Effect of several 5-hydroxytryptamine(1A) receptor ligands on the micturition reflex in rats: comparison with WAY 100635.
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Several novel N-arylpiperazine derivatives were synthesized and tested for their 1) affinity and functional activity on 5-hydroxytryptamine(1A) (5-HT(1A)) receptors in vitro; 2) activity in models predictive of antagonism at somatodendritic and postsynaptic 5-HT(1A) receptors; and 3) effects on the micturition reflex in anesthetized and conscious rats. These studies also included 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN 190), 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4, 5]decane-7,9-dione dihydrochloride (BMY 7378), and N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl)cyclohex anecarboxamide (WAY 100635). Almost all compounds were found to be potent and selective for the human recombinant 5-HT(1A) receptor, with K(i) values in the nanomolar range. [(35)S]GTPgammaS binding in HeLa cells expressing the recombinant human 5-HT(1A) receptor allowed classification of the compounds into neutral antagonists and partial agonists. Almost all neutral antagonists were active in blocking 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT)-induced forepaw treading in rats (postsynaptic model) and hypothermia in mice (somatodendritic model) with the same potency, whereas compounds showing partial agonistic activity were active in the postsynaptic model but were inactive, or poorly active, in the somatodendritic model. Neutral antagonists potently inhibited volume-induced bladder-voiding contractions in anesthetized rats. Contractions were completely blocked, and the disappearance of bladder contractions lasted 7 to 13 min after the highest doses tested. Furthermore, neutral antagonists increased bladder volume capacity in conscious rats during continuous transvesical cystometry, whereas micturition pressure was only slightly, and not dose-dependently, reduced. Partial agonists were inactive or poorly active, inducing a disappearance time of bladder contractions that did not exceed 6 min in anesthetized rats, and failing to increase bladder volume capacity in conscious rats. These findings indicate that only neutral 5-HT(1A) receptor antagonists are endowed with inhibitory effects on the bladder. (+info)
Renal carbonic anhydrase activity in DBA/2FG-pcy/pcy mice with inherited polycystic kidney disease.
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DBA/2FG-pcy/pcy (D2-pcy) mice are a hereditary murine model of slowly progressive polycystic kidney disease (PKD) and characterized by the persistent excretion of acidic urine, in association with polyuria, after weaning. In this study, the activity of carbonic anhydrase (CA) and it histological distribution in the kidney of D2-pcy mice were investigated by immunohistochemistry. Significantly higher CA activity was detected in the cytosolic, but not membrane, fraction of kidney homogenates in 5-week-old D2-pcy mice than in age-matched, control DBA/2 (D2) mice, and a more rapid rate of urine acidification was noted in 11-week-old mice when acetazolamide, an inhibitor of the enzyme, was administered orally. By immunohistochemistry for the major renal CA isoenzyme (CA II), epithelial cells in the distal straight tubules and the cortical collecting ducts were stained intensely, whereas those of the proximal convoluted tubules had only weak and diffuse staining. The glomeruli, the proximal straight tubules and the ascending thin limb of Henle's loop were almost free from staining. In the cells lining cysts and/or dilated tubules, CA II activity was well preserved, although the staining intensity was considerably reduced in fully-flattened, lining cells of cysts, but no difference was found between D2-pcy and D2 mice in any segmental localization of renal CA II activity. From these results it seems that D2-pcy mice in the early stages of the cystic disease continue to secrete excess protons through the CA-mediated reaction that is stimulated for regulation of acid-base balance in the distal portion of the nephron and the collecting duct in kidney. It also suggests that monitoring urine pH may be useful in predicting the effects of early interventions on the progression of slowly developing renal cysts. (+info)
Measurement of changes in glomerular filtration rate induced by atrial natriuretic peptide in the rat kidney.
