Concentration effect relationships of infused histamine in normal volunteers

Histamine was infused in six normal volunteers at rates of 16, 32, 64 and 96 ng/kg/min increasing at 5-min intervals followed by 128 ng/kg/min for 45 min. Heart rate increased, diastolic blood pressure decreased and skin temperature increased in a dose-dependent fashion. Mean heart rate increased by 15.6±5.7 beats/min, mean diastolic pressure fell by 8.8±3.2 mmHg and mean skin temperature increased by 1.2±0.3°C at the highest infusion rate. Mean plasma histamine rose from a basal level of 0.20±0.03 ng/ml to 1.97±0.25 ng/ml at the end of the highest infusion rate. The threshold infusion rate for physiological effects was 64–96 ng/kg/min corresponding to 0.77–0.97 ng/ml. Salivary flow was stimulated by 21% after 30 min at the highest dose infusion (P=0.05). Plasma adrenaline increased 132% but plasma noradrenaline was unchanged.There was a linear decline in heart rate after terminating the histamine infusion with a half time of 82 sec. The half life of infused histamine in the plasma was 102 sec. The clearance of histamine from the plasma was 6.1±0.2 l/min or 83 ml/kg/min.These concentration effect relationships in normals throw doubt on some of the high endogenous plasma histamine values in the literature.     

Effects of infused histamine: correlation of plasma histamine levels and symptoms

Plasma and urine histamine levels were measured during sequential infusions of histamine (0.05, 0.1, 0.25, 0.5, and 1.0 microgram/kg/min histamine base for 30 min each) to determine the plasma level required to elicit flushing, headaches, tachycardia, and diastolic hypotension. Each study was performed with subjects on no medications or after pretreatment with hydroxyzine and/or cimetidine in order to confirm the receptor subtype involved in each of the responses. Resting plasma histamine levels were 0.62 +/- 0.12 ng/ml, and levels rose progressively indirect proportion to the concentration of infused histamine. Plasma levels of histamine required to elicit symptoms were as follows: 1.61 +/- 0.30 ng/ml = 30% increase in heart rate, 2.39 +/- 0.52 ng/ml = significant flush and headache, and 2.45 +/- 0.13 ng/ml = 30% increase in pulse pressure. Cimetidine pretreatment failed to influence the histamine level required to elicit symptoms, hydroxyzine pretreatment significantly raised the level required to increase heart rat by 30%, and the combination of antihistamines significantly raised the threshold for histamine to elicit all the response. Urine histamine was increased in direct proportion to the histamine infusions, and because of stability, accessibility, and the capacity for retrospective diagnosis, urine is the suggested fluid to employ to measure histamine release in humans.     

Chronotropic cardiac effects of histamine in the conscious dog with chronic atrioventricular block: interactions with the autonomic nervous system

Chronotropic effects of histamine and dimaprit were studied in the conscious dog with chronic atrioventricular block. Histamine at 0.2–5 g/kg and dimaprit at equimolar doses (i. e. 0.25–6.25 g/kg) increased atrial rate dose-relatedly. Blockade of muscarinic receptors reduced these effects and simultaneous blockade of muscarinic and beta-adrenergic receptors abolished them. Histamine and dimaprit moderately increased ventricular rate. Blockade of muscarinic receptors did not modify these effects, suppressed them. After blockade of beta-adrenoceptors, histamine and more rarely dimaprit sometimes decreased atrial and ventricular rates. These effects were prevented by additional muscarinic blockade. Histamine and dimaprit lowered mean blood pressure to the same degree before and after each antagonist. The positive chronotropic effects of histamine and dimaprit, at these doses, are probably reflex responses to their hypotensive effects. The negative chronotropic effects of histamine after pindolol are due to muscarinic receptor activation. No evidence was found to implicate histamine-specific receptors in any of the chronotropic effects of histamine and dimaprit.     

