Biomedical subjects

J L Ellis

Publications and source records attributed to J L Ellis.

At least 37 records · Page 2Linked to original sources

PubMed1994

Potentiation of nonadrenergic noncholinergic relaxation of human isolated bronchus by selective inhibitors of phosphodiesterase isozymes.

Human bronchial rings were contracted with histamine (3 microM), and inhibitory responses were obtained with electrical field stimulation (EFS) in the presence of propranolol (1 microM), atropine (1 microM), and indomethacin (3 microM). These nonadrenergic noncholinergic (NANC) relaxations were frequency-dependent (1 to 32 Hz) and inhibited by either tetrodotoxin or Nw-nitro-L-arginine (L-NNA, 100 microM). The selective cAMP-specific phosphodiesterase (PDE) type IV inhibitors rolipram (3 microM) and Ro 20-1724 (3 microM) significantly potentiated NANC relaxations at each frequency of stimulation. The selective cGMP-specific PDE type V inhibitor zaprinast (3 microM) failed to significantly alter the maximal NANC response, but it caused a slight potentiation of the response at lower frequencies. The adenylyl cyclase stimulant forskolin, the nitric oxide donor compound 3-morpholinosydnonimine (SIN-1), and the guanylyl cyclase stimulant sodium nitroprusside caused concentration-dependent relaxation of histamine-contracted airway smooth muscle. Rolipram significantly potentiated the relaxation elicited by forskolin. Rolipram also potentiated responses to SIN-1 and sodium nitroprusside. Considered together these data support the hypothesis that cAMP plays a facilitory role in NANC relaxation of the human bronchi.

Atropine↗

PubMed1994

Recombinant stem cell factor-induced mast cell activation and smooth muscle contraction in human bronchi.

The effect of human recombinant stem cell factor (SCF) on inflammatory mediator release and smooth muscle contraction was evaluated in human isolated intralobar bronchi. Bronchi from 21 of 26 donors contracted in response to SCF. The threshold concentration was approximately 0.01 micrograms/ml. At 1 micrograms/ml, the tissues contracted to about 60% of the carbamylcholine-induced maximum contraction. The responses to SCF mimicked those obtained with anti-IgE. Thus, the contractions to SCF and anti-IgE were inhibited to a similar extent by a combination of a cysteinyl-leukotriene receptor antagonist and a histamine H1 receptor antagonist. SCF also mimicked the effect of anti-IgE in releasing histamine, i-LTD4, and PGD2 from the bronchi. At a threshold concentration for contraction (0.01 micrograms/ml), SCF had no effect on subsequent responses to anti-IgE in the bronchi. The data suggest that human recombinant SCF contracts airway smooth muscle by stimulating the release of contractile mediators from bronchial mast cells. The data fail to support the hypothesis that SCF primes bronchial mast cells to subsequent immunologic stimuli.

Antibodies, Anti-Idiotypic↗

PubMed1994

L-citrulline reverses the inhibition of nonadrenergic, noncholinergic relaxations produced by nitric oxide synthase inhibitors in guinea pig trachea and human bronchus.

Nonadrenergic, noncholinergic relaxations were elicited by field stimulation (8 Hz, 1 msec, 12 V for 15 sec) of guinea pig trachea desensitized with capsaicin (1 microM), pretreated with atropine (1 microM), propranolol (1 microM), indomethacin (3 microM) and alpha-chymotrypsin (2 U/ml) and contracted with 3 microM histamine. These relaxations averaged 60 to 80% of the contractions to histamine. The relaxations were inhibited markedly by the addition of the nitric oxide (NO) synthase inhibitor L-nitro-n-arginine (L-NNA)(30 microM), suggesting that these relaxations are due to the release of NO. The inhibition produced by L-NNA was reversed by either L-arginine or L-citrulline. L-Citrulline was both more potent and efficacious than L-arginine in this regard. The ability of L-citrulline to reverse the inhibition produced by L-NNA was not altered by L-glutamine (1 mM). The addition of L-citrulline (1 mM) added before L-NNA was without effect on the relaxant responses to field stimulation but was able to prevent the inhibition produced by L-NNA. L-Citrulline also reversed the inhibition produced by another NO synthase inhibitor, L-nitro monomethyl arginine. Relaxations to field stimulation (16 Hz, 1 msec, 12 V for 15 sec) of human bronchus also were inhibited by 30 microM L-NNA and, as in the guinea pig, this inhibition by L-NNA could be reversed by L-citrulline. These results suggest that L-citrulline is able to overcome the inhibition of NO synthase by NO synthase inhibitors in the guinea pig trachea and human bronchus.

