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1. Kallidin (5-500 nmol), hypertonic saline (0.9-20% NaCl) or low pH medium (citric acid: pH 2.5-1) applied (50 microliters) to the human nasal mucosa produced a pain response (evaluated by a visual analogue scale) that was related to the concentration of the peptide, NaCl or hydrogen ions, respectively. 2. Application (50 microliters) of capsaicin (50 nmol) to the human nasal mucosa produced overt pain. After repeated administrations (once a day for 5-7 days) to one nostril this effect underwent almost complete desensitization, while in the contralateral nostril, treated with the vehicle, the response to capsaicin was unaffected. 3. The pain response produced in the human nasal mucosa by topical application (50 microliters) or kallidin (50-500 nmol), NaCl (10-20%) or citric acid (pH 1.5-1) solutions was then studied before and after local capsaicin desensitization. 4. The pain response to pH 1.5 or 1 citric acid was markedly reduced (by 60% and 75%, respectively) in the capsaicin-treated nostril. However, the pain response to 10% or 20% NaCl or the mild pain response to 50 or 500 nmol kallidin were unaffected by capsaicin pre-treatment. 5. The present results suggest that prolonged topical capsaicin treatment to the human nasal mucosa may lead to selective desensitization to certain algesic stimuli such as capsaicin itself and hydrogen ions.

1. The effect of 5-hydroxytryptamine (5-HT) on the release of calcitonin gene-related peptide (CGRP) was studied directly in the isolated perfused heart and indirectly in the isolated left atria of guinea-pig. 2. 5-HT injection into the guinea-pig isolated and perfused heart evoked a dose-dependent (1-100 microM) release of CGRP-like immunoreactivity (LI) that was abolished by in vitro pretreatment with capsaicin and was not affected by indomethacin. 3. Chlorophenyldiguanide (CPD, 100 microM), but not 8-hydroxy-dipropylaminotetralin (8-OH-DPAT, 100 microM), sumatriptan (100 microM) or 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 100 microM) evoked a release of CGRP-LI. Ondansetron (10 microM) or ICS205-930 (20 microM) completely abolished the 5-HT (100 microM)-evoked CGRP-LI release. 4. In the isolated electrically driven left atria of the guinea-pig 5-HT (1-10 microM) and CPD (3-100 microM) produced a positive inotropic response, which was abolished by capsaicin pretreatment. 8-OH-DPAT (10 microM) and DOI (10 microM) were inactive. Ondansetron inhibited the response to 5-HT with a pA2 of 6.50 (CL 6.08-6.91). 5. It is concluded that 5-HT causes a release of CGRP in the whole heart and a positive inotropic response in the isolated atria of guinea-pig. Both these effects are sensitive to capsaicin pretreatment and to 5-HT3 antagonists.

This study investigated the role of capsaicin-sensitive fibers on trinitrobenzensulphonic acid (TNB)-induced colitis in rats. Capsaicin pretreatment (164 + 164 mumol/kg sc in 2 days) produced an increase of damaged area and colon wet weight at 24 h and 1 week after the challenge. On the other hand, acute stimulation of sensory nerves by local application of capsaicin (1.2-60 mumol/kg) as well as exogenous administration of CGRP (2.6-26.3 nmol/kg sc) ameliorated the lesions and reduced the increase of colon weight in TNB-colitis. The protective effect of acute capsaicin (7.7 mumol/kg) was transient and lost in capsaicin-desensitized animals, showing its specificity and the likely participation of acute release of peptides in this mechanism. Moreover, development of TNB colitis was associated with a selective decrease in tissue CGRP-like immunoreactivity. These findings provide evidence that capsaicin-sensitive nerves, probably via the release of protective neurotransmitters such as CGRP, play a defensive role in colitis.

Electrical field stimulation (5 Hz) evoked a prompt outflow of calcitonin gene-related peptide- and substance P-like immunoreactivities (CGRP-LI and SP-LI, respectively) from superfused slices of the dorsal but not ventral half of the rat spinal cord. The evoked outflow was abolished by tetrodotoxin, calcium-free medium or previous exposure to capsaicin, indicating that it is produced through action potentials invading the central terminals of capsaicin-sensitive primary afferents. Adenosine as well as gamma-aminobutyric acid (GABA) or the GABAB receptor agonist (-)-baclofen produced a concentration-dependent inhibition of the evoked CGRP-LI outflow. Adenosine also inhibited the evoked SP-LI outflow. These findings demonstrate that inhibition of transmitter release from primary afferent neurons should be considered as a possible mechanism of the antinociceptive action of adenosine and adenosine analogs.