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This study was undertaken to improve the measurement of glomerular filtration rate (GFR) during the acute diuretic phase induced by atrial natriuretic peptide (ANP), which may indeed alter the renal clearance of inulin (GFRCL) due to dead space error. A technique to measure GFR without urine collections was therefore developed in anaesthetized rats prepared as for micropuncture. To do so, arterial blood was periodically collected and renal venous blood was withdrawn simultaneously from a catheter inserted into the left suprarenal vein to determine the renal extraction coefficient of inulin (CEIN). In addition, renal blood flow (RBF) was continuously measured with an electromagnetic flow transducer fitted around the left renal artery to estimate renal plasma flow (RPF). GFR (GFRCE) was then calculated as the product of RPF and CEIN. To study the effects of ANP on GFR, rats were injected i.v. with 10 microliters of saline without (n = 6; vehicle) or with 1 microgram ANP (n = 6; ANP) and GFRCE and GFRCL were compared before and after each treatment. They did not differ significantly during baseline measurements in each experimental group and were not modified after vehicle. Similarly, RBF remained constant. In contrast, RBF and GFRCE increased rapidly and simultaneously 90 s after ANP, from 9.07 +/- 0.25 to 10.07 +/- 0.35 (12%) and from 1.209 +/- 0.188 to 1.715 +/- 0.190 ml min-1 (42%), respectively (P < 0.05). GFRCL increased to an even greater extent (88%). Moreover, the peak enhancement of GFRCL was delayed and occurred 180 s after ANP. The renal clearance of inulin was thus unduly elevated due to sudden changes in the dead space induced by the diuretic effect of ANP. In conclusion, determination of glomerular filtration rate by the method of renal extraction of inulin provided more reliable results than those achieved using the classical method of renal clearance of inulin. Moreover, it was sufficiently sensitive to detect small and transient changes in GFR induced by the injection of 1 microgram ANP. (+info)
Effect of capsaicin on the micturition reflex in normal and chronic spinal cord-injured cats.
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The effect of capsaicin (10-80 mg/kg sc) on reflex activity of the urinary bladder was examined in anesthetized normal as well as anesthetized and awake chronic spinal cord-injured (SCI) cats. In normal cats, capsaicin elicited a transient increase in the frequency of isovolumetric bladder contractions and reduced the volume threshold for inducing micturition, but did not depress the amplitude of bladder contractions or the reflex firing on bladder nerves. In anesthetized SCI cats, capsaicin depressed reflex bladder activity and firing on bladder nerves. In awake SCI cats, capsaicin initially decreased the volume threshold for inducing micturition; however, after a delay of 3-6 h the volume threshold increased and intravesical voiding pressure decreased. This effect persisted for 4-12 days. It is concluded that capsaicin-sensitive C fiber bladder afferents are not involved in initiating reflex micturition in normal cats, but play an essential role in triggering automatic micturition in chronic SCI cats. The results are consistent with the clinical data indicating that C fiber bladder afferents contribute to bladder hyperactivity and incontinence in patients with neurogenic bladder dysfunction. (+info)
Preclinical toxicity screening of intrathecal adenosine in rats and dogs.
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BACKGROUND: Intrathecally administered adenosine receptor agonists have antinociceptive effects in animals, suggesting that intrathecal adenosine might provide analgesia in humans. The authors performed preclinical neurotoxicity studies to define the safety of intrathecally administered adenosine in rats and dogs. METHODS: Eighteen rats with long-term intrathecal catheters received daily injections of saline or 100 microg adenosine for 4 days and were observed for general behavior and thermal nociception before being killed on day 6. Nine beagle dogs were prepared with long-term, lumbar intrathecal catheters and infused continuously with saline or adenosine, 2.4 mg/day for 48 h, then 7.2 mg/day for 26 days. Animals were then anesthetized and perfused with preservative and their spinal cords were examined systematically. RESULTS: No disturbances in neurologic function were detected in either animal species. intrathecal adenosine caused transient sedation in rats and increased muscle tone in dogs, resolving with continued exposure to drug. Neither adenosine-nor saline-treated rats or dogs showed acute thermal analgesia. Adenosine groups did not differ from saline groups regarding histopathology, although a moderate fibrotic and inflammatory reaction was noted in both, and protein concentrations in cerebrospinal fluid were increased in both. CONCLUSION: The current study in rats and dogs failed to provide behavioral or histologic evidence of neurotoxicity from intrathecal administration of adenosine. This provides evidence for the presumption of safety of adenosine in this dose range, and supports phase I safety trials of acute intrathecal adenosine administration in humans. (+info)
Preliminary results of pelvic autonomic nerve-preserving surgery combined with intraoperative and postoperative radiation therapy for patients with low rectal cancer.
