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Topic:Histamine

Histamine is an organic compound involved in various physiological processes in horses, including immune response, gastric acid secretion, and neurotransmission. It is synthesized from the amino acid histidine and is stored in mast cells and basophils, which release histamine in response to allergens or tissue injury. In horses, histamine plays a role in allergic reactions and inflammatory responses, influencing conditions such as equine asthma and urticaria. The compound interacts with specific histamine receptors, which mediate its effects on target tissues. This page compiles peer-reviewed research studies and scholarly articles that explore the synthesis, function, and clinical implications of histamine in equine health.
Autologous blood instillation alters respiratory mechanics in horses.
Equine veterinary journal    January 1, 1995   Volume 27, Issue 1 46-50 doi: 10.1111/j.2042-3306.1995.tb03031.x
Aguilera-Tejero E, Pascoe JR, Tyler WS, Woliner MJ.To investigate physiological consequences of autologous blood instillation in the lungs of healthy horses, respiratory mechanics and bronchial response to histamine were studied in 8 Thoroughbreds before and after introducing autologous blood (n = 5) and sterile saline solution (n = 3) into their lungs. Blood instillation resulted in a decrease in dynamic compliance (Cdyn) and increased respiratory resistance (R). Bronchial sensitivity and reactivity were unchanged after blood introduction. There were no significant changes in pulmonary mechanics or bronchial response after saline instillation...
Platelet activating factor mimics antigen-induced cutaneous inflammatory responses in sweet itch horses.
Veterinary immunology and immunopathology    January 1, 1995   Volume 44, Issue 2 115-128 doi: 10.1016/0165-2427(94)05299-8
Foster AP, Lees P, Cunningham FM.Hypersensitivity responses to biting flies such as Culicoides are believed to be the cause of sweet itch, a seasonal intensely pruritic skin condition of horses. Little is known about the mediators released by antigen in the skin of affected horses. In the present study the cutaneous vascular and cellular responses to intradermally injected platelet activating factor (PAF) have been characterised in sweet itch cases during the active phase of the disease and compared with those of Culicoides antigen extract. Histamine was used as a positive control in vascular permeability studies. Responses w...
Modulation of bronchial smooth muscle function in horses with heaves.
Journal of applied physiology (Bethesda, Md. : 1985)    November 1, 1994   Volume 77, Issue 5 2149-2154 doi: 10.1152/jappl.1994.77.5.2149
Yu MF, Wang ZW, Robinson NE, Derksen FJ.Four mechanisms that modulate airway smooth muscle function in normal horses were studied in the bronchi of horses affected by the airway obstructive disease heaves. Results were compared with data from historical controls studied by the same personnel in the same laboratory. Rings from the left cranial lobar bronchus (LB1) and small bronchi (5 mm OD) were suspended in muscle baths, and the isometric tension were measured. The inhibitory nonadrenergic noncholinergic (iNANC) function was studied in LB1. After the LB1 segments were pretreated with atropine and contracted with histamine, electric...
Effect of sodium cromoglycate on light racehorses with elevated metachromatic cell numbers on bronchoalveolar lavage and reduced exercise tolerance.
Journal of veterinary pharmacology and therapeutics    June 1, 1994   Volume 17, Issue 3 237-244 doi: 10.1111/j.1365-2885.1994.tb00239.x
Hare JE, Viel L, O'Byrne PM, Conlon PD.Some young horses with clinical signs of small airway disease demonstrate increased metachromatic cell numbers on bronchoalveolar lavage. The purpose of this study was to determine the effect of sodium cromoglycate treatment on clinical signs, bronchoalveolar lavage cytology and bronchoalveolar lavage histamine parameters in these horses. Twelve racehorses (age: 3.4 +/- 1.6 years) with a history of respiratory embarrassment at exercise, clinical signs of obstructive airway disease and bronchoalveolar lavage metachromatic cell differential greater than 2% were selected. Horses were randomly ass...
Secretagogue-induced [14C]aminopyrine uptake in isolated equine parietal cells.
