Calcitonin gene-related peptide in the regulation of urinary tract motility.
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Animals↗
Biomedical subjects
P Geppetti
Publications and source records attributed to P Geppetti.
Veratridine evokes release of calcitonin gene-related peptide from capsaicin-sensitive nerves of rat urinary bladder.
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.
Animals↗
Release of calcitonin gene-related peptide like-immunoreactivity induced by electrical field stimulation from rat spinal afferents is mediated by conotoxin-sensitive calcium 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.
Animals↗
Release of sensory CGRP by hypertonic NaCl is not blocked by tetrodotoxin, omega-conotoxin, nifedipine and ruthenium red.
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.
Animals↗
Pharmacologic and neurochemical evidence for the activation of capsaicin-sensitive sensory nerves by lipoxin A4 in guinea pig bronchus.
Exogenous administration of lipoxin A4 (LXA4) to guinea pig isolated bronchus produced contractile effects in a concentration-dependent manner (1, 3, and 6 microM). These responses were potentiated when preparations were previously incubated with thiorphan (10 microM), an inhibitor of tachykinin breakdown, but were significantly depressed when sensory nerves were previously desensitized in vitro by capsaicin (10 microM for 15 min) challenge. Ruthenium red (10 microM for 20 min), a blocker of the cationic channel coupled to the capsaicin receptor, also produced, although in a weaker manner, a reduction in bronchomotor responses elicited by LXA4. On the other hand, preexposure to omega-conotoxin (0.1 microM for 45 min), a blocker of neuronal voltage-dependent Ca2+ channels, did not modify the LXA4 contractile effects. Furthermore, LXA4 (6 microM) superfusion of guinea pig bronchial tissue elicited a significant calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) release that was reduced by capsaicin (10 microM, 30 min) desensitization. Finally, LXA4 (10 microM) was unable to displace [3H]resiniferatoxin binding in dorsal root ganglion of rat and guinea pig. These findings support (1) a role for LXA4 in activating motor sensory function of capsaicin-sensitive nerves; (2) this activation mechanism is marginally ruthenium red-sensitive and omega-conotoxin-resistant; and (3) the interaction does not involve the recognized binding site on the vanilloid receptor. As a whole this study presents LXA4 as an endogenous mediator activating sensory nerves potentially involved in basic mechanisms of airway diseases.
Animals↗
Different pathways by which extracellular Ca2+ promotes calcitonin gene-related peptide release from central terminals of capsaicin-sensitive afferents of guinea pigs: effect of capsaicin, high K+ and low pH media.
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)
Afferent Pathways↗
Kallidin applied to the human nasal mucosa produces algesic response not blocked by capsaicin desensitization.
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.
Adult↗
Hypertonic media produce Ca(2+)-dependent release of calcitonin gene-related peptide from capsaicin-sensitive nerve fibres in the rat urinary bladder.
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.
Animals↗
Sensory denervation with capsaicin reduces the liver collagen deposition induced by common bile duct obstruction in rats.
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Animals↗
Beneficial effects of intranasal applications of capsaicin in patients with vasomotor rhinitis.
Capsaicin, a nonenamide derived from Capsicum plants, has proven useful in patients with vasomotor rhinitis. In the present study, we studied the effects of 15 micrograms capsaicin suspended in 100 microliters solution in patients with known vasomotor rhinitis. Drug was given 3 times/day for 3 days to each patient by means of a spray delivered to the nasal mucosa. Acute effects induced by the drug included painful sensation and secretion of nasal fluid but were no longer observed at the last capsaicin application. Patients recorded their symptoms over a 1-month period. The mean symptom score involving nasal obstruction and nasal secretion was markedly reduced by capsaicin treatment. We advance the hypothesis that the beneficial effect of drug treatment may be due to its specific action on the peripheral endings of primary sensory neurons leading to their functional blockade. Further randomized, double-blind, placebo-controlled trial is now needed.
Administration, Intranasal↗
Calcitonin gene-related peptide in rat arterial and venous vessels: sensitivity to capsaicin, bradykinin and FMLP.
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.
Animals↗
Differential effect on neuropeptide release of different concentrations of hydrogen ions on afferent and intrinsic neurons of the rat stomach.
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.
Animals↗
GABAA and GABAB receptors modulate the K(+)-evoked release of sensory CGRP from the guinea pig urinary bladder.
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.
Animals↗
Low pH medium induces calcium dependent release of CGRP from sensory nerves of guinea-pig dural venous sinuses.
Low pH medium has been shown to activate the 'efferent' function of capsaicin-sensitive primary sensory neurons. Calcitonin gene-related peptide (CGRP) is released from capsaicin-sensitive afferents of guinea-pig superior sagittal and transverse sinuses (SSTS), by capsaicin or bradykinin. Here, we report that low pH medium produces a remarkable release of CGRP from SSTS, which was dependent on the concentration of hydrogen ions of the medium (pH 7-5). Moreover, the pH 5-evoked release of CGRP-LI was markedly reduced (by about 70%) in a calcium-free medium containing 1 mM EDTA or abolished in samples pre-exposed to 10 microM capsaicin. The present observation that lowering of the pH promotes release of a powerful vasoactive peptide from perivascular capsaicin-sensitive sensory nerves may have some relevance in the pathophysiology of brain injury and migraine headaches.
