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PubMed1986

Endogenous modulation of alpha-adrenergic contraction in canine tracheal muscle.

We studied the effect of passive stretch on the contraction of canine tracheal smooth muscle (TSM) to alpha-adrenergic agonists and acetylcholine (ACh) in 211 epithelium-free TSM strips from 42 dogs in vitro. Passive stretch at a resting tension of 100 g/cm2 caused a time-dependent decrease in the contractile response to alpha-adrenergic agonists after beta-adrenergic blockade with propranolol. Initial contraction elicited by 10(-3) M phenylephrine (PE) and clonidine (CLO) decreased at 2 h by 31 and 100%, respectively. Decrease in alpha-adrenergic contractility did not result from tachyphylaxis; no contraction was elicited by PE or CLO given for the first time after 4-h passive stretch at 100 g/cm2. The TSM response to ACh was unchanged over the same time in the same strips. When TSM strips were incubated at zero resting tension for 6 h, some attenuation of the alpha-adrenergic contractile still occurred but was not substantial. Similarly, when strips were incubated with 10(-6) M indomethacin (INDO) or 10(-5) M mefenamic acid (MEF) at 100 g/cm2 resting tension, time-dependent attenuation of the response to PE and CLO was reduced for at least 6 h, and initial contraction elicited by PE was augmented. Response of TSM to ACh was not affected by prostaglandin synthetase inhibition with INDO. We conclude that passive stretch of canine TSM in vitro leads to decreased responsiveness to alpha-adrenergic stimulation that can be prevented with INDO or MEF. These data are consistent with the synthesis of an inhibitory eicosanoid in epithelium-free canine TSM that may be activated by mechanical deformation of the muscle.

Adrenergic alpha-Agonists↗
PubMed1989

Evidence for platelet-activating factor secretion during immune activation in dogs.

To elucidate the potential physiological significance of platelet-activating factor (PAF) in acute bronchoconstriction, we studied the effect of Ascaris suum antigen on the tachyphylactic response to PAF in 15 natively allergic mongrel dogs in vivo. Active bronchial tension was measured isometrically, and mediator secretion was measured as the arteriovenous difference (AVd) in plasma concentration across the lungs. Administration of PAF into the bronchial artery caused dose-related contraction in five control dogs (maximal active tension = 11.8 +/- 1.68 g/cm) that paralleled the increase in the AVd for serotonin (4,188 +/- 175 pg/ml) but not histamine (maximal AVd less than 6.0 ng/ml). The response to PAF was highly tachyphylactic. In contrast to PAF, 1:10 concentration of intra-arterial antigen caused substantial release of histamine (AVd = 308 +/- 57.1 ng/ml; P less than 0.001 vs. PAF). Diminished responsiveness (2-log shift in threshold and maximal contraction; P less than 0.001) to PAF was demonstrated in five dogs after 1:10 antigen, compatible with endogenous release of PAF during prior immune challenge in the same animals. Administration of Ascaris antigen caused a leftward shift in the dose-response curve to serotonin and only mild tachyphylaxis to the maximal response to histamine. Our data are compatible with physiological participation of PAF in eliciting bronchial smooth muscle contraction during the acute phase of immune activation caused by A. suum antigen.

Animals↗
PubMed1993

Comparison of the secretory response of the nasal mucosa to methacholine and histamine.

To better understand the secretory response of the nasal mucosa, we must be able to accurately measure its physiological response. To this end, we developed a localized challenge technique using paper disks to stimulate the mucosa on one side and measure secretions from both sides to study both direct and reflex responses. Both methacholine and histamine induced a dose-dependent increase in secretion weights on the challenge side, whereas only histamine induced a contralateral reflex. Repeated stimulation with histamine, but not methacholine, resulted in tachyphylaxis. Pretreatment with atropine resulted in inhibition of the contralateral secretory response to histamine and the ipsilateral response to methacholine with only partial inhibition of the ipsilateral histamine response. Terfenadine pretreatment resulted in the complete inhibition of both the ipsilateral and contralateral responses to histamine with no effect on methacholine-induced secretions. Ipsilaterally applied lidocaine had no effect on the histamine response but, when applied contralaterally, partially inhibited that response. Topical diphenhydramine applied ipsilaterally led to significant inhibition of the ipsilateral and contralateral secretory responses to histamine but had no effect when applied contralaterally. We conclude that methacholine and histamine have different effects on the nasal mucosa. We speculate that methacholine stimulates glands directly, whereas histamine includes both direct and neurogenic stimulation.