American journal of veterinary research    January 1, 1994   Volume 55, Issue 1 132-137 
Campbell-Thompson M.Equine oxyntic mucosal cells were obtained by sequential exposure to pronase and collagenase. Acid production by parietal cells was assessed by uptake of [14C]aminopyrine (AP), a weak base that accumulates in intracellular acidic spaces. Incubation for various times revealed a maximal AP uptake at 10 minutes for histamine and carbachol. Similar secretagogue responses were observed for parietal cells from the mucosal cell preparation or after enrichment by elutriation. Histamine and isobutyl-methylxanthine (IBMX) stimulated AP uptake with a dose-dependent response and maximal effective concentr...
Inhibitory nerve distribution and mediation of NANC relaxation by nitric oxide in horse airways.
Journal of applied physiology (Bethesda, Md. : 1985)    January 1, 1994   Volume 76, Issue 1 339-344 doi: 10.1152/jappl.1994.76.1.339
Yu M, Wang Z, Robinson NE, Leblanc PH.The distribution of inhibitory nerves and the mediator of the inhibitory nonadrenergic noncholinergic (iN-ANC) nervous system were investigated in smooth muscle preparations from seven regions of equine airways. In tissues incubated with atropine and precontracted with histamine, electrical field stimulation produced frequency-dependent relaxation, and the magnitude of the relaxation decreased from trachea to central bronchi and was absent in peripheral airways. The degree of relaxation in bronchi was not simply a function of bronchial size or generation. Propranolol inhibited part of the rela...
Vasomotor effects of histamine on bovine and equine basilar arteries in vitro.
Veterinary research communications    January 1, 1994   Volume 18, Issue 6 447-456 doi: 10.1007/BF01839422
Miyamoto A, Nishio A.The vasomotor effects of histamine on isolated bovine and equine basilar arteries were examined. Histamine induced contractions in both these preparations. The maximal response to and pEC50 value for histamine of the equine artery were larger than those of bovine tissue. Similar results were obtained with endothelium-denuded basilar arteries. Diphenhydramine (H1-receptor antagonist) inhibited histamine-induced contractions of the basilar arteries from both species in a concentration-dependent manner and its pA2 values (with 95% confidence limits) were 7.61 (7.39-7.83) and 8.15 (8.01-8.29) for ...
A comparison of the actions of platelet activating factor (PAF) antagonists WEB 2170 and WEB 2086 in the horse.
Journal of veterinary pharmacology and therapeutics    December 1, 1993   Volume 16, Issue 4 477-487 doi: 10.1111/j.1365-2885.1993.tb00214.x
Foster AP, Cunningham FM, Andrews MJ, Lees P.The effects of the selective platelet activating factor (PAF) receptor antagonist WEB 2170 on PAF-induced responses in equine cells and tissues have been examined and compared with those of WEB 2086. In initial experiments WEB 2170 was shown to inhibit in vitro platelet aggregation in a dose-dependent, competitive reversible manner (pA2 = 7.21). Co-administration of the antagonists with either PAF or histamine also inhibited PAF, but not histamine, induced wheal formation and PAF-induced neutrophil accumulation in vivo in equine skin. Intravenous (i.v.) administration of both drugs at a dose o...
Responsiveness of basophil granulocytes of horses suffering from chronic obstructive pulmonary disease to various allergens.
Veterinary immunology and immunopathology    October 1, 1993   Volume 38, Issue 3-4 217-227 doi: 10.1016/0165-2427(93)90082-f
Dirscherl P, Grabner A, Buschmann H.As basophils are the major effector cells of allergic reactions, confirmation of the allergic etiology of chronic obstructive pulmonary disease (COPD) was sought by the demonstration of a specific in vitro response of equine basophilic blood cells to some potential allergens (Aspergillus, Cladosporidium, Mucor, Penicillium, extracts of dust particles of hay and straw). The allergen induced degranulation of basophils and the histamine and protease release from basophils during incubation with the allergens were tested. By evaluating the results obtained from 14 COPD horses and eight controls it...
Modulation of bronchial responsiveness in horses by phenylbutazone and furosemide.
American journal of veterinary research    October 1, 1993   Volume 54, Issue 10 1703-1709 
Aguilera-Tejéro E, Pascoe JR, Woliner MJ.Effects of phenylbutazone (PBZ) and furosemide (FUR) on the respiratory tract of horses were evaluated, focusing on bronchial responsiveness. Four healthy Thoroughbreds were used and data were analyzed by use of a Latin square design. Histamine provocation tests (0.5, 1, 2, and 4 micrograms/min, i.v.) were done: (1) without prior treatment with PBZ or FUR, (2) 30 minutes after administration of PBZ (8 mg/kg, i.v.), (3) 1 hour after administration of FUR (1 mg/kg, i.v.), and (4) after administration of PBZ plus FUR. Pulmonary function tests (dynamic compliance, resistance, respiratory frequency...