Adult↗

PubMed1994

Effect of potassium channel blockers on relaxations to a nitric oxide donor and to nonadrenergic nerve stimulation in guinea pig trachea.

Nonadrenergic, noncholinergic (NANC) relaxations were elicited by field stimulation (1-16 Hz, 1 msec, 12 V for 15 sec) of guinea pig trachea desensitized with capsaicin (3 microM); pretreated with atropine (1 microM), propranolol (1 microM), indomethacin (3 microM) and alpha-chymotrypsin (2 U/ml) and contracted with 3 microM histamine. The nitric oxide (NO) synthase inhibitor L-nitro-N-arginine (L-NNA) significantly inhibited these responses, which is indicative of NO involvement. The ability of the large conductance Ca(++)-activated K+ channel antagonists iberiotoxin (IbTx) and charybdotoxin (ChTx) and the small conductance Ca(++)-activated K+ channel antagonist apamin to modify relaxations to NANC nerve stimulation and to the NO donor 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1) was studied. Both IbTx (100 nM) and ChTx (100 nM) were found to inhibit the L-NNA-sensitive relaxations elicited by field stimulation and to inhibit the relaxations to SIN-1. In contrast, apamin did not inhibit the relaxations to either field stimulation or SIN-1. These results suggest that in the guinea pig trachea, responses to endogenous or exogenously added NO are at least in part mediated by the large conductance Ca(++)-activated K+ channel.

Animals↗

PubMed1994

Mucinous adenocarcinoma of the colon metastatic to the intestinal mucosa.

Autometastasis of colon cancer to the intestinal mucosa is a condition that has not been previously described. The 70-year-old man presented in this case report was seen for routine surveillance colonoscopy 14 months after low anterior resection, without anastomosis, of a Dukes' stage C mucinous adenocarcinoma of the rectosigmoid. The patient had received adjuvant chemotherapy according to Southwest Oncology Group protocol 8899. The routine colonoscopy revealed many new polypoid lesions in the remaining left and transverse colon, and the patient underwent completion total abdominal colectomy. Examination of the specimen revealed more than 100 polyps; the histologic examination identified these polyps as metastatic signet ring mucinous adenocarcinoma.

Adenocarcinoma, Mucinous↗

PubMed1994

Inhibition by capsazepine of resiniferatoxin- and capsaicin-induced contractions of guinea pig trachea.

The site of action of resiniferatoxin (RTX) and capsaicin and the pharmacological consequences of the resultant tachykinin release were examined in the guinea pig trachea. RTX and capsaicin were both potent and efficacious contractors of isolated tracheal smooth muscle. RTX was about 20-fold more potent than capsaicin, with -log (M) EC50 values of 8.88 +/- 0.09 (n = 14) and 7.55 +/- 0.07 (n = 14), respectively. The putative capsaicin receptor antagonist capsazepine (10 microM) effectively inhibited responses to both RTX and capsaicin in a competitive fashion. The -log (M) pKB values for capsazepine against resiniferatoxin and capsaicin were 6.28 +/- 0.25 and 6.04 +/- 0.13, respectively. Contractile responses to RTX and capsaicin were unaffected by the NK-1 antagonist CP 96345 (0.3 microM), partially inhibited by the NK-2 antagonist SR 48968 (0.3 microM) but nearly abolished by a combination of the antagonists. Capsaicin and RTX desensitized tissues to subsequent additions of either capsaicin (1 microM) or RTX (0.1 microM). Capsaicin showed maximal desensitization at 1 microM, and RTX at 0.1 microM. This study shows that RTX is a potent activator of capsaicin-sensitive tachykinin-containing nerves in the airways. The site of action of RTX and capsaicin appears to be a receptor sensitive to capsazepine. Moreover, RTX and capsaicin both release tachykinins that act on both NK-1 and NK-2 receptor subtypes.

Animals↗

PubMed1993

Pharmacological examination of receptors mediating contractile responses to tachykinins in airways isolated from human, guinea pig and hamster.

