Effects of capsaicin in rat and pigeon on peripheral nerves containing substance P and calcitonin gene-related peptide

Summary Substance P and calcitonin gene-related peptide were immunohistochemically identified in axons innervating the cornea and the ureter of adult rats and pigeons. The two neuropeptides were similarly distributed in both species. Capsaicin pretreatment induced depletion of the immunoreactivity; this was quantitatively and qualitatively different in rats and pigeons. Topical application of capsaicin (1%) reduced the immunoreactivity in the cornea in both species by 50%. Systemic capsaicin treatment completely depleted both peptides from the corneal innervation of rats but reduced the peptide content only by 50% in the cornea of pigeons. In the ureter of rats, capsaicin pretreatment completely depleted the peptide immunoreactivity. In pigeons the peptide depletion was only complete in the outer longitudinal muscle layer. Whereas only a few immunoreactive fibres were observed in the circular muscle layer, about 50% of the peptide remained in the inner longitudinal muscle layer. The results demonstrate that peptidergic afferents in the cornea and ureter of pigeons are sensitive to capsaicin, although birds do not show nociceptive responses to local administration of the drug. The long-term depletion of substance P and calcitonin gene-related peptide by capsaicin is discussed with regard to the possibility that functionally capsaicin receptors may exist in the axon but not at nerve endings.Part of the thesis of Gerhard Harti, to be presented to the Fachbereich Biologie, Justus-Liebig-Universität, Giessen     

Neonatal capsaicin treatment alters basal pulmonary mechanics and response to methacholine in F344 rats.

Full methacholine dose-response curves were performed on anesthetized tracheostomized Fischer 344 adult rats treated neonatally with capsaicin (50 mg/kg) or with vehicle alone. Capsaicin, the hot extract of pepper, releases substance P (SP) from nonmyelinated sensory nerve endings and causes acute bronchoconstriction and airway microvascular leakiness. Chronic treatment with capsaicin leads to depletion of SP and other tachykinins from afferent C-fibers and can therefore be used as a tool to investigate the contribution of SP innervation to airway responses. The rats (9 controls and 6 treated with capsaicin) were paralyzed with succinylcholine and mechanically ventilated at a constant tidal volume and frequency. Airway resistance (RL) and dynamic compliance (Cdyn) were determined at each dose of methacholine from measurements of volume, flow, and transpulmonary pressure. Capsaicin-treated rats were found to have a significantly reduced baseline RL [0.150 +/- 0.039 (SD) vs. 0.225 +/- 0.050 cmH2O.ml-1.s, P = 0.009] and a correspondingly significantly elevated Cdyn (0.371 +/- 0.084 vs. 0.268 +/- 0.053 ml/cmH2O, P = 0.012). There was no significant difference in sensitivity to methacholine, but the maximal response to methacholine was significantly greater in the capsaicin-treated rats. In terms of RL, the maximal response for capsaicin-treated rats was 6.03 x baseline +/- 0.98 vs. 4.30 x baseline +/- 1.80 (P = 0.05) for controls, and for Cdyn changes the maximal decrease was 5.75 x baseline +/- 1.22 vs. 3.83 +/- 0.69 (P = 0.002). The observed differences in RL and Cdyn coupled with the differences in maximal responses can be attributed to the selective destruction of a subpopulation of pulmonary afferent C-fibers.(ABSTRACT TRUNCATED AT 250 WORDS)     

Capsaicin Does Not Change Tissue Levels of Glutamic Acid, Its Uptake, or Release in the Rat Spinal Cord

Capsaicin treatment (50 mg/kg, subcutaneous) of newborn rats resulted in 1 75% decrease of substance P immunoreactivity in the dorsal spinal cord of the adult animal, but failed to affect levels of the proposed sensory neurotransmitter glutamic acid or to alter high-affinity uptake of [3H]glutamic acid into synaptosomes of the same tissue. Furthermore, capsaicin (30 microM) in vitro had no influence on the release of [3H]glutamic acid from spinal cord P2 fractions of untreated adult rats, but induced a marked release of substance P. The results suggest that, in contrast to substance P fibers, neurons containing glutamic acid are not sensitive to capsaicin. Eleven other neurochemical parameters measured in the spinal cord did not appear to be changed by the treatment with capsaicin, suggesting a considerable neurochemical selectivity of the lesion.     

Regulatory peptide and serotonin content and brush-border enzyme activity in the rat gastrointestinal tract following neonatal treatment with capsaicin; lack of effect on epithelial markers.

