Effect of ruthenium red on responses mediated by activation of capsaicin-sensitive nerves of the rat urinary bladder

Summary (1) Topical administration of Ruthenium Red (10–100 M in saline) to the serosal surface of the urinary bladder in urethane-anesthetized rats prevented the motor response of the urinary bladder to topical administration of capsaicin and protected the sensory fibers from capsaicin desensitization, but had no effect on the volume-evoked contractions (micturition reflex). At 1 mM increased bladder capacity and decreased amplitude of micturition contraction were observed. (2) At 100 M, topical Ruthenium Red prevented the blood pressure rise produced by topical administration of capsaicin onto the bladder but did not affect the blood pressure rise produced by sudden bladder distension in spinal rats. (3) After intrathecal administration, Ruthenium Red (80–800 ng/rat) produced a long lasting inhibition of the micturition reflex in urethane-anesthetized rats, this effect being evident in both vehicleor capsaicin- (50 mg/kg s. c. 4 days before) pretreated rats. At 800 ng/rat, intrathecal Ruthenium Red did not affect the blood pressure rise produced by topical administration of capsaicin onto the rat bladder nor that produced by bladder distension. (4) These findings provide further evidence that Ruthenium Red acts quite selectively as a capsaicin antagonist preventing both reflex and efferent responses activated by peripherally administered capsaicin. By contrast, sensory impulse generation by a natural stimulus such as bladder distension is apparently unaffected by Ruthenium Red. The marked inhibition of the micturition reflex observed after intrathecal administration of Ruthenium Red does probably not involve an interaction with primary afferents in the spinal cord.     

The differential contractile responses to capsaicin and anandamide in muscle strips isolated from the rat urinary bladder

The contractile responses to capsaicin and anandamide, exogenous and endogenous agonists for transient receptor potential vanilloid receptor 1 (TRPV1), respectively, were investigated in muscle strips isolated from the rat urinary bladder. Capsaicin and anandamide produced concentration-dependent contractions of the muscle strips. The contractile response induced by capsaicin disappeared within approximately 20 min. In contrast, anandamide produced contractile responses lasting at least for 30 min. Capsaicin produced additive contractile responses in anandamide-treated muscle strips. The contractile response to anandamide was attenuated, but not abolished in strips desensitized by capsaicin. The response to capsaicin was abolished in the presence of a TRPV1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chlorphyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC), but not altered in the presence of either tetrodotoxin, atropine or indomethacin. In the presence of SR140333, a tachykinin NK₁ receptor antagonist or SR48968, an NK₂ receptor antagonist, the response to capsaicin was attenuated. The response to anandamide was partially attenuated in the presence of ONO8130, a prostanoid EP₁ receptor antagonist, URB597, a fatty-acid amide hydrolase inhibitor, BCTC, SR140333 or SR48968, and almost completely abolished by indomethacin. Neither tetrodotoxin, atropine, a cannabinoid CB₁ receptor antagonist, AM251, nor a cannabinoid CB₂ receptor antagonist, AM630, had any effect on the response to anandamide. These results indicate that capsaicin produces muscle contractions by stimulating the TRPV1 receptor, followed by release of neuropeptides that can activate tachykinin NK₁ and/or NK₂ receptors in the bladder and that the contractile response to anandamide is mediated at least in part by activation of prostanoid EP₁ receptors due to production of prostaglandins in addition to TRPV1 receptor activation.     

Capsaicin-sensitive afferents in the rat urinary bladder activate a spinal sympathetic cardiovascular reflex

