Plasma histamine and clinical tolerance to infused histamine in normal,atopic and urticarial subjects

Five subjects with a recent history of urticaria (U), five atopic (A) subjects and a non-atopic (NA) control group were given intravenous infusions of histamine starting at 0.05 g/kg/min, increasing by 0.05 g/kg/min every 30 minutes to a maximum of 0.35 g/kg/min. Plasma histamine levels were monitored every 15 minutes. The infusion was stopped when an objective clinical endpoint was reached, involving either evidence of peripheral vasodilatation (rise of skin temperature by at least 1 °C) or a 20% fall of peak expiratory flow rate.There were no significant differences in resting plasma histamine in the three groups. Those with urticaria reached the clinical endpoint at a lower infusion rate than non-atopic subjects (U 0.22±0.02 g/kg/min; A 0.26±0.02 g/kg/min; NA 0.32±0.2 g/kg/min.p<0.008) they also received a lower total histamine dose (U 1.12±0.33 mg; A 1.42±0.38 mg, NA 2.2±0.51 mg,p<0.008). Atopic subjects with a history of asthma, eczema or rhinitis also tolerated histamine poorly, some subjects reaching a clinical endpoint while the plasma histamine level was still relatively low (U 1.52±0.4 ng/ml, A 0.85±0.19 ng/ml, NA 1.4±0.44 ng/ml,p=0.05). After the histamine infusion was stopped, the fall in the blood level of histamine was slower in urticarial subjects than in the other two groups, with a half-life of 6.2±1.3 min (A 3.0±1.2 min, NA 4.0±0.7 min,p<0.02). There were thus differences in the metabolism of histamine in our non-atopic urticarial subjects and increased histamine sensitivity in atopic subjects which require further study.     

Histamine and Nt-methylhistamine in the circulation during intravenous infusion of histamine in normal volunteers

Plasma levels of histamine and N^t-methylhistamine were measured simultaneously by high performance liquid chromatography during the intravenous infusion of histamine acid phosphate in six normal volunteers. Progressive, dose-related increases in plasma histamine were noted, reaching a maximum value of 3.1±0.14 ng ml^–1 corresponding to a maximum infusion rate of 180 ng kg^–1 min^–1 (means±SEM). Increases in plasma histamine were accompanied by a significant dose-related fall in mean diastolic blood pressure (baseline 74.0±4.4 mm Hg falling to 60.0±3.3 mm Hg at maximum infusion rate,p<0.001) and an increase in pulse rate (baseline 76.3±2.8 beats min^–1 rising to 89.24 beats min^–1 at maximum infusion rate,p<0.05). All subjects exhibited facial flushing, the threshold plasma histamine level for this effect being 1.3±0.15 ng ml^–1 corresponding to an infusion rate of 60 ng kg^–1 min^–1. Elevation of plasma N^t-methylhistamine was seen in only one subject, who exhibited a level of 0.5 ng ml^–1 at the highest infusion rate. These results suggest that measurements of plasma N^t-methylhistamine are unlikely to provide a useful index of histamine release into the circulation.     

Responsiveness of the ANP providing system to volume load in conscious dogs

We examined in detail changes in arterial plasma ANP concentration in response to volume load in conscious dogs. In a 5-min volume load experiment, 18 ml/kg of isosmotic and isooncotic 3% Dextran 40 in saline was infused over a period of 5 min. Mean left atrial pressure (MLAP) increased transiently by 7.6±0.9 mm Hg. Plasma ANP level (P-ANP) did not significantly increase. Assayed P-ANP levels were corrected for hemodilution. Corrected P-ANP (C-ANP) significantly increased from 206±17 to 348±34 pg/ml. However, the level of C-ANP did not reach a steady state. No significant linear correlation was found between increases in MLAP and normalized C-ANP. In a 45-min volume load experiment, the elevated level of MLAP caused by the 5-min volume load was maintained for 40 min by supplemental infusion. C-ANP significantly increased from 196±18 pg/ml to 435±73 ng/ml. The level of C-ANP reached a steady state. A close linear correlation was observed between increases in MLAP and normalized C-ANP. However, the peak time of C-ANP lagged 10 min behind MLAP. These results indicate that it takes 10 min for P-ANP to reach a steady state in fully responding to a volume load, and that the long-term volume load is a prerequisite to the response of the ANP providing system.     

