Biomedical subjects

C A Maggi

Publications and source records attributed to C A Maggi.

At least 379 records · Page 21Linked to original sources

PubMed1990

The dual function of capsaicin-sensitive sensory nerves in the bladder and urethra.

The sensory innervation of the urinary bladder and urethra plays a key role in a variety of reflexes involved in urine storage and voiding. Dysfunction of these systems is a possible cause of many disturbances related to urine continence but basic knowledge in this field has been hampered by the lack of tools for studying sensory nerves. The use of capsaicin, the pungent ingredient of red peppers, allowed us to investigate the anatomical and functional properties of a specific subset of sensory neurons in the lower urinary tract. These 'capsaicin-sensitive' neurons play a dual sensory and 'efferent' function, determined by transmitter release from their central and peripheral nerve endings. Tachykinins, including substance P, and other neuropeptides such as calcitonin gene-related peptide, mediate the functions of these sensory neurons. The 'sensory' function includes regulation of micturition threshold, activation of cardiovascular reflexes and perception of pain from the urinary bladder. The 'efferent' function includes local regulation of muscle cell activity, nerve excitability, blood flow and plasma protein extravasation. Recent data suggest that capsaicin-sensitive sensory nerves could be present in the human bladder.

Capsaicin↗

PubMed1990

Human isolated ileum: motor responses of the circular muscle to electrical field stimulation and exogenous neuropeptides.

(1) Circularly-oriented muscle strips from the human ileum responded to electrical field stimulation (1-50 Hz) with frequency-related primary relaxation at low frequency and primary contractions at high frequencies of stimulation. Both responses were abolished or markedly reduced by tetrodotoxin (1 microM). (2) Atropine (3 microM) or omega conotoxin (0.1 microM) reduced but dit not abolish contraction to electrical field stimulation and enhanced the relaxation. Omega conotoxin (0.1 microM) did not affect carbachol-induced contraction nor isoprenaline-induced relaxation. (3) Neurokinin A and substance P (1 nM-1 microM) produced a concentration-dependent contraction. The NK-1 receptor selective agonist, [Pro9]SP sulfone and the NK-2 receptor selective agonist [beta Ala8]NKA(4-10) produced a contraction superimposable to that of substance P and neurokinin A, respectively. On the other hand, [MePhe7]-neurokinin B, an NK-3 receptor selective agonist was ineffective up to 1 microM. The response to substance P or neurokinin A was unaffected by atropine (3 microM). (4) Galanin, up to 0.1 microM, produced a weak and inconsistent contraction. (5) Vasoactive intestinal polypeptide (10 nM-1 microM) produced a concentration-dependent relaxation while human alpha calcitonin gene-related peptide exerted a weak and inconsistent relaxant effect. (6) These findings indicate that both cholinergic excitatory and non-cholinergic inhibitory nerves affect the motility of the circular muscle of the human small intestine. Transmitter release from excitatory nerves seems largely mediated by activation of omega conotoxin-sensitive (N-type) calcium channels. Tachykinins exert a potent contractile effect, independently of cholinergic nerves, via NK-1 and NK-2 receptors.

Aged↗

PubMed1990

Effects of carbonyl cyanide p-trichloromethoxyphenylhydrazone (CCCP) and of ruthenium red (RR) on capsaicin-evoked neuropeptide release from peripheral terminals of primary afferent neurones.

In the superfused isolated rat urinary bladder, capsaicin as well as electrical field stimulation evoked the release of calcitonin gene-related peptide-like immunoreactivity (CGRP-IR). Carbonyl cyanide p-trichloromethoxyphenylhydrazone (CCCP, threshold 2 microM) reduced both, the capsaicin- and the electrical field stimulation-evoked release of CGRP-IR while a low concentration of Ruthenium Red (RR, 0.6 microM and 2 microM) selectively attenuated the capsaicin-evoked release of CGRP-IR but did not influence the effect of electrical field stimulation. 20 microM RR nearly abolished the capsaicin-evoked release, but also attenuated the effect of electrical field stimulation. In the isolated guinea-pig bronchus, electrical field stimulation and capsaicin induced non-cholinergic contractions which are known to be caused by tachykinin release from afferent nerve terminals. CCCP (0.6 microM) only reduced the response to field stimulation; a ten-fold higher concentration of CCCP attenuated field stimulation as well as capsaicin-induced contractions. This is in contrast to the reported selective inhibition of capsaicin-induced contractions by RR. The present data demonstrate that CCCP generally inhibits evoked neuropeptide release, regardless of the kind of stimulation used while low concentrations of RR preferentially inhibit capsaicin-evoked neuropeptide release.