Summary In urethane-anesthetized rats with an intact spinal cord, application of capsaicin on the outer surface of the urinary bladder produced a transient bradycardia, hypotension and negative cardiac inotropism which were neither prevented by i. v. atropine (0.5 mg/kg) nor by cervical vagotomy. In acute spinal rats (C2-C3) application of capsaicin (0.2 and 2 pg in 25 pl) on the urinary bladder induced a transient hypertension, tachycardia and positive cardiac inotropism. A second application (30 min later) induced minor cardiovascular effects, expecially with the higher dose, indicating desensitization. All cardiovascular responses to topical capsaicin were abolished by systemic capsaicin desensitization (50 mg/kg s. c., 4 days before). The excitatory cardiovascular response to capsaicin in acute spinal rats was markedly reduced by bilateral section of pelvic but not hypogastric nerves. Further, it was abolished by pretreatment with hexamethonium (20 mg/kg i.v.) or reserpine (5 mg/kg i. p., 2 days before) and reduced, at various extent for the different components, by phentolamine (0.5 mg/kg i. v.) or propranolol (1 mg/kg). In rats with pelvic and hypogastric nerves intact, section of the cord at a level (T12-L1), just above the medullary segments which receive primary afferent input from the bladder (L6-S1), abolished the excitatory cardiovascular response to application of capsaicin on the bladder. In spinal rats (C2-C3) rapid distension of the urinary bladder with saline produced transient tachycardia, hypertension and positive cardiac inotropism similar to that evoked by capsaicin. These responses were not observed in rats systemically pretreated with capsaicin. These findings indicate that certain bladder afferents which are susceptible to capsaicin desensitization in adult rats activate a spinal reflex having excitatory influence on cardiovascular function. This response is apparently mediated by spinal centers located above the site of entry of bladder pelvic afferents into the cord and most likely involves excitation of preganglionic sympathetic neurons in the spinal cord.Send offprint requests to S. Giuliani at the above address     

Capsaicin-like activity of some natural pungent substances on peripheral endings of visceral primary afferents

Summary 1. The effects of some naturally occurring pungent substances, piperine, mustard oil, eugenol and curcumin, were compared to those of capsaicin in the rat isolated urinary bladder. 2. All test compounds dose-dependently contracted the rat bladder and produced desensitization toward capsaicin (1 mol/l). Development of cross-tachyphylaxis among the natural pungent substances on one hand and capsaicin on the other, suggested a common site of action on visceral primary afferents. 3. Contractile responses to piperine, mustard oil and eugenol were partially tetrodotoxin and ruthenium red-sensitive, suggesting that activation of sensory terminals by these agents takes place indirectly, as well as by a direct action on sensory receptors. 4. The presence of the secondary acylamide linkage (present in the backbone of capsaicin, but not in that of test compounds) does not appear to be essential to produce desensitization of sensory nerve terminals. Send offprint requests to R. Patacchini at the above address     

Reflex activation of the adrenal medulla during hypoglycemia and circulatory dysregulations is regulated by capsaicin-sensitive afferents

Summary 1. Catecholamines were measured in the adrenal venous outflow during hypoglycemia, hypotension, hypovolaemia and efferent splanchnic nerve stimulation in anaesthetized capsaicin-pretreated rats and their vehicle controls. In control rats, efferent splanchnic nerve stimulation caused a marked rise in adrenaline and noradrenaline levels. In contrast, the other stimuli mainly elicited adrenaline release. 2. The release of adrenaline and noradrenaline evoked by splanchnic nerve stimulation was of the same magnitude in capsaicin-pretreated rats (whose afferent C-fibres were destroyed by this pretreatment) as in their untreated controls. 3. Capsaicin-pretreatment of rats resulted, however, in a reduced adrenaline release during insulin-induced hypoglycemia for up to 30 min and, as a consequence, generated a greater fall in blood glucose. The adrenal response to hypoglycemia in the first 30 min was also reduced by bilateral vagotomy indicating the existence of glucoreceptors on peripheral vagal terminals. 4. Adrenaline secretion following central glucopenia induced by 2-deoxy-d-glucose remained unaffected by capsaicin-pretreatment, indicating an intact function of the central regulation of adrenaline release. 5. Hypotension evoked either by sodium nitroprusside or by haemorrhage resulted in a pronounced increase in adrenaline release which was almost absent in the capsaicin-pretreated rats. 6. It is concluded that the stimulation of the adrenal medulla during hypoglycemia, hypotension, and hypovolaemia is based on a reflex mechanism initiated by capsaicin sensitive afferents.This work was supported by the Austrian Scientific Research Funds, grant No. P6646, the Austrian National Bank (grant No. 2811) and the Pain Research Commission of the Austrian Academy of Sciences Send offprint requests to J. Donnerer at the above address     

The effects of oral treatment with transfluthrin on the urothelium of rats and its metabolite, tetrafluorobenzoic acid on urothelial cells in vitro

