Influence of body temperature on histamine-induced bronchoconstriction in guinea pigs

The effects of body temperature on histamine-induced bronchoconstriction were investigated in anesthetized, paralyzed, and mechanically ventilated guinea pigs. Four groups of guinea pigs were studied with constant body temperatures of 40, 38, 35, and 32 degrees C, respectively. Histamine was infused for 5 min at a rate of 50 ng.kg-1.s-1. Body cooling from 40 to 32 degrees C augmented the bronchomotor responses to histamine, which eventually rose almost fourfold. The enhancement of histamine-induced bronchoconstriction induced by body cooling was not suppressed by pretreating guinea pigs with 5 mg/kg hexamethonium or 5 mg/kg hexamethonium plus 3 mg/kg atropine; neither was the enhancement of histamine-induced bronchoconstriction suppressed in pithed guinea pigs, demonstrating that the autonomic nervous system is not involved in potentiating bronchoconstriction at low body temperatures. These results suggest that, at low body temperatures, increased airway responsiveness to histamine may be because of some direct effect of temperature on bronchial airway smooth muscle.     

Atrial natriuretic peptide ameliorates hypoxic pulmonary vasoconstriction without influencing systemic circulation.

Hypoxic pulmonary vasoconstriction (HPV) is encountered during ascent to high altitude. Atrial natriuretic peptide (ANP) could be an option to treat HPV because of its natriuretic, diuretic, and vasodilatory properties. Data on effects of ANP on pulmonary and systemic circulation during HVP are conflicting, partly owing to anesthesia, surgical stress or uncontrolled dietary conditions. Therefore, ten conscious, chronically tracheotomized dogs were studied under standardized dietary conditions. The dogs were trained to breathe spontaneously at a ventilator circuit. Protocol: 30min of normoxia [inspiratory oxygen fraction (F(i)O(2))=0.21] were followed by 30min of hypoxia without ANP infusion (Hypoxia I, F(i)O(2)=0.1). While maintaining hypoxia an intravenous infusion of atrial natriuretic peptide was started with 50ng x kg body wt(-1) x min(-1) for 30min (Hypoxia+ANP1=low dose), followed by 1000ng x kg body wt(-1) x min(-1) for 30min (Hypoxia+ANP2=high dose). Thereafter, ANP infusion was stopped and hypoxia maintained for a final 30min (Hypoxia II). Compared to normoxia, mean pulmonary arterial pressure (MPAP) (16+/-0.7 vs. 26+/-1.3mmHg) and pulmonary vascular resistance (PVR) (448+/-28 vs. 764+/-89dyn x s(-1) x cm(-5)) increased during Hypoxia I and decreased during Hypoxia+ANP 1 (MPAP 20+/-1mmHg, PVR 542+/-55dyn x s(-1) x cm(-5)) (P<0.05). The higher dose of ANP did not further decrease MPAP or PVR, but started to have a tendency to decrease mean arterial pressure and cardiac output. We conclude that low dose ANP is able to reduce HPV without affecting systemic circulation during acute hypoxia.     

Met-enkephalin effects on histamine-induced bronchoconstriction in guinea pigs

We investigated the effects of the neuropeptide met-enkephalin on histamine-induced bronhoconstriction in an experimental model of asthma. Classic Konzett and R?ssler's method of whole body plethysmography modified by Gjuris, was applied in the study. This method represents a standard experimental model of bronchoconstriction, suitable for the evaluation of peptide effects on the histamine-induced bronchoconstriction. The results of the measurements implicate a dose-related modulatory effect of met-enkephalin on the bronchoconstrictor action of histamine. Met-enkephalin doses of 1 mg/kg and 10 mg/kg, respectively, caused statistically significant reduction of the histamine-induced bronchoconstriction. Estimated ED50 dose was 0.235 mg/kg. Further studies are needed to define practical and therapeutical use of the presented observations in respiratory pharmacology.     