Effect of various neurotransmitters and electrical field stimulation on smooth muscle preparations from the esophagus of horses.
Zentralblatt fur Veterinarmedizin. Reihe A    September 1, 1993   Volume 40, Issue 7 501-508 doi: 10.1111/j.1439-0442.1993.tb00658.x
Denac M, Bebié P, Scharrer E.The effects of various neurotransmitters and electrical field stimulation on muscle strips from the distal equine esophagus were studied. Acetylcholine (ACH) caused concentration dependent (1.1-55 x 10(-6) mol/l) contractions of the longitudinal and circular muscle strips from the distal esophagus as well as from the lower esophageal sphincter (LES). Atropine (10(-5) mol/l) blocked these contractions. Noradrenaline (NA) induced concentration related (1.1-55 x 10(-6) mol/l) contractions of the muscle strips from the LES. This excitatory effect of noradrenaline was antagonized by the alpha 1-rec...
Quantification of histamine in plasma and pulmonary fluids from horses with chronic obstructive pulmonary disease, before and after ‘natural (hay and straw) challenges’.
Veterinary immunology and immunopathology    April 1, 1993   Volume 36, Issue 3 223-237 doi: 10.1016/0165-2427(93)90021-u
McGorum BC, Dixon PM, Halliwell RE.A commercial radioimmunoassay kit was used to quantify histamine concentrations of plasma, bronchoalveolar lavage fluid (BALF) and pulmonary epithelial lining fluid (PELF) of normal horses and horses with chronic obstructive pulmonary disease (COPD), before and after 'natural (hay and straw) challenge' (NC). There were no significant changes in the concentrations of histamine in plasma or BALF at 0.5 or 5 h after NC, but the PELF histamine concentration of COPD affected horses was significantly increased at 5 h, but not at 0.5 h, following NC. As the histamine concentrations of whole BALF lysa...
Temporal effects of inhaled histamine and methacholine aerosols on the pulmonary mechanics of thoroughbred horses.
Journal of veterinary pharmacology and therapeutics    December 1, 1992   Volume 15, Issue 4 317-331 doi: 10.1111/j.1365-2885.1992.tb01024.x
Guthrie AJ, Beadle RE, Bateman RD, White CE.This paper presents a method for on-line determination of pulmonary mechanics in standing, non-sedated horses during and following inhalation of aerosolized drug solutions. This method was used to evaluate the temporal effects of inhaled histamine and methacholine aerosols on pulmonary mechanics in 18 Thoroughbred horses. The following were concluded from this study. The extremely large between-breath variation, for all variables used to evaluate pulmonary mechanics in the horse, limits the usefulness of these variables for modeling the non-specific pulmonary responses to inhaled stimulants on...
Decreased airway mucosal prostaglandin E2 production during airway obstruction in an animal model of asthma.
The American review of respiratory disease    September 1, 1992   Volume 146, Issue 3 586-591 doi: 10.1164/ajrccm/146.3.586
Gray PR, Derksen FJ, Broadstone RV, Robinson NE, Peters-Golden M.Heaves is a respiratory disorder of horses and ponies characterized by bouts of acute airway obstruction and airway hyperresponsiveness. We measured prostaglandin E2 (PGE2) and 15-hydroxyeicosatetraenoic acid (15-HETE) production in vitro in tracheal epithelium obtained from six affected horses at the time of acute airway obstruction as compared with six matched control horses. Strips of epithelium and subepithelial tissue were prepared and stimulated with A23187, histamine, and bradykinin. The PGE2 and 15-HETE in media from strips was quantitated by radioimmunoassay. 15-HETE above the limits ...
Effect of a histamine H2 type receptor antagonist (WY 45, 727) on the healing of gastric ulcers in ponies.
