Gert Baumann

Impaired beta-adrenergic stimulation in the uninvolved ventricle post-acute myocardial infarction: Reversible defect due to excessive circulating catecholamine-induced decline in number and affinity of beta-receptors

Left ventricular infarction (AMI) was produced in experimental animals and the contractile response to isoproterenol was tested in the isolated perfused heart preparation. Adenylate cyclase activity, phosphodiesterase activity, and beta-receptor binding characteristics were determined in a sarcolemmal preparation of the right ventricle of the same hearts. Three days post-AMI the dose-response curve for isoproterenol of right ventricular dP/dtmax was significantly depressed, while the inotropic effect of histamine was not impaired. Stimulation of adenylate cyclase activity by isoproterenol was reduced by 70% in the membrane preparation, whereas histamine and NaF stimulation rates were unaltered; phosphodiesterase activity was unchanged. In contrast, beta-receptor binding studies with [3H]-DHA1 indicated 74% loss and 10 times lowered affinity (KD) of the remaining beta-receptors, while specific [3H]-QNB1 binding was unchanged. All of the above alterations were prevented by pretreatment with reserpine or metoprolol. It is concluded that these abnormalities in the nonischemic surviving myocardium post-AMI are the result of specific reversible damage of sarcolemmal beta-receptors due to excessive levels of circulating catecholamines.

Usefulness of dopexamine hydrochloride versus dobutamine in chronic congestive heart failure and effects on hemodynamics and urine output

The hemodynamic effects of dopexamine hydrochloride and dobutamine were compared during dose-response infusions of dopexamine (1.0 to 4.0 micrograms/kg/min) and dobutamine (2.5 to 10.0 micrograms/kg/min) and during 48-hr infusions at doses producing initial matched increases in cardiac output. Thirty-three patients with severe, stable, chronic congestive heart failure (CHF) (New York Heart Association class III to IV) participated. Both drugs produced an increase in cardiac index, brought about by increased stroke volume index and heart rate, and systemic vasodilatation. The relative contribution of these mechanisms differed, dopexamine proving the more potent vasodilator. The effects of dopexamine were maintained without variation during the 48-hr infusion, apart from a reduction in the increase in heart rate. The effects of dobutamine, while remaining above control at most time-points during the 48-hr infusion, attenuated toward control values. Dopexamine also appeared to promote increased urine output and creatinine clearance during the 48-hr infusion. Both drugs were well tolerated. Dopexamine elicited larger peak hemodynamic effects at dosages that had equivalent effects on cardiac output, and favorable renal responses, and demonstrated no long-term attenuation of effect.

Systemic anaphylaxis—separation of cardiac reactions from respiratory and peripheral vascular events

SummaryAn anaphylactic reaction in the isolated perfused heart is characterized by a drastic coronary constriction, arrhythmias, and an impairment of contractility. In vivo anaphylaxis is associated with respiratory distress and cardiovascular failure. The present investigation was designed to ascertain the electrocardiographic and cardiovascular changes during systemic hypersensitivity reactions. In addition, an attempt was made to differentiate cardiac from respiratory events. In guinea pigs, sensitization was produced by s.c. administration of ovalbumin together with Freunds adjuvant solution. Fourteen days after sensitization, the effects of an i.v. infusion of ovalbumin were tested in the anesthetized guinea pigs, which were ventilated with room air or 100% oxygen. A second administration of the antigen induced the development of cardiovascular collapse, leading to death within 12 min. Within 3 min, cardiac output decreased by 90% and end-diastolic left ventricular pressure increased significantly, indicating left ventricular pump failure. In the same time range, ECG recordings uniformly showed signs of acute myocardial ischemia. In addition, arrhythmias occurred in the form of atrioventricular block. Left ventricular contractility declined continuously within the first 4 min. Finally, after 4 min, blood pressure steadily decreased. During ventilation with room air, severe hypoxia developed, with arterial PO2 decreasing from 94 mm Hg to 14 mmHg after 3 min. However, under ventilation with 100% oxygen, a dissociation between cardiac damage and respiratory distress occurred. Myocardial ischemia and signs of cardiac failure preceded the development of hypoxia by a significant time interval. It is to be concluded that cardiac damage is a primary event in anaphylactic shock. Furthermore, the electrocardiographic signs of ischemia are interpreted as a result of coronary artery spasm.