Slices of human iris or ciliary body, obtained post-mortem (8-12 h after death, n = 5), were superfused in vitro with capsaicin (10 microM) and the immunoreactivity for substance P (SP-LI) or calcitonin gene-related peptide (CGRP-LI) was measured in the effluent. In the iris and in the ciliary body CGRP-LI was 3.71 +/- 0.74 pmol/g and 3.01 +/- 0.55 pmol/g and SP-LI was 6.68 +/- 0.75 pmol/g and 6.55 +/- 0.84 pmol/g, respectively. A first exposure to capsaicin increased the CGRP-LI outflow from the ciliary body (427 +/- 46 fmol/g/30 min), whereas a second challenge with the drug 30 min later, failed to significantly enhance the CGRP-LI outflow (21.8 +/- 15.6 fmol/g/30 min). Likewise, the capsaicin-evoked increase in CGRP-LI outflow from the iris slices (472 +/- 62 fmol/g/30 min) was no longer observed at the second drug administration (38.4 +/- 12.8 fmol/g/30 min). Capsaicin failed to increase the SP-LI outflow from either the iris or the ciliary body. Reverse phase HPLC analysis of CGRP-LI indicated that authentic CGRP was contained in the tissue and in the superfusate collected during exposure to capsaicin. The present results show that in the human iris and ciliary body, capsaicin releases CGRP possibly contained in terminals of sensory nerves.

We have measured the endogenous levels of gastric and duodenal calcitonin gene-related peptide (CGRP)-, neurokinin A (NKA)-, galanin-vasoactive intestinal polypeptide (VIP)- and neuropeptide Y (NPY)-like immunoreactivity (li) in relation to cysteamine-induced gastric lesions and duodenal ulcers in rats. CGRP-li but not NKA-, galanin-, VIP- or NPY-li was decreased in gastric and duodenal samples following a single ulcerogenic dose of cysteamine (900 mg/kg p.o.). Temporal relationships of this phenomenon showed that CGRP-li was selectively decreased (stomach 45%, duodenum 68% as compared to controls, respectively after 24 h) concomitantly to the formation of acute gastric lesions and duodenal ulcers. Animals bearing healed ulcers 12 days after cysteamine, had gastroduodenal CGRP-li similar to control values. Pretreatment with the selective sensory neurotoxin capsaicin decreased gastroduodenal CGRP-li but not NKA-, galanin-, VIP- or NPY-li, showing that CGRP might be considered a marker of the afferent innervation of the gastroduodenal tract. The residual gastroduodenal CGRP-li levels in capsaicin-pretreated animals were not decreased by cysteamine administration, indicating that the effect of cysteamine is restricted to a peptide pool of primary afferent origin. Duodenal CGRP-li is selectively decreased by the duodenal ulcerogen cysteamine during the acute phase of ulcers formation and might be among the local mediators which afford protection against the ulcerogenic stimuli.

The effect of superfusion with veratridine on the release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) was studied in slices of rat urinary bladder. Exposure to veratridine (1-200 microM) produced a concentration-related release of CGRP-LI. Veratridine (50 microM)-evoked CGRP-LI release was abolished in slices pre-exposed to capsaicin (10 microM for 40 min) or superfused in a Ca(2+)-free medium containing 1 mM EDTA. After exposure to veratridine (50 microM for 40 min), capsaicin (10 microM) was still able to release CGRP-LI. CGRP-LI release evoked by veratridine (50 microM) was inhibited by about 60% by tetrodotoxin (0.3 microM), attenuated (30%) by nifedipine (1 microM), and not affected by omega-conotoxin (0.1 microM). The capsaicin antagonist ruthenium red (10 microM) did not affect veratridine (50 microM)-evoked CGRP-LI release. The present results indicate that depolarization by veratridine induces CGRP-LI release from capsaicin-sensitive nerve fibres, an effect that is entirely dependent on extracellular Ca2+. The Ca2+ influx that promotes CGRP-LI release is mediated mostly by nifedipine-, omega-conotoxin- and ruthenium red-insensitive channels.