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.     

Catecholamine responses to histamine infusion in man

To evaluate the effects of histamine-induced hypotension on plasma catecholamine levels, eight normal men, aged 20 to 40 years, were infused with incremental doses of histamine starting at 0.2 microgram/kg/min at a 30 degree tilt position with monitoring of blood pressure (BP) and heart rate. Histamine dosage was increased every 5 minutes by 0.1 to 0.2 microgram/kg/min until mean BP fell greater than 15 mm Hg or a dosage of 1.6 micrograms/kg/min was reached. Plasma catecholamine samples were taken between the fourth and fifth minute of each histamine dosage. Identical measurements were made during nitroglycerin-induced hypotension in these subjects. Histamine produced threefold greater increases in heart rate and plasma norepinephrine (NE) levels than did nitroglycerin for comparable decreases in BP. Although NE levels increased twofold to fivefold from baseline with histamine infusion, epinephrine levels increased minimally at the highest doses or not at all. Our data demonstrate that histamine selectively releases NE from adrenergic nerve terminals without significant adrenal catecholamine release. We suggest that neural NE release plays an important role in the cardiac effects of histamine.     

Comparison of canine corticosteroid responses to mean and phasic increases in ACTH

To determine the dynamics and magnitudes of adrenal corticosteroid responses to ACTH, we measured arterial plasma ACTH and corticosteroid concentrations in conscious dogs during infusions of ACTH or saline. Synthetic alpha 1-24-ACTH was infused at rates of 300,900, or 4,500 ng/30 min either as constant infusions or as three equal short infusions at 10-min intervals. In dogs infused with saline, plasma ACTH fluctuated, whereas corticosteroids did not, suggesting that ACTH is secreted episodically in dogs as in man. The magnitudes of the plasma corticosteroid responses to ACTH infusions were linearly related to the logarithm of the total amount of ACTH infused in 30 min and not to the pattern of administration. In all ACTH infusion experiments, the lag between an increase in arterial ACTH and corticosteroids was not less than 3 min. Mean ACTH half-disappearance time, metabolic clearance rate, and volume of distribution estimated from the different experiments ranged between 1.8 and 2.1 min, 24 and 38 ml . kg-1 . min-1, and 95 and 114 ml/kg, respectively. Collectively, these results explain the apparent paradox that corticosteroid responses to ACTH-releasing stimuli can be initiated before a detectable increase in ACTH above the highest control value (Wood et al. Apparent dissociation of ACTH and corticosteroid responses to ml/kg hemorrhage in conscious dogs. Endocrinology In press).     

Pharmacokinetics and pharmacodynamics of intravenous digoxin and digitoxin

Summary Healthy volunteers received single 1.0-mg doses of intravenous digoxin (n=10) or digitoxin (n=12). Glycoside pharmacokinetics were determined from multiple plasma samples drawn over the 48 hours (for digoxin) or 14 days (for digitoxin) after the dose. Electrocardiogram, echocardiogram, and blood pressure were recorded at multiple time points 24 h after the dose. To control for nonspecific cardiovascular changes, pharmacodynamic measurements were repeated on a second occasion for 8 hours after an intravenous injection of saline. Mean (±S.E.) kinetic variables for digoxin were: volume of distribution (Vd), 8.3 (±0.6) l/kg; elimination half-life (t1/2), 49 (±5) h; clearance 2.1 (±0.2) ml/min/kg. Changes in blood pressure, ventricular rate, and corrected QT-interval attributable to digoxin were small. However, echocardiographically-determined mean rate of circumferential fibre shortening (mVcf) and ejection fraction (EF) increased significantly following digoxin when compared to saline infusion. Changes were maximal at 4–6 h after dosage, and were highly correlated with plasma digoxin concentration. mVcf and EF returned to baseline by 24 h post-dosage. Mean kinetic variables for digitoxin were: Vd, 0.63 (±0.03) l/kg; t1/2, 7.3 (±0.4) days; clearance, 0.043 (±0.003) ml/min/kg. Like digoxin, digitoxin infusion produced minimal change in blood pressure, ventricular rate, or QT-interval. However, mVcf and EF increased significantly when compared to saline control. Changes were maximal at 4–8 h after infusion, and were correlated with plasma digitoxin concentration; at 24 h post-dosage, mVcf and EF were still increased over baseline. Thus, digoxin and digitoxin significantly increase myocardial contractility in healthy humans, but without important change in heart rate and blood pressure. Changes in contractility are of slow onset, probably due to slow distribution of glycoside to sites of pharmacologic activity.Supported in part by Grant Oc 10/4 from Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, FRG; and by Grant MH-12279 from the United States Public Health Service     