Transfluthrin, a pyrethroid insecticide, induced urinary bladder tumors in rats but not in mice in 2-year bioassays. We investigated the urothelial effects of transfluthrin in vivo in rats and the effects of its major metabolite tetrafluorobenzoic acid (TFBA) in vitro on rat (MYP3) and human (1T1) urothelial cell lines. Rats were fed diet containing 0, 2000 or 5000 (with and without 1.25% NH₄Cl) ppm transfluthrin for 4 weeks or 0 or 2000 ppm transfluthrin for 13 weeks. After 4 weeks, there was no evidence of hyperplasia or increased proliferation in any treatment group. After 13 weeks treatment with 2000 ppm, cytotoxicity and necrosis of the rat urothelial superficial layer were detected by scanning electron microscopy. The urinary concentration of TFBA in rats fed 2000 ppm transfluthrin was 2.94 ± 0.67 mM. The LC₅₀ of TFBA was 2.25 mM for MYP3 cells and 2.43 mM for 1T1 cells. These studies support cytotoxicity and regenerative proliferation as the mechanism for induction of bladder tumors with high oral doses of transfluthrin due to metabolism of transfluthrin to the weakly cytotoxic TFBA which is excreted at high concentrations in the urine of rats administered high doses of transfluthrin (?2000 ppm) for an extended period.     

Neural circuits controlling cardiorespiratory responses: baroreceptor and somatic afferents in the nucleus tractus solitarius

1. A vast array of peripheral receptors provide the central nervous system (CNS) with sensory signals that coordinate autonomic motor outflow to cardiovascular organs, such as the heart and peripheral vasculature, during locomotion. 2. Much of this sensory input is mediated by cardiovascular receptors located in blood vessels (arterial baroreceptors) and skeletal muscle (skeletal muscle ergoreceptors). 3. Several medullary nuclei are targets for cardiovascular receptors, including the nucleus tractus solitarius (NTS). 4. In the present review, the interaction between arterial baroreceptor and somatosensory receptor afferents in the NTS is examined while placing particular emphasis on the neurochemical and electrophysiological mechanisms involved in processing these signals. 5. Data from anaesthetized animals, as well as from an innovative working heart-brainstem preparation, will illustrate the potential role of GABAergic transmission on baroreceptor signalling in the caudal NTS during locomotion.     

辣椒碱多囊脂质体的制备及在大鼠体内的药动学研究

目的 制备辣椒碱多囊脂质体,并考察其包封率和在大鼠体内的药动学.方法采用复乳法制备辣椒碱多囊脂质体、单因素筛选处方,并考察大鼠sc辣椒碱多囊脂质体后的体内药动学.结果制备的辣椒碱多囊脂质体的外观圆整,大小均匀,包封率为71.9%±3.8%,平均粒径为8.1 μm.大鼠sc辣椒碱多囊脂质体后,与辣椒碱溶液相比,Cmax分...     

Excitatory and inhibitory urinary bladder reflexes induced by stimulation of cervicovaginal capsaicin-sensitive sensory fibers in rats

We have investigated the effect of intravaginal application of capsaicin on micturition reflex in female rats. Urinary bladder contractility was measured by transurethral pressure recording at isovolumetric and subthreshold conditions in anaesthetized rats. The intravaginal application of capsaicin (15 mug/50 mul rat) induced reproducible bladder phasic contractions, without desensitization upon repeated applications, that were blocked by intravenous atropine (1 mg/kg) or hexamethonium (5 mg/kg) and prevented by removal of paracervical ganglia or systemic capsaicin pretreatment (125 mg/kg, s.c.). The inhibition of sympathetic transmission by guanethidine (30 mg/kg, s.c.) produced significant increase of the bladder reflex contractions activated by intravaginal capsaicin. Intravenous administration of the TRPV1 antagonist, capsazepine (3 mg/kg), significantly reduced the excitatory reflex response to capsaicin. Intravaginal administration of capsaicin (15 mug/50 mul), during distension-induced reflex bladder contractions, produced a transient block of reflexes, unaffected by guanethidine pretreatment. In conclusion, the stimulation of capsaicin-sensitive sensory nerve endings in the rat cervix-vagina induced a dual excitatory or inhibitory bladder response in anaesthetized female rats depending on the degree of bladder distension.     

