Effects of halothane on beta-adrenoceptors and M-cholinoceptors in human myocardium: radioligand binding and functional studies.

We investigated whether a postsynaptic sensitization by halothane for beta-adrenoceptor-mediated effects occurs in diseased human myocardium. In addition, we hoped to achieve further insights into the cellular mechanism and, in particular, the role of M-cholinoceptors and beta-adrenoceptors. The experiments were performed on isolated, electrically driven atrial and ventricular preparations and membranes isolated from human hearts obtained at cardiac surgery.

Studies about the effects of positive inotropic and vasoactive substances.

The present study describes an in vitro method to characterize inotropic and vascular effects of compounds on isolated human cardiovascular tissues. In vitro, the positive inotropic effect in electrically driven left ventricular papillary muscle strips of nonfailing and failing human myocardium was studied and compared to experiments performed in muscle preparations of guinea pigs. In radioligand binding experiments the receptor subclasses mediating the inotropic effects were characterized.

Increase of the extracellular magnesium concentration reduces cardiac glycoside toxicity in the human myocardium.

We studied the influence of magnesium on contractility and on force-frequency-relationship as well as on the positive inotropic and toxic effects of ouabain (OUA) on electrically driven human right auricular trabeculae. Radioligand binding experiments were performed with myocardial tissue from nonfailing and from terminally failing patients. Magnesium produced a concentration-dependent negative inotropic effect (P < .

Positive inotropic effects due to partial agonistic activity of the beta-adrenoceptor antagonist celiprolol following amplification of cAMP formation in failing human myocardium.

The present study investigated the effects of celiprolol a novel beta 1-antagonist with partial beta 2-agonist activity on the human failing heart. Experiments were performed on isolated electrically driven atrial and ventricular cardiac preparations and in membrane preparations from the left ventricles of nine patients (four with dilated cardiomyopathy; five with ischemic cardiomyopathy) undergoing cardiac transplantation for terminal heart failure. Celiprolol produced a negative inotropic effect in atrial and ventricular heart muscle.

Existence of PAF receptors in human platelets and human lung tissue but not in the human myocardium.

The aim of this study was to investigate whether platelet-activating factor (PAF), PAF receptors, and PAF receptor-mediated effects in the human myocardium play a role in cardiac depression during anaphylaxis or septic shock. The effects of PAF, the biologically inactive derivative lyso-PAF, and the specific PAF antagonist WEB 2086 were studied in human myocardial tissue, in human coronary arteries, in human platelets, and in human lung tissue. PAF (C16-PAF, C18-PAF; 0.

Effect of the phosphodiesterase inhibitor UK 61260 on human myocardial inotropy and diastolic relaxation.

The phosphodiesterase inhibitor UK 61260 exhibits positive inotropic activity in animal studies and is under clinical investigation for treatment of congestive heart failure (CHF). We examined the lusitropic and inotropic responses to UK 61260 in electrically driven (1 Hz, 37 degrees C) human auricular trabeculae (AUT, aortocoronary bypass operation, nonfailing hearts, n = 13) and in papillary muscle strips (PAP) from moderately (New York Heart Association, NYHA II-III, mitral valve replacement, n = 6) and terminally (NYHA IV, heart transplantation, n = 7) failing human hearts. For comparison, we studied the effects of UK 61260 after prestimulation with forskolin (FOR 0.

Force-frequency relationship and inotropic stimulation in the nonfailing and failing human myocardium: implications for the medical treatment of heart failure.

In isolated papillary muscle strips from nonfailing donor hearts (NF) and from the hearts of patients with dilated cardiomyopathy with severe heart failure (NYHA IV), the force-frequency relationship was studied. Experiments were performed under basal conditions and in the presence of 0.01 microM or 0.

Heart failure and electrolyte disturbances.

Electrolyte abnormalities are a frequent and potentially hazardous complication in patients with heart failure. This may be due to the pathophysiological alterations seen in the heart failure state leading to neurohumoral activation (stimulation of the renin-angiotensin-aldosterone system, sympathoadrenergic stimulation), and due to the complications of therapy with diuretics, cardiac glycosides or ACE inhibitors. Patients with heart failure may exhibit hyponatremia due to a decrease in water excretion, which may be related to the enhanced release of both angiotensin and vasopressin and can be exaggerated by diuretic therapy.

Na(+)-channel activators increase cardiac glycoside sensitivity in failing human myocardium.

Na(+)-channel activators increase intracellular Na+ and thereby enhance the transport rate of sarcolemmal Na+,K(+)-ATPase. We investigated the interaction of the new Na(+)-channel activator BDF 9148 (BDF) with the cardiac glycoside ouabain (OUA) in human myocardium. The influence of OUA (0.

Triamterene may preserve lymphocyte magnesium and potassium in patients with congestive heart failure.

Electrolyte abnormalities are a frequent and potentially hazardous complication in the treatment of patients with congestive heart failure. Medical treatment with diuretics and/or digitalis, as well as neurohumoral activation most likely initiated by the compromised cardiac function, contributes to this alteration. The addition of potassium- and magnesium-sparing diuretics (triamterence, amiloride) to therapy with frusemide or hydrochlorothiazide is of possible value in preventing intracellular electrolyte abnormalities.

Alterations of the force-frequency relationship in the failing human heart depend on the underlying cardiac disease.

We investigated the force-frequency relationship (0.5-3 Hz) in non-failing human myocardium and in end-stage failing human myocardium due to dilated cardiomyopathy or subacute myocarditis. In non-failing myocardium, force of contraction increased with increasing stimulation frequency.

[Adrenergic beta receptors and guanine nucleotide binding proteins (G-proteins) of the failing human heart].