Kinetics of histamine and tele-methylhistamine elimination from rat plasma

Plasma levels of histamine (Hi) and tele-methylhistamine (MeHi) were measured by HPLC after intravenous bolus injection of Hi (45 g/kg) or MeHi (55 g/kg) in the rat. Increases in plasma Hi (from baseline 2.8±0.4 to about 50 ng/ml at 2 min after the injection) were accompanied by a significant increase in MeHi levels (baseline 1.2±0.3 ng/ml rising up to 11 ng/ml, 6 min after Hi application). After rapid intravenous injection, Hi and MeHi elimination from plasma could be fitted by a double exponential function with half lives in the and phases of about 20 sec and 4 min (Hi) or 1 min and 43 min (MeHi). The results suggest that measurement of plasma MeHi, as an indirect marker of Hi release, has an advantage over measuring Hi itself.     

Effect of H1- and H2-receptor antagonists on the hemodynamic changes induced by the intravenous administration of ketamine in sevoflurane-anesthetized cats

Objective: The anesthetic ketamine has been reported to cause both an increase of the plasma histamine concentration, notably in cats, and a cardiovascular depression. The latter has been described in humans and in other species. However the relevance of the histamine fluctuation for the ketamine-induced hemodynamic changes has not been determined.Subjects and treatment: We studied the contribution of histamine to the hemodynamic effects induced by IV ketamine (7 mg/kg) in 12 sevoflurane anesthetized cats, of which half had been pre-treated with combined H₁- and H₂ -receptor antagonists.Methods: The mean arterial pressure (MAP) and the heart rate (HR) from both untreated (group C) and pre-treated (group AH) cats were recorded before and after the ketamine administration. The plasma histamine concentration was also measured.Results: Plasma histamine fluctuations in the control and the antihistamine-treated group followed a similar pattern (no statistical differences); an initial rise that peaked 2 min after ketamine injection (from 0.63 ± 0.11 ng/ml to 2.22 ± 0.69 ng/ml in the C group, and from 0.71 ± 0.10 ng/ml to 1.09 ± 0.28 ng/ml in the AH group) followed by an immediate decrease in plasma concentrations. As for the hemodynamic variables under analysis, in the control group ketamine administration was followed by an early 30.3 ± 8.1% reduction (p < 0.005) in the MAP with no associated changes in the HR. In the antihistamine pre-treated group, ketamine caused a further decrease of the MAP (41.7 ± 2.3%), and a significant (p < 0.01) 11.6 ± 2.9% reduction of the HR.Conclusion: Ketamine in anesthetized cats triggers histamine release and induces cardiovascular depression. The depression is more pronounced under the blockade of histamine activity through histamine receptor antagonists.Received 22 October 2004; returned for revision 5 January 2005; accepted by A. Falus 14 February 2005     

Pharmacokinetic studies of high-dose metoclopramide with and without forced diuresis

Summary The pharmacokinetics of high-dose metoclopramide (10 mg/kg body wt. in five infusions of 2 mg/kg body wt. each) was studied in 11 patients (5 females, 6 males) in two groups: group A with and group B (consisting of five patients) without forced diuresis. When the drug was infused, forced diuresis had no influence on the pharmacokinetics of metoclopramide (serum level after the 1st infusion was 851±361 ng/ml in group A versus 840±348 ng/ml in group B; after the 5th infusion it was 2,005±588 ng/ml in group A versus 2,463±1,350 ng/ml in group B). There were significant differences in the 24-h serum levels (582±308 ng/ml in group A versus 379±170 ng/ml in group B;P<0.05) and in the elimination half life (8.5±2.6 h in group A versus 6.1±1.1 h in group B;P<0.05). The results demonstrate that the dosage regimen originally suggested by Gralla for cytostatic drugs, with forced diuresis for high-dose metoclopramide therapy, may also be applied, with no dosage reduction, with to other cytostatic drugs which do not require forced diuresis.     