Histamine-releasing properties of Polysorbate 80in vitro andin vivo: correlation with its hypotensive action in the dog

The solvent of commercial amiodarone (Polysorbate 80) has been reported to produce haemodynamic responses in humans and in dogs similar to those produced by histamine infusion. We therefore evaluated the correlation between hypotension induced by the solvent of amiodarone and its histamine-releasing properties in the awake dog.The solvent of amiodarone administered to a dog, over 5 min in a dose of 10 mg/kg of Polysorbate 80, produced severe hypotension after the first administration; the second injection (24 h later) caused fewer hypotensive effects.Histamine release in the peripheral tissues was demonstrated by a marked increase in plasma histamine concentrations, with the maximum value 10 min after the solvent administration. H₁- and H₂-receptor blockade with mepyramine (5 mg/kg) and cimetidine (10 mg/kg) significantly reduced the cardiovascular effects of the solvent.Isolated peritoneal mast cells from rats also released histamine in response to Polysorbate 80. These studies show that Polysorbate 80 releases histamine bothin vitro and in isolated mast cells from rats andin vivo in the dog, and that the plasma concentrations are correlated with the haemodynamic responses.     

Effects of insulin on experimental catecholamine cardiomyopathy.

We have recently shown that insulin attenuates norepinephrine (NE) dose-response curves in both isolated cardiac muscle and intact heart preparations. Accordingly, an intact rabbit model was used to determine if insulin would reduce the extent of myocardial damage following a standard NE infusion. Each animal was given pentobarbital, 30 mg/kg, and heart rate, arterial pressure, glucose, blood gases, and pH were measured. NE (2 microgram/min/kg) was given intravenously for 90 minutes. After 48 hours the rabbits were killed and the hearts were examined microscopically and assigned a histologic score. Florid lesions were present in 17 of 24 sections (71%) from 12 animals. They were characterized by myofiber necrosis and an intense cellular reaction. However, only 5 of 40 sections (12.5%) from 20 rabbits given insulin (10 units/kg) 30 minutes before the NE infusion showed advanced lesions (P less than 0.001). The mean histologic score was reduced from 1.7 to 1.0 (P less than 0.001). The frequency of advanced lesions increased to 86% in animals given a higher dose of NE (3 microgram/kg/min) and was reduced to 53% by pretreatment with insulin. A dosage of 5 units/kg was as effective as 10 units/kg, but rabbits given 1 unit/kg manifested cardiomyopathic changes identical to those in rabbits not pretreated with insulin. No differences in heart rate, arterial pressure, PO2, or pH were evident between the groups. It is concluded that large doses of insulin reduce myocardial damage produced by NE in this model. This may be linked with the phenomenon of insulin inhibition of the inotropic action of NE.     

Histamine and human heart

Heart fragments obtained from human right atrium contain 1.5 +/- 0.2 micrograms of histamine per gram of wet tissue. Human heart spontaneously synthesizes significant amounts of PGI2, PGF2 alpha, PGE2 and TxA2. The Ca2+ ionophore A 23187 (0.5-3 micrograms/ml) dose-dependently induces histamine release and prostanoid production. Histamine (0.5-1 micrograms/kg/min) infusion in 10 normal donors produced an increase in heart rate and a significant depression of the ST segment. Selective H1 receptor stimulation in patients undergoing cardiac catheterization resulted in a decrease of the mean aortic pressure and of coronary vascular resistance.     

Adrenergic mechanisms and blood pressure regulation in diabetes mellitus

Summary Changes in blood pressure (BP) and plasma norepinephrine (NE) following various stimuli of the sympathetic nervous system were studied in six healthy subjects and in 17 diabetic patients. The latter were subdivided in three groups: (1) six patients with neither peripheral neuropathy nor autonomic dysregulation, (2) six patients with severe peripheral neuropathy without autonomic dysregulation, and (3) five patients with autonomic dysregulation, three of whom suffered also from peripheral neuropathy. The following procedures were performed: (1) cold pressor test (2 min), (2) mechanical irritation of the skin by suction (0.75 kg/cm², 10 min), (3) orthostasis (10 min), and (4) i.v. infusion of NE (50, 100, 200 ng kg^–1 min^–1 for 15 min each). Both the stimulated endogenous plasma NE levels and BP response to exogenous NE were the same in normal subjects, in diabetic controls and in diabetics with peripheral neuropathy without autonomic dysregulation. In contrast, diabetics with postural hypotension showed a less pronounced release of NE to standing (P<0.05), but not to cold pressor test and mechanical skin irritation. Furthermore, they showed increased vasoreactivity to the highest dose (P<0.05), but not to the lower doses of exogenous NE. Thus NE release and adrenergic BP regulation seem to be altered only in diabetics with clinical signs of autonomic dysregulation. These alterations can only be evaluated when patients are exposed to stimuli of higher intensity, such as orthostasis or infusion of a high NE dose.     

