Biomedical subjects

A Meli

Publications and source records attributed to A Meli.

At least 37 records · Page 2Linked to original sources

PubMed1990

Further studies on the response of the guinea-pig isolated bronchus to endothelins and sarafotoxin S6b.

Endothelin-1 (ET-1), endothelin-3 (ET-3) and sarafotoxin S6b (SRFTX) produced a concentration-dependent contraction of the guinea-pig isolated bronchus. In untreated preparations, SRFTX was about 10 times more potent than ET-1 or ET-3 and produced a greater maximal effect. Mechanical removal of the bronchial epithelium (rubbing) or the addition of indomethacin (5 microM) increased the potency of all peptides, ET-3 being enhanced more than ET-1 or SRFTX. Further, the activity of ET-3 was enhanced by a mixture of peptidase inhibitors (thiorphan, captopril, bestatin, 1 microM each). When the three potentiating factors were combined (rubbed bronchi in presence of indomethacin and peptidase inhibitors), the following order of potency was found, ET-3 congruent to SRTFX greater than ET-1. For comparison, the activity of the three peptides was also studied in the rubbed rat isolated aorta in the presence of indomethacin and peptidase inhibitors and the following rank order of potency was found: ET-1 greater than SRFTX greater than ET-3. When the activity of the peptides was compared in these two preparations, ET-1 was 4 times more potent in the aorta than in the bronchus, while SRFTX and ET-3 were 8.7 and 133 times more potent in the bronchus than the aorta, respectively. These findings indicate that, in the guinea-pig bronchus, the contractile activity of these peptides is attenuated by the concomitant production of epithelium-derived relaxant factor(s), prostanoid production via the cyclooxygenase pathway and, possibly, enzymatic inactivation of added peptides. Further, the existence of multiple receptors mediating the contractile response to these peptides is suggested.

Animals↗

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

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

Effect of serotoninergic drugs on stress-induced hyperthermia (SIH) in mice.

8-OH-DPAT (2.5-10 mg/kg) and buspirone (10 mg/kg) but not 5,7-DHT (200 micrograms/mouse), pCPA (75 and 150 mg/kg, three times), ritanserin (0.1 and 0.2 mg/kg), LY 53857 (1.5 and 3 mg/kg), GR 38032 F (0.1-100 micrograms/kg), TFMPP (5 and 20 mg/kg) and mCPP (2.5 and 5 mg/kg) antagonized the rise in body temperature that occurs to the last mice removed from their group housing, which was termed as stress-induced hyperthermia (SIH). Ro 15-1788, at a dose which blocked the effect of diazepam on SIH, did not reverse the anxiolytic effect of buspirione. Instead, when cerebral 5-HT content was reduced to 50% by 5,7-DHT-induced lesion, the effect of buspirone on SIH was decreased. TFMPP 5 mg/kg did not shorten significantly the onset of SIH as could have been expected by an anxiogenic drug, while the dose of 20 mg/kg did not modify the pattern of SIH at all. The lower dose of TFMPP evoked a hyperthermic and the higher a hypothermic response.

5,7-Dihydroxytryptamine↗

PubMed1990

Pharmacological validation of a novel animal model of anticipatory anxiety in mice.

The current study investigates the action of anxiolytics, antidepressants, neuroleptics, antipyretics, muscle relaxants, antihypertensives and naloxone in a novel animal model of anxiety, based on the evidence that mice removed last from their cage develop hyperthermia (stress-induced hyperthermia, SIH) when compared to those removed first. Alprazolam (0.15-0.6 mg/kg), chlordiazepoxide (25 mg/kg), estazolam (1 mg/kg), phenobarbital (20 mg/kg), ethanol (2 and 4 g/kg), buspirone (5 and 10 mg/kg) and prazosin (1 and 2 mg/kg), as well as repeatedly administered diazepam (5 mg/kg), inhibited SIH. In contrast, tofisopam (12.5-200 mg/kg), desipramine (15 and 30 mg/kg), amitriptyline (10 mg/kg), fluoxetine (10 and 20 mg/kg), tranylcypromine (5 and 10 mg/kg), chlorpromazine (1 and 2 mg/kg), clozapine (2 and 4 mg/kg), pimozide (0.5 and 1 mg/kg), l-sulpiride (15 and 30 mg/kg), l-propranolol (5 and 10 mg/kg), acetyl salicylic acid (200 and 400 mg/kg), indomethacin (2.5 and 5 mg/kg), verapamil (2.5 and 5 mg/kg), captopril (25 and 50 mg/kg), dantrolene (10 and 20 mg/kg), mephenesin (300 and 600 mg/kg), d-amphetamine (1 and 4 mg/kg) and naloxone (2.5 and 15 mg/kg) were inactive, as were 10 mg/kg imipramine, amitriptyline and fluoxetine injected every day for 21 days. Reserpine at high doses (1.25 and 2.5 mg/kg) but not at a lower dose (0.62 mg/kg) prevented SIH, but in this case animals showed a behavioural syndrome which could have interfered with the occurrence of the hyperthermia.

