompanied by a minor decrease in the speed of responding, and a slight increase in the number of missed trials. Lower doses of CPP had no significant effects on either matching accuracy or sedation. In contrast, IP administration of MK 801 (0.1 and 0.2 mg/kg) caused a markeddelay independent impairment in the accuracy of delayed matching performance, suggesting a non-specific disruption of performance. A lower dose (0.05 mg/kg) of MK 801 had no significant effect on matching accuracy. The two lower doses of MK 801 increased the number of nose pokes made during the delays and tended to increase the speed of responding, suggesting a stimulant-like action. The highest dose of MK 801 had the opposite effects and also decreased the number of trials completed. The results with CPP therefore support the hypothesized role of NMDA receptors in learning and memory, and the contrasting effects of these two NMDA antagonists support previous suggestions of different behavioural effects resulting from administration of competitive and non-competitive NMDA antagonists.     

5-HT1A receptor agonists improve the performance of normal and scopolamine-impaired rats in an operant delayed matching to position task

A series of experiments examined the effects of 5-HT_1A ligands alone and in combination with the muscarinic antagonist scopolamine on short term working memory in the rat. The behavioural paradigm was a discrete trial, operant delayed matching to position task, with delays of 0, 5, 15 and 30 s. The 5-HT_1A ligands tested were the full agonist, 8-OH DPAT (0, 0.1, 0.3 and 1 mg/kg), the partial agonist, ipsapirone (0, 1, 3 and 10 mg/kg), and the purported antagonist, NAN 190 (0, 1, 2, and 4 mg/kg). 1-PP (0, 0.1, 0.3, 1 mg/kg), the major metabolite of ipsapirone, was also tested. The lowest dose of 8-OH DPAT significantly improved matching accuracy at the longest delay, whereas the highest dose impaired matching accuracy and increased the latency to respond. Ipsapirone also significantly improved the accuracy of performance at a dose of 3 mg/kg, but the doses of 1 and 10 mg/kg did not significantly affect performance. NAN-190, at the highest dose tested (4 mg/kg), impaired matching accuracy, whereas the two lower doses did not significantly affect performance. The highest dose also increased the latency to respond. 1-PP had no effect on performance. Scopolamine HBr (0.14 mg/kg) caused a delay dependent impairment in matching accuracy, and had no effect on missed trials or the latency to respond. Low doses of 8-OH DPAT (0.1 and 0.3 mg/kg) significantly attenuated the scopolamine induced accuracy impairment, whereas 1 mg/kg 8-OH DPAT potentiated the impairment. Ipsapirone (3 mg/kg) also significantly improved the performance of scopolamine impaired rats. NAN-190 increased the latency to respond and reduced the number of nose pokes made during the delays in scopolamine-treated rats, and tended to potentiate the scopolamine-induced accuracy impairment. 1-PP did not affect the performance of scopolamine treated rats. Taken together, these results suggest that modulation of 5-HT_1A receptors influences short term spatial working memory in the rat.     

Dissociation between the attentional effects of infusions of a benzodiazepine receptor agonist and an inverse agonist into the basal forebrain

The effects of infusions of the benzodiazepine receptor (BZR) full agonist chlordiazepoxide (CDP) or the full inverse agonist -CCM into the basal forebrain on behavioral vigilance were tested. Vigilance was measured by using a previously characterized task that requires the animals to discriminate between visual signals of variable length and non-signal events. Measures of performance included hits, misses, correct rejections, false alarms, side bias, and errors of omission. Following the infusion of saline (0.5 µl/hemisphere), the relative number of hits varied with signal length. In response to shorter signals, the number of hits decreased over time, indicating a vigilance decrement. Infusions of CDP (20, 40 µg/hemisphere) initially decreased the relative number of hits in response to shorter signals and, later in the course of the test sessions, to longer signals as well. CDP did not affect the relative number of correct rejections. In contrast, infusions of the inverse agonist -CCM (1.5, 3.0 µg/hemisphere) did not affect the relative number of hits but decreased the relative number of correct rejections (i.e., increased the number of false alarms). These data suggest that the basal forebrain mediates the attentional effects of BZR ligands. As systemic or intrabasalis administration of BZR agonists and inverse agonists was previously demonstrated to decrease and augment, respectively, activated cortical acetylcholine (ACh) efflux, their effects on behavioral vigilance are hypothesized to be mediated via their effects on cortical ACh.     

