Previous studies on sarcoplasmic reticulum calcium release channel (ryanodine receptor) demonstrated that protein levels are unchanged in myocardium from hearts with end-stage failing dilated cardiomyopathy. In ischemic cardiomyopathy, ryanodine receptor mRNA levels were shown to be decreased but no data on protein levels are available. Accordingly, protein levels of ryanodine receptor, calsequestrin, and sarcoplasmic reticulum calcium-ATPase (SR-Ca(2+)-ATPase) were measured by Western blot analysis in nonfailing human myocardium (n = 7) and in end-stage failing myocardium due to ischemic cardiomyopathy (n = 14). Protein levels of calsequestrin which is the major sarcoplasmic reticulum calcium storage protein were similar in nonfailing myocardium and in myocardium from end-stage failing hearts with ischemic cardiomyopathy. Ryanodine receptor protein levels, normalized to total protein or calsequestrin were also unchanged in ischemic cardiomyopathy. In contrast, protein levels of SR-Ca(2+)-ATPase normalized to total protein or calsequestrin were decreased by 31 and 30%, respectively (p < 0.05). The data indicate that (1) sarcoplasmic reticulum calcium uptake sites are decreased relative to the release sites in ischemic cardiomyopathy, and (2) alterations of sarcoplasmic proteins are similar in ischemic and dilated cardiomyopathy.

Adult↗

PubMedDate not supplied

Influence of endothelin 1 on human atrial myocardium--myocardial function and subcellular pathways.

The influence of endothelin 1 on isometrically contracting human atrial muscle strip preparations was investigated under physiological conditions (37 degrees C, 1 Hz, Ca2+ 2.5 mM). Endothelin dose-dependently increased isometric tension from 3 x 10(-10) M to 1 x 10(-7) M. At 1 x 10(-7) M the inotropic effect of endothelin was maximum with isometric tension being increased by 32 +/- 6% (n = 11, p < 0.05). At 1 x 10(-7) M endothelin the positive inotropic effect was preceded by a transient negative inotropic effect with a decline in tension by -5 +/- 1% (n = 11, p < 0.05). Endothelin prolonged time from peak tension to 50% relaxation (RT50) by 29 +/- 5%. With BQ123 a competitive antagonist of the ETA receptor positive inotropic effect and the prolongation of relaxation was significantly reduced and initial negative a inotropic effect was abolished, indicating a ETA receptor mediated effect. Preincubation with phorbolmyristateacetate (10(-5) M) to downregulate proteinkinase C (PKC) eliminated the positive inotropic effect of endothelin. Similarly, N-5,5-dimethylamiloride (10(-5) M) which inhibits Na+/H(+)-exchanger activity, abolished the positive inotropic effect of ET. However, with either PMA or DMA the initial transient negative inotropic effect was still present (-13 +/- 7%, n = 9, p < 0.05 and -3 +/- 1%, n = 6, p < 0.05). Furthermore, both substances did not abolish the prolongation of twitch time parameters observed under endothelin. After preincubation with PMA, endothelin prolonged RT50 by 18 +/- 6% and with DMA by 11 +/- 2%. Using the photoprotein aequorin as an indicator for intracellular calcium concentrations showed that the positive inotropic effect was mainly mediated by an increase of systolic intracellular calcium concentrations. Thus, the present data indicate that the positive inotropic effect of endothelin in human atrial myocardium results from activation of PKC with a subsequent activation of the Na+/H(+)-exchanger. However, the initial negative inotropic effects as well as the prolongation of relaxation seem to result from a different intracellular mechanism of endothelin.

Aequorin↗

PubMedDate not supplied

Differential cytokine production in stimulated blood cultures from intensive care patients with bacterial infections.

Mice infected with bacteria develop an interferon-gamma (IFN-gamma) dependent hypersensitivity to lipopolysaccharide (LPS) and other bacterial components. The broader aim of this study is to find out whether such hypersensitivity also occurs in patients suffering from bacterial infections. The capacity of stimulated peripheral blood cells from infected, intensive-care patients to produce cytokines (IFN-gamma, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6)) was compared to that of healthy donors. Culturing of the cells was carried out preferentially in whole blood diluted 1:3. Whole blood cultures (WBC) were stimulated with lipopolysaccharide (LPS), whole killed Salmonella typhimurium and Staphylococcus aureus and concanavalin A (ConA), and the cytokine production was determined. Two main findings emerged from this study: The IFN-gamma production by WBC of patients was, compared to healthy donors, markedly suppressed, regardless of stimulus used. Further, patients' WBC exhibited a suppressed TNF-alpha production after stimulation with LPS. Surprisingly, following stimulation with bacteria (S. typhimurium and S. aureus) an elevated TNF-alpha and IL-6 response was obtained. Thus, in severely infected patients the cytokine responses of peripheral blood cells to LPS may be suppressed, while the response to other bacterial components is enhanced.

Adolescent↗

PubMedDate not supplied

Systemic and regional vascular effects of atrial natriuretic peptide in a rat model of chronic heart failure.