The possible trophic influence of the capsaicin-sensitive extrinsic innervation of the gastrointestinal mucosa was investigated. Rats were treated neonatally with capsaicin. The gastrointestinal content of serotonin and glucagon-like immunoreactivity were used as a measure of the effect on the endocrine gut mucosa and gastrointestinal aminopeptidase and alkaline phosphatase activities were used as a measure of the effect on the gut brush-border. The gastrointestinal content of the neuropeptides substance P, VIP and CGRP were used to monitor effects on the innervation of the gut. The depletion of substance P-immunoreactivity(-IR) and calcitonin gene-related peptide(CGRP)-IR in extracts of urinary bladder and lung from the capsaicin-treated rats is evidence of the efficacy of capsaicin treatment in affecting a loss of C-fibre sensory nerves. The significant depletion of CGRP-IR measured in the stomach and duodenum of capsaicin-treated rats indicated the loss of the C-fibre sensory innervation to the gastrointestinal tract. The gastrointestinal content of VIP and substance P, which are predominantly within intrinsic gut neurones, were unaffected by capsaicin treatment. In all regions of the gastrointestinal tract of capsaicin-treated rats, the serotonin and glucagon-IR levels were not significantly different from those in controls. Similarly the levels of activity of the brush-border enzymes were not significantly effected by capsaicin treatment. This suggest the absence of any major trophic influence of capsaicin-sensitive sensory nerves on the gut endocrine mucosa and the brush border.     

Experimental colitis decreases rat jejunal amino acid absorption: role of capsaicin sensitive primary afferents.

Ulcerative colitis and experimental colitis are known to be associated with functional and structural abnormalities of the small intestine. The aim of this study was to determine whether experimental colitis in the rat has any effect on jejunal amino acid absorption and to investigate the neural mechanisms involved. In Sprague Dawley rats, colitis was induced by intracolonic administration of 0.1 ml of 6% iodoacetamide. Alanine absorption in the jejunum was measured using the single pass intraluminal perfusion technique in vivo and the three-compartment model in vitro. Experiments were done in normal and sham treated rats, as well as in rats that underwent neonatal capsaicin treatment, adult capsaicin treatment, or subdiaphragmatic vagotomy. Colitis was more severe in rats subjected to neonatal or adult capsaicin treatment, but was not affected by subdiaphragmatic vagotomy. In rats with colitis, jejunal alanine absorption was reduced by 2% (P>0.05), 28%, 40%, and 18% (P<0.001) at 1, 1.5, 2, and 3 days post rectal iodoacetamide administration. A rebound increase of 12% above baseline was noted at 4 days (P<0.05). Similar results were noted in vitro. In rats that received two consecutive injections of iodoacetamide, the decrease in jejunal alanine absorption occurred earlier, was more severe, and persisted for more than 30 days. Neonatal as well as adult capsaicin treatment aggravated both the colitis and the decrease in jejunal alanine absorption. On the other hand, subdiaphragmatic vagotomy attenuated the decrease in jejunal alanine absorption, but had no significant effect on colitis severity. It is concluded that iodoacetamide induced colitis impairs jejunal amino acid absorption and that this effect involves vagal efferents as well as capsaicin sensitive primary afferents.     

Aging reduces the GABA-dependent 36Cl- flux in rat brain membrane vesicles

The function of the chloride channel associated to GABAA receptor complex was analyzed in the brain of aged rats by measuring the chloride flux across the neuronal membrane and its modulation by drugs acting at the level of the GABA receptor complex and 35S-TBPS binding. The basal 36Cl- uptake by brain membrane vesicles of aged rats was higher (22%) than that observed in those of adult rats. The higher 36Cl- uptake found in cortical membrane vesicles of senescent rats was not sensitive to the action of bicuculline indicating that it was not the consequence of a tonic GABAergic modulation. Moreover, the stimulation of 36Cl- uptake induced by GABA was markedly lower in membrane vesicles of aged rats than that observed in those of adult rats. Accordingly, the stimulation of 36Cl- efflux elicited by GABA (18%) and pentobarbital (26%) was higher in membrane vesicles of adult rats with respect to that (8 and 16%, respectively) of old rats. Finally, a significant decrease of 35S-TBPS binding was observed in membrane preparation from the cerebral cortex, cerebellum and hippocampus of aged-rats. Scatchard plot analysis indicated that the decrease was entirely due to a reduction in the total number of binding sites with no change in their affinity. All together the results indicate that in the rat brain the function of the chloride channel coupled to the GABA/benzodiazepine/barbiturate receptor complex is reduced by aging.     