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

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

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↗

PubMed1990

Effect of thiorphan on the response of guinea-pig isolated urinary bladder to exogenous and endogenous tachykinins.

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.

Animals↗

PubMed1990

Immunoblockade by a specific tachykinin antiserum of the non-cholinergic contractile responses in the guinea-pig isolated bronchus.

1. In the guinea-pig isolated bronchus, capsaicin produced a concentration-dependent contraction which was tetrodotoxin- (1 microM) resistant but abolished by previous exposure to capsaicin. 2. Previous incubation with E7 antiserum (which crossreacts with neurokinin A but not with substance P), but not with control rabbit serum, strongly inhibited the contractile response to capsaicin. 3. The E7 antiserum shifted to the right the concentration-response curve to exogenous neurokinin A but not that to substance P. 4. The E7 antiserum also inhibited the non-cholinergic, slowly developing contraction produced by electrical field stimulation (1-5 Hz). 5. These findings provide additional evidence that tachykinin-like peptides play a major role in the bronchoconstrictor response produced by transmitter secretion from peripheral endings of capsaicin-sensitive afferents in guinea-pig bronchi evoked either by capsaicin or by electrical field stimulation.

Airway Resistance↗

PubMed1990

Tachykinin receptors in the circular muscle of the guinea-pig ileum.

1. We have studied the mechanical response of circular strips of the guinea-pig ileum to tachykinins and characterized the receptors involved by means of receptor-selective agonists. 2. The strips responded to both substance P (SP) and neurokinin A (NKA), as well as to [Pro9]-SP sulphone (selective NK1-receptor agonist), [beta Ala8]-NKA(4-10) (selective NK2-receptor agonist) and [MePhe7]-neurokinin B (selective NK3-receptor agonist). The ED50s of the various peptides (calculated as the concentration of agonist which produced 50% of the response to 10 microM carbachol) were similar, in the range of 40-200 nM, i.e. no clearcut rank order of potency was evident. 3. The response to a submaximal (10 nM) concentration of SP or NKA was unaffected in the presence of peptidase inhibitors (thiorphan, captopril and bestatin, 1 microM each). 4. The response to the NK1-agonist was totally atropine-resistant, but was reduced (about 30% inhibition) by tetrodotoxin. The response to the NK3-receptor agonist was halved by atropine and abolished by tetrodotoxin. The response to the NK2-agonist was unaffected by either atropine or tetrodotoxin. 5. The response to the selective NK2-agonist was unchanged after desensitization of NK1- or NK3-receptors. 6. The response to the NK2-selective agonist was strongly inhibited by [Tyr5, D-Trp6,8,9, Arg10]-NKA(4-10) (MEN 10,207) a selective NK2-receptor antagonist which did not modify the response to the NK1-selective agonist. 7. Our findings indicate that all the three known types of tachykinin receptors mediate the contractile response of the circular muscle of the guinea-pig ileum to peptides of this family. The response to activation of NK3-receptors is totally neurogenic and partially mediated by endogenous acetylcholine, the response to activation of NK1-receptors is partly neurogenic and largely myogenic and the response to activation of NK2-receptors is totally myogenic.

Animals↗

PubMed1990

Motor response of the human isolated small intestine and urinary bladder to porcine neuromedin U-8.

1. Porcine neuromedin U-8 produced a concentration (0.3 nM-1 microM)-dependent contraction of the longitudinal muscle of the human isolated ileum, which was unaffected by either atropine (1 microM) or tetrodotoxin (1 microM). 2. By contrast, neuromedin U-8 had only a weak effect on the circular muscle of the human isolated ileum. 3. Neuromedin U-8 also produced a concentration-dependent contraction of mucosa-free muscle strips from the dome of the human isolated urinary bladder, its action being unaffected by either atropine or tetrodotoxin. 4. These findings indicate that neuromedin U-8 exerts a direct contractile effect on smooth muscle of the human intestinal and urinary tract.

Aged↗

PubMed1990

Competitive antagonists discriminate between NK2 tachykinin receptor subtypes.