Comparison of several benzodiazepine receptor ligands in two models of anxiolytic activity in the mouse: an analysis based on fractional receptor occupancies

This study compared the effects of the -carboline anxiolytic, abecarnil, with other benzodiazepine receptor (BZR) ligands, including the full agonists diazepam and alprazolam, and the partial agonists ZK 95962 and bretazenil (Ro 16-6028), and alpidem, in the mouse four-plate test and plus-maze. The efficacy and potency of each compound was related to the fraction of BZR occupied by the drug. Abecarnil was efficacious in both tests and showed anxiolytic effects comparable with alprazolam and diazepam. In the four-plate test, abecarnil, bretazenil, and ZK 95962 had selective effects on releasing exploratory locomotor activity suppressed by footshock (punished crossings). None of these compounds significantly altered non-punished crossings. In contrast, diazepam and alprazolam increased both unpunished and punished crossings at low to medium doses (receptor occupancies of approximately 20–60%). The number of punished and unpunished crossings fell to control levels or below at higher, more sedative doses (approximately 80% receptor occupancy). Alpidem had very weak anxiolytic-like effects in this test and markedly reduced unpunished crossings at relatively low receptor occupancies (> 15%). In the plus-maze, abecarnil increased the time spent in the open arms and the percentage open arm entries to an extent equal to that observed following diazepam or alprazolam administration. Bretazenil and ZK 95962 had weak effects on the measures of anxiolytic activity in this test. Alpidem also had little anxiolytic-like activity in the plus-maze but markedly reduced the total number of arm entries. The fractional BZR occupancies required to increase the time spent in the open arms of the maze to 250% of control levels were approximately 45% for abecarnil and alprazolam, 60% for diazepam, and 100% for ZK 95962. Bretazenil did not reach this potentiation at the doses tested (up to 89% receptor occupancy). Abecarnil appeared to act as a full agonist on the measures of anxiolytic activity in both tests (i.e. required low fractional BZR occupancies) but on the measures of stimulation or sedation was more similar to the BZR partial agonists (i.e. had no significant effects even at receptor occupancies approaching 100%). On this basis abecarnil could be described as a selective agonist. In general, the four-plate test was more sensitive than the plus-maze. For example, lower BZR occupancies were needed to produce significant anxiolytic effects in the four-plate test than in the plus-maze. In addition, the partial agonists bretazenil and ZK 95962, which both produced weak effects in the plus-maze, had similar anxiolytic potencies to the full BZR agonists, diazepam and alprazolam, in the four-plate test.     

Behavioural similarities between mother rats and benzodiazepine-treated non-meternal animals

Mother rats nursing large litters are hyperphagic, aggressive towards conspecifics, and show less freezing behaviour than non-maternal animals. These naturally occurring adaptations resemble those elicited by benzodiazepine treatment in virgin rats, indicating a common neurochemical change in the brains of mother rats and benzodiazepine-treated virgins. In line with this hypothesis, it was found that three functional benzodiazepine antagonists (FG 7142, pentylenetetrazol, caffeine) decreased food intake, lowered aggression and strengthened freezing in lactating mother rats. These psychopharmacological observations support the idea that GABA neurotransmission is enhanced during motherhood in the rat.     

Effects of salbutamol upon performance on an operant screen for antidepressants

The adrenergic () agonist salbutamol increased reinforcement rates and decreased response rates on a differential-reinforcement-of-low-rate (DRL) 72-S schedule.These changes in DRL 72-S schedule performance are also produced by most clinically used antidepressants.The effects of salbutamol on a DRL 72-S schedule were dose-dependently antagonized by the antagonist metoprolol, but not changed by the 5HT antagonist methysergide. Additionally, neither salbutamol nor the antagonism of salbutamol by metoprolol caused disruption of DRL 72-S schedule performance. These results indicate that stimulation of receptors, and not of 5HT receptors, mediates salbutamol antidepressant-like effects on a DRL 72-S schedule.This work supported by NIMH PHS MH-19111Recipient Research Scientist Award MH-10562     

Comparison of the renal effects of dilevalol and carteolol in patients with mild to moderate essential hypertension