Role of pancreatic polypeptide in canine gastric acid secretion.

The interrelationships of canine pancreatic polypeptide (cPP) and gastric acid secretion were studied in dogs following infusion of histamine or pentagastrin. Pentagastrin stimulated gastric acid release 30-fold and simultaneously increased plasma cPP secretion by an average of 120 pg/ml. Although histamine stimulated gastric acid secretion to a comparable degree, it had no effect on plasma cPP levels. Three mechanisms of inhibition of acid secretion (cimetidine, duodenal acidification, and somatostatin) had different effects on pancreatic polypeptide (PP) levels. With a background infusion of pentagastrin, cimetidine did not affect cPP levels. In contrast, somatostatin dramatically inhibited both gastric fistula output and cPP release. Finally, a 10-min duodenal irrigation with 0.1 N HCl resulted in a brief spike in cPP levels (from 266 +/- 12 to 347 +/- 31 pg/ml) at the time of greatest inhibition of histamine-stimulated acid secretion. Infusions of histamine + porcine pancreatic polypeptide (pPP) at concentrations of 1.0 and 2.25 microgram/kg per h and of pentagastrin + pPP at 2.25 microgram/kg per h closely simulated postprandial cPP levels (mean 1306 +/- 18 pg/ml at 30 min) but produced no change in gastric fistula output. These studies demonstrated that PP levels and rates of gastric acid secretion are unrelated and that at physiologic concentrations PP plays no significant role in the regulation of gastric acid secretion.     

Dose-response studies of the suppression of whole blood histamine and basophil counts by prednisone

If some clinical problems (e.g., radiographic contrast media reactions) arise from mediator release by circulating basophils, prednisone's capacity to prevent such is likely to be at least partly related to its suppressive effects on whole blood histamine and basophil levels. To establish an optimal dosage schedule, 15 healthy male volunteers entered a two-phased study to determine (1) the single dose of prednisone required to produce maximal suppression of histamine and basophil levels and (2) the effects of repeated prednisone doses. Parameters monitored were whole blood histamine, quantitative basophil counts, white blood cell (WBC) and differential counts, and plasma prednisone, prednisolone, and cortisol levels. Fifty milligrams prednisone suppressed whole blood histamine levels as much as a larger dose and also showed a marked effect on circulating basophils and other leukocytes. Three 50-mg prednisone doses given at 6-hr intervals had a greater effect on whole blood histamine and circulating leukocytes than fewer doses. Thus, the commonly used empirical prednisone dosage regimen is supported. One implication of the results of this study is that greater suppression of blood basophils and histamine levels might be obtained by administering the last prednisone dose about 6 hr before procedures in which a very rapid release of mediators from basophils is anticipated.     

Inhibitory effect of AA-673 eye drops on ocular provocation for Japanese cedar pollinosis

The inhibitory effect of 0.25% AA-673 eye drops on histamine release in tears was examined by an ocular provocation test with antigen in 11 patients with Japanese cedar pollinosis during the off-season. AA-673 eye drops were administered into the right eye, while the left eye was given placebo eye drops. Five minutes later, a cedar antigen solution at 1:20 w/v was applied to the eyes. Levels of histamine in collected tears were determined by radioimmunoassay. Histamine levels in tears before, and 5 min and 10 min after provocation amounted to 0.2 +/- 0.2 ng/ml, 1.2 +/- 1.3 ng/ml and 1.3 +/- 1.6 ng/ml, respectively, while they were 0.2 +/- 0.2 ng/ml, 3.4 +/- 2.4 ng/ml and 3.6 +/- 3.6 ng/ml in the placebo-treated eyes at the same time points, showing a significant inhibitory effect of the drug on histamine release in the eyes treated with AA-673 (p less than 0.01 at 5 min; p less than 0.05 at 10 min). Inhibition rates of AA-673 eye drops on histamine release were 73.0% at 5 min and 69.6% at 10 min after provocation, indicating the excellent effect of this preparation in inhibiting histamine release. From the above findings it is considered that 0.25% AA-673 eye drops are an effective new therapeutic agent for Japanese cedar pollinosis.     