Electrical field stimulation (EFS, 10 V, 50 mA/cm2, 5-50 Hz, 1 ms pulse duration, 10 s train every 20 s for 5 min) produced a rapid and reproducible outflow of calcitonin gene-related peptide like-immunoreactivity (CGRP-LI) from superfused slices from the dorsal half of the rat spinal cord which is abolished by tetrodotoxin (TTX, 0.3 microM), in vitro capsaicin desensitization (10 microM for 30 min) and in Ca-free medium. The response was unaffected by ruthenium red (10 microM), indomethacin (10 microM) and nifedipine (1 microM) while it was abolished by omega-conotoxin (omega-CTX, 0.1 microM) and, in a naloxone-sensitive manner, by morphine (3 microM). Since CGRP release from capsaicin-sensitive afferents evoked by EFS in rat peripheral tissues is conotoxin-resistant, these findings provide direct evidence for a qualitative difference between central and peripheral endings of capsaicin-sensitive primary afferents in the mechanisms regulating transmitter release in the same species.

We have assessed the ability of compound 48/80, a mast cell degranulating agent, to activate the sensory and efferent function of capsaicin-sensitive primary afferents in the rat urinary bladder. Compound 48/80 produced a calcium-dependent release of calcitonin gene-related peptide-like immunoreactivity from the superfused rat urinary bladder. This effect was prevented by in vitro capsaicin desensitization, but was not affected by indomethacin, methysergide, ondansetron, chlorpheniramine or cimetidine, nor by systemic pretreatment with compound 48/80 at a dose regimen which prevented lethality produced by intravenous administration of it in anesthetized rats. Compound 48/80 also produced a contraction of the rat isolated bladder which was not reduced by methysergide, indomethacin or in vitro capsaicin desensitization. In vivo, topical application of compound 48/80 on the serosal surface of the rat urinary bladder activated a series of high amplitude rhythmic bladder contractions which were hexamethonium-sensitive (micturition reflex). This effect was prevented by systemic capsaicin desensitization while it was unchanged by chlorpheniramine, methysergide, indomethacin or ondansetron. Administered intravenously, compound 48/80 produced a plasma protein extravasation (Evans blue leakage technique) in the rat urinary bladder which was abolished by systemic capsaicin pretreatment or chlorpheniramine while it was unaffected by methysergide or indomethacin. The present findings provide direct neurochemical evidence that compound 48/80 activates the peripheral endings of capsaicin-sensitive primary afferent neurons, leading to a stimulation of their sensory and efferent functions in the rat urinary bladder. The possibility of a direct action of compound 48/80 in producing excitation of capsaicin-sensitive sensory nerves should be considered.

We have investigated the effect of the C-terminal fragment of human calcitonin gene-related peptide (human-CGRP8-37), a CGRP antagonist, on alpha-CGRP and salmon Calcitonin (sCT)-induced inhibition of gastric acid secretion stimulated by pentagastrin (24 nmol kg-1 h-1 i.v.) and gastric lesions induced by acetylsalycilic acid (ASA; 25 mM) in rats anaesthetized with urethane. Close intra arterial infusion of alpha-CGRP (2-5 nmol kg-1) and sCT (5 nmol kg-1) produced a reduction in gastric acid hypersecretion induced by pentagastrin. The concomitant infusion with human-CGRP8-37 (10 nmol kg-1) reversed the effect of both agonists. ASA-ulcers were reduced in a dose-dependent manner by infusion of alpha-CGRP (1-2 nmol kg-1 i.a.), but not by sCT (10 nmol kg-1 i.a.). Human-CGRP8-37 at a dose of 10 nmol kg-1 i.a. was unable to reverse the alpha-CGRP antiulcer effect. An higher dose of human-CGRP8-37 (50 nmol kg-1 i.a.) showed agonistic properties reducing ASA ulcers. These results suggest that the inhibitory effects of alpha-CGRP on stimulated acid secretion and aspirin ulcers are mediated by different mechanisms and/or different receptors.