Animals↗

PubMed1990

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

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 mumol/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 acrylamide 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.

Alkaloids↗

PubMed1990

Sensory nerves, vascular endothelium and neurogenic relaxation of the guinea-pig isolated pulmonary artery.

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)

Animals↗

PubMed1990

Effects of capsaicin, tachykinins, calcitonin gene-related peptide and bradykinin in the pig iris sphincter muscle.

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)

Animals↗

PubMed1990

Comparative bioavailability of diclofenac hydroxyethylpyrrolidine vs diclofenac sodium in man.

A phamacokinetic study in man has been made of a new dosage form of diclofenac hydroxyethylpyrrolidine (DIEP); soluble salt packed in sachets was compared with diclofenac sodium as enteric coated tablets. Oral DIEP 2 X 50 mg showed a significant difference in absorption kinetics (ka, lag time and tmax) as compared to oral diclofenac sodium 2 X 50 mg. A relevant plasma concentration of diclofenac was detected just 15 min after DIEP, while diclofenac sodium produced a measurable plasma concentration only 0.5-1 h after the treatment. Cmax and t1/2 after DIEP and diclofenac sodium were comparable. Comparison of the two AUC values showed that DIEP was bioequivalent to diclofenac sodium (Q = 100%).

Biological Availability↗

PubMed1990

Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells.

We have investigated the possible effect of substance P (SP), a main mediator of neurogenic inflammation, on the growth of capillary vessels in vivo, and on the proliferation of cultured endothelial cells in vitro. Slow release preparations of SP were implanted into the avascular cornea of New Zealand White rabbits and vessel growth was monitored daily through a slit lamp stereomicroscope. SP (1-5 micrograms/pellet) induced a marked neovascularization. A selective NK-1 receptor agonist [beta-Ala4, Sar9, Met(O2)11]-SP(4-11) also induced neovascularization. The addition of SP to serum-free cultured endothelial cells, isolated from bovine adrenals (BACE) and from human umbilical cord veins (HUVE), increased proliferation of both cell lines in a concentration-dependent manner with maximal activity at 10(-8) M (BACE) and 10(-10) M (HUVE). The selective NK-1 receptor agonist induced a similar proliferative action on both cell lines, while the selective NK-2 receptor agonist [beta-Ala8]-NKA(4-10) and the selective NK-3 receptor agonist [MePhe7]-NKB had no significant effect. Two different SP antagonists [D-Pro2, D-Trp7,9]-SP and [D-Pro4, D-Trp7,9,Phe11]-SP (4-11) blocked the response to SP. These findings indicate that SP can directly stimulate the process of neovascularization, probably through induction of endothelial cell proliferation. This hitherto unraveled activity of SP could play a key role in the trophic action produced by activation of the efferent function of peripheral endings of primary sensory neurons.

Animals↗

PubMed1990

Effect of endothelin-1, endothelin-3 and C-terminal hexapeptide, endothelin (16-21) on motor activity in rats.

Intracerebroventricular administration of ET-1 (12.5 and 25 pmol/rat) and ET-3 (25 and 50 pmol/rat) induced the loss of the righting reflex and barrel-rolling behaviour in rats. The C-terminal hexapeptide ET(16-21) did not produce these effects. The automated recording of motor activity revealed that, unlike ET (16-21), both ET-1 and ET-3 evoke a dose-regulated increase of the immobility time. Pretreatment with peptidase inhibitors did not modify the activity of subthreshold doses of peptides. Since ET (16-21) display full agonist properties at ETB but does not interact with ETA receptors, the present data suggest that the behavioural syndrome induced by centrally administered ET-1 and ET-3 may be mediated by stimulation of ETA receptors.