Deleterious effects of cimetidine in the presence of histamine on coronary circulation. Possible clinical implications in anaphylactic states in individuals with coronary heart disease.

SummaryThe present study characterizes effects of histamine in the presence of the H2-antagonist cimetidine on the coronary circulation of the isolated perfused spontaneously beating guinea pig heart. Infusion of histamine (2 ⋅ 10−8 mol/1–5 ⋅ 10−6 mol/l) induced a dose-dependent coronary dilation, comparable to the effect of isoproterenol and two highly selective H2-agonistic compounds, impromidine and dimaprit. In the presence of cimetidine (5 ⋅ 10−6 mol/l), however, coronary response to histamine was reversed in a manner that a dose-dependent coronary constriction occurred with coronary spasm and a flow rate approaching zero at histamine concentrations above 8 ⋅ 10−7 mol/l, whereas the dilatory effect of impromidine and dimaprit was completely antagonized. In contrast, the histamine-induced constriction in the presence of cimetidine could be nearly abolished by additional infusion of the H1-antagonistic compound mepyramine (5 ⋅ 10−5 mol/l).Is is concluded that H1- and H2-receptors are present in the coronary smooth muscle, H1-receptors mediating constriction and H2-receptors mediating coronary dilation. Speculation is provided that histamine may have hazardous effects in anaphylactic states if cimetidine is administered simultaneously, e.g., to prevent or cure peptic ulcer. Other possible clinical implications will be discussed.

Synthesis and histamine H2 agonistic activity of arpromidine analogues: replacement of the pheniramine-like moiety by non-heterocyclic groups☆

Abstract Analogues of the potent histamine H 2 agonist arpromidine, characterized by non-heterocyclic groups (phenyl, cyclohexyl, alkyl) instead of the pheniramine-like portion, were prepared and tested for their H 2 agonistic and H 1 antagonistic activity in the isolated guinea pig right atrium and ileum, respectively. In the diphenylpropylguanidine series an increase in H 2 agonistic potency resulted from mono- or difluorination at one or both phenyl rings in the meta and/or para position (p D 2 ≤ 7.75 vs p D 2 = 7.15 for the unsubstituted parent compound). Compounds chlorinated at both phenyl rings were considerably less potent. Highest combined H 2 agonistic/H 1 antagonistic potency was found in the 4-fluorophenyl series. The arpromidine analogue with cyclohexyl and methyl group instead of phenyl and pyridine ring proved to be 30 times more potent than histamine in the atrium. The H 1 antagonistic potency in cyclohexyl compounds was lower than in the diaryl series. Thus, aromatic rings appear not to be required for high H 2 agonistic potency but are useful for combined H 2 agonistic/H 1 antagonistic activity.

Effects of histamine H1- and H2-receptor antagonists on cardiovascular function during systemic anaphylaxis in guinea pigs

The heart is a target organ of anaphylaxis. In isolated perfused hearts, an anaphylactic reaction is characterized by arrhythmias, coronary constriction, and severe impairment of ventricular contractile force. Various mediators such as PAF, thromboxane A2 and leukotrienes, are responsible for anaphylactic coronary constriction and negative inotropic effects. The cardiac effects of anaphylactic histamine release are related to the stimulation of two antagonistic receptor types. Histamine induces atrioventricular conduction delay and constriction of the epicardial coronary vessels via H1-receptor stimulation. H2-receptors, however, mediatecoronary vasodilation and an increase in heart rate and myocardial contractility. It may therefore be concluded that administration of histamine H2-receptor antagonists is disadvantageous. During anaphylactic states, the cardiodepressive effects of the other mediators of anaphylaxis are unmasked, resulting in a sustained coronary constriction and impairment of myocardial contractility. To verify this speculation, we investigated the effects of H1- and H2-receptor antagonists on cardiovascular function of guinea pigs during systemic anaphylaxis.In guinea pigs, sensitization was produced by subcutaneous application of ovalbumin. Fourteen days after sensitization, the effects of an intravenous infusion of ovalbumin were tested in the anesthetized artificially ventilated guinea pigs. The renewed administration of the antigen induced severe cardiac dysfunction. Within a few minutes, cardiac output markedly decreased and left ventricular end-diastolic pressure increased significantly, indicating left ventricular pump failure. In the same time range, ECG recordings uniformly showed signs of acute myocardial ischemia. In addition, arrhythmias occurred in terms of an atrioventricular block. After 4 min, blood pressure rapidly declined. All animals died within 12 min. Pretreatment with the selective H1-receptor antagonist astemizol (5 mg/kg i.v.) delayed the onset of myocardial ischemia, arrhythmias and cardiac pump failure. After 10 min, however, left ventricular contractility and blood pressure steadily declined, leading to severe hypotension within 30 min. In the case of a pretreatment with astemizol (5 mg/kg i.v.) and the H2-receptor antagonist famotidine (10 mg/kg i.v.), no relevant changes of cardiovascular function were seen compared to pretreatment with astemizol alone. It is therefore concluded that endogenous histamine, via H1-receptor stimulation plays an important part during the early phase of systemic anaphylaxis, whereas mediators other than histamine are involved at a later stage of the process. Furthermore, H2-receptor-mediated effects are of minor importance in cardiovascular manifestation of anaphylaxis. Pretreatment with H2-receptor antagonists has no detrimental effects on cardiovascular function during anaphylactic reactions in guinea pigs underin vivo conditions.