Hemodynamic effects of moderate increase of the plasma vasopressin level in conscious dogs

Summary The influence of moderate increase of the plasma ADH level on aortic and central venous pressures, heart rate, cardiac output, stroke volume, central blood volume, systemic peripheral resistance and plasma volume was examined in conscious dogs. The animals were given 0.75 mU ADH/kg b.w. in single intravenous injection as a priming dose. This was followed by a constant infusion of the hormone at a rate of 0,12 mU/min/kg/0.2 ml 0.9% NaCl solution lasting one hour. Plasma ADH level measured at 30 min of the infusion was equal to 22 ± 4 U/ml. A significant increase of aortic (mean systolic and diastolic) and central venous pressures, systemic peripheral resistance and of plasma volume was observed in the course of the infusion. It was accompanied by a decrease of heart rate, cardiac output and central blood volume. Changes of stroke volume were not significant.As the plasma level produced by the infusion was such as that following a moderate nonhypotensive haemorrhage [30], the rôle of the hemodynamic effects of vasopressin in maintenance of the blood pressure and volume in hypovolemia is discussed.     

Effect of chemical sympathectomy on coronary flow and cardiovascular adjustment to exercise in dogs

Summary The exercise capacity and the increase of coronary and systemic hemodynamics under treadmill exercise were studied in 5 dogs, chemically sympathectomized with 6-hydroxy-dopamine.Completeness of adrenergic denervation was verified by stimulation of the right stellate ganglion, by intravenous administration of tyramine, and by demonstration of supersensitivity to exogenous norepinephrine.These dogs demonstrated a retarded adaptation of hemodynamics to a sudden start of exercise. A fall in mean arterial pressure below 45 mmHg within 10 to 15 sec lead to collapse. After a recovery period of 60–90 sec, moderate treadmill exercise could be continued; steady state attainment of hemodynamic parameters was considerably delayed.A steady state of exercise with an O₂-consumption (vO₂) of 29.6±2.6 ml/min · kg and a cardiac outupt (CO) of 307±16 ml/min · kg was tolerated for at least 20 min.An increase of vO₂ up to 42.0±1.7 ml/min · kg and of CO up to 357±13 ml/min · kg under exercise was tolerated for 5 min with steady state, maximal heart rate being 160±4 min^–1 at this level of exercise.Mean arterial pressure and total peripheral resistance were significantly reduced at rest and during steady state of exercise as compared to controls prior to sympathectomy identical vO₂, whereas CO remained unchanged.The significant fall in left circumflex coronary flow was proportional to the decline in external heart work due to sympathectomy both at rest and under exercise.Supported by Deutsche Forschungsgemeinschaft.     

Renal handling of norepinephrine and epinephrine in the pig

To investigate the renal handling of catecholamines in the pig, intravenous infusions of⁵¹Cr-EDTA and PAH were performed in 7 animals, and samples for simultaneous measurement of norepinephrine (NE), epinephrine (E),⁵¹Cr-EDTA and PAH were obtained through catheters placed into the aorta, left renal vein and both urethers. For both kidneys together,⁵¹Cr-EDTA clearance [GFR] averaged 48±14 (±SD) ml/min (2.23±0.66 ml/kg/min). In the left kidney, GFR averaged 22±9 ml/min, arteriovenous PAH extraction 0.87±0.09, and calculated total renal plasma flow 91±30 ml/min. Plasma NE and E were lower in renal venous than arterial blood (P<0.005), extraction ratios averaging 0.36 and 0.77, respectively. NE excretion rate in final urine (8.9±4.3 ng/min) exceeded transrenal NE extraction rate (5.2±3.9 ng/min) by 3.7±4.4 ng/min. In contrast, urinary E excretion rate (2.9±2.0 ng/min) was slightly lower than transrenal E extraction rate (3.6±3.8 ng/min). These observations suggest that in pig kidneys, plasma PAH extraction rate and GFR related to body weight are quite similar to values in man. Three quarters of circulating E are extracted for the most part by tubular secretion, and the slightly smaller amount appearing in urine is consistent with some intrarenal metabolism. NE, presumably originating from intrarenal neuronal release and/or de novo production, is secreted into the urine.This study was supported by the Swiss National Science Foundation     