Animals↗

PubMed1990

Involvement of capsaicin-sensitive nerves of the rat urinary bladder in acrylamide neuropathy.

Acrylamide monomer is neurotoxic in man and experimental animals, producing a sensorimotor distal axonopathy. In spite of remarkable effect of acrylamide on micturition, resulting in urine retention in both man and rat, bladder autonomic innervation has been little studied. This study focused on the effect of acrylamide on capsaicin-sensitive nerves of the rat bladder, because of the role played by these fibres in regulating the afferent arm of reflex micturition.

Acrylamide↗

PubMed1990

Effect of urethane anesthesia on the micturition reflex in capsaicin-treated rats.

Cystometry was performed on rats with a chronically implanted intravesical catheter (2 days before cystometry) before and after induction of urethane-anesthesia. Four groups of animals were investigated: group A, vehicle-treated; group B, capsaicin-treated as adults (50 mg/kg s.c.) 4 days before cystometry; group C, capsaicin-treated as adults (125 mg/kg s.c.) 4 days before cystometry; and group D, capsaicin-treated as newborns (50 mg/kg) 2 months before. Rats of group D had a markedly enlarged bladder. Before induction of urethane anesthesia, the bladder capacity of rats of groups A, B and C was not significantly different from each other, while that of rats of group D was larger than controls. After induction of anesthesia bladder capacity in groups B and C was significantly increased as compared to group A and micturition was abolished in group D (overflow incontinence). Amplitude of micturition contraction was significantly reduced in all groups after induction of anesthesia but was unaffected by capsaicin pretreatment. It is concluded that the facilitatory action of capsaicin-sensitive nerves on micturition threshold is more evident in anesthetized than awake rats and that capsaicin-resistant bladder afferents are more sensitive to the depressant action of urethane than the capsaicin-sensitive ones.

Anesthesia↗

PubMed1990

Effect of sensory denervation with capsaicin on liver fibrosis induced by common bile duct ligation in rat.

Hepatic fibrosis represents an important stage in the progression of chronic liver disease to cirrhosis. In the present paper we have investigated whether capsaicin-sensitive neuropeptide-containing sensory neurons may participate in the development of liver fibrosis. The expression of hepatic fibrosis induced by common bile duct obstruction has been studied both in capsaicin- and vehicle-treated rats. Common bile duct-induced liver fibrosis was less marked in capsaicin-treated rats than in vehicle-treated rats. Diffuse alterations of liver parenchyma structure with marked collagen deposition and nodular regeneration occurred 8 weeks after common bile duct ligation in vehicle-treated animals, while none of the capsaicin-treated rats exhibited the formation of complete connective septa altering the parenchyma architecture. Both vehicle- and capsaicin-treated rats showed an increasing number of desmin-positive cells in the perivenular zone, but the density of these cells was lower in treated animals than in untreated rats. The hydroxyproline content of the liver increased after common bile duct ligation in a time-dependent manner. Eight weeks after bile duct obstruction vehicle-treated rats showed a 7-fold increase of liver collagen content in comparison to normal animals. This enhancement was about 3.5-fold in capsaicin-treated rats. These findings raise the possibility that the peripheral release of neuropeptides stored in sensory nerves might participate in the development of liver fibrosis following common bile duct obstruction.

Animals↗

PubMed1990

Motor and inflammatory effect of hyperosmolar solutions on the rat urinary bladder in relation to capsaicin-sensitive sensory nerves.

1. Intravesical administration of hyperosmolar NaCl or urea solutions produced a concentration-dependent stimulatory action on the micturition reflex in urethane-anesthetized rats. This effect was not modified in rats pretreated with capsaicin as adults (50 mg/kg s.c. 4 days before). 2. Hyperosmolar NaCl also produced Evans blue leakage (plasma extravasation) in the rat bladder. This effect was greatly reduced by extrinsic bladder denervation and in rats desensitized to capsaicin as newborns but not as adults. 3. Cumulative addition of NaCl produced a concentration-dependent increase in tone and biphasic effects on neurogenic contractions of the rat isolated bladder. These effects were not modified by in vitro capsaicin desensitization. 4. These findings do not support the idea that true osmoreceptors are present in the rat urinary bladder. The neurogenic component of the inflammatory response to hyperosmolar NaCl could involve activation of a subpopulation of bladder sensory fibers susceptible to the neurotoxic action of capsaicin in the early postnatal period only.