Hypertonic NaCl (160 mM added to the physiological salt solution) releases CGRP in a Ca(2+)-dependent manner from capsaicin-sensitive sensory nerves of the rat urinary bladder. The NaCl (160 mM)-evoked CGRP release was not affected by tetrodotoxin (0.3 microM), nifedipine (1 microM), omega-conotoxin (0.1 microM) and ruthenium red (10 microM). NaCl (160 mM)-evokes release of sensory neuropeptides without the involvement of axon reflexes, and by promoting Ca2+ influx via a dihydropyridine omega-conotoxin and ruthenium red insensitive pathway.

Different modes by which Ca2+, entering the nerve terminal, promotes transmitter secretion as well as the ability of protons to release neuropeptides, have been shown in peripheral endings of capsaicin-sensitive afferents. We have studied these two aspects in the central endings of these neurons by measuring the release of calcitonin-gene related peptide-like immunoreactivity (CGRP-LI) from slices of the dorsal half of the guinea pig spinal cord. Although capsaicin (1 microM) released both CGRP-LI and substance P-like immunoreactivity (SP-LI), CGRP-LI was chosen as the sole suitable marker of peptides released from central terminals of capsaicin-sensitive afferents, since after in vitro desensitization to capsaicin (1 microM capsaicin for 20 min), high K+ (80 mM) failed to evoke CGRP-LI release, whereas SP-LI release was still observed. The capsaicin (1 microM)-evoked CGRP-LI release was entirely dependent on extracellular Ca2+. It was unaffected by 0.3 microM tetrodotoxin (TTX), slightly reduced by 0.1 microM omega-conotoxin (CTX) and blocked by 10 microM Ruthenium red (RR). The Ca(2+)-dependent K+ (80 mM)-evoked CGRP-LI release was unaffected by TTX, markedly reduced by CTX and only moderately inhibited by RR. Low pH (pH 5) produced a remarkable increase in CGRP-LI outflow that was abolished after exposure to capsaicin, reduced by about 50% in Ca(2+)-free medium and unaffected by TTX (0.3 microM). The Ca(2+)-dependent component of the proton-evoked CGRP-LI release was abolished in the presence of RR (10 microM) and slightly inhibited by CTX (0.1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

In the muscle layer of the glandular portion of the rat stomach, in vivo capsaicin pretreatment markedly reduced calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) but did not affect substance P-like immunoreactivity (SP-LI). Accordingly, in vitro superfusion of slices of this tissue with capsaicin (10 mumol/L) released CGRP-LI but not SP-LI, whereas both neuropeptides were released by 80 mmol/L K+. Exposure to relatively low-pH (pH 6) physiological salt solution induced an increase in the CGRP-LI outflow that was reduced by 70% in a Ca(2+)-free medium and was completely abolished by a previous exposure to capsaicin. However, superfusion with pH-6 medium did not produce any detectable SP-LI release. After exposure to pH-6 medium, both capsaicin and high-K+ medium were still able to release a consistent quantity of CGRP-LI and SP-LI, respectively. Increased mucosal blood flow induced by acid back-diffusion is considered a protective mechanism against mucosal gastric lesion. The present findings suggest that hydrogen ions diffusing into the gastric wall may promote protective vasodilatation by activating the "efferent" function of capsaicin-sensitive nerves without affecting the secretory process of other intrinsic peptidergic neurons.

Sensitivity of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) to capsaicin was investigated in different arterial and venous tissues (mesenteric, renal and femoral artery and vein and carotid artery and jugular vein) of the rat. In vivo capsaicin pre-treatment depleted or reduced tissue CGRP-LI in all the vessels examined with the exception of the carotid artery. Likewise, in vitro exposure to capsaicin evoked release of CGRP-LI from all vessels, excluding the carotid artery. Remarkable amount of CGRP-LI sensitive to capsaicin was present in both mesenteric artery and vein as compared to the other vascular tissues. Endogenous (bradykinin) or exogenous (N-formyl-methionyl-leucyl-phenylalanine) proinflammatory agents, were found to release CGRP-LI from mesenteric veins.