Adult↗
PubMed1996

H2O2 sensitivity of afferent splanchnic C fiber units in vitro.

1. Single-unit impulse activity evoked by transient, focal application of hydrogen peroxide (H2O2) to identified visceral receptive fields has been characterized in an in vitro rat splanchnic nerve-mesentery preparation. In addition to H2O2 responsiveness, units were characterized in terms of sensitivity to mechanical stimuli, warming, and bradykinin. 2. Mesenteric receptive fields of single splanchnic afferent C fibers in vitro were located with the use of warm (approximately 45 degrees C saline) or mechanical search stimuli. After delimitation of the warm-sensitive and/or mechanosensitive receptive field, units were tested for responsiveness to transient, focal application of H2O2. Microliter volumes (usually 1 microliter) of H2O2 (88-880 mM) evoked responses in 25 of 42 (60%) units with identified warm-sensitive and/or mechanosensitive receptive fields, and in an additional 10 units for which H2O2 was the only effective stimulus. 3. Tachyphylaxis to repeated H2O2 stimulation was observed with interstimulus intervals <30 min, but did not indicate irreversible inactivation of the terminal, because 1) during this period warm and mechanical stimuli elicited responses equal to or greater than those before H2O2 treatment, and 2) H2O2 sensitivity was restored after units were allowed to recover. 4. Eight units unresponsive to an initial dose of H2O2 responded vigorously to a repeated application at the same site, suggesting a potentiating effect of prior H2O2 exposure. 5. Sixty-two percent (8 of 13) of H2O2-responsive units, but no (0 of 6) H2O2-unresponsive units responded to transient, focal bradykinin (9-90 nM) application. 6. An indirect mode of H2O2-evoked afferent excitation in some units was suggested by several observations, including the prolonged (up to 8 min) duration of the response of some units to transient H2O2 application, and the occasionally long (>2 min) response latencies to focal application of H2O2 to defined receptive fields. 7. Excitation of splanchnic neurons by H2O2 may be relevant to the modulation of reactive oxygen species production by immunocompetent cells, because sensory neuropeptides contained in these afferent fibers are known to influence the respiratory burst of macrophages and neutrophils.

Animals↗
PubMed1998

Activation of neurons in rat trigeminal subnucleus caudalis by different irritant chemicals applied to oral or ocular mucosa.

To investigate the role of trigeminal subnucleus caudalis in neural mechanisms of irritation, we recorded single-unit responses to application of a variety of irritant chemicals to the tongue or ocular mucosa in thiopental-anesthetized rats. Recordings were made from wide dynamic range (WDR) and nociceptive-specific units in superficial layers of the dorsomedial caudalis (0-3 mm caudal to obex) responsive to mechanical stimulation and noxious heating of the ipsilateral tongue ("tongue" units) and from WDR units in ventrolateral caudalis (0-2 caudal to obex) responsive to mechanical and noxious thermal stimulation of cornea-conjunctiva and frequently also surrounding skin ("cornea-conjunctival" units). The following chemicals were delivered topically (0.1 ml) onto the dorsal anterior tongue or instilled into the ipsilateral eye: capsaicin (0.001-1% = 3.3 x 10(-2) to 3.3 x 10(-5) M), ethanol (15-80%), histamine (0.01-10% = 9 x 10(-1) to 9 x 10(-4) M), mustard oil (allyl-isothiocyanate, 4-100% = 4 x 10(-1) to 10 M), NaCl (0.5-5 M), nicotine (0.01-10% = 6 x 10(-1) to 6 x 10(-4) M), acidified phosphate buffer (pH 1-6), piperine (0.01-1% = 3.5 x 10(-2) to 3.5 x 10(-4) M), serotonin (5-HT; 0.3-3% = 1.4 x 10(-1) to 1.4 x 10(-2) M), and carbonated water. The dose-response relationship and possible tachyphylaxis were tested for each chemical. Of 32 tongue units, 31 responded to one or more, and frequently all, chemicals tested. The population responded to 75.3% of the various chemicals tested (</=10 per unit). The incidence of responses was independent of the order of chemicals tested, except for capsaicin, which reduced subsequent responses. Responses to histamine, nicotine, 5-HT, and ethanol had a more rapid onset and shorter duration compared with capsaicin, acid, and mustard oil. Responses to all chemicals increased in a dose-related manner. Successive responses to repeated application decreased significantly for nicotine, 5-HT, capsaicin, and piperine. Spontaneous firing increased significantly 5-10 min after initial application of capsaicin. Of 31 corneal-conjunctival units, 29 responded to one or more chemicals, and the population responded to 65% of all chemicals tested. Responses increased in a dose-related manner for all chemicals, and successive responses decreased significantly for histamine, nicotine, ethanol, acid, and capsaicin. Responses of tongue units to histamine and nicotine were reduced significantly by ceterizine (H1 antagonist) and mecamylamine, respectively. Mecamylamine also significantly reduced responses of corneal-conjunctival units to nicotine. Different classes of irritant chemicals contacting the oral or ocular mucosa can activate individual sensory neurons in caudalis, presumably via independent peripheral transduction mechanisms. Multireceptive units with input from the tongue or cornea-conjunctiva exhibited a similar spectrum of excitability to different irritant chemicals. Such neurons would not be capable of discriminating among different chemically evoked irritant sensations but could contribute to a common chemical sense.