The effect of a novel leukotriene C4/D4 antagonist, BAY-x-7195, on experimental allergic reaction

The effects of a novel leukotriene (LT) C₄/D₄ antagonist, BAY-x-7195 on experimental allergic reactions in airway and skin were compared to that of ONO-1078. BAY-x-7195 showed an antagonistic action to LTD₄-induced bronchoconstriction in vitro and in vivo. In in vitro experiments, BAY-x-7195 inhibited LTD₄-induced contraction of isolated guinea pig tracheal muscle (pA2=8.03). BAY-x-7195 at doses of 3 – 30 mg/kg clearly inhibited LTD₄-induced increases in respiratory resistance (Rrs) in guinea pigs. In contrast, BAY-x-7195 inhibited significantly U-46619-induced increases in Rrs at a dose of 30 mg/kg in guinea pigs. BAY-x-7195 at doses of 3 — 30 mg/kg inhibited the aerosolized antigen-induced biphasic increase in Rrs in guinea pigs. Moreover BAY-x-7195 inhibited repeated aeroantigen-induced airway hyperreactivity in guinea pigs. In mice, aeroantigen-induced airway inflammation were clearly inhibited by BAY-x-7195. These results show the efficacy of BAY-x-7195 against the antigen-induced increase in airway resistance and antigen-induced airway hyperreactivity in guinea pigs and mice, probably due to anti-LTD₄ antagonistic action and the inhibition of antigen-induced airway inflammation.     

Histamine inhibits atrial myocytic ANP release via H2 receptor-cAMP-protein kinase signaling

Changes in cyclic nucleotide production and atrial dynamics have been known to modulate atrial natriuretic peptide (ANP) release. Although cardiac atrium expresses histamine receptors and contains histamine, the role of histamine in the regulation of ANP release has to be defined. The purpose of the present study was to define the effect of histamine on the regulation of ANP release in perfused beating rabbit atria. Histamine decreased ANP release concomitantly with increases in cAMP efflux and atrial dynamics in a concentration-dependent manner. Histamine-induced decrease in ANP release was a function of an increase in cAMP production. Blockade of histamine H2 receptor with cimetidine but not of H1 receptor with triprolidine abolished the responses of histamine. Cell-permeable cAMP analog, 8-Br-cAMP, mimicked the effects of histamine, and the responses were dose-dependent and blocked by a protein kinase A (PKA)-selective inhibitor, KT5720. Nifedipine failed to modulate histamine-induced decrease in ANP release. Protein kinase nonselective inhibitor staurosporine blocked histamine-induced changes in a concentration-dependent manner. KT5720 and RP-adenosine 3',5'-cyclic monophosphorothioate, another PKA-selective inhibitor, attenuated histamine-induced changes. These results suggest that histamine decreases atrial ANP release by H2 receptor-cAMP signaling via PKA-dependent and -independent pathways.     

Tracheal narrowing during histamine-induced bronchoconstriction

To determine whether tracheal narrowing accompanies histamine-induced bronchoconstriction and whether a cholinergic reflex is involved in the tracheal and bronchial responses, we determined specific pulmonary resistance between the carina and the pleura (sRL) and tracheal volume (Vtr) with an indicator-dilution technique in conscious sheep. Immediately postdelivery of histamine aerosol (7.5 mg histamine base) mean sRL increased by 223% (P less than 0.05), and mean Vtr decreased by 25% (P less than 0.05). The duration of the changes was similar, with a return to base-line values within 60 min. With increasing doses of histamine up to 30 mg, there was a corresponding increase in mean sRL, whereas the maximum effect on Vtr was already reached after 7.5 mg of histamine. Atropine (0.2 mg/kg iv) increased mean Vtr by 77% (P less than 0.05) and blunted the histamine effects on sRL, whereas the histamine effects on Vtr were abolished. Intravenous histamine or carbachol aerosol had similar effects on sRL and Vtr. We conclude that in conscious sheep 1) histamine produces both tracheal and bronchial constriction with a similar time course, 2) there is a base-line vagal tone in the trachea and not the bronchi, 3) the cholinergic reflex component of histamine-induced constriction is greater in the trachea than the bronchi, and 4) this difference between the trachea and bronchi is not due to differential aerosol deposition or cholinergic responsiveness.     