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BACKGROUND: In Japan, lateral lymphadenectomy was widely performed for patients with stage II-III rectal tumors because it was thought to contribute to good local control, but the pelvic autonomic nerves were thus sacrificed. Although autonomic nerve-sparing surgery with lateral lymph node dissection has been tried from around 1987, the type of nerve sparing varied and the indications were not established. To examine the possibility of expanding the indications for total pelvic autonomic nerve preservation for patients with low rectal cancer, we conducted a pilot study. METHODS: Between 1993 and 1997, a total of 50 patients with low rectal cancer underwent pelvic autonomic nerve preservation with lateral lymphadenectomy of both sides and intraoperative radiation therapy followed by postoperative radiation therapy. RESULTS: The median follow-up period for surviving patients was 41 months. The 3-year local control rates for all patients, with stage I-II and stage III tumors were 88% (95% confidence interval, 78-97%), 97% (90-100%) and 73% (52-94%), respectively. The site of local recurrences was not near or within the preserved plexus. CONCLUSIONS: The preliminary results showed good local control rate for patients with stage I-II tumors. For patients with stage III tumors, the local control rate was unsatisfactory, but nerve sparing was not the cause of local recurrence. Further investigation of function-preserving surgery without decreasing curability is needed. (+info)
Early increases in renal kallikrein secretion on administration of potassium or ATP-sensitive potassium channel blockers in rats.
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1 This study aimed to examine whether administration of potassium or ATP-sensitive potassium channel (KATP channel) blockers caused early increases in renal kallikrein (KK) secretion. To clarify this mechanism, the effect on renal KK secretion of a KATP channel blocker was compared with the effect resulting from use of an osmotic diuretic or volume load. Furthermore, the effect on potassium-induced increases in renal KK secretion by an additional treatment using a KATP channel blocker was examined. Lastly, the effect of a KATP channel blocker on renal KK secretion was also examined in superfused slices of kidney cortex. 2 Intravenous infusion of potassium augmented renal KK secretion within 30 min while urine volume increased gradually in both the potassium loading and control groups. 3 Administration of the KATP channel blocker, 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (PNU-37883A) or glibenclamide, caused a dose-dependent increase in renal KK secretion. 4 The concentration of KK in urine was higher in the PNU-37883A group as compared to the osmotic-diuretic or volume-load group. 5 PNU-37883A had no additive effect on the potassium-induced increase in renal KK secretion. 6 Renal KK secretion increased in slices of kidney cortex incubated with PNU-37883A within 10 min of superfusion. 7 In conclusion, administration of both potassium and KATP channel blockers induced early increases in renal KK secretion in the absence of the washout phenomenon. Potassium loading may have increased renal KK secretion through the same mechanism as the KATP channel blocker. (+info)
Impact of water-induced diuresis on excretion profiles of ethanol, urinary creatinine, and urinary osmolality.
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This article reports the impact of diuresis on urinary excretion of ethanol in seven healthy volunteers who drank 1000 mL of export beer (44 g ethanol) in 30 min and, 120 min later, ingested 500 or 1000 mL of water within 5 min. Urine was voided before drinking started and every 30-60 min for 360 min after the start of drinking. The concentration of ethanol in urine (UAC) was determined by headspace gas chromatography, the creatinine content was determined by Jaffe's method, and osmolality was measured by freezing point depression. Maximum diuresis coincided with the peak UAC and was reached 60-90 min after the end of drinking. The urinary creatinine and osmolality dropped appreciably after drinking beer, and the lowest values coincided with peak diuresis. Creatinine was < 0.2 g/L in 22% of urine specimens, and osmolality was < 200 mOsm/kg in 31% of specimens. Production of urine decreased as UAC entered the postabsorptive phase but increased again after the subjects drank water 120 min after alcohol consumption. The amount of ethanol recovered in urine was 681 mg (standard deviation [SD] 203 mg) corresponding to 1.5% (SD 0.46%) of the dose administered. The concentrations of ethanol in successive voids during the postabsorptive phase were not influenced after subjects drank 500 or 1000 mL of water although diuresis increased and urinary creatinine and osmolality decreased. Measuring UAC provides a reliable way to monitor recent drinking, and unlike the analysis of illicit drugs in urine, the concentrations of ethanol are not influenced by diuresis. (+info)