Alkaloids↗
PubMed2001

B2 receptor-mediated enhanced bradykinin sensitivity of rat cutaneous C-fiber nociceptors during persistent inflammation.

Bradykinin (BK), which has potent algesic and sensitizing effect on nociceptors, is of current interest in understanding the mechanisms of chronic pain. BK response is mediated by B2 receptor in normal conditions; however, findings that B1 receptor blockade alleviated hyperalgesia in inflammation have been highlighting the role of B1 receptor in pathological conditions. It has not yet been clear whether nociceptor activities are modified by B1 receptor agonists or antagonists during inflammation. In addition, previous studies reported the change in BK sensitivity of nociceptors during short-lasting inflammation, and data in persistent inflammation are lacking. Therefore we investigated whether an experimentally induced persistent inflammatory state modulates the BK sensitivity of nociceptors and which receptor subtype plays a more important role in this condition. Complete Freund's adjuvant was injected into the rat-tail and after 2-3 wk, persistent inflammation developed, which was prominent in the ankle joint. Using an in vitro skin-saphenous nerve preparation, single-fiber recordings were made from mechano-heat sensitive C-fiber nociceptors innervating rat hairy hindpaw skin, and their responses were compared with those obtained from C-fibers tested similarly in normal animals. BK at 10(-8) M excited none of the 10 C-fibers in normal animals while it excited 5 of 11 (45%) C-fibers of inflamed animals, and at 10(-6) M BK excited all of the 11 inflamed C-fibers (or 94% of 36 tested C-fibers) but only 4 of 10 (or 45% of 58 tested C-fibers) in normal animals. Thus the concentration-response curves based on the incidence of BK induced excitation, and the total number of impulses evoked in response to BK were significantly shifted to the left. Moreover, an increased percentage of the inflamed C-fibers responded to 10(-6) M BK with bursting or high-frequency discharges. Thirty-percent of inflamed C-fibers had spontaneous activity, and these fibers showed comparatively less tachyphylaxis to consecutive second and third 10(-6) M BK stimulation. A B2 receptor antagonist (D-Arg-[Hyp3, Thi5,8,D-phe7]-BK) completely eliminated BK responses in inflamed rats, while B1 receptor antagonists (B 9958 and Des-Arg9-[Leu8]-BK) had no effect. Selective B1 receptor agonist (Des-Arg10-Kallidin) excited 46% (n = 13) of inflamed C-fibers at 10(-5) M concentration, which is 1,000 times higher than that of BK needed to excite the same percentage of inflamed C-fibers. We conclude that in chronically inflamed tissue, sensitivity of C-fiber nociceptors to BK, which is B2 receptor mediated, is strongly increased and that B1 receptor may not be important to a persistent inflammatory state, at least at the primary afferent level.