The abilities of agonists selective for neurokinin (NK)-1 (Ac-[Arg6,Sar9,Met(O2)11]-SP6-11, ASMSP), NK-2 ([beta-Ala8]-NKA4-10) and NK-3 ([Asp5,6,MePhe8]-SP5-11, senktide analog) receptors to contract human bronchus and guinea pig and hamster trachea were studied. The antagonism of these responses by selective antagonists was also examined. In the human bronchus and hamster trachea, [beta-Ala8]-NKA4-10 was the most potent agonist, whereas ASMSP and senktide analog failed to elicit contractions greater than 50% of the maximum response even at concentrations reaching 1 to 3 x 10(-4) M. By contrast, both ASMSP and [beta-Ala8]-NKA4-10 were potent contractile agonists in guinea pig trachea. In all tissues, the selective NK-1 receptor antagonist (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-a zab icyclo- [2.2.2]octan-3-amine (CP 96,345) was without effect on contractile responses to [beta-Ala8]-NKA4-10. Blockade by CP 96,345 of responses to ASMSP was, however, observed in the guinea pig trachea, but not in human bronchus or hamster trachea. Responses to ASMSP in human bronchus and hamster trachea were inhibited by NK-2 antagonists, whereas these compounds had little effect on responses to ASMSP in guinea pig trachea. In all tissue types, responses to senktide analog were inhibited by NK-2 antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗

PubMed1992

Inhibition by L-NG-nitro-L-arginine of nonadrenergic-noncholinergic-mediated relaxations of human isolated central and peripheral airway.

Human isolated central (5 to 12 mm) and peripheral (< 2 mm) bronchi were contracted with 3 microM histamine. Relaxations were then evoked by electrical field stimulation (EFS) (1 to 32 Hz, 1 ms, 12 V for 15 s in the presence of indomethacin, atropine, and propranolol). The magnitude, time-course, and frequency-response relationship of these nonadrenergic, noncholinergic (NANC) relaxations were similar in the central and the peripheral airways. NG-Nitro-L-arginine (L-NOARG) (10 microM) inhibited the tetrodotoxin-sensitive NANC relaxations in both central and peripheral bronchi, whereas the stereoisomer D-NOARG was without effect. This inhibition was reversed by L-arginine (1 mM) but not be D-arginine (1 mM). The nitric oxide donor compound, 3-morpholinosydnonimine (SIN-1), was equipotent at relaxing the central and peripheral airways. Vasoactive intestinal peptide (VIP), although it relaxed central airways, was virtually ineffective in relaxing the peripheral airways. In addition, the peptidase, alpha-chymotrypsin, at a concentration that blocked relaxations to VIP, was without effect on NANC relaxations in the central bronchi. The results support the following hypotheses: (1) both central and peripheral airways receive nonadrenergic relaxant innervation; (2) the relaxant response to electrical stimulation of this system is dependent on a pathway involving L-arginine; and (3) the relaxant response does not appear to involve VIP, but it may involve the production of nitric oxide.

Arginine↗

PubMed1992

Antigen-induced enhancement of noncholinergic contractile responses to vagus nerve and electrical field stimulation in guinea pig isolated trachea.

Nonadrenergic, noncholinergic contractions were elicited by electrical field stimulation (EFS) (2 Hz, 1 msec, 12 V for 15 sec) of the distal aspect of guinea pig trachea pretreated with atropine (1 microM), propranolol (1 microM) and indomethacin (3 microM). The contractions were abolished by pretreatment with the sensory C-fiber toxin capsaicin or by a combination of the neurokinin (NK)1 receptor antagonist, CP 96,345 (0.1 microM), and the NK2 receptor antagonist, MEN 10376 (3 microM), and were markedly attenuated by tetrodotoxin. In animals actively sensitized to ovalbumin, the addition of threshold concentrations of antigen markedly increased the noncholinergic contractile responses to EFS (approximately 3- to 6-fold). This potentiation was long lasting, persisting virtually unchanged for 60 min, whereas the antigen-induced contractions were shorter lived, usually lasting less than 30 min. The ovalbumin-induced potentiation of the neuronal response was not observed in tissues pretreated with capsaicin or treated with tetrodotoxin. This antigen-induced potentiation of capsaicin-sensitive, EFS-induced contractions was not mimicked by serotonin or prostaglandin D2. However, it was mimicked by histamine. Moreover, the histamine H1 receptor antagonist pyrilamine (0.3 microM) reversed the potentiation elicited by ovalbumin. The effect of ovalbumin challenge was also examined on the distal trachea with the right vagus nerve intact. Noncholinergic contractions to EFS and vagus nerve stimulation were enhanced equally by threshold concentrations of antigen. The results support the hypothesis that antigen challenge releases histamine which acts via H1 receptors to enhance noncholinergic contractions due to the release of tachykinins from capsaicin-sensitive fibers in the guinea pig trachea.