Plasma histamine and hemodynamic responses following administration of nalbuphine and morphine

A comparative study of plasma histamine levels following administration or morphine and nalbuphine in pentobarbital anesthetized dogs was performed. Two concentrations, 3 mg/kg and 0.3 mg/kg of these drugs were investigated. High dose morphine caused an immediate marked increase in plasma histamine from 5.0±0.4 to 340±72 ng/ml. Simultaneous with this increase in plasma histamine was a marked decrease in mean arterial blood pressure within the first minute. In contrast significant alterations in plasma histamine levels were not observed with high or low doses of nalbuphine. A low dose of morphine (0.3 mg/kg) did not increase plasma histamine levels. Heart rate was not changed by any drug treatment. The use of compound 48/80 a specific mast cell degranulating agent allowed for the identification of a specific pool of mast cells capable of responding to morphine.In vitro exposure of purified dog leukocytes to high doses of morphine did not result in histamine release. These results indicate that nalbuphine does not increase plasma histamine, while morphine does, and that the source of the increase in plasma histamine is from tissue mast cells.This work has been supported in part by NIH grant GM 25926 and USUHS grant RO8004.     

Dehydration elevates osmotic threshold for salt gland secretion in the duck.

Acute salt and water balance measurements were made in two conscious salt water-acclimated Pekin ducks at and above their osmotic threshold for salt gland secretion. Intravneous infusion of 1,000 mosmol/kg H2O NaCl at 0.350 ml/min increased plasma tonicity less than 0.5% and increased secretion from nearly zero to a rate matching the infusion. Continuous secretion at a similar submaximal rate was driven by 5,600 mosmol/kg H2O NaCl infused at 0.070 ml/min. Osmolality of secreted fluid was constant for any secretion rate, so that net water loss occurred when the concentration of infusate exceeded that of secreted fluid. Threshold plasma osmolality increased by 9 mosmol/kg H2O after the loss of 77 g water (3% body wt). Solutes were always secreted at the infusion rate, even when body fluid osmolality increased while body water decreased. We conclude that the salt gland controller is sensitive to more than just extracellular fluid (ECF) tonicity, and we suggest that elevation of the osmotic threshold may occur in response to decreased ECF volume.     

Effects of atrial natriuretic peptide on systemic and renal hemodynamics and renal excretory function in patients with chronic renal failure