Various kinins (dissolved in 50 microliters) were applied to the nasal mucosa of healthy human volunteers to test the algesic and proinflammatory effects of these peptides in an intact human tissue. [des-Arg9]-bradykinin (0.5 mumol) was found to be inactive, while bradykinin (0.05-0.5 mumol) and especially kallidin (0.005-0.5 mumol) induced: (a) a mild painful sensation described as burning and pricking (latency 30 s, duration 3-5 min), (b) perception of pulsatility and obstruction in the nasal cavity (onset 1 min, duration 6-8 min). Substance P (0.5 mumol) and neurokinin A (0.5 mumol) produced slight obstruction and weak pulsatile sensation but not pain. Capsaicin (0.05 nmol) produced pain and secretion of fluid, but not pulsatile sensation. The effects of kallidin were not affected by repeated (to induce desensitization) applications of capsaicin (0.5 mumol). Likewise, ipratropium bromide (80 mg in 100 microliters) did not affect responses to kallidin. In an intact human tissue, kallidin produces various effects, including an algesic response, that are apparently independent from activation of B1 receptors and from desensitization of capsaicin-sensitive primary afferents.

1 Platelet activating factor (PAF), but not the carrier molecule bovine serum albumin (BSA) induced bronchoconstriction in the anaesthetized rabbit. This bronchoconstriction was not altered by prior treatment with capsaicin. 2 Rabbits demonstrated increased airways responsiveness to histamine 24h after exposure to PAF but not to BSA. PAF failed to increase airways responsiveness to histamine in animals pretreated with capsaicin (80 mg kg-1). 3 A significant increase in inflammatory cells was obtained in bronchoalveolar lavage (BAL) 24h after PAF exposure in vehicle-treated rabitts. This was associated with an increase in the numbers of neutrophils and eosinophils. Capsaicin treatment inhibited the PAF-induced influx of inflammatory cells found in BAL, although this was not associated with an inhibition of PAF-induced pulmonary eosinophilia. 4 Capsaicin-induced motor effects were modest in epithelium-intact rabbit bronchial preparations, but were significantly enhanced in epithelium-denuded preparations in the presence of thiorphan. The contractile response to capsaicin was significantly inhibited in tissues exposed to a consecutive dose of capsaicin. Furthermore, ruthenium red abolished capsaicin-induced contraction in epithelium-denuded preparations. 5 Tissue content of calcitonin gene-related peptide-like immunoreactivity and substance P-like immunoreactivity was not reduced in bronchus and iris obtained from capsaicin-treated rabbits, although capsaicin-induced contractile responses in rabbit bronchus obtained from animals previously treated with capsaicin were significantly reduced. Furthermore, airway responses to histamine, methacholine and electrical field stimulation in vitro, were not altered by pretreatment of rabbits in vivo for 3 days with capsaicin. 6. In conclusion, PAF-induced airways responsiveness and pulmonary cell accumulation is inhibited by in vivo capsaicin pretreatment in the rabbit, via a mechanism that may not involve depletion of sensory neuropeptides.

Superfusion of slices of the rat urinary bladder with hypertonic NaCl produced a remarkable and concentration-dependent (150-280 mM) increase in the outflow of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI). This effect was completely abolished by pre-exposure of the tissue to capsaicin (10 microM for 20 min) or by superfusion with a Ca(2+)-free medium. Capsaicin (10 microM) was still able to release a consistent amount of CGRP-LI from tissue pre-exposed (20 min) to 280 mM NaCl. Similarly, hypertonic sucrose (160 mM added to the physiological salt solution) induced a consistent release of CGRP-LI that was abolished by capsaicin-pretreatment or in a Ca(2+)-free medium. The experiments demonstrate that hypertonic solutions activate the efferent function of capsaicin-sensitive neurons and suggest that this event may have some relevance in pathophysiological conditions of the lower urinary tract in which hypertonic urine may diffuse to submucosal layers.