Summary The effects of 6 weeks of treatment with dilevalol 100 mg once daily, or carteolol 10 mg once daily, on renal blood flow (RBF), glomerular filtration rate (GFR) and total renal vascular resistance (TRR) were studied in 10 patients with mild-to-moderate essential hypertension in a randomised cross-over experiment.Both drugs lowered the systolic and diastolic blood pressures to a similar extent without altering the heart rate. Carteolol non-significantly decreased RBF by 9.2% and GFR by 12.3% without altering. TRR, whereas dilevalol produced a significant reduction in TRR by 13.2% (p<0.05), a non-significant decrease in RBF by 4.6% and no change in GFR.Neither drug changed plasma osmotic pressure, serum total protein concentration, electrolytes or plasma aldosterone concentration. Plasma renin activity tended to be lower in the dilevalol phase as compared to the carteolol phase.The results suggest that dilevalol may cause a greater decrease in TRR and less reduction in GFR when compared to carteolol in patients with mild-to-moderate essential hypertension. The difference in the renal effects might be due to the difference in the potency of vasodilatory properties of both drugs at the doses applied.     

Effects of small doses of bisoprolol on blood pressure and lipoprotein concentrations in hypertensive patients

Summary The effects of bisoprolol 2.5 and 5 mg per day on blood pressure, and lipoprotein and apolipoprotein concentrations were compared in 18 newly detected hypertensives in a double-blind, crossover study. All treatment results were related to the values at the end of a four-week placebo run-in period. Each of the two following treatment periods lasted for 3 months.The systolic and diastolic pressures in the supine position were reduced by 19.5/11.7 mm Hg and 14.6/10.4 mm Hg by 2.5 and 5 mg bisoprolol per day, respectively, with no significant difference in effect. Supine heart rate was reduced by 4.7 and 8.2 beats · min^–1, respectively, (P=0.0517 for different effects).The cholesterol concentration in low-density (LDL) and high-density (HDL) lipoproteins was reduced during both regimens, by about 0.3 and 0.1 mmol·l^–1, respectively, difference not significant. Triglyceride concentrations were not significantly affected during either regimen.We conclude that, in this study population, treatment with bisoprolol 2.5 mg per day was equally effective as 5.0 mg per day in reducing blood pressure. The effects on lipoprotein concentrations were small and included an unexpected reduction in LDL-cholesterol concentration. A low dose of a highly selective -adrenoceptor blocker like bisoprolol appears to retain the blood pressure reducing capacity and has lost most of the unfavourable effects on lipoproteins characteristic of higher doses.     

Identification of harman in the rat arcuate nucleus

Summary This communication describes the presence of 1-methyl--carboline (harman) in the hypophysiotropic area of the hypothalamus which incorporates the arcuate nucleus. Diethyl ether extracts of boratebuffered arcuate homogenates were subjected to silica column chromatography and thin-layer chromatography (TLC). Identification of the -carboline was accomplished by use of fluorescent spectrometry, gas chromatography (GC), mass spectrometry (MS) and combined gas chromatography-mass spectrometry (GC-MS).Presented in a preliminary report at the 10th Annual Meeting of the American Society for Neurochemistry, Charleston, South Carolina, USA, March 1979     

The Effects of Cyclodextrins on the Disposition of Intravenously Injected Drugs in the Rat

Naproxen and flurbiprofen form complexes with hydroxypropyl--cyclodextrin; with stability constants of 2207 and 12515 M ^–1 respectively. However, only small fractions of the drug remain complexed when the drug–cyclodextrin complex is added to plasma in vitro. This result can be explained by albumin effectively competing with cyclodextrin for drug binding and by the simultaneous displacement of the drug from cyclodextrins by plasma cholesterol. Naproxen and flurbiprofen were administered intravenously to rats as cyclodextrin complexes. The disposition in the body of naproxen was not significantly altered by the complexation. This indicates that immediately after administration all drug is removed from the cyclodextrin complex. However, the initial distribution of flurbiprofen was changed upon complexation. Drug concentrations in liver, brain, kidney, and spleen were increased, indicating that hydroxypropyl--cyclodextrin may improve the presentation of the flurbiprofen to biomembranes, as compared with plasma proteins. The effect was transient; 60 min after injection the differences in tissue concentration compared with controls were dissipated. Finally, the importance of protein binding in determining the mode of interaction of cyclodextrins on drug disposition is discussed.     