MEN 11,420, a peptide tachykinin NK2 receptor antagonist, reduces motor responses induced by the intravesical administration of capsaicin in vivo

This study investigates the role of tachykinin NK₁ and NK₂ receptors in motor responses induced by the intravesical instillation of capsaicin in urethane-anaesthetized rats. SR 140,333 (1 μmol/kg, i.v.), a non-peptide NK₁ receptor antagonist, abolished urinary bladder contractions induced by the selective NK₁ receptor agonist [Sar⁹]SP-sulfone (0.1-100 nmol/kg, i.v.) without affecting those induced by the NK₂ receptor agonist [?Ala⁸]NKA(4-10). MEN 11,420 (100 nmol/kg, i.v.), a cyclic peptide NK₂ receptor antagonist, abolished bladder contractions induced by [?Ala⁸]NKA(4-10) (0.3-300 nmol/kg, i.v.) without modifying those induced by [Sar⁹]SP-sulfone. Intravesical instillation of capsaicin (6 nmol/0.6 ml/rat) produced a motor response consisting in a primary contraction followed by a series of high amplitude phasic contractions. The intravesical instillation of saline (0.6 ml/rat) produced a primary contraction of lower amplitude with respect to that induced by capsaicin and the total area under the curve was also lower in saline-instilled rats, however the number and the amplitude of phasic contractions was similar to that induced by capsaicin. MEN 11,420 (100 nmol/kg, i.v.) did not modify motor responses induced by the intravesical administration of saline. In contrast, in capsaicin-instilled rats, MEN 11,420 (100 nmol/kg, i.v.) reduced the primary contraction, the area under the curve and also the number of phasic contractions. SR 140,333 (1 μmol/kg, i.v.) reduced the primary contraction but not other parameters. The combination of SR 140,333 (1 μmol/kg, i.v.) and MEN 11,420 (100 nmol/kg, i.v.) produced an additive inhibitory effect on the primary contraction but not a further inhibition on other parameters with respect to that observed with MEN 11,420 alone. In hexamethonium (110 μmol/kg, i.v.)-pretreated animals the intravesical instillation of capsaicin produced a tonic contraction having greater amplitude and area than that induced by saline. MEN 11,420, but not SR 140,333, significantly reduced the bladder response to capsaicin in hexamethonium-pretreated rats. Again, the combined administration of MEN 11,420 and SR 140,333 did not produce further inhibitory effect in comparison to MEN 11,420 alone. It is concluded that the motor responses induced by the intravesical instillation of capsaicin are mediated by the activation of peripheral tachykinin NK₂ receptors. Received: 11 February 1997 / Accepted: 17 April 1997     

Species-related differences in the capsaicin-sensitive innervation of the rat and guinea-pig ureter

Summary 1. Comparison of the tissue content of calcitonin gene-related peptide (CGRP)-immunoreactivity (IR) and tachykinin (TK)-IR in the rat and guinea-pig ureter showed that in the rat tissue levels of CGRP-IR were 33-fold higher than those of TK-IR. In the guinea-pig ureter, both peptides were present in nearly the same concentration. 2. The in-vitro release of neuropeptides from guinea-pig and rat ureters was investigated using capsaicin as a stimulus for afferent neurons. Capsaicin induced the simultaneous release of CGRP-1R and TK-IR from the guinea-pig ureter while in the rat only the release of CGRP-IR was detectable. 3. It is known that TK potently stimulate and CGRP inhibits ureteric smooth muscle contractions. When the effect of capsaicin on ureteric motility was investigated in guinea-pig and rat, only in the guinea-pig ureter a stimulatory action ascribable to capsaicin-induced TK release was observed thus supplementing the results obtained by radioimmunoassay. 4. The results show that considerable species differences exist concerning the ratio of CGRP and TK which is stored and released from ureteric afferent nerve terminals. As a consequence, different functional responses are obtained in both species upon stimulation of these neurons by capsaicin. In the rat ureter, the capsaicin-sensitive innervation seems to be only inhibitory while in the guinea-pig stimulatory and inhibitory transmitters are released. The physiological significance of the simultaneous release of transmitters with opposing effects needs further investigation.Send offprint requests to F. Lembeck at the above address     

Involvement of capsaicin-sensitive neurones in hyperalgesia and enhanced opioid antinociception in inflammation