Influence of tidal volume on histamine-induced bronchoconstriction in guinea pigs

The effects of tidal volume amplitude on bronchopulmonary reactivity were investigated in three groups of 14 anesthetized paralyzed mechanically ventilated guinea pigs. Animals of group 1 served as control; in animals of group 2, both the sympathetic and parasympathetic nervous systems were blocked; in animals of group 3, only the parasympathetic system was blocked. In each group, the animals were randomly divided into two subgroups characterized by their ventilatory pattern: rate of 60/min with a 6-ml/kg tidal volume or rate of 40/min with a 9-ml/kg tidal volume. Bronchopulmonary reactivity to infused histamine was assessed by the respiratory compliance and conductance values measured during bronchoconstriction and expressed as a percentage of the corresponding basal values. In group 1 the animals ventilated with a 9-ml/kg tidal volume were found significantly less reactive than those ventilated with a 6-ml/kg tidal volume. This difference was abolished in groups 2 and 3. These results demonstrate that the effects of increased tidal volume on bronchopulmonary reactivity are vagally mediated and suggest that the decrease observed in histamine-induced bronchoconstriction is mainly due to reflex effects evoked by stretch receptor stimulation.     

Acute hypoxia alters eicosanoid production of perfused pulmonary artery endothelial cells in culture.

Hypoxia alters vascular tone which regulates regional blood flow in the pulmonary circulation. Endothelial derived eicosanoids alter vascular tone and blood flow and have been implicated as modulators of hypoxic pulmonary vasoconstriction. Eicosanoid production was measured in cultured bovine pulmonary endothelial cells during constant flow and pressure perfusion at two oxygen tensions (hypoxia: 4% O2, 5% CO2, 91% N2; normoxia: 21% O2, 5% CO2, 74% N2). Endothelial cells were grown to confluence on microcarrier beads. Cell cartridges (N = 8) containing 2 ml of microcarrier beads (congruent to 5 x 10(6) cells) were constantly perfused (3 ml/min) with Krebs' solutions (pH 7.4, T 37 degrees C) equilibrated with each gas mixture. After a ten minute equilibration period, lipids were extracted (C18 Sep Pak) from twenty minute aliquots of perfusate over three hours (nine aliquots per cartridge). Eicosanoids (6-keto PGF1 alpha; TXB2; and total leukotriene [LT - LTC4, LTD4, LTE4, LTF4]) were assayed by radioimmunoassay. Eicosanoid production did not vary over time. 6-keto PGF1 alpha production was increased during hypoxia (normoxia 291 +/- 27 vs hypoxia 395 +/- 35 ng/min/gm protein; p less than 0.01). Thromboxane production (normoxia 19 +/- 2 vs hypoxia 20 +/- 2 ng/min/gm protein) and total leukotriene production (normoxia 363 +/- 35 vs hypoxia 329 +/- 29 ng/min/gm protein) did not change with hypoxia. These data demonstrated that oxygen increased endothelial prostacyclin production but did not effect thromboxane or leukotriene production.     