Histaminergic modulation of hormonal control in the exocrine guineapig pancreas

The effects of histamine upon secretin- or cholecystokinin (CCK)-evoked exocrine pancreatic secretion were investigated in the anaesthetised guinea pig. Histamine (0.1 µmol/kg/min) induced a slight increase in pancreatic juice flow and total protein release compared to saline controls. Secretin (0.5 pmol/kg/min) and CCK-8 (0.75 pmol/kg/min) evoked marked time course increases in both the rate of pancreatic juice flow and total protein output in the anaesthetised guinea pig. Administration of either secretin or CCK-8 simultaneously with histamine elevated the exocrine pancreatic secretion compared to the smaller response obtained when administered separately. These results indicate that histamine may play an important physiological role in modulating the hormonal control of exocrine guinea pig pancreas.     

Effects of histamine on slowly adapting pulmonary stretch receptor activities in vagotomized rabbits

Thirty-two SAR fibers located below the carina were used in 32 anesthetized, bilaterally vagotomized, and artificially ventilated rabbits. After intravenous administration of histamine (20, 40, and 80 micrograms/kg, n = 13) or ACh (10, 20, and 40 micrograms/kg, n = 13), SARs became active during expiration but decreased their inspiratory activity. The effects of both drugs were dose-dependent. The injection of histamine or ACh at all doses examined had no effect on tracheal pressure (PT). Atropine (3 mg/kg) and isoprenaline (100 micrograms/kg) blocked the responses of SAR activity to low doses of histamine (20 and 40 micrograms/kg) and to all doses of ACh. The response of SARs to 80 micrograms/kg of histamine was not altered by atropine (n = 10) nor by isoprenaline (n = 10). These results suggest that low-dose effects of histamine on SARs occur as the result of ACh release whereas with high doses the effect of histamine on the receptors is mainly independent of ACh released from the nerve endings. In another series of experiments (n = 6) where animals were treated with isoprenaline (100 micrograms/kg) and, subsequently, physostigmine (200 micrograms/kg), histamine (20 and 40 micrograms/kg) or ACh (10 and 20 micrograms/kg) increased the inspiratory discharge in SARs and the level of PT. From these results, it is assumed that the changes of SAR activity following histamine injection in vagotomized animals reflect a local bronchomotor effect which takes place in a peripheral bronchial tree that does not affect the level of PT. Histamine seems to release ACh and to elicit bronchoconstriction that can be manifested by physostigmine treatment.     

The role of gastric histamine release in the acid secretory response to pentagastrin and methacholine in the dog