Behavioral activities of opioid peptides and morphine sulfate in golden hamsters and rats

The behavioral effects of -endorphin, [D-Ala², D-Leu⁵]-enkephalin and morphine were investigated in golden hamsters and in rats. In golden hamsters, -endorphin and [D-Ala², D-Leu⁵]-enkephalin induced loss of righting reflex, whereas morphine caused no such effect. Both opiate peptides and morphine caused the inhibition of tail-flick response and catalepsy in rats. -Endorphin was the most potent, followed by [D-Ala², D-Leu⁵]-enkephalin and then by morphine. The catalepsy induced in rats by [D-Ala², D-Leu⁵]-enkephalin was different from that of -endorphin and morphine in that it produced catalepsy without muscular rigidity. -Endorphin and [D-Ala², D-Leu⁵]-enkephalin caused hypothermia in golden hamsters; morphine was less active in altering the body temperature. -Endorphin caused hypothermia at high doses and hyperthermia at low doses in rats. These heterogenous behavioral responses indicate that multiple types of receptors mediate the effects of opiates in the central nervous system.     

Effects of dopamine on whole kidney function and proximal transtubular volume fluxes in the rat

Summary The renal effects of dopamine were studied using clearance and micropuncture techniques in rats. Intravenous infusion of dopamine (4.7 · 10^–6 mol · kg^–1 · h^–1) increased glomerular filtration rate and renal blood flow. Renal blood flow was measured by an electromagnetic flowmeter. The increase in filtered fluid and sodium was nearly completely matched by increased tubular reabsorption. Thus, only a small rise in urine flow and in urinary sodium excretion was observed.The micropuncture experiments using the split oil droplet method of Gertz demonstrated a stimulation of the transepithelial fluid transfer after injection of dopamine (10^–4M) into the proximal tubular lumen. This effect was abolished by simultaneous injection of propranolol (10^–3 M) which, by its own, did not affect transtubular volume fluxes. It is concluded that dopamine, by stimulation of -adrenoceptors, may increase reabsorptive capacity of the proximal tubular epithelium independent of changes in renal hemodynamics.Supported by Deutsche Forschungsgemeinschaft     

Effect of elevated brain GABA concentrations on the actions of bicuculline and picrotoxin in mice

-Acetylenic GABA and -vinyl GABA, two catalytic irreversible inhibitors of mammalian brain GABA transaminase that produce several-fold increases in brain GABA concentrations were tested for their effects on bicuculline and picrotoxin-induced seizures and mortality in mice. Neither inhibitor influenced the frequency of seizures or death produced by either bicuculline or picrotoxin. Both inhibitors, however, produced a dose-dependent prolongation of the time to onset of seizures and death induced by picrotoxin but not by bicuculline. These results suggest differences in the antagonism by bicuculline and picrotoxin of GABA-mediated neural functions.     

Respiratory effect of acute and subacute exposure to endotoxin-contaminated metal working fluid (MWF) aerosols on Sprague-Dawley rats

Male Sprague-Dawley rats were exposed to a water-soluble metal working fluid (MWF) (5% v/v) contaminated with endotoxins (10,000 eu/ml or 100,000 eu/ml) at 10 mg/m³ for six hours per day for three days (acute exposure) or two weeks (subacute exposure). The geometric mean diameter of the MWF aerosols was 1.56 m, and the airborne endotoxin concentrations ranged from 1,231 to 2,173 eu/m³ (10,000 eu/ml in the bulk MWF) for the low dose and 19,263–27,386 eu/m³ (100,000 eu/ml in the bulk MWF) for the high dose. Minimal effects were observed after exposure to 10 mg/m³ of the MWF without endotoxins for three days or two weeks. However, an increase in the number of polymorphonuclear cells (PMNs) and the level of protein was noted in the bronchoalveolar lavage (BAL) fluid from the rats acutely exposed to the MWF with endotoxins. The acute exposure produced a greater increase in the number of PMNs and total cell number in the BAL fluid than the subacute exposure. The number of white blood cells in the peripheral blood and the weight of the lungs both increased after the subacute exposure to the MWF aerosol with endotoxins, indicating increased vascular permeability in response to the endotoxin exposure. The levels of cyotokines such as IL-4, INF-, and IL-1 in the BAL fluid from the rats exposed to the MWF with or without endotoxins remained unchanged. Although the level of nitric oxide (NO_x) in the BAL supernatant did not show any change, the induction of NO_x from the alveolar macrophages increased in the rats acutely or subacutely exposed to the MWF contaminated with endotoxins. The ConA-induced proliferation response showed no change, yet the LPS-induced proliferation response was significantly increased in the splenocytes from the rats subacutely exposed to the MWF with and without endotoxins. The level of TNF- in the spleen cell culture obtained from the rats exposed to the MWF with or without endotoxins increased without changing the levels of IL-1, IL-4, and INF-. The level of endotoxin-specific IgE in the serum obtained from the rats exposed to the MWF with endotoxins increased dose-dependently, while the levels of total immunoglobulins (IgG₁, IgG_2a and IgE) and endotoxin-specific IgG₁ and IgG_2a remained unchanged. Accordingly, the current results indicate that lung inflammation can be immediately induced by acute or subacute exposure to an MWF contaminated with endotoxins, and macrophages would appear to play a role in the induction of inflammation along with B-cell functions rather than T-cell functions, after subacute exposure to an MWF with endotoxins. In addition, endotoxin-specific IgE is an early marker for endotoxin exposure in the workplace.     