Apparent superiority of H2-receptor stimulation and simultaneousβ-blockade over conventional treatment withβ-sympathomimetic drugs in post-acute myocardial infarction: Cardiac effects of impromidine — a new specific H2-receptor agonist — in the surviving catecholamine-insensitive myocardium

Left ventricular infarction (AMI) was produced in experimental animals and the contractile response to β-adrenergic and H2-histaminergic stimulation by isoproterenol and impromidine tested in the isolated perfused heart preparation. Adenylate cyclase activity as well as binding characteristics of [3H]-dihydroalprenolol ([3H]-DHA), [3H]-methyl-tiotidine ([3H]-TIOT) and [3H]-quinuclidinyl benzilate ([3H]-QNB) to cardiacβ1-, H2- and cholinergic muscarinic receptors were determined in sarcolemmal membrane preparations of the right ventricle of the same hearts. In addition, an attempt was made to elucidate the therapeutic value of post-AMI treatment with impromidine in the presence and absence ofβ-sympathomimetic, in contrast to administration of prenalterol and the conventional therapy with β-sympathomimetic drugs, e.g. dobutamine. Three days post-AMI the dose-response curve for isoproterenol of right ventriculardP/dtmax was significantly depressed, while the inotropic effect of impromidine was not impaired. Stimulation of adenylate cyclase activity by isoproterenol was reduced by 80% whereas impromidine and NaF stimulation rates were unaltered. Receptor-binding studies indicated a 90% loss and 10-times lowered affinity (KD) of the remaining β-receptors while specific [3H]-TIOT- and [3H]-QNB-binding was unchanged.Administration of dobutamine increased mortality rates and extension of infarct size, led to a further decrease in contractile response to isoproterenol, induced complete insensitivity of adenylate cyclase to isoproterenol stimulation and caused pronounced additional reduction of number and affinity of [3H]-DHA-binding sites. In contrast, all above alterations were prevented by treatment with either prenalterol or combined administration of impromidine plus metoprolol. It is concluded, that these alterations in the non-ischemic, uninvolved myocardium post-AMI are the result of catecholamine-induced specific damage of sarcolemmal β-receptors. Furthermore, treatment with H2-agonists in combination with β-blocking agents may have beneficial effects, whereas conventional therapy with β-sympathomimetic drugs tends to worsen the already depressed function of the β-adrenergic stimulation mechanism.

Cardiovascular reactions and respiratory events during platelet activating factor-induced shock.

SummaryThe platelet activating factor (PAF), a low molecular phospholipid, plays an important role in inflammation, anaphylaxis, and shock state development. In the isolated perfused guinea pig heart, PAF induces a decrease in coronary flow and cardiac contractility and atrioventricular conduction disturbances. Furthermore, PAF mediates a powerful bronchoconstrictory action causing a severe impairment in respiratory function. In the present study an attempt was made to separate cardiac from respiratory events during PAF-induced shock in vivo. PAF was injected intravenously (0.1–10 μg/kg) into anesthetized guinea pigs ventilated with room air or 100% oxygen. Administration of 10 μg/kg PAF was uniformly lethal: already within 2 min, cardiac output decreased by 60% and end-diastolic left ventricular pressure increased markedly indicating cardiac failure. ECG recordings showed signs of acute myocardial ischemia. Arrhythmias occurred in terms of atrioventricular conduction delay. Blood pressure initially increased, then declined continuously to below baseline within 10 min. All animals died within 25 min. Ventilation with room air was paralleled by development of severe hypoxia. However, under ventilation with 100% oxygen a dissociation between PAF-mediated cardiac and respiratory effects occurred. It is concluded that the PAF-induced shock is primarily based on direct cardiac damage. Furthermore, the ECG signs of ischemia are most likely due to coronary spasms.