1. We have investigated the ability of the N-formyl-methionyl-leucyl-phenylalanine (FMLP) a synthetic analogue of a chemotactic peptide derived from a variety of bacteria, to activate capsaicin-sensitive primary afferents in the guinea-pig atria and urinary bladder. 2. In the isolated, electrically-driven left atria from reserpine-pretreated guinea-pigs (atropine in the bath), FMLP (3 nM-1 microM) produced a biphasic positive inotropic response. The late component of this response was selectively abolished by in vitro capsaicin pretreatment while both the early and late responses were abolished by indomethacin. 3. The inotropic response to FMLP in the guinea-pig atria was unaffected by ruthenium red. The late but not the early response was strongly inhibited or abolished by tetrodotoxin (TTX), omega-conotoxin (CTX) or by the C-terminal fragment (8-37) of human alpha-calcitonin gene-related peptide (hCGRP). hCGRP-(8-37) acts as competitive antagonist at CGRP receptors. 4. In the guinea-pig isolated bladder, FMLP (10 nM-10 microM) produced a concentration-dependent contraction which was unchanged by previous in vitro capsaicin, TTX or CTX pretreatment. The response to low concentrations of FMLP was suppressed by indomethacin, irrespective of the capsaicin pretreatment. 5. FMLP (10 microM) produced a significant increase in the outflow of CGRP-like immunoreactivity (CGRP-LI) from superfused guinea-pig atria or urinary bladder. CGRP-LI outflow induced by FMLP was blocked by indomethacin or in vitro capsaicin pretreatment. 6. These findings indicate that FMLP activates the 'efferent' function of capsaicin-sensitive primary afferents via prostanoid generation. This action could provide a neurogenic contribution to the overall inflammatory response produced by bacteria-derived peptides in inflamed tissues. In addition the present data indicate that endogenous prostanoids generated during exposure to FMLP produce peptide secretion from sensory nerves via a TTX- and CTX-sensitive but ruthenium red-resistant mechanism.

Superfusion of mucosa-free muscle slices of guinea-pig urinary bladder with 40 mM K+ produced a remarkable increase in calcitonin gene-related peptide-like immunoreactivity (CGRP-LI), that in this organ is entirely contained in capsaicin-sensitive nerves. GABA (1 mM) did neither affect the basal nor the 40 mM K+ evoked CGRP-LI release. Baclofen (0.1 mM) or muscimol (1 mM) did not affect the basal CGRP-LI outflow. However, baclofen (0.1 mM) significantly reduced by 32% and muscimol (0.1-1 mM) significantly increased by 60% and 70%, respectively the K(+)-evoked CGRP-LI release. These findings add neurochemical evidence to the functional data suggesting the existence of GABAA and GABAB receptors which modulate the efferent function of capsaicin-sensitive afferents.

1. The ability of capsaicin and antidromic stimulation of perivascular nerve fibers to release sensory neuropeptides (SP-LI and CGRP-LI) have been investigated in rat mesenteric arteries and veins. 2. Both in mesenteric arteries and veins substantial SP-LI and CGRP-LI tissue levels were measured. A significant reduction in sensory neuropeptides levels was observed in tissues obtained from capsaicin-pretreated animals. 3. Superfusion of isolated vessels with capsaicin (1 microM) produced a prompt and remarkable release of both SP-LI and CGRP-LI, which can be evoked only once in each preparation. 4. Electrical field stimulation (EFS, 20 Hz, 50 V, 0.5 msec, trains of 10 sec every 20 sec for 15 min) of isolated vessels resulted in a significant release of CGRP-LI. This release was significantly greater in veins as compared to arteries. EFS-induced CGRP-LI release was unaffected by atropine or guanethidine and absent in preparations obtained from capsaicin-pretreated rats. 5. These neurochemical findings further suggest that the local release of sensory neuropeptides from capsaicin-sensitive nerve endings might be important in the regulation of mesenteric circulation.

Thiorphan, a well known inhibitor of 'enkephalinase' (endopeptidase 24.11) potentiated and prolonged the contractile response to substance P (SP) and neurokinin A (NKA) on strips of the guinea-pig isolated urinary bladder and this effect was evident both in presence and absence of the mucosal layer. Thiorphan also enhanced and prolonged the capsaicin-induced contraction in strips from the bladder dome which is thought to be mediated by release of endogenous tachykinins. Exposure to capsaicin produced simultaneous release of SP- and tachykinin-like immunoreactivity both in presence and absence of mucosa. This effect of capsaicin was potentiated by thiorphan. Endopeptidase 24.11 activity was detected in the guinea-pig urinary bladder, being more concentrated in the mucosal than the muscular layer. These findings indicate that endopeptidase 24.11 terminates the activity of tachykinins in the guinea-pig urinary bladder and modulates the intensity of the biological response produced after their release from peripheral endings of sensory nerves.