Animals↗

PubMed1991

Role of peptidoleukotrienes in capsaicin-sensitive sensory fibre-mediated responses in guinea-pig airways.

1. The right bronchus with the right vagus nerve remaining intact was isolated from the guinea-pig. Stimulating the end of the right vagus nerve distal to the bronchus resulted in a biphasic contractile response with a rapid first phase and a second phase which persisted after the cessation of stimulation. The first phase was selectively sensitive to atropine, while the second phase was non-cholinergic, but abolished by pre-treatment with the sensory C fibre toxin, capsaicin. This biphasic contraction was mimicked by electrical field stimulation of the bronchus and strips of the distal aspect of the trachea. 2. The capsaicin-sensitive second phase produced by either vagus nerve stimulation or electrical field stimulation, was inhibited by greater than 50% by the selective peptidoleukotriene receptor antagonist SKF 104353, whereas the inactive stereoisomer of SKF 104353, SKF 104373, was without effect. SKF 104353 did not inhibit the cholinergic first phase, nerve conduction along the vagus nerve, or contractions to exogenously added substance P and neurokinin A. 3. The inhibitory effect of SKF 104353 on second-phase contractions was mimicked by two structurally unrelated selective peptidoleukotriene receptor antagonists, WY 48252 and ICI 198615, and by the 5'-lipoxygenase inhibitor REV 5901. 4. Exogenously added leukotriene D4 (1 nM) potentiated the second-phase contractions in the trachea and this effect was reversed by 0.1 microM-SKF 104353. Leukotriene D4 did not affect responses to exogenously added substance P or neurokinin A. 5. Stimulation of the right vagus nerve produced plasma extravasation in the trachea and in the main bronchi of atropine- and propranolol-pre-treated guinea-pigs. This was inhibited by about 50% by SKF 104353 (10 mg/kg, I.V.), whereas SKF 104373 (10 mg/kg, I.V.) was without effect. 6. It is suggested that endogenous peptidoleukotrienes make a significant contribution to the airway smooth muscle and vascular effects of capsaicin-sensitive nerve stimulation in the guinea-pig.

Animals↗

PubMed1990

Prejunctional alpha 1-adrenoceptors modify release of [3H]noradrenaline in the guinea-pig vas deferens.

1. Several alpha 1- and alpha 2-adrenoceptor agonists and antagonists were examined for effects on spontaneous and stimulus-evoked release of [3H]noradrenaline from sympathetic nerves in guinea-pig vas deferens. 2. Prazosin (0.1 and 1 microM), phentolamine (30 microM) and yohimbine (10 microM) each enhanced the stimulus-evoked release of [3H]noradrenaline. 3. Prazosin and phentolamine increased the spontaneous outflow of [3H]noradrenaline, whereas yohimbine was without effect. 4. Methoxamine (10 microM) and clonidine (0.1 microM) inhibited the stimulus-evoked release of [3H]noradrenaline, whereas only methoxamine (1 microM) decreased the spontaneous outflow of [3H]noradrenaline. 5. The identity of prejunctional alpha-adrenoceptors in the guinea-pig vas deferens is discussed.

Animals↗

PubMed1990

Modulation by prostaglandin E2 of ATP and noradrenaline co-transmission in the guinea-pig vas deferens.

1. In the guinea-pig vas deferens, prostaglandin E2 (100 nM) enhanced the overflow of ATP, whereas it inhibited [3H]-noradrenaline overflow due to field stimulation at 2 Hz. At 20 Hz, prostaglandin E2 still inhibited the overflow of [3H]-noradrenaline, whereas it was without effect on ATP overflow. 2. Prostaglandin E2 enhanced contractions to exogenously added noradrenaline and alpha, beta-methylene ATP. 3. These results provide evidence for pre- and postjunctional modulation of purinergic and adrenergic transmission by PGE2 in the guinea-pig vas deferens. The importance of these findings in relation to co-transmission is discussed.

Adenosine Triphosphate↗

PubMed1990

Non-adrenergic, non-cholinergic contractions in the electrically field stimulated guinea-pig trachea.

