Biomedical subjects

M Näbauer

Publications and source records attributed to M Näbauer.

27 records · Page 2Linked to original sources

PubMed1989

Regulation of calcium release is gated by calcium current, not gating charge, in cardiac myocytes.

In skeletal muscle, intramembrane charge movement initiates the processes that lead to the release of calcium from the sarcoplasmic reticulum. In cardiac muscle, in contrast, the similarity of the voltage dependence of developed tension and intracellular calcium transients to that of calcium current suggests that the calcium current may gate the release of calcium. Nevertheless, a mechanism similar to that of skeletal muscle continues to be postulated for cardiac muscle. By using rapid exchange (20 to 50 milliseconds) of the extracellular solutions in rat ventricular myocytes in which the intracellular calcium transients or cell shortening were measured, it has now been shown that the influx of calcium through the calcium channel is a mandatory link in the processes that couple membrane depolarization to the release of calcium. Thus, intramembrane charge movement does not contribute to the release of calcium in heart muscle.

Animals↗

PubMed1989

Modulation of Ca2+ channel selectivity and cardiac contraction by photorelease of Ca2+.

The effect of rapid increases of extracellular Ca2+ concentration on tension development and Ca2+ channel selectivity has been investigated in frog (Rana pipiens) ventricular myocardium using a novel light-sensitive Ca2+ chelator, dimethoxy-nitrophen. Dimethoxy-nitrophen is a photolabile tetracarboxylate Ca2+ chelator that on photolysis to dicarboxylate fragments alters its affinity (Kd) for Ca2+ from 5 X 10(-9) to 2 X 10(-3) M. A single 160-microseconds ultraviolet light pulse induced the release of approximately 80-100 microM Ca2+ with a half-time of 200 microseconds. In low extracellular Ca2+ concentration, Na+ current through the Ca2+ channel was blocked by photorelease of extracellular Ca2+ in less than 500 microseconds; nevertheless, 60-80 ms were required to activate or enhance tension. Enhancement of tension was more effective when Ca2+ was released during the activation of the Ca2+ channel than during its inactivation. The voltage dependence of enhanced tension, caused by photorelease of Ca2+, was bell shaped and was similar to that of Ca2+ current. These findings suggest that Ca2+ transport through the Ca2+ channel is the primary mechanism for the transport of Ca2+ to activate tension in the frog heart. The use of dimethoxy-nitrophen makes it possible to examine the rapid kinetics of the Ca-dependent processes involved in regulation of channel function and contraction.

Action Potentials↗

PubMed1988

Positive inotropic effects of the calcium channel activator Bay K 8644 on guinea-pig and human isolated myocardium.

1. The positive inotropic effects of the dihydropyridine calcium activator Bay K 8644 were studied in guinea-pig isolated contracting myocardium and human papillary muscle strips obtained from patients undergoing mitral valve replacement or cardiac transplantation. 2. Bay K 8644 produced a slowly developing, concentration-dependent positive inotropic response in all cardiac tissues studied. In guinea-pig papillary muscle, the increase in force of contraction was half-maximal at 3.9 x 10(-8) mol/l and the maximal inotropic effect was comparable to that obtained with ouabain, dobutamine or calcium. The guinea-pig left atrium (EC50, 2.1 x 10(-7) mol/l) was fivefold less sensitive than the papillary muscle. 3. The maximal inotropic response to dihydroouabain was significantly increased after preincubation with Bay K 8644 (1 x 10(-6) mol/l) in papillary muscles from both guinea-pig and human. In guinea-pig papillary muscles, the maximal inotropic response to dobutamine was not changed by preincubation with Bay K 8644 whereas in human papillary muscle strips, Bay K 8644 increased the inotropic response to dobutamine. 4. Bay K 8644 increased force of contraction (EC50, 4 x 10(-8) mol/l) in human papillary muscle strips from patients undergoing mitral valve replacement. However, the maximal inotropic response to Bay K 8644 was reduced to 32 +/- 4.4% that of calcium (15 mmol/l) measured in the same muscle strips. 5. A further reduction in maximal inotropic response to Bay K 8644 to 13 +/- 1.2% that of calcium (15 mmol/l) with no change in potency was measured in human papillary muscle strips taken from terminally failing hearts of cardiac transplant recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1988

Reduction of beta-adrenoceptor density and evaluation of positive inotropic responses in isolated, diseased human myocardium.

Cardiac beta-adrenoceptors and the positive inotropic effects of adenylate cyclase-dependent (dobutamine, histamine, forskolin) and adenylate cyclase-independent agents (isobutylmethylxanthine (IBMX), dibutyryl-cAMP (db-cAMP), digoxin, digitoxin and calcium were measured in papillary muscle strips from severely failing (NYHA IV), moderately failing (NYHA II-III) and non-failing (NYHA I) human hearts. The density of beta-adrenoceptors in three NYHA I patients were 40.0, 42.0 and 42.9 fmol mg-1 protein. The density of cardiac beta-adrenoceptors was significantly reduced in NYHA II-III to 18.0 +/- 1.1 fmol mg-1 protein (n = 16) and further reduced in NYHA IV to 9.5 +/- 1.6 fmol mg-1 protein (n = 7). The KD values did not differ between the groups. Correspondingly, the positive inotropic effect of dobutamine was significantly reduced in NYHA II-III and almost lost in NYHA IV. The positive inotropic effect of histamine was similar in non-failing and moderately failing myocardium but reduced in preparations from severely failing hearts (NYHA IV). The positive inotropic effect of IBMX was diminished in moderately and severely failing myocardium depending on the functional class of heart failure. In contrast, the effects of forskolin, db-cAMP, digoxin and digitoxin were not impaired in NYHA IV when compared with the maximal positive inotropic effect of calcium. It is concluded that in the failing human heart (a) the number of cardiac beta-adrenoceptors is reduced proportional to the severity of heart failure; (b) the receptor coupling of H2-receptors to adenylate cyclase may be impaired, but only in severe heart failure; (c) the basal cAMP formation may be diminished; and that (d) the catalytic subunit of the adenylate cyclase and the cAMP-dependent protein kinases may be promising targets for drugs to restore force of contraction in human heart failure.