Abrogation of peripheral cholecystokinin-satiety in the capsaicin treated rat

Cholecystokinin (CCK) is a peripheral and central mediator of short-term satiety. When given i.p., CCK decreases food intake in previously fasted rats for a period of 30 min. The effect has been previously shown to be abolished by vagotomy and more specifically by severing of vagal sensory rootlets. These studies were designed to determine the effects on rat feeding behavior, and in particular CCK-satiety, of the sensory neurotoxin capsaicin. In neonates, capsaicin selectively and permanently destroys unmyelinated sensory fibers including those in the vagus nerve. Rat neonates were treated with capsaicin, 50 mg/kg or vehicle, and surviving females studied at 8-10 weeks of age. The weights, 24-h food intake, and feeding responses to insulin were the same in adult capsaicin treated (Cap Rx) and vehicle treated (Veh Rx) rats. CCK (8 micrograms/kg i.p.) reduced 30 min food intake 61 +/- 18% in Veh Rx animals (mean +/- S.D., P less than 0.01). In capsaicin denervated animals, CCK also significantly reduced 30 min food intake from 5.09 +/- 1.10 to 3.92 +/- 0.84 g (P less than 0.01), but the mean reduction, 23 +/- 6%, was significantly less than in Veh Rx rats (P less than 10(-4]. A separate group of females, similarly treated as neonates with capsaicin or vehicle, were subjected to bilateral lesioning of the ventromedial hypothalamus. Both Cap Rx and Veh Rx animals gained significantly and equally more than non-lesioned controls. 24 h vagal transport of substance P was reduced 70% in age matched capsaicin treated animals compared to controls. These studies demonstrate that peripheral CCK-satiety is partly mediated by capsaicin sensitive fibers, presumably in the vagus nerve. Substance P is one possible transmitter mediating this reflex. Further conclusions are that active inhibition of an intact peripheral CCK-stimulated reflex arc is not necessary for full expression of central inducers of feeding, e.g., insulin or lesioning of the ventromedial hypothalamus, and that destruction of these fibers does not alter long-term weight regulation in rats receiving a normal diet.     

Mechanisms of depletion of substance P by capsaicin

Capsaicin is a neurotoxin that can deplete sensory nerves of their content of substance P and interfere with certain sensory functions, such as responses of animals to noxious heat stimuli. In adult guinea pigs, a species that is susceptible to the effects of capsaicin on both substance P content and sensory function, capsaicin induces selective depletion of substance P from dorsal root ganglia and the dorsal spinal cord, sites of the cell bodies and central terminals of primary afferent neurons, respectively. As the onset of thermal analgesia in guinea pigs precedes depletion of substance P, direct neural actions of capsaicin probably account for its effects on sensory function. Capsaicin interferes with the retrograde transport of nerve growth factor (NGF) to the cell bodies of sensory nerves. Decreased availability of NGF at the site of neural protein synthesis leads to decreased synthesis of substance P. After failure of synthesis of substance P, the content of the peptide in sensory nerves gradually decreases until depletion occurs.     

Effect of castration and testosterone administration on the neuromuscular junction in the levator ani muscle of the rat

Summary The ultrastructure of the neuromuscular junction (n.m.j.) of the androgen-sensitive levator ani muscle was studied in normal adult male rats, in 8-month-old rats castrated at the age of one month and in castrated rats treated with testosterone propionate (TP). Castration does not result in significant changes of the n.m.j. The density of synaptic vesicles and the postsynaptic junctional folds remain practically normal in spite of marked atrophy of the muscle. TP administration for 7 days results in marked changes in preand postsynaptic structures. There is slow progressive depletion of synaptic vesicles, appearance of cisternae and coated vesicles in axon terminals, and coalescence of coated vesicles with the plasma membrane. Coated vesicles are also found inside Schwann cells and among junctional folds. Dense core vesicles appear both in the axon terminals and in the postsynaptic area. Collateral sprouting of terminal axons with the formation of new immature junctions is observed. After 35 days of TP administration depletion of synaptic vesicles continues. Glycogen -particles, mostly freely dispersed, occasionally seen in axon terminals 7 days after TP administration, subsequently increase in number. In the endplate zone of the muscle fibre increased protein synthesis is indicated by a rapid increase in ribosomes and irregularly located myofilaments and myofibrils. The appearance of n.m.j. after testosterone administration resembles that described after nerve stimulation; the degree of change is however less pronounced.The authors wish to acknowledge the skillful technical assistance of Mrs. L. Vedralová     