Journal of veterinary internal medicine    September 1, 1992   Volume 6, Issue 5 271-275 doi: 10.1111/j.1939-1676.1992.tb00351.x
MacAllister CG, Sangiah S, Mauromoustakos A.Using video gastroscopy, the efficacy of a Histamine-H2 type receptor antagonist (WY 45, 727) was investigated in young ponies with spontaneous and experimentally induced gastric ulcers. Oral administration of WY 45, 727 at 2 mg/kg and 10 mg/kg of body weight every 12 hours for 14 days resulted in complete healing of spontaneous gastric ulcers in the non-glandular portion of the stomach in 2/5 (40%) and 3/4 (75%) of the ponies, respectively, compared (P < 0.05) to 0/5 (0%) placebo-treated ponies. After intramuscular administration of flunixin meglumine at 1.5 mg/kg body weight every 8 hours fo...
Gastric ulceration in horses: 91 cases (1987-1990).
Journal of the American Veterinary Medical Association    July 1, 1992   Volume 201, Issue 1 117-120 
Murray MJ.Gastroendoscopy was performed on 111 horses (1 to 22 years old) that had signs of abdominal discomfort of variable duration and severity. At least 1 episode of colic had been observed within 48 hours of examination in 31 horses. Recurrent episodes of colic were observed in 28 horses within 2 to 10 days of examination, 31 horses within 11 to 30 days, 12 horses within 31 to 60 days, and in 9 horses at more than 60 days after the initial examination. Gastric ulceration was found in 91 of 111 horses examined. Other abnormalities involving the gastrointestinal tract or other abdominal viscera were ...
Loss of absorptive capacity for sodium and chloride in the colon causes diarrhoea in Potomac horse fever.
Research in veterinary science    May 1, 1992   Volume 52, Issue 3 353-362 doi: 10.1016/0034-5288(92)90037-3
Rikihisa Y, Johnson GC, Wang YZ, Reed SM, Fertel R, Cooke HJ.Ehrlichia risticii, an obligate intracellular bacterium in the family Rickettsiaceae, causes Potomac horse fever which is often associated with severe watery diarrhoea. The mechanism of the diarrhoea is unknown. The aim of this study was to determine whether sodium and chloride transport, morphology and cyclic adenosine 3', 5'-monophosphate (cyclic AMP) content of colonic mucosa was altered in E risticii-infected horses. Mucosa-submucosa sheets from the large and small colon of nine infected and seven to nine uninfected horses were set up in Ussing chambers for measurement of short-circuit cur...
Inflammatory effects of platelet activating factor (PAF) in equine skin.
Equine veterinary journal    May 1, 1992   Volume 24, Issue 3 208-214 doi: 10.1111/j.2042-3306.1992.tb02817.x
Foster AP, Cunningham FM, Lees P.Intradermal administration of PAF (0.001-1 micrograms/site), but not lyso-PAF (10 micrograms/site), in the horse caused an increase in cutaneous vascular permeability which was maximal by 32 min. Responses to PAF and histamine were reduced by coadministration of the histamine 1 receptor antagonist chlorpheniramine, although only the inhibition of histamine-induced responses was dose-related and statistically significant. The cyclo-oxygenase inhibitor indomethacin was without effect on PAF-induced increases in vascular permeability. These findings suggest that the actions of PAF on equine skin ...
Epithelial strips: an alternative technique for examining arachidonate metabolism in equine tracheal epithelium.
American journal of respiratory cell and molecular biology    January 1, 1992   Volume 6, Issue 1 29-36 doi: 10.1165/ajrcmb/6.1.29
Gray PR, Derksen FJ, Robinson NE, Slocombe RF, Peters-Golden ML.We have developed an alternative method for examining equine tracheal epithelial arachidonic acid (AA) metabolism that utilizes strips of pseudostratified columnar epithelium attached to a layer of elastic tissue 80 to 130 microns thick. We compared the responses of this preparation with those of enzymatically dispersed suspensions of tracheal epithelium obtained from the same animal. Strips incubated with [3H]AA incorporated 40.8 +/- 3.6% of added radioactivity and released 2.55 +/- 0.23% of incorporated radioactivity when stimulated with 5 microM A23187. Values for the cell suspension were 5...
Mucosal histamine inhibits Na absorption and stimulates Cl secretion across equine tracheal epithelium.