Effects of histamine H1-receptor blockade on respiratory and cardiac manifestation of systemic anaphylaxis

SummaryIn vivo anaphylaxis is associated with respiratory distress and cardiovascular failure. The present investigation was designed to further characterize respiratory and cardiac anaphylactic events. In guinea pigs, sensitization was produced by subcutaneous application of ovalbumin together with Freunds adjuvant. Fourteen days after sensitization, the effects of an intravenous infusion of ovalbumin were tested in the anesthetized artificially ventilated guinea pigs. The renewed application of the antigen induced an initial increase of left ventricular pressure which was followed by a rapid decrease 5 min after antigenic challenge. Enddiastolic left ventricular pressure increased within 3 min, thus indicating left ventricular pump failure. In the same time range, ECG recordings uniformly showed signs of acute myocardial ischemia. In addition, heart rate steadily decreased. All animals died within 15 min. Simultaneously with cardiac anaphylactic malfunction, severe arterial hypoxia and carbon dioxide retention occurred, revealing respiratory distress.Histamine is known as a potent bronchoconstrictor via histamine H1-receptor stimulation. Administration of H1-recpetor antagonists to improve respiration may therefore provide further information on the contribution of pulmonary malfunction to anaphylactic cardiovascular shock. Therefore, additional experiments were performed with sensitized guinea pigs pretreated with the histamine H1-receptor blocker mepyramine. In these experiments the antigenic challenge induced a dissociation of cardiac and respiratory manifestation of anphylaxis. Despite inhibition of hypoxia and carbon dioxide retention, left ventricular pump failure and occurrence of myocardial ischemia were delayed but not suppressed.It is concluded that histamine is an important mediator of anaphylactic respiratory distress. However, vasoactive anaphylactic mediators other than histamine are primarily involved in anaphylactic cardiac malfunction occurring during the later phase of systemic anaphylaxis.

Effects of platelet-activating factor on β- and H2-receptor-mediated increase of myocardial contractile force in isolated perfused guinea pig hearts

SummaryPlatelet-activating factor (PAF) has been termed an important mediator of cardiovascular shock due to immunological reactions, including anaphylaxis and endotoxic reactions. Previous studies have shown that PAF is a potent cardiodepressive agent inducing a drastic coronary constriction and a sustained impairment of myocardial contractility. In this study, an attempt was made to further characterize the prolonged PAF effects on coronary circulation and myocardial contractile force in the isolated guinea pig heart perfused at constant pressure. An intracoronary PAF bolus (0.18 nmol, related to coronary flow rates of 1 ml/min) induced a precipitous decrease of coronary flow rates, left ventricular pressure, and left ventricular contraction (peak positive dP/dt), which was followed by a slow increase reaching new steady states after 15 min (−48%, −40%, −42% below baseline, respectively). If the specific PAF antagonist WEB 2086 (3.65 nmol/min, related to coronary flow rates of 1 ml/min) was infused 30 min after PAF administration, the prolonged PAF-mediated cardiodepressive effects were rapidly reversed. Several studies indicate that PAF induces a down regulation of β-adrenoreceptors in different cell types, including human lung tissue. Therefore, a further objective of the study was to evaluate whether PAF selectively impairs the positive inotropic effcts of β-receptor agonists or also inhibits the contractile effects of inotropic drugs, which are known to enhance cardiac contractility independently of β-receptors. In these experiments, the β-agonist isoproterenol and the H2-agonist impromidine were administered as intracoronary boluses (0.35 nmol and 0.14 nmol, respectively, related to coronary flow rates of 1 ml/min) prior to PAF injection and 30 min after PAF. PAF caused a comparable reduction of the positive inotropic effects of isoproterenol (−60%) and impromidine (−64%). However, if an intracoronary infusion of WEB 2086 (3.65 nmol/min, related to coronary flow rates of 1 ml/min) was started 30 min after PAF, the inhibition of positive inotropic effects of both β-adrenoceptor and H2-receptor stimulation was significantly antagonized.