Animals↗

PubMed1990

Opioid receptors and prejunctional modulation of capsaicin-sensitive sensory nerves in guinea-pig left atrium.

1. In the isolated electrically driven left atria from reserpine-pretreated guinea-pigs and in presence of 1 microM atropine, electrical field stimulation (EFS) at 10 Hz produces a delayed positive inotropic response (DPIR) involving activation of capsaicin-sensitive afferents. 2. Opioids inhibited the DPIR with the following order of potency: dermorphin greater than [D-Ala2,N-MePhe4, Gly5-ol]-enkephalin (DAGO) greater than or equal to [D-Ala2,D-Leu5]-enkephalin (DADLE) greater than morphine greater than dynorphin A (1-13) greater than [D-Pen2,D-Pen5]-enkephalin (DPDPE). U-50488 was ineffective up to 10 microM. 3. Opioids also inhibited resting inotropism (3 Hz) with the following rank order of potency: DADLE greater than DAGO greater than U-50488 = dynorphin A (1-13) = morphine = DPDPE. 4. Both inhibition of the DPIR and inhibition of resting inotropism were prevented by 10 microM naloxone. 5. Neither dermorphin (0.1 microM) nor DAGO (0.3 microM) or DADLE (1 microM) inhibit responses produced by capsaicin (30 nM) or calcitonin gene-related peptide (3 nM). 6. These findings indicate that capsaicin-sensitive nerves in the guinea-pig atrium are endowed with mu opioid receptors which inhibit transmitter release when sensory nerve terminals are activated by EFS but not by capsaicin.

Animals↗

PubMed1990

Contractile responses of the human urinary bladder, renal pelvis and renal artery to endothelins and sarafotoxin S6b.

1. Endothelin-1 (ET-1), endothelin-3 (ET-3) and sarafotoxin S6b (SRFTX) produced a concentration-dependent tonic contraction of the human isolated urinary bladder, renal pelvis and renal artery with threshold at nM concentration. 2. In the bladder, the following order of potency was found: ET-1 greater than SRFTX greater than ET-3. In the renal pelvis, all peptides displayed similar affinity but, at high concentrations the maximal response was highest for SRFTX followed by ET-1 and ET-3. In the renal artery ET-1 and SRFTX were about equipotent and equieffective while ET-3 produced only a slight and inconsistent (2 out of 5 cases) vasoconstrictor response. 3. As shown previously for the human bladder muscle, the response to ET-1 in the renal pelvis was nifedipine (1 microM)-resistant while a consistent fraction of the response was blocked by nifedipine in the human renal artery. 4. These findings indicate that peptides of the endothelin family exert a potent contractile effect on various human smooth muscles. Participation of dihydropyridine- and voltage-sensitive calcium channels in the contractile response produced by these peptides may vary from one organ to another.

Endothelins↗

PubMed1990

Bradykinin-induced release of calcitonin gene-related peptide from capsaicin-sensitive nerves in guinea-pig atria: mechanism of action and calcium requirements.

The mechanism of neuropeptide secretion induced by bradykinin from capsaicin-sensitive afferents was studied in guinea-pig atria. Both the inotropic response induced by bradykinin (0.1 microM) in the electrically driven isolated guinea-pig left atria and the bradykinin (10 microM)-induced release of calcitonin gene-related peptide calcitonin gene-related peptide-like immunoreactivity from slices of guinea-pig atria were abolished in vitro by capsaicin pretreatment or in the presence of indomethacin. Bradykinin-induced calcitonin gene-related peptide-like immunoreactive release was unaffected by tetrodotoxin (0.3 microM), the protein kinase C inhibitor, 1-(5-isoquinolinesulphonyl)-2-methylpiperazine (30 microM), nefedipine (1 microM) or Ruthenium Red (10 microM). It was significantly reduced by 79% in a Ca2(+)-free medium and by 52% in the presence of 0.1 microM omega-conotoxin (fraction GVIA). It is proposed that bradykinin releases calcitonin gene-related peptide from capsaicin-sensitive afferents in guinea-pig atria, via prostanoid generation. This mode of activation of the "efferent" function of capsaicin-sensitive nerves appears to be distinct from those produced by capsaicin or electrical field stimulation as they have been characterized in previous works. In fact, the bradykinin activation of capsaicin-sensitive afferents is not affected by tetrodotoxin and Ruthenium Red, but is partially sensitive to the selective blocker of N-type Ca2(+)-channels, omega-conotoxin.