To characterize the systemic and regional vascular effects of atrial natriuretic peptide (ANP) in chronic heart failure, central hemodynamics, regional blood flow and plasma ANP levels were determined in a rat model of myocardial infarction and failure and in sham-operated animals. Measurements were made in the conscious state before and after intravenous rANP [99-126] (8 micrograms bolus followed by continuous infusion of 1.0 microgram/kg/min). With this protocol, ANP significantly decreased cardiac output, right atrial, left ventricular end-diastolic and arterial pressures and there were increases in heart rate, systemic and intestinal vascular resistances in sham animals. Renal blood flow per gram of tissue was unchanged with ANP, but when expressed as a percentage of cardiac output, increased significantly, indicating a preferential renal vasodilatory effect of ANP. In rats with infarction and failure, this dose did not alter cardiac output or arterial pressure, but decreased right atrial and left ventricular blood flow. Although significantly reduced as compared to the control group, renal blood flow was not improved with ANP in the heart failure group. ANP plasma levels of the heart failure group were elevated at baseline (p less than 0.01), and increased 5-10 times after infusion of rANP. Thus, in rats with chronic heart failure, the renal vascular effects of ANP are blunted, which may, in part, explain the failure of ANP to restore the altered volume homeostasis in heart failure despite elevated ANP plasma levels. However, the effects on venous return were preserved which, in turn, improved cardiac performance via a reduction of preload.

Animals↗

PubMedDate not supplied

Effect of tetrodotoxin, lidocaine, and quinidine on the transient inward current of sheep Purkinje fibres.

The effect of tetrodotoxin (TTX), lidocaine, and quinidine on the transient inward current (TI) was studied in voltage-clamped sheep cardiac Purkinje fibres. The TI was induced by elevation of extracellular Ca or addition of strophanthidin. Reduction of external Na had a biphasic effect on the steady state TI magnitude; a moderate (less than 50%) reduction of external Na had an enhancing effect on the TI; a further decrease of extracellular Na was accompanied by a decline of TI amplitude. The TI could not be induced in Na-free medium (external Ca less than or equal to 9.0 mM). TTX, lidocaine, and quinidine reduced the magnitude of the TI in a dose-dependent way. The blocking effect of these agents could be compensated for by a moderate (less than 50%) reduction of external Na or an elevation of extracellular Ca. It is suggested that the blocking effect of TTX, lidocaine, and quinidine on the TI is due to a reduction of intracellular Na, which causes a decay of intracellular Ca via the Na-Ca exchange mechanism.

Animals↗

PubMedDate not supplied

Regulation of myocardial contractility and cardiac growth.

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Heart↗

PubMedDate not supplied

Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine.

Hypercholesterolaemia impairs endothelial function, possibly by interference with the intracellular formation of endothelium-derived relaxing factor from its precursor L-arginine. Whether L-arginine reverses hypercholesterolaemia-induced endothelial dysfunction in the coronary circulation was thus investigated. Epicardial artery cross-sectional area and coronary blood flow velocity were measured in 8 hypercholesterolaemic patients (mean serum cholesterol 7.8 [SE 0.3] mmol/l) and 7 age-matched controls before and after graded intracoronary infusions of the endothelium-dependent agent acetylcholine (0.036, 0.36, 3.6 micrograms/min). The effect of intracoronary infusion of L-arginine (160 mumol/min via the guiding catheter) on these measurements was then examined. In controls, acetylcholine induced a moderate dose-dependent constriction of the epicardial artery segment of the left anterior descending artery and increased coronary blood flow (by 239% [SE 57] at the highest dose). In patients with hypercholesterolaemia, the vasoconstrictive effect of acetylcholine on epicardial segments was similar to that in controls, but the increase in coronary blood flow with acetylcholine was significantly attenuated (highest dose: 61%, p less than 0.02 vs controls). L-arginine restored the acetylcholine-induced increase in blood flow in patients with hypercholesterolaemia (198% [61] vs baseline) but did not affect coronary blood flow in controls. The findings suggest that hypercholesterolaemia impairs endothelium-dependent dilatation of the coronary microcirculation and that this impairment can be restored by short-term administration of L-arginine. The possibility that L-arginine might form the basis of treatment for coronary endothelial abnormalities induced by hypercholesterolaemia could be worth investigating.

Acetylcholine↗

PubMedDate not supplied

Electrophysiological actions of lorcainide in patients with cardiac disease.

Lorcainide is a new antiarrhythmic agent which effectively suppresses ventricular premature contractions. Its electrophysiological actions were studied in 15 cardiac patients with and without cardiac conduction abnormalities. In a dose of 2 mg/kg body weight, lorcainide decreased the sinus cycle length (SCL) and increased the corrected sinus node recovery time. The intra-atrial, atrioventricular (AV), and intraventricular conduction times were prolonged. A third-degree AV block developed in 2 patients with pre-existing conduction abnormalities. QRS widening showed that intramyocardial conduction was also affected. The effective refractory period of the atrioventricular node (ERP-AVN) was shortened, whereas the effect on the functional refractory period of the AVN was variable. The decrease in SCL and ERP-AVN may be due to a possible anticholinergic effect of the drug. The accessory pathway was blocked in 3 patients with a Wolff-Parkinson-White syndrome. The ERP of the ventricle was slightly prolonged. The electrophysiological profile of the drug, i.e., slowing of conduction velocity throughout the heart combined with shortening of SCL and ERP-AVN, differs from other antiarrhythmic agents.

Acetanilides↗