Animals↗
Substance P induces migration of capillary endothelial cells: a novel NK-1 selective receptor mediated activity.
Substance P (SP) has been indicated as a main mediator of neurogenic inflammation, leading to vasodilation, increase in vascular permeability and modulation of immune cell function. Certain vascular effects produced by SP are endothelium mediated. We have studied the effect of SP and of selective NK-1, NK-2 and NK-3 receptor agonists on migration of cultured capillary endothelial cells of bovine origin. Our results indicate that SP (10(-14)-10(-6) M) induces a concentration-dependent migration of endothelial cells with maximal activity at 10(-10) M. This effect was mimicked by the selective NK-1 receptor agonist which showed a similar concentration-dependent curve, while selective NK-2 and NK-3 receptor agonists were ineffective. Our conclusions are that endothelial cells possess specific receptors for SP of the NK-1 type which affect mobilization of capillary endothelial cells.
Animals↗
Capsaicin-induced release of neurokinin A from muscle and mucosa of gastric corpus: correlation with capsaicin-evoked release of calcitonin gene-related peptide.
It has been proposed that capsaicin-sensitive nerves might participate in a gastric defence mechanism, possibly via a local release of sensory neuropeptides. In this study, it was examined whether capsaicin might induce the release of neurokinin A (NKA), substance P (SP) and calcitonin gene-related peptide (CGRP) from different regions of rat stomach. Firstly, the tissue content of NKA-, SP- and CGRP-like immunoreactivity (LI) was measured in the fundus, in the corpus, in the muscle layer and in the mucosa of corpus of control rats and rats pre-treated with systemic capsaicin, s.c. (50 mg/kg as newborn). A large depletion (about 80%) of CGRP-LI following capsaicin treatment was observed in all regions examined, while no difference was observed for NKA-LI and SP-LI. NKA-LI, SP-LI and CGRP-LI release induced by capsaicin was measured in different regions of the rat stomach. Both in the gastric fundus and in the corpus, capsaicin (10 microM) produced a remarkable release of of CGRP-LI and NKA-LI, but not of SP-LI. A second administration of the drug had no longer effect, indicating desensitization. In the gastric corpus, the capsaicin-induced NKA-LI and CGRP-LI release was larger from the muscle layer than from the mucosa. The present findings provide neurochemical evidence that both NKA-LI and CGRP-LI are released from different regions of the rat stomach and both peptides should therefore be taken into account when considering the efferent function of capsaicin-sensitive primary afferents at gastric level.
Animals↗
Neurochemical evidence of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) release from capsaicin-sensitive nerves in rat mesenteric arteries and veins.
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.
Animals↗
Low pH-induced release of calcitonin gene-related peptide from capsaicin-sensitive sensory nerves: mechanism of action and biological response.
Protons can release in a Ca(2+)-dependent manner, calcitonin gene-related peptide (CGRP)-like immunoreactivity from peripheral endings of capsaicin-sensitive afferents. Here we have studied the mechanism by which proton promotes CGRP-like immunoreactivity release and whether the neuropeptide released might exert a biological action. In muscle slices of guinea-pig urinary bladder high pH (pH 8 or 9) media neither enhanced CGRP-like immunoreactivity outflow nor affected the capsaicin-evoked CGRP-like immunoreactivity release. The CGRP-like immunoreactivity release evoked by superfusion with pH 5 medium was not affected by tetrodotoxin (0.3 microM) indomethacin (10 microM) or the protein kinase C inhibitor H-7 (30 microM). However, it was reduced by 35% in the presence of the voltage-sensitive Ca(2+)-channel antagonists nifedipine (1 microM) and omega-conotoxin (0.1 microM) and by 80% in presence of the capsaicin "antagonist" Ruthenium Red (10 microM). The CGRP-like immunoreactivity release by capsaicin (10 microM) was reduced by 80% in the presence of Ruthenium Red, and not affected by voltage-sensitive Ca(2+)-channel blockers, while that evoked by 80 mM K+ was decreased by 82% in the presence of nifedipine and omega-conotoxin. The Ca(2+)-channel agonist Bay K 8644 enhanced the high K(+)-evoked CGRP-like immunoreactivity release but not that induced by capsaicin or pH 5 medium. Exposure to pH 6 solution of one half of the neck of guinea-pig urinary bladder induced a slowly developing inhibition of electrically evoked contractions, that was absent in the half pre-exposed in vitro to a desensitizing dose of capsaicin.(ABSTRACT TRUNCATED AT 250 WORDS)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