In this study the concentration of plasma breakdown products of cross-linked fibrin (XDP), serum fibrinogen-fibrin degradation products (FDP), and plasma fibrinogen were measured before and at the end of the administration of single-chain recombinant tissue-type plasminogen activator (rt-PA, 100 mg IV over three hours) or streptokinase (1.5 million units over one hour), respectively, in two groups, each composed of 22 patients with acute myocardial infarction. The XDP concentration was not statistically different between the two groups at the end of thrombolytic treatment, whereas FDP and fibrinogen concentrations were significantly different (FDP: streptokinase 396 +/- 287 vs rt-PA 177 +/- 222 micrograms/mL, p less than 0.01; fibrinogen: streptokinase 71 +/- 43 vs rt-PA 181 +/- 49 mg/dL, p less than 0.001). These results indicate that the two drugs have equipotent thrombolytic activity at this administration regimen but that rt-PA causes a markedly more selective lysis of fibrin in comparison with streptokinase.

In the guinea pig ureter, substance P-(SP) and calcitonin gene-related peptide-(CGRP) like immunoreactivity (LI) were depleted by systemic capsaicin pretreatment, indicating that they are entirely stored in peripheral endings of primary afferent neurons. Electrical field stimulation (20 Hz, 60 V, 0.5 ms) evoked the simultaneous release of SP- and CGRP-LI from superfused guinea pig ureters which was abolished by tetrodotoxin (0.3 microM). omega-Conotoxin (0.1 microM), a potent blocker of N-type voltage-sensitive calcium channels, reduced by 50-70% the evoked release of both peptides. These findings provide direct neurochemical evidence indicating that conotoxin-sensitive calcium channels play a role in transmitter secretion evoked by antidromic invasion of peripheral terminals of capsaicin-sensitive primary afferents.

1. In the presence of atropine and guanethidine (3 mumol/l each), electrical field stimulation (1-20 Hz) produced frequency-dependent relaxations of the histamine- (3 mumol/l) induced vascular tone in isolated rings from the guinea-pig pulmonary artery. The electrically-evoked relaxations were abolished by tetrodotoxin (1 mumol/l). The amplitude of these nerve-mediated, non-adrenergic non-cholinergic (NANC) relaxations was unaffected by removal of the vascular endothelium produced through rubbing of the internal surface. 2. Capsaicin (1 mumol/l) produced a prompt and sustained relaxation of the histamine-induced tone which was unaffected by removal of the endothelium. A second application of capsaicin 60-120 min later had no further relaxant effect, indicating desensitization. After in vitro capsaicin desensitization, the electrically-evoked NANC relaxations were abolished, both in the presence or absence of the vascular endothelium. 3. Substance P evoked a prompt and transient relaxation in precontracted arterial rings with intact endothelium and a transient small contraction in rings in which the endothelium had been mechanically removed. The selective NK-1 receptor agonist, [Pro9]-substance P sulfone closely mimicked the relaxation produced by substance P while the selective NK-2 or NK-3 receptor agonists had no relaxant effect. Tachyphylaxis to substance P did not modify the amplitude of the capsaicin-induced relaxation. 4. Human alpha calcitonin gene-related peptide (CGRP) produced a prompt and sustained relaxation both in the presence and absence of the vascular endothelium. 5. Ruthenium red (10 mumol/l) blocked the relaxation to capsaicin while leaving unaffected the relaxation to electrical field stimulation or CGRP (0.1 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Lowering of the pH of the superfusion solution (physiological phosphate buffers derived from normal Krebs solution) of mucosa-free muscle strips of the guinea-pig urinary bladder from 7.4 to 6 or 5, produced a marked increase of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) outflow (total evoked release being 1677 +/- 287 fmol/g/35 min and 5283 +/- 484 fmol/g/35 min, respectively). The increase in CGRP-LI outflow evoked by exposure to pH 5 was abolished in strips pre-exposed to capsaicin (10 microM for 20 min), and was reduced by approximately 80% when superfusion was performed with Ca2(+)-free media. After application of pH 5 solution, capsaicin (10 microM) evoked a CGRP-LI release that amounted to 21% of controls. It is concluded that lowering of the pH induces a Ca2(+)-dependent release of CGRP-LI from capsaicin-sensitive nerves in the guinea-pig urinary bladder.