Neurally mediated control of enzymes involved in the synthesis of norepinephrine; are they regulated as an operational unit?

Summary Cold-exposure of rats for 1–4 days leads to a gradual increase in tyrosine hydroxylase and dopamine -hydroxylase activity in superior cervical ganglia and adrenals. This increase is neurally mediated, since it can be abolished by decentralization of the ganglia and transsection of the splanchnic fibres supplying the adrenal medulla. Enzyme kinetic data suggest that the increased enzyme activity results from an increased synthesis of enzyme protein. The activity of dopa decarboxylase, the third enzyme involved in the synthesis of norepinephrine, remains unchanged both in ganglia and in adrenals. In the adrenals, the gradual rise in tyrosine hydroxylase and dopamine -hydroxylase activity is virtually parallel and reaches more than twice the control values. In the superior cervical ganglion, however, there is a marked difference between the rise in activity of the two enzymes. The increase in tyrosine hydroxylase activity amounts to 217% after 4 days of cold-exposure, that of dopamine -hydroxylase to 131% of controls (100%) only. The determination of enzyme turnovers by measuring the decay in activity after inhibition of protein synthesis by cycloheximide was attempted but the turnover of tyrosine hydroxylase both in adrenals and superior cervical ganglia was too slow to be determined by this method. The same was true for dopamine -hydroxylase in the adrenal medulla. However, in the superior cervical ganglion the turnover of the latter enzyme could be determined; the half-life amounts to 13 h. The fact that the turnover of dopamine -hydroxylase in the superior cervical ganglion is more rapid than that of tyrosine hydroxylase could explain the difference in the increase in enzyme activity in spite of a similar rise in the rate of synthesis. It is concluded that the enzymes involved in the synthesis of norepinephrine are not regulated as an operational unit, but that the results are compatible with the assumption that the synthesis of the two enzymes, tyrosine hydroxylase and dopamine -hydroxylase, which are specifically located in adrenergic neurons, may be regulated by a common mechanism.     

Differential effects of Bay k 8644, a presumed calcium channel activator,on sinoatrial nodal and ventricular automaticity of the dog heart

Summary In 10 healthy volunteers the effects of acute increases in concentrations of catecholamines in plasma induced by dynamic exercise (on a bicycle for 15 min at 80% of maximum heart rate) on lymphocyte ₂-adrenoceptor density (determined by (±)-¹²⁵iodocyanopindolol binding) and-responsiveness (determined by cyclic AMP responses to 10 mol/l isoprenaline) were investigated. Immediately after exercise plasma catecholamines were increased about 4-fold; concomitantly receptor density and cyclic AMP production increased 55% and 65%, respectively. One hour after exercise -adrenoceptor density and plasma catecholamines had reached values, which were not significantly different from preexercise values, while cyclic AMP production was significantly diminished. It is concluded, that acute increases in concentrations of catecholamines in plasma may increase -adrenoceptor density and — responsiveness in human lymphocytes.     