Summary We examined the effects of 60 min-hANP infusion (24 ng/min/kg) on glomerular filtration rate (GFR), renal blood flow (RBF), cardiac index (CI) and blood pressure (BP) in 8 patients with chronic renal failure (CRF) with GFR ranging from 18 to 80 ml/min/1.73 m² and in 8 control (C) subjects with normal renal function. Basal plasma levels of ANP and cGMP were elevated in CRF (ANP: 60.6±9.1 vs 13.6±1.9 pmol/l,p<0.05; cGMP: 14.3±2.9 vs 6.6±1.1 pmol/ml,p<0.05). During ANP infusion, peak levels of cGMP were higher in CRF than in C (27.5±3.2 vs. 17.3±1.3 pmol/ml,p<0.05). During ANP infusion, GFR increased in CRF by 70.7±4.2% from 34.5±6.8 to 57.4±9.9 ml/min/1.73m² (p<0.001) as compared to 16.2±1.4% in C (p<0.001 vs CRF). RBF increased in CRF by 43.6±6.4% and in C by 3.1±1.2% (p<0.01). Basal urinary sodium excretion (U_NaV) was slightly lower in CRF than in C but rose to the same level in both groups during ANP infusion. In CRF, as opposed to C, U_NaV remained elevated above baseline after the end of the infusion. The effect of ANP on fractional sodium excretion (FE_Na), however, was more pronounced in C. Basal FE_Na was higher in CRF (12.8±2.5% vs 2.4±1.5% in C,p<0.001), FE_Na remained elevated at 180% over baseline in C sixty minutes after cessation of ANP infusion, while it had returned to baseline in CRF. During ANP infusion, CI increased in CRF after 30 min from 2.91±0.08 to 3.12±0.091/min/m² (p<0.001) and in C from 3.20±0.11 to 3.39±0.13 l/min/m² (p< 0.05). Mean arterial BP was higher in CRF and its decrease was greater than in C (21.1±2.7% vs 9.1±1.0%,p<0.001). In patients with CRF GFR, RPF, and CI remained significantly elevated and BP was still significantly decreased 60 min after ANP infusion. Total peripheral vascular resistance (TPR) was elevated in CRF and declined during ANP infusion in both CRF and C. The decline of TPR was sustained and more pronounced in CRF than in C. Renal vascular resistance (RVR) was high in CRF and dropped by nearly 50% during ANP infusion, whereas only a moderate decline in RVR during ANP application was observed in C. Thus, exogenous ANP had greater and prolonged effects on systemic hemodynamics and renal function in CRF than in C. They may be due to higher levels of ANP following ANP infusion and appear to be mediated by a more sustained formation of the second messenger cGMP.Abbreviations ANP atrial natriuretic peptide - CRF chronic renal failure; - GFR glomerular filtration rate - FF filtration fraction - ERPF effective renal plasma flow - ERBF effective renal blood flow - BP blood pressure - MAP mean arterial blood pressure - HR heart rate - SV stroke volume - CO cardiac output - CI cardiac index - TPR total peripheral resistance - RVR renal vascular resistance - U_NaV urinary sodium excretion - FE_Na fractional sodium excretion - PRA plasma renin activity - ECFV extracellular fluid volume - PAH paminohippuric acid Dedicated to Prof. Dr. med. F. Krück on the occasion of his 70th birthday     

Effects of elevated plasma adrenaline levels on substrate metabolism, effort perception and muscle activation during low-to-moderate intensity exercise

The aim of this study was to differentiate the role of raised plasma adrenaline (Adr) concentrations from sympathoadrenal activation associated with moderate-intensity exercise, on muscle activation, cardiopulmonary responses, fuel metabolism, and ratings of perceived exertion (RPE) during low-intensity exercise. Two groups of subjects (MOD, n=6; LOW, n=7) cycled on two occasions for 90 min. MOD cycled at 68% VO_2max with saline infusion, and at 34% VO_2max with Adr infusion. LOW cycled twice at 34% VO_2max, with either Adr or saline infusion. Infusions (0.015 g Adr/kg/min) started at 15 min and increased plasma [Adr] somewhat higher than during exercise at 68% VO_2max (~1.9 vs. 1.4 nM, at 75 min). Mean plasma glucose and lactate concentrations during LOW were significantly higher with Adr than saline infusion (5.1±0.6 vs. 4.4±0.3 mmol/l, P<0.01 and 2.1±0.8 vs. 1.3±0.5 mmol/l, P<0.01, respectively). Elevated [Adr], without increased exercise intensity, did not alter glycogenolysis. There were also no effects of Adr infusion at 34% VO_2max on heart rate, oxygen consumption, [FFA], respiratory exchange ratio, intramuscular triglyceride utilization, muscle activation or RPE. In conclusion, elevated [Adr] similar to those found during moderate-intensity exercise increased plasma glucose and lactate availability, but did not alter intramuscular fuel utilization, effort perception or muscle activation.     