Effects of histamine on bronchial artery blood flow and bronchomotor tone

The effects of aerosolized 5% histamine (10 breaths) on bronchial artery blood flow (Qbr), airflow resistance (RL), and pulmonary and systemic hemodynamics were studied in mechanically ventilated sheep anesthetized with pentobarbital sodium. Histamine increased mean Qbr and RL to 252 +/- 45 and 337 +/- 53% of base line, respectively. This effect was significantly different from base line for 30 min after challenge. The histamine-induced increase in RL was blocked by pretreatment with the histamine H1 receptor antagonist, chlorpheniramine, whereas the histamine-induced elevation in Qbr was prevented by the H2 antagonist, metiamide. Both responses were blocked only when both antagonists were present. Changes in Qbr were not directly associated with alterations in systemic and pulmonary hemodynamics or arterial blood gas composition. In vitro histamine caused a dose-dependent contraction of ovine bronchial artery strips that was prevented by H1 antagonist. The H2 agonist, impromidine, caused relaxation of precontracted arterial strips and was more potent and efficacious than histamine, whereas H1 agonists failed to elicit a relaxant response. Thus these findings indicate that histamine aerosol induces a vasodilation in the bronchial vascular bed; histamine has a direct effect on Qbr that is independent of alterations in RL, systemic and pulmonary hemodynamics, or arterial blood gas composition; and, histamine-induced bronchoconstriction is mediated predominantly by H1-receptors, whereas increased Qbr is controlled predominantly by H2-receptors, probably located in resistance vessels. This local effect of histamine on Qbr may have important implications in the pathophysiology of bronchial asthma and pulmonary edema.     

Atrial natriuretic peptide in acute hypoxia-induced pulmonary hypertension in rats.

To test the hypothesis that exogenous atrial natriuretic peptide (ANP) prevents the acute pulmonary pressor response to hypoxia, ANP (20-micrograms/kg bolus followed by 1-microgram.kg-1.min-1 infusion) or vehicle was administered intravenously to conscious rats beginning 3 min before exposure to hypoxia or room air for 90 min. Exogenous ANP abolished the acute pulmonary pressor response to hypoxia in association with marked and parallel increases in plasma ANP and guanosine 5'-cyclic monophosphate (cGMP) and with a significant increase in lung cGMP content. To examine whether endogenous ANP modulates the acute pulmonary pressor response to hypoxia, rats were pretreated with a monoclonal antibody (Ab) to ANP and exposed to hypoxia. Mean pulmonary arterial pressure (MPAP) in the Ab-treated rats was not different from control over the first 6 h of hypoxic exposure. Thereafter, the Ab-treated group had significantly higher MPAP than control. Our data suggest that 1) exogenous ANP blocks the pulmonary pressor response to acute hypoxia via stimulation of cGMP accumulation in the pulmonary vasculature, and 2) endogenous ANP may modulate the subacute, but not acute, phase of hypoxic pulmonary hypertension.     

Cardiovascular response to histamine during normoxaemia and hypoxaemia in piglets

The cardiovascular effects of exogenously administered histamine were investigated in conscious newborn piglets aged 10-11 days during normoxia (21% (v/v) O2) and during isocapneic alveolar hypoxia (10% O2, 3% CO2, 87% N2) to determine its influence on preexisting vascular tone. In the first set of experiments (n = 6), four histamine doses (1,10,50,100 micrograms/kg) were tested in sequence during normoxia. Histamine was injected intravenously and cardiovascular variables were recorded. Heart rate increased at all doses studied. Pulmonary and systemic arterial pressures, cardiac output and stroke volume were unchanged at the low histamine doses (1 and 10 micrograms), but all decreased at the high doses (50 and 100 micrograms). Pulmonary and systemic vascular resistances were unchanged at each dose. In the second set of experiments (n = 7), two histamine doses (1 and 5 micrograms/kg) were administered during alveolar hypoxia. Hypoxia caused increases in heart rate and pulmonary arterial pressure and resistance. After injection of each dose of histamine, pulmonary pressure and resistance decreased but remained higher than baseline. No other measured cardiovascular variables were altered. Thus, during normoxia histamine did not alter vascular tone, but high doses did adversely affect myocardial function. During alveolar hypoxia histamine caused weak pulmonary vasodilation at doses that did not alter systemic vascular tone. Histamine is not a potent modifier of the circulation in the newborn piglet during conditions of normoxaemia or hypoxaemia.     