Animals↗
PubMed1975

Change of activity in rabbit aorta of three analogs of angiotensin substituted in nh2-terminal position.

Activity of Asp-1 -beta-amide-Val-5 -angiotensin II (A II), Sar-1 -Ile-5 -angiotensin II (SA II) and (N,N-dimethyl) Gly-1 -Ile-5 angiotensin II (DMGA II ) was studied in the isolated continuously superfused rabbit aortic strips. The myotropic activity of SA II was found to be 20 times greater than that of A II and DMGA II. A rapid tachyphylaxis occurred to SA II but not to A II and DMGA II. A II and DMGA II but not SA II significantly decreased in their myotropic activities when superfused over the rabbit aortic strips. The observed decrease in activities of A II and DMGA II is probably due to their metabolic degradation in the aortic tissue. The enzymes responsible for this degradation are probably aminopeptidases, as evidence by the fact the SA II, as aminopeptidase-resistant analog of A II, does not lose its activity when superfused over aortic strips.

Angiotensin II↗
PubMed1993

Iterative stimulation of pancreatic islets by glipizide.

Iterative administrations of glipizide (2 mumol/l) for 10 min each to perifused rat pancreatic islets provoked at low glucose concentration (2.8 mmol/l) rapid and rapidly reversible decreases in 86Rb outflow, rapid and rapidly reversible increases in 45Ca outflow and modest stimulations of insulin release. In the presence of Ca2+, the reascension in 86Rb outflow was preceded by a transient fall in effluent radioactivity upon withdrawal of the sulfonylurea. At a higher concentration of D-glucose (8.3 mmol/l), glipizide provoked, each time, biphasic and rapidly reversible increases in both 86Rb and 45Ca outflow, as well as in insulin release. These results are compatible with the view that glipizide decreases K+ conductance, leading to depolarization of the B-cell plasma membrane and gating of voltage-sensitive Ca2+ channels. In the presence of 8.3 mmol/l D-glucose, however, the inhibitory effect of glipizide on effluent K+ permeability may be masked by activation of Ca(2+)-sensitive K+ channels. The present data also indicate that glipizide is able to evoke, at the occasion of iterative administrations, biphasic ionic and secretory responses, without evidence of tachyphylaxis.

Animals↗
PubMed1975

Pharmacological receptors of the cerebral arteries of the goat.

5-Hydroxytryptamine (5-HT), norepinephrine (NE), histamine (H) and potassium (K+) chloride induce dose-dependent changes in tension of the isolated middle crerbral artery of the goat. Vasopressin produces highly variable responses followed by tachyphylaxis; angiotensin II is ineffective over a wide dose range. The order of potencies of these vasoactive agents is 5-HT greater than NE greater than H greater than K+. With regard to their ability to induce maximal contractile responses, the order is: H greater than 5-HT, K+ greater than NE. Lysergic acid diethylamide (LSD) antagonizes the actions of 5-HT in a manner which progresses from surmountability to unsurmountability of the blockade depending on the concentration of LSD. The blockade exerted by LSD is reversed by washing. Phentolamine and diphenhydramine competitively antagonize the actions of NE and H, respectively. The potency of phentolamine and diphenhydramine in the cerebral arteries of the goat is similar to that determined in different tissues obtained from a variety of animal species. It is concluded that the cerebral arteries of the goat possess receptors for biogenic amines, the most effective of which is 5-HT; receptors for vasoactive peptides are ill defined.?25

Angiotensin II↗
PubMed1976

Comparison of the excitatory and inhibitory effects of angiotensin and vasopressin on mammalian portal vein.

Angiotensin produced inhibitory and excitatory responses in guinea pig portal vein and excitatory responses in rabbit and rat portal vein. Vasopressin produced inhibitory responses in guinea pig and rabbit portal vein and excitatory and inhibitory responses in rat portal vein. In guinea pig portal vein, inhibition by angiotensin and vasopressin was associated with an increase in membrane potential which was, on average, smaller than that produced by isoprenaline, and with a suppression of spike discharges. Tachyphylaxis of the responses to angiotensin and vasopressin in portal vein was not observed and their effects were unaffected by tetrodotoxin, atropine and phentolamine plus propranolol.