1. We have compared the ability of various tachykinins and selective tachykinin receptor agonists to induce contraction of the endothelium-denuded rabbit pulmonary artery (RPA) and hamster trachea (HT) and have estimated the affinity of some newly developed NK2 selective antagonists in the same tissues. 2. In confirmation of previous findings, experiments with the agonists indicated that NK2 receptors are the main if not the sole mediators of the response to tachykinins in both RPA and HT. No evidence for significant degradation of neurokinin A (NKA) was found in either tissue when experiments were repeated in the presence of a mixture of peptidase inhibitors (thiorphan, captopril and bestatin, 1 microM each). 3. The peptide antagonists tested were: Peptide I = [Tyr5, D-Trp6,8,9, Arg10]-NKA(4-10); Peptide II = [Tyr5, D-Trp6,8,9, Arg10]-NKA(3-10); Peptide III = Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2. The three peptides produced a concentration-dependent rightward shift of the concentration-response curve to NKA in both RPA and HT with no significant depression of the maximal response attainable. The slopes of the Schild plots were not significantly different from unity, indicating a competitive antagonism. Peptides I and II were about 100 times more potent in the RPA than in the HT, while Peptide III was about 100 times more potent in the HT than RPA. 4. The pA2 values obtained in these two tissues with the three antagonists were not significantly different when tested in the absence or presence of peptidase inhibitors, or when a selective NK2 receptor agonist, [beta Ala8]-NKA(4-10) was used instead of NKA. Similar pA2 values were obtained after 15 or 90min of incubation with the antagonists. Peptides I, II and III had no inhibitory effect on contractions produced by noradrenaline in the RPA or by carbachol in the HT. 5. Peptides I, II and III showed weak or no antagonistic activity toward the vasodilatator effect of substance P in the dog carotid artery (NK, receptor-mediated) or toward the contractile effect of neurokinin B in the rat portal vein (NK3 receptor-mediated). 6. These results provide pharmacological evidence for heterogeneity of NK2 receptors in the RPA and HT. The NK2 receptors present in these tissues are not discriminated by natural tachykinins or selective agonists, but are recognized with very different affinity by NK2 receptor antagonists.

Amino Acid Sequence↗

PubMed1990

Desipramine and nortriptyline antagonize apomorphine and reserpine hypothermia by a different mechanism.

The reversal of hypothermia, induced by reserpine or by a high (16 mg) dose of apomorphine, in male Swiss mice, does not seem to utilize a common mechanism. Desipramine (20 mg kg-1 i.p., 60 min) or nortriptyline (8 mg kg-1 i.p., 60 min) increased temperature in both reserpine (2.5 mg kg-1 s.c., 18-19 h) and apomorphine (16 mg kg-1 s.c., 30 min) treated mice. In apomorphine-treated animals the effect of both drugs was reversed by the mixed dopaminergic D1- D2-antagonist haloperidol (1 mg kg-1 i.p., 90 min), the D1-receptor blocking drug SCH 23390 (0.05 mg kg-1 s.c., 30 min), the alpha 1-adrenoceptor blocking drugs prazosin (3 mg kg-1 s.c., 90 min) and phenoxybenzamine (20 mg kg-1 i.p., 65 min), the beta-adrenoceptor blocking drug (+/-)-propranolol (10 mg kg-1 i.p., 120 min), and the opioid antagonist naloxone (2 mg kg-1 i.p., 15 min). In contrast the selective D2-antagonist (+/-)-sulpiride (100 mg kg-1 i.p., 90 min), and the alpha 2-antagonist yohimbine (2 mg kg-1 i.p., 75 min), failed to effect the reversal of apomorphine hypothermia brought about by desipramine or nortriptyline. Their temperature effects in reserpinized mice were not modified by any of the antagonists tested.

Animals↗

PubMed1990

Dual effects of cholecystokinin-octapeptide on duodenal motility of urethane-anesthetized rats.

Intravenous administration of cholecystokinin octapeptide (CCK-8) to urethane-anesthetized rats produced both inhibitory and excitatory effects on intestinal motility. The inhibitory effect, evident as a transient relaxation or inhibition of distension-induced reflex contractions, was abolished by adrenoreceptor blockade, guanethidine pretreatment or removal of the celiac ganglion complex, but was hexamethonium-and atropine-insensitive. The excitatory action of CCK-8 was atropine- and hexamethonium-sensitive, while being unaffected by guanethidine pretreatment. Ligation experiments indicated that the excitatory effect of CCK-8 originates from a stimulant action on structures in the upper duodenum/pyloric sphincter from which a propagated contraction travels to the distal duodenum. We conclude that i.v. CCK-8 inhibits small intestinal motility by directly activating sympathetic neurons in the celiac ganglion and initiates a propagated form of intestinal motility by stimulating neural elements in the upper part of the small intestine.

Animals↗

PubMed1989

The activity of peptides of the endothelin family in various mammalian smooth muscle preparations.

The activity of natural endothelins such as ET-1, ET-2, ET-3 and of sarafotoxin S6b (SRFTX) as compared to that of the C-terminal hexapeptide ET-(16-21) was investigated in several smooth muscle preparations in the presence of indomethacin, captopril, bestatin and thiorphan. In some tissues (rat thoracic aorta, guinea-pig ileum, human urinary bladder, renal pelvis or renal artery), ET-(16-21) had little if any agonist activity. In other preparations (guinea-pig bronchus, rat vas deferens, rabbit pulmonary artery) ET-(16-21) was a full agonist. The amidated form of ET-(16-21) was either inactive or less potent than ET-(16-21). These findings provide evidence that at least two receptors exist for peptides of the ET family; these receptors were termed ETA and ETB. ET-(16-21) is a full agonist at ETB receptors while being inactive or weakly active at ETA receptors. The free acid of tryptophan in position 21 plays a key role in the activity of these peptides at ETB receptors.

Animals↗