Effects of histamine H1-receptor stimulation on coronary hemodynamics in man

Exogenous histamine in man induces significant cardiovascular effects mediated by activation of H₁ and H₂-receptors present on human heart and on coronary arteries. We studied the effects of selective H₁-receptor stimulation on human coronary hemodynamics in 10 patients undergoing cardiac catheterization. All patients were pretreated with cimetidine before the histamine infusion (0.5 g/kg/min i.v. for 5 min). Six of these patients had normal coronary arteries and four had single vessel coronary artery disease (CAD) and vasospastic angina. During the study heart rate was held constant (100 beats/min) by coronary sinus pacing. We measured mean aortic pressure (MAP), coronary sinus blood flow (CSBF), coronary vascular resistance (CVR) and myocardial oxygen consumption (MVO₂) at rest, during histamine infusion, and 10 min after the end of the infusion. During infusion, MAP decreased from 103±5 to 85±6 mmHg (p<0.02) and CVR from 1.00±0.16 to 0.81±0.14 mmHg/ml/min (p<0.05); CSBF and MVO₂ did not significantly change. All parameters returned to baseline at the end of the infusion. The response was similar in patients with normal coronary arteries and in 3 patients with CAD. Only one patient with CAD developed angina with ST segment elevation in D₃, reduction in CSBF and an increase in CVR. These results indicate that H₁-receptor stimulation in man induces significant coronary dilatation and that histamine infusion after cimetidine pretreatment is unlikely to provoke coronary spasm in patients with vasospastic angina.     

Histamine release and pseudoallergic reactions induced by radiographic contrast media: Comparison of Angiographin®, Hexabrix® and Telebrix® using anin vivo canine model

Radiographic contrast media (RCM) in clinical use cause unwanted allergic/pseudoallergic reactions of all grades of severity. They also induce histamine release from a variety of mast cell populations, the extent of the histamine release reaction depending on both the organ and species. In this study 3 RCM, which had been previously shown to be effective histamine releasing agents with canine liver cells, were investigated using anin vivo canine model based on the clinical situation. The dogs (n=36) were randomly allocated to one of 3 treatment groups and received a bolus injection (2 ml/kg body weight) of either Angiographin^®, Hexabrix^® or Telebrix^®. Blood pressure was monitored continuously and blood sampling, for plasma histamine measurements, was performed before and 1, 5, 10, 20 and 30 min after RCM injection. All 3 RCM caused elevated plasma histamine levels in some animals: Angiographin^® 9 of 12 dogs, 0.40 ng/ml, (0–1.9 ng/ml) median (range); Hexabrix^® 11/12, 0.5 ng/ml (0–3.8 ng/ml); Telebrix^® 7/12, 0.4 ng/ml (0–2.0 ng/ml). Cardiovascular reactions were observed in most animals. The hypotensive reactions occurred with a maximum 30 sec after RCM application and recovery was normally observed after 1–1.5 min. The response after Angiographin^® or Telebrix^® was significantly greater than after Hexabrix^®. Hypertensive reactions occurred later (15 min (5–25 min)) and did not differ between the groups. All 3 agents tested were able to elicit histamine release and cardiovascular reactions. In comparison to histamine release occurring after intravenous, administration of other agents, such as hypnotics, the degree of histamine release was small. However, the frequency with which it was observed suggests that histamine acts as a contributory condition in adverse reactions to RCM. The possibility of either a localized histamine release (e.g. from liver cells) or complement activation leading to histamine release must be considered.     

Effect of prostacyclin on the circulatory histamine during cardiopulmonary bypass

Changes in plasma histamien levels were studied in sixteen dogs under cardiopulmonary bypass (CPB) or bypass with the addition of prostacyclin (PGI₂) infusion. In both groups, plasma histamine rose immediately after anaesthetic induction (median above pre-induction: 0.4 ng/ml) and following heparin infusion (median above pre-induction: 0.7 ng/ml). During CPB, plasma histamine levels were elevated throughout the 90 minute period of perfusion (median above pre-induction: 0.5–1.2 ng/ml). PGI₂ infusion reduced the elevation in plasma histamine levels (median above pre-induction: 0–0.7 ng/ml). These data support the hypothesis that histamine release occurs during CPB. Platelet aggregation in the extracorporeal circuit may be contributory since prostacyclin premedication reduces histamine release.