Laryngeal resistance immediately after panting in control and constricted airways

Laryngeal resistance (Rla) in the postpanting interval (PPRla) was examined in five normal subjects in the control state and with methacholine- and histamine-induced bronchoconstriction. Respiratory resistance (Rrs) was measured by the forced oscillation technique at 10 Hz, and Rla was measured by the low-frequency sound method (Sekizawa, K., C. Shindoh, W. Hida, S. Suzuki, et al. J. Appl. Physiol. 55:591-597, 1983). Inspiratory Rrs (IRrs) was lower than expiratory Rrs (ERrs), and Rrs immediately after panting (PPRrs) was not significantly different from IRrs in the three airway conditions. Rla increased with bronchoconstriction and inspiratory Rla (IRla) was lower than expiratory Rla (ERla). PPRla was lower than IRla (P less than 0.01) by an amount corresponding to the decrease in Rrs in the control airway. However, in constricted airways, PPRla was higher than IRla and about the same as ERla. We suggest that the panting maneuver is suitable for minimizing the effect of laryngeal artifact in the control airway, but in the constricted airway the panting maneuver may fail to cause widening of the laryngeal orifice.     

ET-1 induced bronchoconstriction in the early phase but not late phase of anesthetized dogs is inhibited by indomethacin and ICI 198615.

Intratracheally injected or aerosolized ET-1 induced quick and long-lasting bronchoconstriction of anesthetized mongrel dogs, thus increasing respiratory resistance(Rrs) with concomitantly decreasing dynamic compliance(Cdyn). As collateral resistance(Rcs) was measured postexposure to aerosolized ET-1 using wedged bronchoscope technique, ET-1 increased Rcs in a dose and time dependent manner. The increase attained maximal in 2 min and then, gradually declined. When the dogs were pretreated with the intravenous injection of 0.1 micrograms/kg ICI 198615, an inhibitor of lipoxygenase, the constrictive response was slowed down. Essentially similar results were also observed with the intravenous injection of 5 mg/kg indomethacin. Our observations suggest that the early phase of the ET-1 induced bronchoconstriction is mediated by eicosanoid metabolites.     

OKY-046 inhibits anaphylactic bronchoconstriction and reduces histamine level in bronchoalveolar lavage fluid in sensitized guinea pigs.

We investigated the effects of OKY-046, a potent and selective thromboxane A2 (TxA2) synthetase inhibitor, on anaphylactic bronchoconstriction and release of chemical mediators into airway lumen in sensitized guinea pigs in vivo. OKY-046 dose-dependently inhibited antigen-induced anaphylactic bronchoconstriction with or without mepyramine, a histamine H1 antagonist. In the presence of mepyramine, OKY-046 (300 mg/kg, p.o.) elicited significant reductions in histamine (1 min) and TxB2 increases (1-15 min) in bronchoalveolar lavage (BAL) fluid but significantly increased the plasma level of 6-keto-PGF1 alpha, a stable PGI2 metabolite, after antigen challenge. On the contrary, indomethacin only significantly reduced increases in TxB2 levels. These results suggest that the antiasthmatic effect of OKY-046 is probably due to inhibition of TxA2 synthesis and suppression of histamine release via a PGI2 shunting mechanism.     

Atriopeptin does not augment the transvascular flux of macromolecules in the hamster cheek pouch.

Natriuretic peptides elaborated by atrial myocytes promote marked renal sodium and water excretion as a mechanism for fluid and electrolyte balance. Recent evidence suggests that atriopeptin (ANP) also targets the non-renal vasculature as a site for enhanced fluid exchange. It remains unclear whether ANP alters microvascular integrity to facilitate the efflux of both plasma and proteins across the endothelial barrier, or if fluid exchange is selectively enhanced. This study evaluated the influence of ANP on macromolecular transport through the direct observation of microvessels in the hamster cheek pouch using fluorescent intravital microscopy. Fluorescein isothiocyanate conjugated to either bovine serum albumin or dextran 150,000 Mw was utilized as a permeability probe. Macromolecular efflux was quantified as fluorochrome clearance. The clearance of fluorescein-conjugated bovine serum albumin (57.94 +/- 7.03) or fluorescein-conjugated dextran 150 (4.09 +/- 1.35) remained unaltered by intravascular injection of 1 microgram/kg ANP. Topical application of 40 ng to cheek pouch microvessels produced similar results. All pouches demonstrated positive leakage response to histamine 2.5 x 10(-6) M, increasing fluorochrome clearance approximately 2- to 11-fold. Bolus injection of 1 microgram/kg ANP reduced mean arterial pressure, increased urine flow from 6.63 +/- 2.59 microliters/min to 8.20 +/- 6.13 microliters/min, and elevated sodium excretion from 1.37 +/- 0.49 microEq/min to 2.54 +/- 0.99 microEq/min. These results suggest that ANP fails to significantly alter the integrity of the protein-transporting channels in the microvascular exchange barrier.     