Summary The effects of capsaicin pretreatment of adult rats was investigated on consequences of unilateral paw inflammation induced by inoculation with Freund's adjuvant. Decrease in mechanical nociceptive threshold in the inflamed paw, as measured by the paw pressure test, was dose-dependently inhibited by capsaicin (20–150 mg/kg s.c.). In control rats, the antinociceptive action of morphine (0.8–1.9 mg/kg s. c.) was greater in the inflamed than in the non-inflamed paw; this difference was absent in capsaicin-treated animals. Increased volume or skin temperature of the inflamed paw was not influenced by capsaicin. It is concluded that capsaicin-sensitive, presumably C-fibre neurones, but not an alteration of the inflammation itself by capsaicin, mediate hyperalgesia and increased morphine antinociception in the rat paw with adjuvant-induced inflammation. Send offprint requests to L. Barthó at the above address     

Effect of sub-chronic endosulfan exposure on humoral and cell-mediated immune responses in albino rats

The present study was designed to evaluate the effect of sub-chronic doses of endosulfan on humoral and cell-mediated immune (CMI) responses in albino rats. Male albino rats were given a diet containing 5, 10 or 20 ppm endosulfan for 8–22 weeks and immunized with tetanus toxoid in Freund's complete adjuvant subcutaneously 20 days before terminating the exposure. The humoral immune response was studied by serum globulin level, immunoglobulin (IgM and IgG) concentration and antibody titre against tetanus toxoid. The CMI response was studied by leucocyte migration inhibition (LMI) and macrophage migration inhibition (MMI) factors. The antigen-induced increases in serum globulin fraction and immunoglobulin level were reduced at high doses of the endosulfan after 12 weeks of exposure. Antibody titre was significantly decreased in endosulfan-exposed rats at 10 and 20 ppm levels and a consistent trend was observed. Rats in the 10 and 20 ppm dose groups had significantly depressed LMI and MMI responses. Results obtained in this study revealed marked suppression of the humoral and CMI responses in rats administered with sub-chronic doses of endosulfan. Both cellular and humoral immune responses were decreased in a dose-time dependent pattern. Suppression of immune responses by endosulfan is clearly an important aspect of its toxicology.     

Role of capsaicin-sensitive afferent neurons in receptive relaxation induced by gastric distension in rats

We investigated the role of capsaicin-sensitive afferent neurons in receptive relaxation of the rat stomach in response to distension. Under urethane anesthesia, a balloon with barostat was inserted through the pylorus and placed in the forestomach. Isobaric distension was performed in a stepwise increment of 2 mmHg, each lasting for 2 min, while the corresponding intragastric volume was recorded. Gastric distension produced the intraballoon volume in a progressive manner with saturation, suggesting the occurrence of receptive relaxation of the stomach during distension. Intragastric application of capsaicin significantly enhanced the degree of receptive relaxation. The capsaicin-induced enhancement of receptive relaxation was totally abolished by bilateral vagotomy as well as chemical ablation of capsaicin-sensitive afferent neurons. Likewise, the enhanced receptive relaxation in response to stomach distension was also significantly attenuated by pretreatment of the animals with N^G-nitro-L-arginine methyl ester (L-NAME, an inhibitor of nitric oxide (NO) synthase), calcitonin gene related peptide (CGRP)_8-37 (CGRP antagonist), indomethacin and ONO-8711 (EP1 receptor antagonist). These results suggest that capsaicin significantly enhanced the receptive relaxation induced by gastric distention through both vagal nerves and capsaicin-sensitive afferent neurons. This process is intervened by endogenous NO and CGRP in addition to prostaglandins (PGs), and the effect of PGs may be mediated by EP1 receptors. Received 9 October 2006; accepted 10 November 2006     

Desensitization of capsaicin-evoked neuropeptide release — Influence of Ca2+ and temperature