Animals↗

PubMed1990

Motor response of the human isolated colon to capsaicin and its relationship to release of vasoactive intestinal polypeptide.

The aim of this study was to obtain indirect evidence of the presence of capsaicin-sensitive afferents in the human colon by studying the motor response to capsaicin of longitudinal strips from the human isolated taenia coli in parallel to the ability of capsaicin or KCl to induce peptide release from the human superfused colon. Capsaicin (1 microM) evoked a relaxation of the taenia, approaching 60-80% of the response to isoprenaline. Tachykinins evoked contractions of the taenia, while calcitonin gene-related peptide induced a relaxation. Neither tachyphylaxis to calcitonin gene-related peptide nor preincubation with an anti-calcitonin gene-related peptide serum did block the response to capsaicin which was also unaffected by tetrodotoxin, apamin, naloxone or an anti-galanin serum. Vasoactive intestinal polypeptide produced a concentration-dependent tetrodotoxin-resistant relaxation which was shifted rightward in the presence of anti-vasoactive intestinal polypeptide serum. The anti-vasoactive intestinal polypeptide serum reduced the response to capsaicin and application of capsaicin prevented the ability of anti-vasoactive intestinal polypeptide serum to block exogenous vasoactive intestinal polypeptide. Capsaicin (1 microM) evoked a significant release of vasoactive intestinal polypeptide-like immunoreactivity from the superfused muscle but not mucosa of the human colon. A significant vasoactive intestinal polypeptide-like immunoreactivity release was also observed in response to KCl (80 mM). KCl but not capsaicin evoked a significant release of neurokinin A-like immunoreactivity from colonic muscle and mucosa. No significant release of either substance P-, neuropeptide Y-, galanin- or calcitonin gene-related peptide-like immunoreactivity was detected in response to capsaicin or KCl although detectable levels of each peptide were evident in tissue extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Apamin↗

PubMed1990

Effect of omega conotoxin on reflex responses mediated by activation of capsaicin-sensitive nerves of the rat urinary bladder and peptide release from the rat spinal cord.

The aim of this study was to assess whether omega conotoxin fraction GVIA, a potent blocker of N- and L-type voltage-sensitive calcium channels, might interfere with reflex responses (micturition, blood pressure rise in spinal rats) produced by activation of capsaicin-sensitive sensory nerves of the rat urinary bladder. The effect of conotoxin was also investigated on reflex micturition persisting after capsaicin pretreatment. Following topical application onto the bladder, conotoxin did not affect the volume threshold to elicit micturition although it reduced the amplitude of volume-evoked bladder contractions. Likewise, topical conotoxin did not prevent the reflex rise in blood pressure elicited by sudden bladder distension or topical application of capsaicin onto the bladder. In contrast, topical lidocaine strongly prevented both reflex responses. After intrathecal administration, conotoxin produced a dose-dependent inhibition of volume-evoked bladder contractions and the cardiovascular reflex produced by mechanical or chemical stimulation of bladder nerves. Intrathecal conotoxin inhibited micturition also in rats pretreated with capsaicin (50 mg/kg s.c., 4 days before). Depolarization by high potassium (80 mM) produced release of both substance P- and calcitonin gene-related peptide-like immunoreactivity from superfused slices of the dorsal half of rat spinal cord. Capsaicin (1 microM) produced a similar effect, and a previous exposure to capsaicin prevented the effect of potassium. Conotoxin (0.1 microM) significantly reduced (about 50%) the potassium-induced release of neuropeptides from the dorsal half of the rat spinal cord. These findings indicate that conotoxin-sensitive calcium channels in the rat spinal cord play a role in the neurotransmission along reflex pathways activated by stimulation of capsaicin-sensitive nerves in the urinary bladder.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