急性低氧对大鼠血液中儿茶酚胺及血小板聚集性的影响

健康ＳＤ雄性大鼠,体重２５０－３００ｇ,麻醉、气管插管,用人工呼吸机经气袋供气,自发吸入氧浓度为９％的氧氮混合气,用高效液相色谱－电化学联合检测法及电阻法检测循环血液中儿茶酚胺及全血血小权聚集性的动态变化。结果：急性低氧１５ｍｉｎ时血液中肾肾上腺素（Ａ）浓度及全血血小板聚集性显著增加（Ｐ〈０．０１）,而去甲肾上腺素（ＮＡ）浓度虽有所增加,但无统计学意义（Ｐ〉０．０５）;复氧１５ｍｉｎ时血液中儿茶酚     

Priming with murine recombinant interleukin-5 resulted in the augmentation of PAF-induced airway hyperresponsiveness to histamine in guinea pigs

The effects of pretreatment with murine recombinant interleukin 5 (mrIL-5) on platelet activating factor (PAF)-induced bronchoconstriction and airway hyperreactivity were investigated in guinea pigs. The intratracheal administration of mr IL-5 (2.5–10 μg) augmented platelet activating factor (PAF; 50 ng/kg)-induced bronchoconstriction in guinea pigs. When IL-5 (2.5 μg) was injected intratracheally, PAF (25 ng/kg)-induced bronchoconstriction was not affected, but PAF-induced airway hyperresponsiveness to histamine was exacerbated. Airway inflammation, in terms of increased capillary permeability and the accumulation of leukocytes in bronchoalveolar lavage fluid, was not produced by pretreatment with PAF (25 ng/kg), mrIL-5 (2.5 μg), or by a combination of these agents. This mrIL-5-induced augmentation of airway hyperreactivity by PAF was clearly inhibited by the phosphodiesterase-type III inhibitors, SDZ-MKS-492 and AH 21–132, but not by aminophylline.     

Atrial natriuretic peptide decreases cardiac output independent of coronary vasoconstriction

Studies were performed in isolated, Langendorff-perfused rat hearts and anesthetized dogs to determine the effects of synthetic atrial natriuretic peptide (ANP 8-33) on the coronary circulation. In vitro studies in the rat examined coronary flow dynamics to ANP 8-33 over a defined range from physiologic to pharmacologic concentrations. No changes in coronary flow or chronotropic and inotropic function of the isolated Langendorff-perfused heart were observed in response to increasing concentrations of ANP 8-33 (10(2) to 10(6) pg/ml). In the dog, a low, nonhypotensive dose of ANP 8-33 (0.05 microgram/kg/min) decreased cardiac output with no change in coronary blood flow or coronary vascular resistance. At a high, hypotensive dose (0.3 microgram/kg/min) ANP 8-33 decreased cardiac output in association with transient coronary vasodilation. Continued infusion resulted in a decrease in coronary blood flow and arterial pressure with no change in coronary vascular resistance. Thus, in vitro physiologic and pharmacologic concentrations of ANP, or in vivo low concentrations of ANP, do not result in an alteration in coronary flow. In vivo ANP 8-33, at both nonhypotensive and hypotensive concentrations, decreased cardiac output in the absence of coronary vasoconstriction.     