Role of capsaicin-sensitive nerve fibers in uterine contractility in the rat

The possible participation of capsaicin-sensitive sensory nerves in the modulation of neurogenic contractions was studied in nonpregnant and term pregnant rat uteri. Neurogenic contractions were elicited by electric field stimulation (40 V, 1-70 Hz, 0.6 msec) in intact uteri and uteri that were previously exposed to capsaicin in vitro. In capsaicin pretreated preparations obtained both from nonpregnant and term pregnant rats, a dose-dependent increase in the amplitude of uterine contractions was detected. Prior systemic treatment of the rats with capsaicin (130 mg/kg, s.c.) abolished the effect of in vitro capsaicin administration on the amplitude of neurogenic contractions. Use of a specific antagonist of calcitonin gene-related peptide revealed that depletion of this peptide, which normally elicits uterine smooth muscle relaxation, may be responsible for the increased responsiveness of the uterus to low-frequency stimulation. Experiments on the localization of calcitonin gene-related peptide in uterine tissue specimens exposed to capsaicin revealed dose-dependent depletion of calcitonin-gene related peptide-immunoreactive nerves innervating blood vessels and the myometrium. The findings indicate that capsaicin-sensitive afferent nerves, by the release of sensory neuropeptides, significantly contribute to the modulation of uterine contractility both in nonpregnant and term pregnant rats. It is suggested that uterine sensory nerve activation may be part of a trigger mechanism leading to preterm contractions evoked by, for example, inflammation.     

Ultrastructural changes in the neurohypophysis of the aged male rat

Summary The neurohypophyses (neural lobes of the pituitary) of young adult (3–6 months) and aged (12–30 months) male rats were studied by means of electron microscopy. Stereomorphometric analyses were performed to determine the size, number and relative volume of the hormone-containing vesicles. The principal observations included: 1) the conspicuous depletion in aged rats of the granular hormone-containing vesicles from the axon terminals and the Herring bodies, with a decrease in the relative volume fraction of the vesicles from 4.8 Vv % in the control animals to 1.1 Vv % in the aged rats; 2) a change in the size-distribution of the hormone vesicles; 3) an increase in the extracellular space around the nerve terminals, axons and capillaries; and 4) lipid accumulations and signs of activation in the pituicytes. The possible physiological significance of the findings is discussed in the light of several regulatory functions known to be altered during the process of ageing.     

Resorptive clearance and transepithelial potential difference in capsaicin-treated F344 rats.

The long-term effects of substance P (SP) depletion on epithelial integrity were assessed by measurements of airway transepithelial potential difference (PD) and resorptive clearance. Both techniques are highly sensitive to differences in epithelial permeability. PD (mV) was assayed with a KCl-saturated agar bridge technique in the lower trachea of Fischer 344 rats depleted of SP by neonatal capsaicin treatment. Capsaicin treatment is known to ablate a subpopulation of primary afferent fibers containing SP. Resorptive clearance (clearance in 1 h) was measured with 99mTc-labeled diethylenetriaminepentaacetic acid administered as a 100-microliters (100 microCi) bolus. Depletion of SP by neonatal treatment with capsaicin resulted in a highly significant increase in resorptive clearance (P less than 0.001). There was also a significant difference in PD in the lower trachea, the values being less negative for the capsaicin-treated rats (P less than 0.005). The increase in resorptive clearance may reflect the leakiness of the epithelial membrane, as also suggested by the decrease in PD. Aside from its known involvement as a neurotransmitter in neurogenic inflammation, SP may, under normal physiological conditions, have an additional role in the maintenance of epithelial barrier function.     

Distribution of calcitonin gene-related peptide-like immunoreactivity in various rat tissues: correlation with substance P and other tachykinins and sensitivity to capsaicin

Calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) has been measured in various tissues of control rats and rats pretreated with systemic capsaicin, s.c. (50 mg/kg as newborns or as adults, 125 mg/kg as adults) and compared with the tissue level of substance P- and tachykinin-like immunoreactivities (SP-LI and TK-LI). The rank order of CGRP-LI concentration in various tissues was as follows: trigeminal ganglion greater than urinary bladder greater than ureter much greater than distal duodenum much greater than proximal duodenum much greater than skin (snout) greater than thymus = right atrium = vas deferens. A complete depletion of CGRP-LI following capsaicin treatment of both adult and newborn animals was observed in urinary bladder, ureter, atrium, vas deferens and skin. Capsaicin pretreatment of both adult and newborn rats reduced CGRP-LI in the duodenum by about 50%. CGRP-LI in trigeminal ganglion was reduced only in newborn animals, while it was not affected in the thymus. The CGRP-LI/SO-LI ratio varied in these tissues between 33.2 (urinary bladder) and 0.9 (proximal duodenum). A significant correlation was found between CGRP-LI and SP-LI or TK-LI in tissues where immunoreactivities were depleted by capsaicin, as well as in the urinary bladder of individual animals. The correlation between CGRP-LI with SP-LI and TK-LI upon treatment with capsaicin indicates that neurons containing SP and TK as well as CGRP, and neurons containing CGRP only, are affected in a similar manner by capsaicin.     

Effects of stimulation and damage of afferent nerves on the glucose and free fatty acid levels in the rat blood under various glycemic conditions

Capsaicin stimulation of afferent neurones increased hyperglycaemic responses to glucose and decreased hypoglycaemia in control rats. Elevation of the free fatty acids level occurred following both the stimulation alone and that combined with insulin. Neonatal capsaicin pre-treatment decreased the hypoglycaemic response effect of insulin and the FFA level. Treatment of adult rats with capsaicin did not affect hypoglycaemia following insulin administration but did decrease the FFA level. In capsaicin pre-treated rats, the capsaicin stimulation exerted no effect upon the hypoglycaemia following insulin administration but abolished the insulin effect on the FFA level. The findings suggest that the capsaicin-sensitive nerves play a major role in mediating the glucose and the FFA metabolic responses.     

Ventilatory responses to hypoxia and hypercapnia in awake rats pretreated with capsaicin.

Ventilatory responses to hypoxia and hypercapnia were measured by indirect plethysmography in unanesthetized unrestrained adult rats injected neonatally with capsaicin (50 mg/kg) or vehicle. Such capsaicin treatment ablates a subpopulation of primary afferent fibers containing substance P and various other neuropeptides. Ventilation was measured while the rats breathed air, 12% O2 in N2, 8% O2 in N2, 5% CO2 in O2, or 8% CO2 in O2. Neonatal treatment with capsaicin caused marked alterations in both the magnitude and composition of the hypoxic but not hypercapnic ventilatory response. The increase in minute ventilation evoked by hypoxia in the vehicle-treated rats resulted entirely from an increase in respiratory frequency. In the capsaicin-treated rats the hypoxic ventilatory response was significantly reduced owing to an attenuation of the frequency response. Although both groups responded to hypoxia with a shortening in inspiratory and expiratory times, rats treated with capsaicin displayed less shortening of both respiratory phases. By contrast, hypercapnia induced a brisk ventilatory response in the capsaicin-treated group that was similar in magnitude and pattern to that observed in the vehicle-treated group. Analysis of the components of the hypercapnic ventilatory responses revealed no significant differences between the two groups. We, therefore, conclude that neuropeptide-containing C-fibers are essential for the tachypnic component of the ventilatory response to hypoxia but not hypercapnia.     

Neuroparalytic keratitis and capsaicin

Subcutaneous injection of 50 mg/kg capsaicin to newborn rats resulted in a marked decrease of heat pain sensitivity and neurogenic inflammation. There was, however, no significant difference between capsaicin-pretreated and control rats in the severity of neuroparalytic keratitis after surgical deafferentation of the eye. Retrobulbar injection of 100 microliters of 0.5% capsaicin produced keratitis-like corneal changes. These changes were not prevented by previous pretreatment with a total subcutaneous dose of 200 mg/kg capsaicin. The findings indicate that corneal changes after deafferentation are not due to excessive release of substance P and other neuropeptides from the degenerating afferent fibres.     

The role of vagal afferents and carbon dioxide in the respiratory response to thyrotropin-releasing hormone

Rats treated neonatally with pargyline and 5,7-dihydroxytryptamine to decrease central serotonin-containing neurons have an accentuated respiratory response to i.c.v. thyrotropin-releasing hormone (TRH). Since these treated rats also evidence an elevated PaCO2, we sought to evaluate the importance of CO2 in determining the magnitude of the respiratory response to TRH. Neonatal treatment with capsaicin or acute vagotomy also produced adult animals whose basal PaCO2 was elevated and whose respiratory response to TRH was greater than that seen in control rats with lower PaCO2 values. In normal rats, however, administration of CO2 immediately before and after TRH administration does not alter the subsequent response to TRH. Thus, it appears that TRH facilitates the processing of CO2-dependent afferent impulses, and that CO2 does not alter disposition or pharmacokinetics of TRH.     