The American journal of physiology    December 1, 1991   Volume 261, Issue 6 Pt 1 L456-L461 doi: 10.1152/ajplung.1991.261.6.L456
Tessier GJ, Traynor TR, Kannan MS, O'Grady SM.When the equine tracheal epithelium is mounted in Ussing chambers and bathed in plasma-like Ringer solution, the tissue generates a lumen-negative transepithelial potential (PD) of 22 mV and a short-circuit current (Isc) of 70-200 microA/cm2. Mucosal addition of 10 microM histamine produces a transient increase in the Isc followed by a return to baseline or below. Mucosal addition of 2 microM diphenhydramine inhibits the Isc response to mucosal histamine, whereas 100 microM mucosal cimetidine produces no effect. The average initial increases in Isc over time for mucosal vs. serosal histamine a...
Plasma histamine levels in laminitic horses and in horses treated with a corticosteroid.
Zentralblatt fur Veterinarmedizin. Reihe A    November 1, 1991   Volume 38, Issue 9 716-719 doi: 10.1111/j.1439-0442.1991.tb01069.x
Rautschka R, Stanek C, Knezevic PF.In seven sound horses histamine plasma levels were evaluated by means of a radioenzymatic method using the enzyme histamine-N-methyltransferase (mean = 4.46 nmol/l, SD = 1.55 nmol/l). Histamine levels of laminitic horses were significantly higher (n = 11; mean = 12.46 nmol/l, SD = 3.24 nmol/l). In three sound horses plasma histamine levels were determined over a two week period following a double administration of 10 mg dexamethasone-21-isonicotinate/100 kg body weight. Histamine levels remained within the range of sound control horses.
Participation of H1-receptors in histamine-induced contraction and relaxation of horse coronary artery in vitro.
The Journal of veterinary medical science    October 1, 1991   Volume 53, Issue 5 789-795 doi: 10.1292/jvms.53.789
Obi T, Miyamoto A, Matumoto M, Ishiguro S, Nishio A.The mechanisms of histamine-induced contraction and relaxation were investigated in rings isolated from a middle part of the left descending coronary arteries of horses. Intact and endothelium-denuded preparations were compared. Rings of horse coronary arteries contracted in response to histamine in a concentration dependent manner, but some of them relaxed with lower concentrations and contracted with higher concentrations. Removal of the endothelium abolished the relaxation and potentiated the contraction. The pD2 values were 4.70 +/- 0.08 in the rings with intact endothelium and 4.95 +/- 0....
Beta-adrenergic receptor activity in ponies with recurrent obstructive pulmonary disease.
American journal of veterinary research    September 1, 1991   Volume 52, Issue 9 1416-1422 
Scott JS, Berney CE, Derksen FJ, Robinson NE.Pulmonary function measurements were made in control ponies and in ponies with recurrent obstructive pulmonary disease (principals) during clinical remission and during an attack of acute airway obstruction. The ponies were given beta-adrenergic antagonists and agonists to determine the role of beta receptors in recurrent obstructive pulmonary disease, and to determine the subtypes of beta receptors mediating bronchodilation in ponies. Aerosol administration of the beta antagonists, propranolol (beta 1 and beta 2), atenolol (beta 1), and butoxamine (beta 2) decreased dynamic compliance (Cdyn) ...
Histamine inhalation challenge in normal horses and in horses with small airway disease. Doucet MY, Vrins AA, Ford-Hutchinson AW.A histamine inhalation challenge (HIC) procedure was developed to assess hyperreactive states in horses. Following clinical evaluation, percutaneous lung biopsies were performed on nine light breed mares aged 6 to 15 years. Five horses, with normal small airways, were classified as group A and four subjects with small airway disease (SAD) lesions formed group B. Pulmonary mechanics parameters were monitored following an aerosol of 0.9% saline and every 5 min for up to 30 min after HIC with 0.5% w/v of histamine diphosphate, administered through a face mask for 2.5 min. Tidal volume (VT) and ai...
In vitro responses of distal airways in horses with recurrent airway obstruction.
American journal of veterinary research    July 1, 1991   Volume 52, Issue 7 999-1003 
LeBlanc PH, Broadstone RV, Derksen FJ, Robinson NE.Distal airway segments (ID, 3 to 4 mm; length, 5 mm) from 2 groups of horses were isolated and suspended in tissue baths filled with Krebs solution, aerated with 5% CO2 in oxygen and maintained at 37 degrees C. Responses to exogenous acetylcholine, isoproterenol, or electrical field stimulation were compared. Control horses (n = 30) had no history of recurrent airway obstruction, whereas principal horses (n = 15) had recurrent airway obstruction and were studied during an acute episode of airway obstruction. Although the distal airways contracted in response to the cumulative half-logarithmic ...