Intracerebroventricular serotonin reduces the degree of acute hypoxic ventilatory depression in peripherally chemodenervated rabbits

Hypoxia causes changes in the rate of synthesis or release of neurotransmitters in the brain. The accumulation of serotonin (5-HT) in the central nervous system might cause hypoxic respiratory depression. In the present study, we aimed to examine the role of central 5-HT on normoxic and acute hypoxic ventilatory depression (AHVD) in peripheral chemoreceptors denervated rabbits. All experiments were performed in peripherally chemodenervated rabbits anesthetized with intravenous injection of urethane (400 mg/kg) and alpha-chloralose (40 mg/kg). For intracerebroventricular (ICV) administration of 5-HT (20 microg/kg) and ketanserin (10 microg/kg), a cannula was placed in left lateral ventricle by stereotaxic method. Respiratory frequency (fR), tidal volume (VT), ventilation minute volume (VE) and systemic arterial bood pressure (BP) were recorded in each experimental phases and mean arterial pressure was calculated (MAP). Heart rate (HR) was also determined from the pulsation of BP. The effects of ICV serotonin and ICV ketanserin on the indicated parameters during air breathing (normoxia) and breathing of hypoxia (8% O2--92% N2) were investigated. During hypoxia, fR, VT, VE, MAP and HR decreased, and AHVD was thus obtained. ICV injection of 5-HT during normoxia caused significant increases in VT (P < 0.001) and in VE (P < 0.01). On the other hand, ICV 5-HT injection reduced the degree of AHVD in peripherally chemodenervated rabbits during hypoxia (fR; P < 0.05, VT; P < 0.05 and VE; P < 0.01). After ICV injection of ketanserin, the enhancement of 5-HT on VE was prevented during normoxia. On the breathing of hypoxic gas after ICV ketanserin, the degree of AHVD was augmented. In conclusion, our findings suggested that central 5-HT increases normoxic ventilation and reduces the degree of AHVD during hypoxia and that ICV ketanserin prevents the stimulatory effect of 5-HT on respiration and augments AHVD.     

Immunologic mast cell-mediated responses and histamine release are attenuated by heparin.

Heparin has been shown to act as a competitive inhibitor of inositol 1,4,5-triphosphate (InsP3) receptors in various cell types. Because InsP3 is one of the second messengers involved in stimulus-secretion coupling in mast cells, it is possible that heparin may inhibit mast cell-mediated reactions. Therefore, in allergic sheep, we tested this hypothesis in two mast cell-mediated reactions induced by immunologic and nonimmunologic stimuli: immediate cutaneous reaction (ICR) and acute bronchoconstrictor response (ABR). In 12 sheep allergic to Ascaris suum antigen, the surface area of the skin wheal was determined 20 min after intradermal injection (0.05 ml) of increasing concentrations of specific antigen, compound 48/80, and histamine, without and after pretreatment with heparin (100, 300, or 1,000 U/kg i.v.). Antigen, compound 48/80, and histamine produced concentration-dependent increases in ICR. Heparin "partially" inhibited the ICR to antigen and compound 48/80 in a dose-dependent manner without modifying the ICR to histamine. The heparin preservative benzyl alcohol was ineffective. In 11 additional sheep, specific lung resistance was measured before and after inhalation challenges with antigen, compound 48/80, and histamine without and with aerosol heparin pretreatment (1,000 U/kg). Heparin blocked the antigen- and compound 48/80-induced bronchoconstriction without modifying the airway effects of histamine. In isolated human uterine mast cells, heparin inhibited the anti-immunoglobulin E- but not the calcium ionophore- (A23187) induced histamine release. These data suggest that heparin inhibits the ICR and ABR induced by stimuli that produce immunologic and nonimmunologic mast cell degranulation without attenuating the effects of histamine.(ABSTRACT TRUNCATED AT 250 WORDS)