BACKGROUND: The present study aimed to characterize the effects of epinine, the active metabolite of ibopamine on tension development in human renal arteries. METHODS AND RESULTS: Experiments were performed on isolated human renal arteries rings obtained during surgery due to kidney tumors (n = 12). Epinine concentration-dependently relaxed isolated precontracted (PGF2 alpha) human renal artery rings (P < 0.05) in the presence of phentolamine, as effectively (epinine -30 +/- 4 mN, dopamine -31 +/- 5 mN) and with the same potency as dopamine (epinine EC50 0.7 mumol/l (0.4-1.2 mumol/l), dopamine 0.5 mumol/l (0.2-1.7 mumol/l). This effect was antagonized by the specific D1-receptor-antagonist SCH 23390. Effective beta-adrenoceptor antagonistic concentrations of propranolol did not affect epinine-induced vasorelaxation. In the absence of alpha- and beta-adrenoceptor-antagonists the potency of epinine to contract renal artery rings was significantly higher compared to dopamine indicating a higher affinity of epinine to alpha-adrenoceptors. CONCLUSION: The present study provides evidence for direct vasodilatory effects of epinine via activation of D1-receptors on human renal arteries.

Adrenergic alpha-Antagonists↗

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EMD 53998 acts as Ca(2+)-sensitizer and phosphodiesterase III-inhibitor in human myocardium.

UNLABELLED: The effect of EMD 53998 (EMD) (0.1-100 mumol/l), chemically a racemic thiadiazinone derivative, suggested to be a potent Ca(2+)-sensitizer, was studied in human failing and nonfailing left ventricular myocardium. For comparison, the effects of the pyridazinone derivative pimobendan (0.1-300 mumol/l), isoprenaline (Iso) (0.001-3 mumol/l) as well as CaCl2 (1.8-15 mmol/l Ca2+) were investigated. The positive inotropic responses were examined in electrically driven (1 Hz, 37 degrees C) human left ventricular papillary muscle strips from terminally failing hearts (NYHAIV, n = 24) and nonfailing donor hearts (NF, n = 9). The effect of EMD on the Ca(2+)-sensitivity of skinned fiber preparations from the very same human failing hearts were studied as well. EMD and pimobendan increased force of contraction (FOC) in a concentration-dependent manner. As judged from the EC50-values, EMD increased FOC more potently than pimobendan. EMD was significantly more effective than pimobendan to increase FOC in papillary muscle strips from NYHA IV (EMD: +2.5 +/- 0.1 mN; pimobendan: +0.8 +/- 0.2 mN) as well as from nonfailing hearts (EMD: +3.1 +/- 0.5 mN; pimobendan: +1.2 +/- 0.2 mN). Only in terminally failing myocardium, EMD increased FOC as effectively as Iso. After inotropic stimulation with EMD, pimobendan, or Iso, carbachol (1000 mumol/l) reduced FOC in left ventricular papillary muscle strips, indicating a cAMP-dependent mode of action. In skinned fiber experiments, EMD increased Ca(2+)-sensitivity significantly more (p < 0.01) than pimobendan. IN CONCLUSION: EMD increases FOC in human myocardium via sensitizing of the contractile proteins towards Ca2+ and by inhibition of phosphodiesterase III-isoenzymes. EMD is a potent calcium sensitizing agent in human myocardium. Thiadiazinone derivatives could be one step in the evolution to more potent and selective calcium-sensitizers.

3',5'-Cyclic-AMP Phosphodiesterases↗

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Myosin P-light chain isoenzymes in the human heart: evidence for diphosphorylation of the atrial P-LC form.

We studied myosin light chains (LC) of human atrium and ventricle of normal and diseased individuals by a high-resolution 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) technique. Atrial LCs (ALC-1, ALC-2 (= P-LC)) revealed both higher molecular weights and lower isoelectric points (IEP) than their ventricular counterparts (VLC-1, VLC-2 (= P-LC)). Different P-LC forms with their distinct myosin isoenzymes have been designated as P-LC-polymorphism and myosin P-LC isoenzymes, respectively. In the dephosphorylated state two VLC-2 forms (VLC-2 and VLC-2*) with the same MW and different IEP, but only one ALC-2 form, were found. In the partially phosphorylated state ALC-2 appeared to be single- and double-phosphorylated (three spots in the 2D-PAGE), whereas the two VLC-2 forms appeared to be single-phosphorylated each (four spots in the 2D-PAGE). Phosphoryl-transfer from ATP to the P-LC forms was studied using skinned fibers incubated with MLCK (myosin light chain kinase) and (gamma-32P)ATP. Ventricular myosin P-LC isoenzyme pattern was usually the same in normal and diseased patients: the VLC-2 to VLC-2* ratio was approx. 70/30, but in one patient with valvular heart disease (VHD) the relation was 55/45 (shift to the VLC-2* form). In hypertrophied atria of VHD patients a shift of the myosin P-LC isoenzyme pattern to the VLC-2* form occurred, too.