Concentrations of arachidonate metabolites, steroids and histamine in preovulatory horse follicles after administration of human chorionic gonadotrophin and the effect of intrafollicular injection of indomethacin.
The Journal of endocrinology    April 1, 1991   Volume 129, Issue 1 131-139 doi: 10.1677/joe.0.1290131
Watson ED, Sertich PL.This study investigated the sequence of hormonal changes within the preovulatory follicles of mares. Mares were injected i.v. with 2500 IU human chorionic gonadotrophin (hCG) when a preovulatory follicle of 35 mm in diameter was detected. Fluid was aspirated from preovulatory follicles before (0 h), and 12, 24 and 36 h after administration of hCG. Concentrations of progesterone, prostaglandin (PG) E2, PGF, 6-keto-PGF1 alpha and thromboxane B2 in follicular fluid increased significantly (P less than 0.01) between 0 and 36 h. At 36 h, PGE2 was present in highest concentrations, followed by PGF a...
Assessment of histamine, bradykinin, prostaglandins E1 and E2 and carrageenin as vascular permeability agents in the horse.
Journal of veterinary pharmacology and therapeutics    March 1, 1991   Volume 14, Issue 1 61-69 doi: 10.1111/j.1365-2885.1991.tb00805.x
Auer DE, Ng JC, Reilly JS, Seawright AA.The vascular leakage induced by histamine, bradykinin, serotonin and prostaglandin E1 and E2 was assessed. The test agents were injected intradermally into the shaved thoracic skin of horses and the vascular leakage estimated either semi-quantitatively by recording the diameter of the lesions or by measuring the actual volume of extravasated plasma in microliters using iodine-125-labelled human serum albumin (125I-HSA) as a marker in the blood plasma. Using the latter method, the vascular leakage induced by carrageenin and the effect of coadministered prostaglandins E1 and E2 upon the vascular...
Effects of a histamine type-2 receptor antagonist (BMY-25368) on gastric secretion in horses.
American journal of veterinary research    January 1, 1991   Volume 52, Issue 1 108-110 
Orsini JA, Dreyfuss DJ, Vecchione J, Spencer PA, Uhlman R.The effects of a potent new histamine-2 (H2) receptor antagonist, BMY-25368, were studied on gastric acid secretion in 5 foals from which food was withheld. Doses of 0.02, 0.11, 0.22, and 1.10 mg/kg of body weight were administered IM in a randomly assigned treatment sequence. Following BMY-25368 administration, hydrogen ion concentration was decreased and mean pH was higher than baseline values in a dose-response pattern. At the 0.22 and 1.10 mg/kg doses, the high pH was sustained for greater than 4 hours. The BMY-25368 thus may be useful for treating gastric ulcer disease in horses.
In vitro responses of airway smooth muscle from horses with recurrent airway obstruction.
Pulmonary pharmacology    January 1, 1991   Volume 4, Issue 4 191-202 doi: 10.1016/0952-0600(91)90011-q
Broadstone RV, LeBlanc PH, Derksen FJ, Robinson NE.The in vitro contractile and relaxant responses of tracheal smooth muscle strips (TSM) and third-generation bronchi (3B) of control horses and horses with recurrent obstructive disease (heaves) were compared. Acetylcholine (ACH) sensitivity of the diseased tissues was less than that of tissues from control horses, especially at the level of the third generation (EC50 controls 15 +/- 11 microM vs 81 +/- 17 microM for heaveys). Despite tracheal and bronchial hyporesponsiveness to ACH, these tissues from heavey horses were hyperresponsive to EFS. The inhibitory effect of isoproterenol and electri...
Plasma histamine levels during exploratory laparotomies in suspected equine grass sickness cases.
Equine veterinary journal    September 1, 1990   Volume 22, Issue 5 362-363 doi: 10.1111/j.2042-3306.1990.tb04291.x
Hodson N, Hunt J, Causon RC.The research article discusses an investigation into how exploratory diagnostic laparotomy affects the circulating histamine levels in acute, subacute, and chronic suspected equine grass sickness cases. The study utilized a […]