Summary Capsaicin-induced stimulation and desensitization of neuropeptide release from primary afferent neurons was investigated in the rat urinary bladder in-vitro. The capsaicin (5 min contact time)-evoked release of calcitonin gene-related peptide-like immunoreactivity (CGRP-IR) was dose-dependent; threshold to produce detectable release was 0.1 μmol/l, the EC₅₀ was 0.17 μmol/l. Pre-exposure of tissues to capsaicin (0.1–1.0 μmol/l, 5 min contact time) caused a dose-dependent reduction of the amount of CGRP-IR which was released by a second exposure to capsaicin. At 0.1 and 0.3 μmol/l, capsaicin was less effective to inhibit the subsequent K⁺-evoked release than that evoked by a second capsaicin exposure. Pre-exposure to 1 μmol/l capsaicin completely prevented subsequent K⁺- or capsaicin-evoked release of CGRP-IR. Exposure of the preparation to capsaicin (0.3μmol/l) in a Ca²⁺-free, EDTA-containing medium did not produce release of CGRP-IR. A subsequent stimulation with capsaicin in a 2.5 mmol/l Ca²⁺-containing superfusion solution was not less effective to release CGRP-IR than in tissues which had not been pre-exposed to capsaicin. At 18°C, the capsaicin-evoked release of CGRP-IR was reduced to 20% of the value obtained by the same dose (0.3 μmol/l for 5 min) of capsaicin at 37°C. Comparison of the desensitizing effect of 0.3 and 0.1 μmol/l capsaicin at 18°C and 37°C, respectively, showed significant inhibition of desensitization at 18°C. Inhibition of desensitization was also observed when the amount of CGRP-IR, which was released during preexposure to capsaicin (0.3 μmol/l for 10 min) at 18°C, was 3-fold higher than that produced by pre-exposure to capsaicin (0.1 μmol/l for 5 min) at 37°C. The present results show that in a narrow range of concentrations, capsaicin induces “selective” desensitization which is entirely dependent on the presence of external Ca²⁺ — and which is attenuated at low temperature.     

Effect of colchicine on micturition reflex in rats

Intracerebral or intraspinal cord, but not intraperitoneal, injection of low doses of colchicine in rats induces specific toxic symptoms. This paper deals in particular with the effect of colchicine on micturition. After the injection of 5–25 μg/rat in cerebral ventricle or 2.5–20 μg/rat intraspinal cord, bladder content was markedly increased, due to a dramatic urine retention. Time of latency of vesical retention was related to the dose and to the route of colchicine administration. Cystometrographic analyses were performed in control and treated rats at various intervals of time after the injection: bladder tone, as expressed by the ΔP/ΔV ratio, monitored from 12 to 120 hr after colchicine injection, decreased more and more during time, suggesting that the observed vesical hypotonicity is an irreversible phenomenon.     

Pharmacologic responses of the mouse urinary bladder

The aim of the study was to determine pathways involved in contraction and relaxation of the mouse urinary bladder. Mouse bladder strips were set up in gassed Krebs-bicarbonate solution and responses to various drugs and electrical field stimulation were obtained. Isoprenaline (b-receptor agonist) caused a 63% inhibition of carbachol precontracted detrusor (EC50=2nM). Carbachol caused contraction (EC50=0.3μM), responses were antagonised more potently by 4-DAMP (M3-antagonist) than methoctramine (M2-antagonist). Electrical field stimulation caused contraction, which was inhibited by atropine (60%) and less by guanethidine and α,β-methylene-ATP. The neurogenic responses were not potentiated by inhibition of nitric oxide synthase. Presence of an intact urothelium significantly depressed responses to carbachol (p=0.02) and addition of indomethacin and L-NNA to remove prostaglandin and nitric oxide production respectively did not prevent the inhibitory effect of the urothelium. In conclusion, b-receptor agonists cause relaxation and muscarinic agonists cause contraction via the M3-receptor. Acetylcholine is the main neurotransmitter causing contraction while nitric oxide has a minor role. The mouse and human urothelium are similar in releasing a factor that inhibits contraction of the detrusor muscle which is unidentified but is not nitric oxide or a prostaglandin. Therefore, the mouse may be used as a model to study the lower urinary tract.     

Morphine and electroacupuncture: Comparison of the effects on the cortical evoked responses after tooth pulp stimulation in rats

The effects of morphine and electroacupuncture on the cortical evoked responses after tooth pulp stimulation were investigated in rats. Morphine suppressed these responses more strongly in secondary somatosensory areas than those in primary somatosensory areas, while electroacupuncture suppressed the response to the same degree in both areas. These results might suggest that there are some differences in noxious-suppressive action between morphine and the endogenous opiates released by electroacupuncture stimulation.     