Angiotensin II↗
PubMed1978

Angiotensin analogs: effect of prostaglandin synthesis inhibitor.

Structurally different inhibitors of prostaglandin synthesis reversed the antagonistic activity of the angiotensin II analog 1-sarcosine, 8-threonine angiotensin II. In isolated rabbit aorta, indomethacin or ETYA (eicosa 5, 8, 11, 14, tetraynoic) reversed the antagonism of the angiotensin II analog without affecting the dose response curves to angiotensin II. Both indomethacin and ETYA were able to reverse the tachyphylaxis to angiotensin II. Investigating the possibility that indomethacin could affect the binding of angiotensin II, it was found that at doses of indomethacin higher than 10(-5)M, binding of tritiated angiotensin to isolated adrenal cortical cells was reduced. It is postulated that indomethacin may have more than one effect on angiontensin, possessing a concentration-dependent effect on binding and prostaglandin synthesis.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1975

The motor-stimulating effect of natural motilin on the lower esophageal sphincter fundus, antrum and duodenum in dogs.

Natural motilin was investigated for its effect on gastrointestinal motor activity in anesthetized dogs. In doses starting from 10 ng/kg as single injection and 100 ng/kg-h as intravenous infusion, motilin induced phasic pressure changes in the lower esophageal sphincter (LES) and in the lumen of the fundus, antrum, and duodenum. Tachyphylaxis was seen in 6 out of 10 dogs. Motilin had no effect on isolated muscle strip preparations of the LES, fundus, antrum, and duodenum in this species.

Animals↗
PubMedDate not supplied

Response to 1-deamino-8-D-arginine vasopressin in von Willebrand disease.

The synthetic agent, 1-deamino-8-D-arginine vasopressin (DDAVP), is generally regarded to be the treatment of choice for persons with type I von Willebrand disease (vWD), and may be useful in type IIA vWD as well. Several formulations of the drug are available, including a highly concentrated intranasal spray formulation which is ideal for home use. The degree of F VIII and vWF response to DDAVP varies among individuals, but is generally consistent in individual patients over time. Some have tachyphylaxis while others do not. While side effects are uncommon, DDAVP is a potent antidiuretic agent. Thus one should be aware of the possibility of hyponatremia and water intoxication if certain precautions are not observed.

Administration, Intranasal↗
PubMed1976

Inhibition of allergic reactions by chromoglycate and by a new anti-allergic drug (10-chloro-1,4,6,9-tetrahydro-4,6-dioxopyrido (3,2-g) quinoline-2,8-dicardoxylic acid). I. Activity in rats.

A new inhibitor of IgE-mediated allergic reactions has been studied in rats. This new inhibitor is chemically quite different from cromoglycate and shows qualitative and quantitative advantages over it. This new inhibitor possesses no bronchodilator or end-organ antagonism activity, but as cromoglycate acts by inhibition of mediator release. Multiple doses in rats lead to tachyphylaxis. This effect is reversed both by decreasing the first dose and increasing the time between doses.

Animals↗
PubMed1982

Pharmacology of a new orally active antiallergic: pyrido[1,2-a]pyrimidine, ucb L140 (CHINOIN 1045) in rats.

ucb L140 (CHINOIN 1045) has been tested in various rat anaphylaxis systems. In models of passive cutaneous anaphylaxis (PCA), passive peritoneal anaphylaxis (PPA) and anaphylactic bronchospasms, ucb L140 appears to be more potent than sodium cromoglycate (DSCG). Upon oral administration, ucb L140 exhibits a marked inhibition of these anaphylactic reactions. Sensitized rat mast cells in vitro display a decreased Nippostrongylus-induced histamine release when treated with a concentration of ucb L140 three times smaller than DSCG. In PCA testing after intravenous administration of ucb L140 a cross-tachyphylaxis with DSCG was observed. These results suggest that the action of ucb L140 is similar to that of DSCG in inhibiting the release of allergic mediators from mast cells and therefore may present antiallergic activity.