We have previously demonstrated that both pentagastrin and methacholine can stimulate histamine release from the canine stomach during short term administration of the secretagogues into the gastrosplenic artery. In this study we tested the hypothesis that gastric histamine release determines the acid secretory response to acid secretagogues. Increasing doses of pentagastrin (2, 6, and 20 ng/kg/min) and methacholine (0.1, 0.3, and 1µg/min) were infused into the gastro-splenic artery in dogs, while gastric acid output, histamine and N-methyl histamine secretory rates were monitored. Histamine and N-methyl histamine concentrations in plasma were measured using GC/NICI-MS. Increasing doses of pentagastrin resulted in increasing gastric output. Total histamine secretory rate expressed as the sum of histamine and N-methyl histamine secretory rate showed a significant increase above basal with the two highest doses of pentagastrin. Regression analysis correlating the dose of pentagastrin to gastric acid output gave a correlation coefficient of 0.586 which was very significant. Regression analysis correlating the total histamine secretory rate to acid output gave a correlation coefficient of 0.498 which was also very significant. Increasing doses of methacholine also resulted in a dose-dependent increase in acid output. Histamine secretory rates showed a statistically significant increase above basal only at the 1µg/min infusion rate, however, the total histamine secretory rates (histamine + N-methyl histamine) were no longer significant at any of the doses of methacholine. Regression analysis correlating the dose of methacholine to gastric acid output gave a correlation coefficient of 0.571 which was significant, while correlating the histamine secretory rate to acid output gave a correlation coefficient of 0.338, not significant, which decreased to 0.079 when the total histamine secretory rates were correlated to acid output. Sixty-eight min infusions of pentagastrin demonstrated a dose-dependent, pulse-like but persistent increase in histamine secretory rate above basal, while long-term infusion of methacholine gave a flat, low-grade histamine stimulation. These data suggest that for pentagastrin, both the dose of pentagastrin and the amount of histamine released determine the acid secretory response with this secretagogue, but the dose of pentagastrin correlates more strongly with acid output. During cholinergic stimulated acid output, only the dose of methacholine correlates with acid output. Thus, for cholinergic stimulated gastric acid output, histamine is not likely to be a final mediator, but for gastrin both its direct action at the parietal cell and the amount of histamine released appear to contribute to the acid secretory response.Supported in part by Public Health Service grant NIH R01 DK38504.     

Effects of histamine on the circulatory system

Summary Experiments have been made in anaesthetised cats and dogs and in healthy, human volunteers to compare the changes in blood pressure and heart rate during systemic administration of histamine.Histamine, 1×10^–9 to 1×10^–7 mol/kg/min, lowered blood pressure in a similar dose-dependent fashion in all three species. In man and the cat this was accompanied by clear dose-dependent tachycardia whereas in the dog heart rate changes were minimal.Pharmacological analysis of the depressor responses to histamine in all three species and the reduction in total peripheral resistance in the cat and dog showed that the immediate responses to histamine in all three species involved H₁-receptors and that sustained responses involved H₂-receptors. Abolition of responses to histamine throughout infusions required H₁- and H₂-receptor blockade.Histamine antagonists, used in doses which cause abolition of cardiovascular responses to large doses of histamine, do not cause any significant change in the resting cardiovascular system.     

Cardiac release of histamine after ventricular fibrillation and defibrillation during insertion of implantable cardioverter defibrillators (ICD)

Histamine has inotropic, chronotropic, arrhythmogenic, and vasoactive effects, and is released from the heart in ischaemia-reperfusion injury. The effect of ventricular fibrillation (VF) and defibrillation (DEF) on histamine release was investigated in 9 anaesthetized patients undergoing transvenous implantation of ICD. Concomitant arterial and coronary sinus (CS) blood samples were drawn before induction of VF (duration 20 seconds), immediately after, and 2 and 5min after DEF (18–24 Joules). Basal arterial histamine was 2.5±6nmol/1, and did not increase after VF. The histamine level in CS was 1.1±0.2nmol/1 before VF (p < 0.008 compared to arterial), and increased to 2.5 ± 0.6 nmol/1 immediately after (p < 0.045 compared to basal), to 3 ± 1.1 nmol/1 2 min after (p < 0.45), and to 2.4 ± 0.8 nmol/1 5min after VF. In the basal state there was an uptake of histamine across the coronary circulation. After VF/DEF the level of histamine increased in coronary venous blood, suggesting cardiac release of histamine.     

Spike conduction properties of T-shaped C neurons in the rabbit nodose ganglion

Noradrenaline (NA) and angiotensin II (A II) were infused intravenously in conscious dogs without (series I) and with (series II) additional infusions of sodium nitroprusside at doses re-establishing normal levels of mean arterial pressure (MAP). In series I, NA infusion (1.6 g/min per kg for 30 min) initially elevated MAP by some 25 mm Hg and lowered heart rate by some 30 beats/min. Plasma concentrations of arginine vasopressin (AVP) remained constant, while those of A II and atrial natriuretic factor were slightly, but significantly, increased. Infusion of A II (10 or 20 ng/min per kg for 30 min) induced similar rises in MAP and slight reductions of heart rate and increased plasma AVP by 70% and atrial natriuretic factor by 60%. In series II, sodium nitroprusside (1–4 g/min per kg) was added for 30 min to infusions of NE (1.6 g/min per kg) and A II (20 ng/min per kg) in order to maintain MAP at its control level. This resulted in an 11-fold increase in plasma AVP during NA infusion and a 19-fold increase during A II infusion. Infusing sodium nitroprusside (4 g/min per kg) alone lowered MAP to clearly hypotensive levels, but the resulting rises in plasma AVP were less than, rather than equal to, those seen at normotensive MAP levels during the combined infusions of sodium nitroprusside with A II or NA, respectively. It is concluded that both NA and A II exert strong stimulatory actions on AVP release which are, however, counteracted by inhibitory influences arising from the hypertensive effects of NA and A II.     