Vasopressor and heart rate responses to systemic administration of bombesin in anesthetized rats

The aim of the present study was to investigate the effects of aortic depressor nerve (ADN) transection, supranodosal vagi denervation (NG vagi cut) and adrenergic receptor blocker treatment on the cardiovascular responses evoked by systemic injection of bombesin. The cardiovascular effects were studied in spontaneously breathing rats that were (i) bilaterally, midcervically vagotomized (MC vagi cut) and subjected to section of the aortic depressor nerves, (ii) midcervically vagotomized and subsequently vagotomized at the supranodosal level or (iii) midcervically vagotomized before and after pharmacological blockade of α- or β-adrenergic receptors with phentolamine and propranolol, respectively. An intravenous bolus of bombesin (10 μg/kg) in midcervically vagotomized and ADN denervated animals increased mean arterial blood pressure (MAP) and heart rate (HR). An approximate 20% increase in blood pressure occurred immediately following bombesin injection and lasted for 2-3 min. Augmentation of the heart rate occurred 30-60 s after the bombesin challenge and persisted for more than 10 min. After section of the supranodosal vagi, bombesin failed to induce an increase in heart rate. Blockade of α-adrenergic receptors with an intravenous dose of phentolamine significantly reduced post-bombesin hypertension. These results indicate that bombesin-evoked increases in blood pressure do not require aortic depressor nerves and supranodosal vagi and are presumably mediated by the activation of peripheral α-adrenergic receptors. Bombesin-induced tachycardia was dependent on an intact supranodose pathway and was amplified by activation of β-adrenoceptors.     

Capsaicin-sensitive afferents and blood pressure regulation during pentobarbital anaesthesia in the rat

Summary (1) Maintenance of blood pressure was investigated during induction of pentobarbital anaesthesia in rats after elimination of capsaicin-sensitive afferent neurons (capsaicin-denervated rats) as compared to vehicle-treated controls. The catecholamine content of heart and adrenals and the rise in blood pressure following electrical excitation of the spinal adrenergic nerves (pithed rat preparation) was also compared between both groups. (2) Capsaicin-denervated rats and their controls had equal amounts of catecholamines in heart and adrenals as well as equal pressor responses to electrical stimulation of spinal sympathetic nerves, thus excluding an influence of capsaicin on efferent pathways. In the state of consciousness, both groups showed the same blood pressure. (3) In capsaicin-denervated rats and in their controls, pentobarbital-induced anaesthesia (50 mg/kg i.p.) was characterized by a decline in blood pressure during the first 6 min. In the controls, this fall in blood pressure was followed by a slow compensatory rise to a level slightly higher than before anaesthesia, and this level was maintained during the following 60 min. This compensation was completely absent in capsaicin-denervated rats, indicating a role for capsaicin-sensitive nerves in this mechanism. An injection of pentobarbital (50 mg/kg i.p.) in pithed rats reduced the pressor response to electrical stimulation of spinal sympathetic nerves by about 40% in capsaicin-denervated rats and in their controls. This inhibitory effect of pentobarbital might be involved in the initial fall in blood pressure in intact animals. (4) The blood pressure which had reached a steady level 20 min after induction of the pentobarbital anaesthesia in intact rats responded to various factors as follows: (A) Bilateral adrenalectomy hardly decreased the blood pressure in the controls and not at all in the capsaicin-denervated rats; thus a substantial influence of the adrenals in the maintenance of blood pressure was excluded. (B) a-Adrenoceptor blockade by phentolamine caused a greater fall of blood pressure in the controls than in the capsaicin-denervated rats; the latter seem therefore under a much lower peripheral adrenergic vasoconstrictor tone. (C) Blockade of the angiotensin-converting enzyme by captopril had a more pronounced and persistent depressor effect in the capsaicin-denervated rats than in the controls; this indicates that the capsaicin-denervated rats have an increased dependence on an angiotensin II-mediated blood pressure regulation. (D) Sodium nitroprusside caused an equally pronounced fall in blood pressure in both groups; its vasodilatory potency thus seems to overrun all other compensatory reflex regulations. It is concluded that the continuous blood pressure regulation under pentobarbital anaesthesia depends upon signals conveyed to the central nervous system via capsaicin-sensitive afferent neurons which activate efferent adrenergic mechanisms. These regulations are regarded supplementary or auxiliary to the baro-and chemoreceptor reflexes. Send offprint requests to F. Lembeck at the above address