Changes in morphology and in polyphosphoinositide turnover of human erythrocytes after cholesterol depletion

Human erythrocytes were cholesterol-depleted (5-25%) by incubation with phosphatidylcholine vesicles in media containing Ca2+ at different concentrations (0, 28 nM, 5 microM or 1 mM). After removal of the vesicles, the cells were reincubated with [32P]phosphate in the same media. Control (incubated in buffer alone) and cholesterol-maintained erythrocytes (incubated with cholesterol/phosphatidylcholine vesicles) were treated similarly. Cholesterol depletion induced the conversion of the cells into stomatocytes III and spherostomatocytes and decreased the turnover rate of phosphatidylinositol phosphate and of phosphatidylinositol bisphosphate. None of these effects were observed in cholesterol-maintained cells. In cholesterol-depleted cells, they occurred without changes in the ATP specific activity or in the polyphosphoinositide concentrations. Moreover, these modifications of shape and of lipid metabolism were proportional to the extent of the cholesterol depletion and were independent of the external Ca2+ concentration. In contrast, other effects of cholesterol depletion, a decrease in the turnover rate of phosphatidic acid, a decrease in diacylglycerol and in phosphatidic acid concentrations were dependent on the external Ca2+ concentration. Thus it appears that the shape change was not correlated with a change in the concentrations of these phospholipids or of diacylglycerol and therefore cannot be explained by a bilayer couple mechanism involving these phospholipids. However, the spherostomatocytic transformation was correlated with the decrease in the turnover rate of the polyphosphoinositides, but not with the turnover rate of phosphatidic acid, suggesting a role for the turnover of the polyphosphoinositides in the maintenance of the erythrocyte shape.     

Effects of hexavalent chromium on reproductive functions of male adult rats

Hexavalent chromium is an environmental contaminant which may be associated with reproductive abnormalities in male rats. In the present study, we examined the effect of hexavalent chromium on male reproductive function of rats. Male Wistar rats received a daily intraperitoneal injection of potassium dichromate (1 or 2 mg/kg body weight) for fifteen consecutive days. A decrease in testis weight and an increase in seminal vesicles and prostate weights were demonstrated after chromium treatment. Moreover, a dose-dependent increase in blood and testis chromium levels as well as an increase in FSH and a decrease in LH and testosterone serum levels were detected in treated rats. Histological analysis revealed pronounced morphological alterations with enlarged intracellular spaces, tissue loosening and dramatic loss of gametes in the lumen of the seminiferous tubules of treated rats. In addition, a decreased sperm motility and number of epididymal spermatozoa together with an increased sperm abnormality rate was found in chromium-treated rats in comparison to controls. In rats receiving the higher chromium dose, histological images presented considerably increased areas filled with seminal vesicle and prostate secretions. The mucosal crypts of seminal vesicles and the typical invaginations of prostate were altered. The results suggest that subacute treatment of potassium dichromate promotes reproductive system toxicity and affects testicular function of adult male rats.     

Capsaicin pre- and post-treatment on rat monocrotaline pneumotoxicity

Monocrotaline (MCT) produces respiratory dysfunction, pulmonary hypertension (PH), and right ventricular hypertrophy (RVH) in rats. Tachykinins, such as substance P (SP) and neurokinin A (NKA), may mediate these effects. The purpose of this study was to investigate the length of tachykinin depletion (via capsaicin treatment) is needed to prevent (or attenuate) PH and/or RVH. Six groups of rats were injected subcutaneously with saline (3 ml/kg); capsaicin followed by saline or MCT (60 mg/kg); or MCT followed 7, 11, or 14 days later by capsaicin. Capsaicin (cumulative dose, 500 mg/kg) was given over a period of 4-5 days. Respiratory function, pulmonary vascular parameters, lung tachykinin levels, and tracheal neutral endopeptidase (NEP) activity were measured 21 days after MCT or saline injection. Capsaicin significantly decreased lung levels of SP but not NKA. Both capsaicin pretreatment and posttreatment blocked the following MCT-induced alterations: increases in lung SP and airway constriction; decreases in tracheal NEP activity and dynamic respiratory compliance. Administration of capsaicin before or 7 days after MCT blocked MCT-induced PH and RVH. The above data suggest that the early tachykinin-mediated airway dysfunction requires only transient elevated tachykinins, while progression of late tachykinin-mediated effects (PH and RVH) requires elevated tachykinins for more than one week.