Adult↗

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Cardiac effects of vanadate.

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Animals↗

PubMedDate not supplied

Stimulation of human cardiac adenylate cyclase by vanadate.

Experiments have been carried out to characterize the influence of the positive inotropic trace element vanadium (used as Na3VO4) on beta-adrenergic receptor coupled adenylate cyclase activity from human myocardium. Na3VO4 (10(4)M) stimulates basal activity as well as isoprenaline (10 microM)- and Mg2+ (20 mM) activated enzyme activity 1.5-2.4-fold. In contrast, adenylate cyclase activity in the presence of maximally activating concentrations of Gpp(NH)p (10 microM) cannot be further increased by Na3VO4. The results confirm the assumption (5) that vanadate stimulates adenylate cyclase by interacting with the nucleotide-binding site of this enzyme.

Adenylyl Cyclases↗

PubMedDate not supplied

Significance of NADH-vanadate-oxidoreductase of cardiac and erythrocyte cell membranes.

Vanadate(V), which has positive inotropic, natriuretic and vasoconstrictive effects, is taken up by cardiac cells and erythrocytes in large quantities. Most of the intracellular vanadium is shown to exist as protein-bound vanadyl(IV), however Vanadate (VO3) is a powerful inhibitor of the (Na+ rK+)-ATPase and the Ca++-ATPase, whereas it stimulates adenylate cyclase of cardiac tissue. Vanadyl (VO2+) has no or much less effects on these enzymes. Plasma membranes of cardiac tissue (cat, calf, human) as well as erythrocytes contain an enzyme that converts vanadate(V) to vanadyl(IV) in the presence of NADH but not NADPH. The optimal conditions for this NADH-vanadate-oxidoreductase are: pH 6.8, 1 mM, NADH, 1.5 mM Va3VO4. Mg++ inhibits the enzyme half-maximally at 3 mM, Ca++ stimulates at low and inhibits at high concentrations (half-maximally at 0.8 mM). The enzyme is supposed to be located at the inner side of the cell membrane. Vanadate has been proposed as an ideal regulator of active cation transport across the cell membrane. The finding of a HADH-vanadate-oxidoreductase converting vanadate into the rather inactive vanadyl further supports this hypotheses. The amount of vanadate at active sites of the target enzymes might be responsible for the known vanadate effects.

Animals↗

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Regulation of active cation flux by vanadate in beating rat heart muscle cells in culture.

Looking for a supposed digitalis-like action of compounds of the trace element vanadium, we have investigated the influence of vanadate (Na3VO4) on beating and on active cation flux of [42K+] and [89Rb+] in cultured rat heart muscle cells: Na3VO4(10(-6)-10(-3)M) exerts a positive chronotropic effect and increases contraction velocity and beating automaticity of the cells. Vanadate-induced alteration of beating is paralleled by stimulated uptake of [42K+] and [86Rb+] up to 75%. This stimulation has to be attributed to increased activity of (Na++)-ATPase and cannot solely be explained by the enhanced beating frequency. In contrast to ouabain, vanadate raises intracellular potassium content up to 15% and prevents cell contractures of ouabain-intoxicated heart muscle cells. The experimental data speak against a possible digitalis-like action of vanadate in cultured rat heart muscle cells.

Animals↗

PubMedDate not supplied

Cell membrane receptors for cardiac glycosides in the heart.

Cell membranes contain special binding proteins for hormones and drugs. These binding sites ("receptors") located on the outside surface are linked to or are part of an enzyme facing the inner side of the membrane and are transducing and probably amplifying the information carried by the pharmacological agent to the cell. As the first step of their action cardiac glycosides reversibly bind with high affinity to specific receptors in cardiac cells and by this inhibit the (Na+ + K+)-ATPase, which is the enzyme system responsible for the active transmembraneous transport of sodium and potassium. It is thought that the inhibition of this active cation transport precedes the positive inotropic effect. Cardio-inactive glycosides have but low affinity to this receptor and thus do inhibit the (Na+ + K+)-activated ATPase only at very high concentrations. The characterization of the cardiac glycoside-receptor interaction in the heart reveals several factors that influence the affinity of the binding sites for the glycosides and thereby determine the sensitivity to this widely used group of potent drugs.

Adenosine Triphosphatases↗