Effects of morphine on sleep in the cat

The effects of morphine sulfate, 300 g/kg s.c., on the sleep of cats was studied by electroencephalographic techniques. In contrast to placebo experiments the animals were awake for approximately 6 h after administration of morphine; the return of regular sleep patterns occurred after about 11 h. A rebound increase in rapid eye movement (REM) sleep time and percentage was noted during the 11th through the 17th hour of the study. Sleep following manual sleep deprivation for 10 h showed a rebound increase in REM and non-rapid eye movement (NREM) sleep time. NREM sleep rebound after manual sleep deprivation exceeded that occurring after morphine. The alerting actions of morphine could be blocked by naloxone, 100 g/kg s.c., for about 90 min. Naloxone alone increased REM sleep time and percentage. Single (84 mg/kg) or multiple (51 mg/kg for 4 injections) doses of dl--methyltyrosine i.p. did not block the alerting action or REM sleep rebound caused by morphine. 5-Hydrotryptophan (30 mg/kg) i.p. did not antagonize the alerting action of morphine.Publication No. 1044 of the Division of Basic Health Sciences of Emory University. A preliminary report of this work was presented at the Fall Meeting of the American Society for Pharmacology and Experimental Therapeutics, Pittsburgh, Pennsylvania, August, 1969. This work was supported by USPHS grant MH12870-04.A predoctoral fellow of Graduate Pharmacology Training Grant 2T1-GM179.     

Regional differences in the effects of capsaicin and tachykinins on motor activity and vascular permeability of the rat lower urinary tract

Summary 1. The effects of capsaicin, substance P (SP) and neurokinin A (NKA) on motor activity and vascular permeability was investigated in the rat lower urinary tract (bladder dome and neck, proximal urethra and ureters). 2. Capsaicin produced contractions of the rat bladder dome and neck and of the proximal urethra in vitro, which were unaffected by tetrodotoxin and abolished by ganglionectomy. SP and NKA were almost equipotent in producing a contraction of the rat isolated bladder dome or neck and urethra. However, the maximal response to NKA was about twice that of SP on the urethra and bladder neck. 3. Capsaicin did not affect motility of the unstimulated rat isolated ureter, while NKA or SP activated rhythmic contractions, NKA being about 850 times more potent than SP. Either capsaicin or field stimulation produced a transient inhibition of the NKA-activated rhythmic contractions of the rat isolated ureter which was prevented by capsaicin-desensitization. 4. The capsaicin-(1 M) or field stimulation-induced inhibition of NKA-activated rhythmic contractions of the rat isolated ureter were unaffected by removal of pelvic ganglia but abolished by cold storage (72 h at 4°C). 5. Intravenous capsaicin induced an inflammatory response (Evans blue leakage) in the bladder, proximal urethra and ureters in vivo. Plasma extravasation was greater in the ureters, urethra and bladder neck than in the dome. SP, NKA and histamine produced a dose-dependent dye leakage in all segments of the rat urinary tract, the response being slightly greater in the bladder neck than in the dome. 6. The capsaicin-induced inflammatory response was abolished by systemic capsaicin-desensitization and reduced, to a variable extent, by pelvic ganglionectomy, in the various tissues examined. Topical application of tetrodotoxin on the bladder dome failed to affect the capsaicin-induced plasma extravasation in the urinary bladder. 7. These findings indicate that chemoceptive, capsaicin-sensitive nerves are present throughout the whole rat lower urinary tract and their activation determines a variety of visceromotor responses and an increase of vascular permeability. In various instances the response to capsaicin may be explained by the action of tachykinins but some effects may involve other sensory neuropeptides. Send offprint requests to C. A. Maggi at the above address     

Interaction of talinolol and sulfasalazine in the human gastrointestinal tract

Summary The absorption of talinolol (TA) 50 mg was investigated without and together with the co-administration of sulfasalazine (SASP) 4 g in 11 healthy young volunteers, in order to clarify gastrointestinal transit of TA.Without SASP, the t_max of TA was 2.8 h, C_max was 112 ng·ml^–1 and the half life was 12 h; the AUC_o-t was 958 ng·ml^–1·h.In the case of concomitant administration of SASP, TA was found only in serum from 3 individuals, with a C_max of 23 ng·ml^–1 and a mean AUC_o-t of 84 ng·ml^–1·h. TA was not detectable in 5 subjects and it was at the limit of detection (2 ng·ml^–1) in 3 subjects. Pharmacokinetic analysis was not possible in any of those individuals.The reason for the interaction appears to be the adsorption of TA by SASP. An interval of 2–3 h should elapse between giving SASP and other drugs.