In heart failure, the sympathetic nervous system is activated. The increased release of norepinephrine from the heart and the elevated levels of circulating catecholamines produce a downregulation of myocardial beta 1-adrenoceptors. In ischemic cardiomyopathy and mitral valve disease, a downregulation of beta 2-adrenoceptors has been observed also.

Inotropic and lusitropic dysfunction in myocardium from patients with dilated cardiomyopathy.

Isometric force of contraction (DT), peak rate of tension increase (+T), peak rate of tension decrease (-T), time to peak tension (TPT), and time to half-relaxation (T 1/2 T) were measured in electrically driven human papillary muscle strips (New York Heart Association [NYHA] class IV heart transplants, dilated cardiomyopathy; nonfailing (NF) donor hearts, brain dead) (1 Hz, 37 degrees C) under basal conditions (1.8 mmol/L Ca2+) and after stimulation with isoprenaline, ouabain, and Ca2+. There was no difference in the isometric contraction (+T, -T, TPT, and T 1/2 T) between NYHA IV hearts and NF hearts under basal conditions.

Different beta-adrenoceptor-effector coupling in human ventricular and atrial myocardium.

To examine whether the downregulation of beta-adrenoceptors is accompanied by reduced beta-adrenoceptor-mediated effects in atrial as well as in ventricular myocardium, we investigated the beta-adrenoceptor-effector coupling in atrial and papillary muscle strips from patients with terminal heart failure (heart transplantation because of dilated cardiomyopathy; New York Heart Association Class IV, NYHA IV) and moderate heart failure (mitral valve replacement, NYHA II-III) and in tissue from non-failing hearts. The isometric force of contraction induced by isoprenaline (0.001-1 mumoll-1) or Ca2+ (1.

Evidence for a sustained effectiveness of sodium-channel activators in failing human myocardium.

Elevation of cytosolic sodium is thought to be correlated with an increase in force of contraction due to an activation of sodium-calcium exchange. We investigated the inotropic response mediated by the new sodium-channel activator BDF 9148 (0.01-100 mumol/l) on failing human myocardium.

Negative inotropic activity of the calcium antagonists isradipine, nifedipine, diltiazem, and verapamil in diseased human myocardium.

The use of calcium antagonists in the treatment of cardiac failure is limited by the negative inotropic effects they exert. The comparative inotropic activity of four calcium antagonists was therefore investigated, using electrically driven human papillary muscle strips and human atrial trabeculae. These inotropic effects were studied with cumulative concentration-response curves.

Effects of xamoterol on inotropic and lusitropic properties of the human myocardium and on adenylate cyclase activity.

The purpose of the present study was to characterize the effects of xamoterol in the human myocardium. In the presence of forskolin or milrinone, xamoterol increased isometric force of contraction, contraction velocity, and relaxation velocity in isolated, electrically driven preparations from human myocardium, but had no effect alone. There was no difference in the effect of xamoterol between right atrial myocardium and left ventricular myocardium from nonfailing (NF), moderately failing (NYHA II-III), and severely failing (NYHA IV) human hearts.

[Magnesium and potassium content in patients with heart failure and in healthy persons. Determination in lymphocytes, erythrocytes and plasma].

Therapy with diuretics and/or digitalis, as well as the compromised cardiac function, contributes to electrolyte alterations (magnesium, potassium) in patients with congestive heart failure. We determined in 29 patients with heart failure (NYHA classes II-IV) the magnesium and potassium content in lymphocytes and in erythrocytes, as well as in 25 healthy subjects. In patients with heart failure, lymphocyte magnesium (4.

[Alterations of the cAMP-adenylate cyclase system in the failing human heart. Consequences for the therapy with inotropic drugs].

In heart failure, an increase in the activity of the sympathetic nervous system takes place to maintain perfusion pressure to vital organs, resulting in increased levels of noradrenaline in the blood of these patients. This permanent stimulation produces a down-regulation of cardiac beta-adrenoceptors. Since noradrenaline acts primarily on the cardiac beta 1-adrenoceptor subtype, beta 1-adrenoceptors decrease in number, whereas the beta 2-adrenoceptor subpopulation remains unchanged in most instances.

Different negative inotropic activity of Ca2(+)-antagonists in human myocardial tissue.

To evaluate the negative inotropic effect of various Ca2(+)-antagonists in human myocardium without additional influences of preload, afterload, or frequency, we examined their effects on isometric force of contraction in isolated human papillary muscle strips and in auricular trabeculae. The 1,4-dihydropyridines isradipine, nitrendipine, and nifedipine, the phenylalkylamine verapamil, and the benzothiazepine diltiazem exerted concentration-dependent negative inotropic effects. The potency of the investigated Ca2(+)-antagonists was identical in papillary muscle strips of patients with only moderate clinical signs of heart failure undergoing mitral valve replacement-operation (NYHA II-III) and in terminally failing (heart transplantation, NYHA IV) human hearts.

Antagonism of novel inotropic agents at A1 adenosine receptors and m-cholinoceptors in human myocardium.

The effects of the new inotropic agents saterinone, sulmazole, UD-CG 212.Cl and milrinone at A1 adenosine receptors and m-cholinoceptors were evaluated in human myocardium from patients with heart failure. At A1 adenosine receptors, all compounds inhibited 3H-DPCPX-binding to ventricular membrane preparations at micromolar concentrations.

Negative inotropic properties of isradipine, nifedipine, diltiazem, and verapamil in diseased human myocardial tissue.

We investigated the inotropic responses to Ca2+ antagonists using electrically driven human papillary muscle strips and human auricular trabeculae. Specimens were obtained during cardiac surgery for mitral valve replacement [New York Heart Association (NYHA) Class II-III] or heart transplantation (NYHA IV) and during aortocoronary bypass operations. The inotropic effects were studied with cumulative concentration-response curves.