Antagonism of histamine edema formation by catecholamines

Histamine (4 microgram base/min) infused into the brachial artery for 60 min greatly increases skin lymph flow and lymph protein concentration in forelimbs perfused either naturally or at constant inflow. In contrast, the simultaneous intrabrachial infusion of histamine and norepinephrine (4 microgram base/min of each) or histamine and isoproterenol (4 microgram base/min and 3 microgram/min, respectively) for 60 min failed to alter lymph protein concentration in forelimbs perfused either naturally or at constant inflow. The edema in forelimbs naturally perfused by histamine (4 microgram base/min) infused into the brachial artery for 60 min was also greatly reduced by the simultaneous histamine-catecholamine infusions. Phentolamine (in concentrations that antagonize the vascular actions of norepinephrine) failed to prevent the antagonism of histamine protein efflux by norepinephrine. Hence, it must be concluded that catecholamines antagonize the protein efflux by locally infused histamine, independent of alpha-adrenergic receptor activity.     

The effects of histamine on skeletal muscle vasculature in cats.

1. Experiments have been made to determine the vascular effects of histamine and the mechanism of histamine-induced oedema formation in cat skeletal muscle. 2. Histamine caused dose-dependent dilatation of resistance vessels and increased intravascular volume over the dose range 1 X 10(-10)-1 X 10(-8) mol/kg min. The dilatation of resistance vessels resulted in dose-dependent increases in capillary hydrostatic pressure. 3. Histamine increased vascular permeability, as measured by accumulation of [131I]human serum albumin in the tissue, during infusions at 1 X 10(-8) mol/kg min but no albumin accumulation could be detected at lower infusion rates. 4. Oedema formation during histamine infusion of 1 X 10(-10) and 1 X 10(-9) mol/kg min seemed to be due to increases in capillary hydrostatic pressure and independent of increased vascular permeability. During infusions of histamine 1 X 10(-8) mol/kg min oedema was due predominantly to increased vascular permeability and to a lesser extent, the increase in capillary hydrostatic pressure.     

Evaluation of histamine elimination curves in plasma and whole blood of several circulatory regions: A method for studying kinetics of histamine release in the whole animal