Administration, Oral↗
PubMed1984

Antiallergic activity profiles in vitro of RHC 3164 and related compounds. II. Comparison of RHC 3164 with disodium cromoglycate.

RHC 3164 has been investigated for its antiallergic activities in 3 in vitro models of anaphylaxis. RHC 3164 was 6 times more potent than DSCG as an inhibitor of antigen-induced release of histamine (AIR) from rat mast cells (RMC) and had an activity profile identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, tachyphylactic properties, cross-tachyphylaxis to DSCG, and inability to inhibit nonimmunologic release of histamine. Neither RHC 3164 nor DSCG had any effect on immunologic release of histamine from human basophils or guinea pig lung slices. We conclude that RHC 3164 is a potent inhibitor of immunologic release of histamine from RMC with a mechanism of action similar to that of DSCG.

Animals↗
PubMed1987

The bronchoconstrictor properties of platelet-activating factor in humans.

Platelet-activating factor (PAF) is an inflammatory mediator that causes bronchial smooth muscle contraction in vitro and in vivo in experimental animals. To characterize the effect of PAF on human airways, 6 normal subjects and 6 subjects with mild asthma inhaled PAF using a standard bronchoprovocation protocol and nebulizer concentrations ranging from 0.1 to 1000 micrograms/ml. Aerosolized PAF produced bronchoconstriction in 5 of 6 normal and 3 of 6 asthmatic subjects as defined by at least a 35% decrease in specific airway conductance (SGaw). However, in these same subjects, flow rates measured at 30% of vital capacity from a partial forced expiratory maneuver (V30P) did not decrease at least 30% nor did the FEV1 decrease by 20%. The 8 PAF responders were 5 to 836 times more sensitive to PAF than to methacholine when SGaw was used to assess the airway response. The relative airway sensitivity of the PAF nonresponders could not be assessed. Normal and asthmatic subjects could not be differentiated by their airway response to PAF, and there were no clinical features that differentiated PAF responders from nonresponders. The maximal airway response to PAF occurred within 2 to 3 min and lasted 15 to 45 min. There were no late reactions. Both normal (p less than 0.01) and asthmatic (p less than 0.05) subjects exhibited tachyphylaxis to PAF. Finally, PAF sensitized the airways of all normal subjects to methacholine, including the one PAF nonresponder (p less than 0.02), but it did not sensitize the airways of the asthmatic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Bronchoconstriction induced by inhaled sodium metabisulfite in the guinea pig. Effect of capsaicin pretreatment and of neutral endopeptidase inhibition.

Sodium metabisulfite (MBS), a commonly used preservative, induces bronchoconstriction in asthmatics, probably through the release of sulfur dioxide (SO2). The mechanisms involved in MBS- and SO2-induced bronchoconstriction are not yet certain. We aerosolized MBS or acid control solution (pH, 2.7) to anesthetized, tracheostomized guinea pigs pretreated intravenously with propranolol (1 mg/kg). MBS was given at increasing doubling concentrations (0.01, 0.02, 0.04, and 0.08 M) every 5 min. Steep concentration-response curves were observed, and most animals responded at 0.02 or 0.04 M. Tachyphylaxis was seen at high concentrations and during a subsequent MBS challenge 15 min later. For pharmacologic studies, we stopped the challenge when lung resistance (RL) had increased by at least 350%; a second challenge was found to be reproducible. MBS response was measured as the concentration needed to increase RL by 350% (PC350). Atropine (1 mg/kg given intravenously) did not affect PC350 or the peak RL response. Inhibition of neutral endopeptidase by inhaled phosphoramidon (7.5 nmol) administered before the repeated challenge did not alter PC350 value to MBS or peak RL responses (phosphoramidon, 201 +/- 49% of first peak; vehicle, 164 +/- 35%). In addition, the increase in RL was not prolonged in the phosphoramidon-treated group. Animals treated subcutaneously with capsaicin (50 mg/kg) 1 wk before the experiment, so as to deplete neuropeptides from airway sensory nerves, had PC350 values similar to those of the control animals. Our data demonstrate that inhaled MBS causes bronchoconstriction in guinea pigs by mechanisms that are due neither to a cholinergic reflex nor to the release of tachykinins from airway sensory nerves.

Aerosols↗