1. The effects of drugs and altering stimulus parameters on neurogenic responses to electrical field stimulation (EFS) have been investigated in distal and proximal portions of the guinea-pig trachea. 2. In the presence of indomethacin (3 microM) and propranolol (1 microM) two contractile phases were evident in both the proximal and distal trachea. The first rapid phase was abolished by atropine (0.1 microM), whereas the prolonged, second phase was abolished by capsaicin (10 microM) pretreatment. Tetrodotoxin (3 microM) abolished the initial response and greatly inhibited the second phase. In proximal trachea this second phase was evident only in 9 of 22 preparations. The addition of the peptidase inhibitor thiorphan (10 microM) however, caused a second phase to be seen in all the proximal tissues examined. 3. The two phases of the contractions to EFS were differentially sensitive to the pulse duration applied. The initial, cholinergic contractions were evident at lower pulse durations than were the prolonged capsaicin-sensitive contractions, with the first phase being approximately 10 fold more sensitive than the second phase. 4. The magnitude of the capsaicin-sensitive contraction to EFS was significantly greater in the distal trachea than in the proximal trachea. This difference prevailed in the presence of thiorphan, an inhibitor of neutral endopeptidase. In contrast, concentration-response curves to capsaicin were similar in segments of proximal and distal trachea. 5. The non-adrenergic non-cholinergic (NANC) relaxant responses were studied in tissues in which excitatory neurogenic responses were pharmacologically abolished by capsaicin and atropine treatment. The NANC relaxant responses in the proximal trachea were evident at lower pulse frequencies and were of greater magnitude compared with NANC relaxant responses in the distal trachea. 6. These results indicate that, by pharmacologically manipulating the trachea and by selecting optimum stimulation parameters, a NANC contractile response to EFS can be seen throughout the length of the guinea-pig trachea. This NANC response is most likely to be due to the release of tachykinins from capsaicin-sensitive sensory fibres. It is suggested that NANC relaxant responses mask NANC contractile responses especially in the proximal trachea where NANC relaxant responses predominate.

Animals↗

PubMed1990

Neuropeptide Y neuromodulation of sympathetic co-transmission in the guinea-pig vas deferens.

1. We examined the neuromodulatory effects of neuropeptide Y (NPY) on purinergic and adrenergic co-transmission in the guinea-pig vas deferens. 2. In superfused vas deferens preparations, NPY (0.3 microM) inhibited the stimulus-evoked overflow of both ATP and [3H]-noradrenaline ([3H]-NA) at 2 Hz, but only the stimulus-evoked release of [3H]-NA at 20 Hz. 3. Postjunctionally, NPY greatly enhanced responses to alpha,beta-methylene ATP and to a lesser extent to exogenous NA. 4. Preparations stimulated in organ baths showed frequency-dependent contractions to field stimulation. NPY abolished responses to field stimulation at low frequency and a small number of pulses. At high frequency (20 Hz), NPY abolished responses elicited by 10 pulses, inhibited responses by 50% at 20 pulses and had little effect on preparations stimulated for 240 pulses. 5. Our study suggests that NPY neuromodulates co-transmission in the vas deferens by inhibiting the release of ATP and NA and that these effects predominate over the postjunctional enhancement by NPY. These results also show that the physiological effect of NPY will be determined both by the frequency at which the nerves are discharging and the duration of their firing.

Adenosine Triphosphate↗

PubMed1989

Coordinate regulation of 3-hydroxy-3-methylglutaryl-coenzyme A synthase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and prenyltransferase synthesis but not degradation in HepG2 cells.

Human hepatoma HepG2 cells were used to demonstrate coordinate regulation of three enzymes of cholesterol synthesis under a variety of conditions. Addition of either delipidized serum and mevinolin or low density lipoprotein, 25-hydroxycholesterol, or mevalonic acid to HepG2 cells resulted in rapid changes both in the levels of the mRNAs and in the rates of synthesis of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase, HMG-CoA reductase, and farnesyl pyrophosphate synthetase (prenyltranferase). In all cases, the changes in mRNA levels were paralleled by changes in the rates of specific protein synthesis. Pulse-chase techniques were used to determine the half-lives of all three proteins. Addition of low density lipoprotein to the media during the chase increased the rate of degradation of HMG-CoA reductase 4.6-fold but had no affect on the half-lives of HMG-CoA synthase or prenyltransferase. Therefore, we conclude that the coordinate regulation of these three enzymes under a variety of conditions occurs at the level of enzyme synthesis and not at the level of protein stability.

Cell Line↗

PubMed1989

Modulation of cholinergic neurotransmission by vasoactive intestinal peptide and peptide histidine isoleucine in guinea-pig tracheal smooth muscle.