Histamine concentrations in canine whole blood and plasma were determined under several pharmacological, pathophysiological, and clinical conditions, using fluorometric methods. The specificity of the assay for whole-blood histamine was investigated by comparing 3 purification procedures for the isolation of histamine from whole blood including butanol extraction (Shore), ion-exchange chromatography on Dowex 50 W-X 8, and the combination of these 2 methods (Lorenz). Histamine in whole blood was identified in analytical and preparative samples by fluorescence spectra, thin-layer chromatography, degradation by diamine oxidase from pig kidney and inactivation by histamine methyltransferase from guinea-pig brain as well as by biological tests on the isolated guinea-pig ileum. Since butanol extraction resulted in significantly higher ‘histamine’ values than the other two purification procedures, ion-exchange chromatography on Dowex 50 was recommended as the method of choice for the specific determination of histamine in dog's whole blood. Normal values of histamine concentrations in canine plasma were tentatively estimated. They depended on the time between pretreatment of the animals (anaesthesia, operation) and the collection of blood and showed an approximately logarithmic normal distribution. The median, the lower/upper quartiles and the range of the plasma histamine levels obtained 30 minutes after the end of pretreatment were 0.2, 0–0.4 and 0–1.2 ng/ml, respectively. Nearly 50% of the values were zero (below 0.1 ng according to the sensitivity of the method), only 1% of them exceeded slightly 1 ng/ml. Thus histamine release by drugs or by other medical treatments was only stated, when plasma histamine levels exceeded 1 ng/ml and decreased in a way to give an elimination curve of approximately first-order kinetics (Bateman function). Histamine concentrations in dog's whole blood showed approximately a logarithmic normal distribution. The median, lower/upper quartiles and range were 47, 34/75 and 13–209 ng/ml respectively. The histamine levels in the whole blood of four circulatory regions did not show any significant differences. The plasma histamine concentrations in the portal vein were slightly higher than in the hepatic veins. The injection of exogenous histamine and the concomitant determination of plasma and whole-blood histamine levels in four circulatory regions showed that the plasma histamine determination was the more sensitive method for measuring histamine elimination curves than the whole-blood histamine assay. The elimination of exogenous histamine administered intravenously was influenced by several drugs including inhibitors of histamine inactivation and histamine receptor antagonists. Aminoguanidine and the H₂-receptor antagonist burimamide slowed down the disappearance of histamine from the plasma, the H₁-receptor antagonist dimethpyrindene enhanced it, but amodiaquine had no significant effects. Dimethpyrindene and burimamide were capable of releasing histamine in dogs, in some cases to a considerable extent. The plasma substitute Haemaccel^®, a chemically modified gelatin, released histamine in dogs. Using batch 3000, from 27 animals investigated, 15 animals showed elevated plasma histamine levels and a hypotensive blood pressure response, whereas in 12 of the dogs it did not show an effect on these parameters. The plasma histamine levels at the time of maximum hypotension showed an approximately logarithmic normal distribution. This frequency distribution in combination with the varying incidence of anaphylactoid reactions depending on the batches used seemed very important for the interpretation of clinical reactions to Haemaccel in human test persons and patients. By histamine determinations in plasma and whole blood of several circulatory regions and in various tissues before and after infusion of Haemaccel it could be demonstrated that the sites of histamine release by Haemaccel in dogs were especially the skin of the upper hemisphere of the body and the liver, whereas the gastro-intestinal tract took up histamine from the circulation. These numerous results under various experimental conditions may be considered as an evidence for the high quality and reliability of the method to study histamine release in the whole animal or in human subjects by evaluating histamine elimination curves in plasma.     

Contribution of catechol O-methyltransferase to the removal of accumulated interstitial catecholamines evoked by myocardial ischemia

Catechol O-methyltransferase (COMT) plays an important role for clearance of high catecholamine levels. Although myocardial ischemia evokes similar excessive catecholamine accumulation, it is uncertain whether COMT activity is involved in the removal of accumulated catecholamines evoked by myocardial ischemia. We examined how COMT activity affects myocardial catecholamine levels during myocardial ischemia and reperfusion. We implanted a dialysis probe into the left ventricular myocardial free wall and measured dialysate catecholamines levels in anesthetized rabbits. Dialysate catecholamine levels served as an index of myocardial interstitial catecholamine levels. We introduced myocardial ischemia by 60 min occlusion of the main coronary artery. The ischemia-induced dialysate catecholamines levels were compared with and without the pretreatment with entacapone (COMT inhibitor, 10 mg/kg, i.p.). Acute myocardial ischemia progressively increased dialysate catecholamine levels. Acute myocardial ischemia increased dialysate norepinephrine (NE) levels (20,453+/-7186 pg/ml), epinephrine (EPI) levels (1724+/-706 pg/ml), and dopamine (DA) levels (1807+/-800 pg/ml) at the last 15 min of coronary occlusion. Inhibition of COMT activity by entacapone augmented the ischemia-induced NE levels (54,306+/-6618 pg/ml), EPI levels (2681+/-567 pg/ml), and DA (3551+/-710 pg/ml) levels at the last 15 min of coronary occlusion. Myocardial ischemia evoked NE, EPI, and DA accumulation in the myocardial interstitial space. The inhibition of COMT activity augmented these increments in NE, EPI, and DA. These data suggest that cardiac COMT activity influences on the removal of accumulated catecholamine during myocardial ischemia.