Capsaicin-sensitive sensory neurons of the rabbit iris, by releasing tachykinins, exert a major role in the control of pupil motility in response to various noxious stimuli. However, the contribution of sensory innervation to the regulation of iris smooth muscle tone in other mammals species is not known. We have studied the effects produced by electrical field stimulation, capsaicin, substance P, neurokinin A, calcitonin gene-related peptide (CGRP), and bradykinin in the isolated iris sphincter muscle of the pig. Capsaicin (10 microM): a) contracted the isolated sphincter muscle and; b) released immunoreactivity for substance P (SP-LI) and CGRP (CGRP-LI) from this preparation. These two effects were no longer observed at the second exposure to the drug. Electrical field stimulation (10 Hz, 60 V, 0.5 ms for 5 s) produced a biphasic contractile response. The rapid component was inhibited by atropine (1 microM), while the delayed response was blocked by previous exposure to capsaicin (10 microM). Substance P and neurokinin A consistently produced contraction of the pig iris sphincter muscle, substance P being more potent than neurokinin A. CGRP induced a contractile response in more than 50% of the preparations. The tachykinin antagonist [D-Arg1, D-Trp7,9, Leu11]-substance P (3 microM) blocked: a) the effect of substance P (1 nM); b) the delayed response to electrical field stimulation and; c) reduced by more than 50% response to capsaicin. Bradykinin (10 microM) failed to release either SP-LI or CGRP-LI. The contractile response evoked by bradykinin was unaffected by in vitro pretreatment with capsaicin (10 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Academic achievement within a child psychiatric sample was examined as a function of six variables: IQ, socioeconomic status, age, sex, neuropsychological status, and the severity of behavioral disturbance. As expected, the results revealed a different pattern of predictors than what is generally the case of normal school-aged children. The results underscored the importance of neuropsychological factors, more than IQ and demographic variables, in understanding the academic deficits often seen in children with significant mental and emotional disturbance.

Alterations in blood rheological properties have been reported in diabetes mellitus. Changes in lipid composition of red blood cell (RBC) membranes resulting in an impairment of RBC deformability may play a role in the altered blood rheological pattern. The aim of this study was to investigate the lipid composition of RBC membrane in a group of patients affected by type II diabetes (age 21-45 years), selected on the basis of the absence of complications and good metabolic control, and in a group of suitable control subjects. Saturated fatty acid amounts in the different phospholipid fractions were significantly higher in diabetics than in controls (p less than 0.05), whereas polyunsaturated fatty acids were decreased (p less than 0.05). Cholesterol/phospholipid molar ratio was not altered. On the contrary, sphingomyelin/phosphatidylcholine ratio was higher in diabetics than in controls (1.10 +/- 0.08 vs 0.96 +/- 0.10, p less than 0.01) due specially to high levels of sphingomyelin. These alterations could account for the impairement of RBC deformability frequently reported in diabetes mellitus, independently of metabolic control and the presence of severe atherosclerotic lesions.

The concept of major depressive disorder in childhood and adolescence is reviewed and it is suggested that contemporary enthusiasm for this diagnosis may have outrun the evidence that it is a distinct categorical entity. To test the hypothesis that major depression is not a qualitatively distinct disorder in adolescence, but rather a continuously distributed, noncategorical syndrome, the behavioral rating scales (CBCL-P) of 216 hospitalized adolescent patients were analyzed first by principal components analysis and then by cluster analysis. Three behavioral syndromes were isolated by principal components analysis. Of three groups of patients identified by a subsequent cluster analysis, one was consistent with the concept of a categorically distinct "nuclear" depression. However, a noncategorical continuously distributed depressive syndrome appears to affect a larger number of patients in this age group, and the "nuclear" disorder may be less prevalent than is currently assumed. One explanation of these findings would combine a categorical model of nuclear depression with a dimensional model of dysthymia.