There is increasing evidence that vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) are non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmitters in airway smooth muscle. The possibility that VIP and PHI may also have neuromodulatory effects on excitatory responses, mediated by cholinergic nerves, to electrical field stimulation (EFS) was studied in guinea-pig isolated trachea. VIP (0.5 nM) pre-junctionally, inhibited the release of acetylcholine (ACh), whereas post-junctionally, responses to methacholine (MCh) were enhanced. At a maximum relaxant concentration (100 nM), VIP inhibited cholinergic neurotransmission both pre- and post-junctionally. Similarly, PHI (30 nM) inhibited neuronal ACh release, but enhanced transmitter action post-junctionally. At 3 microM, PHI inhibited ACh release. VIP- and PHI-induced inhibition of EFS was not affected by methysergide, pyrilamine, naloxone, phentolamine and propranolol. These data suggest that, in airway smooth muscle VIP and PHI may modulate cholinergic transmission via specific receptors.

Acetylcholine↗

PubMed1989

The effects of vasoactive intestinal peptide (VIP) antagonists, and VIP and peptide histidine isoleucine antisera on non-adrenergic, non-cholinergic relaxations of tracheal smooth muscle.

1. The effects of several drugs, including antagonists of vasoactive intestinal peptide (VIP), and antisera to VIP or peptide histidine isoleucine (PHI), on relaxation responses of guinea-pig isolated trachea to electrical field stimulation (EFS) have been examined. 2. beta-Adrenoceptor blockade with propranolol only partially blocked the inhibitory response to EFS, but had no effect in tissues from animals pretreated with 6-hydroxydopamine or reserpine. 3. Neither adenosine deaminase, in the presence of dipyridamole, nor the potent adenosine antagonist NPC205 (1,3-n-dipropyl-8-(4-hydroxyphenyl)-xanthine) had any effect on the inhibitory response to EFS. 4. The VIP antagonists, [Ac-Tyr1, D-Phe2]-GRF(1-29)-NH2 and [4-Cl-D-Phe6, Leu17]-VIP had no effect on the inhibitory response to EFS. Moreover, they were without effect on responses to exogenous VIP or PHI. 5. Overnight incubation with VIP antisera markedly reduced the inhibitory response to EFS. PHI antisera had a similar, but smaller effect. 6. In the presence of a concentration of VIP that is maximal for its relaxant effect, inhibitory responses to electrical stimulation were greatly inhibited. 7. Naloxone and reactive blue 2 each had no effect on inhibitory responses indicating that endogenous opioids and adenosine 5'-triphosphate (ATP) respectively are not involved. 8. The results suggest that VIP and PHI, but not adenosine, contribute to non-adrenergic, noncholinergic inhibitory nerve responses of guinea-pig trachea. Moreover, the surprising lack of effect of both VIP antagonists on these responses, and in particular, on responses to exogenous VIP, suggests that the receptors mediating VIP-induced tracheal relaxation are different from those that mediate pancreatic secretion.

Adenosine↗

PubMed1989

Effects of peptidases on non-adrenergic, non-cholinergic inhibitory responses of tracheal smooth muscle: a comparison with effects on VIP- and PHI-induced relaxation.

1. The effects of peptidase enzymes on non-adrenergic, non-cholinergic (NANC) inhibitory responses of guinea-pig trachea to electrical field stimulation (EFS), and on relaxations induced by vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) have been examined. 2. alpha-Chymotrypsin reduced both the magnitude and, particularly, the duration of the inhibitory response to EFS, whereas papain reduced only the magnitude. Aprotinin, a peptidase inhibitor prevented the effects of alpha-chymotrypsin but was without effect on papain. 3. alpha-Chymotrypsin and papain both abolished relaxant responses to exogenous VIP and PHI. The action of alpha-chymotrypsin was prevented by aprotinin, whereas that of papain was not affected. 4. The peptidases were without effect on concentration-response curves to methacholine or to isoprenaline. It was also observed that, in the absence of the peptidases, aprotinin had no effect on inhibitory responses either to EFS or to exogenous VIP and PHI. 5. It is suggested that neuropeptides, possibly VIP and PHI, released during EFS of guinea-pig trachea, partly mediate NANC relaxations, and that their action may be inhibited by peptidases. However, the lack of effect of aprotinin alone, on responses to EFS, suggests that, if endogenous peptidases are important in terminating the action of neuropeptides, they are resistant to the effect of this particular peptidase inhibitor. It is further suggested that neurogenic relaxation of guinea-pig trachea is also partly mediated by a substance, possibly non-peptide, other than VIP or PHI.

Animals↗