1-Methyl-3-isobutylxanthine↗

PubMed1988

Positive inotropic effects in isolated ventricular myocardium from non-failing and terminally failing human hearts.

The positive inotropic responses to isoprenaline, dobutamine, histamine, forskolin, isobutyl-methylxanthine (IBMX), dibutyryl-cyclic adenosine monophosphate (db-cAMP), ouabain and calcium were studied in isolated, electrically driven papillary muscle strips from either terminally failing human hearts or non-failing donor myocardium. The positive inotropic effect of calcium has been taken to evaluate the maximal force of contraction of each individual muscle strip ('contractile reserve'). In the non-failing heart, the maximal positive inotropic effect of isoprenaline, dobutamine, IBMX, ouabain and calcium were not significantly different, but were significantly greater than histamine. In terminally failing hearts, the positive inotropic effects of agents stimulating the adenylate cyclase by a receptor-dependent mechanism (isoprenaline, dobutamine and histamine) and the phosphodiesterase inhibitor IBMX are less than in the normal heart. Furthermore, these compounds gave a markedly reduced inotropic effect compared with forskolin, db-cAMP and ouabain, which gave maximal responses similar to calcium in the failing hearts. The data did not differ when the increase of force of contraction was related to the diameter of each preparation. These results indicate that a defect in adenylate cyclase occurs in the failing human heart, presumably located at the regulatory stimulatory subunit (Gs) of the adenylate cyclase since effects through stimulatory receptors were reduced. Responses from activation of the catalytic subunit or through cAMP-dependent protein kinases were less affected. Since the positive inotropic effect of IBMX is also impaired, it is suggested that the basal rate of cAMP production is also reduced in heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗

PubMed1987

Reversal of toxic and non-toxic effects of digoxin by digoxin-specific Fab fragments in isolated human ventricular myocardium.

The time course of the reversal of toxic and nontoxic effects of digoxin by digoxin-specific antibody fragments (Fab) was measured in isolated human ventricular myocardium. A concentration of 2 X 10(-6) mol/l digoxin was used to produce positive inotropy followed by mechanical signs of toxicity. After addition of a 1.5-fold higher molar concentration of digoxin-specific Fab, signs of toxicity disappeared within 30 min and digoxin-induced force of contraction decayed with a monoexponential time course with a half-life of 52 min. This rate of decay was almost identical to that observed for the dissociation of the digoxin-(Na+ + K+)-ATPase complex in human heart cell membranes. It is concluded that digoxin-specific Fab are capable of completely removing digoxin from its binding sites, the maximal rate of removal of digitalis glycosides from the (Na+ + K+)-ATPase is limited by the dissociation rate constant, and there is a close correlation between the degree of binding of digitalis glycosides to the (Na+ + K+)-ATPase and the increase in force of contraction.

Binding Sites↗

PubMed1987

Dobutamine: positive inotropy by nonselective adrenoceptor agonism in isolated guinea pig and human myocardium.

Positive inotropic responses to dobutamine have been examined using isolated myocardium from guinea pigs und humans. The potency (EC50) of dobutamine was 1.5 X 10(-6) mol/l on guinea pig papillary muscles, 1.8 X 10(-6) mol/l on guinea pig left atria and 2.5 X 10(-6) mol/l on human papillary muscle strips. In guinea pig cardiac muscles, Schild plots for the beta 1-selective antagonist, 1-practolol, using dobutamine as agonist, had slopes of less than unity. This suggested the involvement of other receptors in the inotropic response to dobutamine. The beta 2-selective antagonist, ICI 118,551, but not the alpha 1-selective antagonist, prazosin, attenuated the dobutamine response in guinea pig papillary muscles. Both ICI 118,551 and prazosin shifted the dobutamine concentration-response curve in guinea pig left atria. The positive inotropic response to dobutamine in human papillary muscles was antagonised by l-practolol and ICI 118,551 but not by prazosin. The maximal inotropic response to dobutamine was 90% that of calcium measured in the same guinea pig papillary muscles but only 37% that of calcium in human papillary muscle strips. This reduced maximal effect of dobutamine in human myocardium is probably a disease-induced change but species variations cannot be excluded.

Animals↗

PubMed1986

Additive positive inotropic effects of milrinone, ouabain and calcium in diseased human ventricular myocardium.

The interactions of milrinone, ouabain and calcium on force of contraction in isolated, contracting human papillary muscle strips were measured. Milrinone (EC50, 8 X 10(-5)M) increased force of contraction maximally by 2.8 +/- 0.8 mN at 5 X 10(-4)M; significantly less than either ouabain (1 X 10(-7)M; 4.8 +/- 0.5 mN increase) or calcium (15 mM; 6.2 +/- 0.6 mN increase). A submaximal, but not a maximal, inotropic effect of ouabain could be increased by the addition of milrinone; in contrast, both ouabain and calcium increased the maximal inotropic effect of milrinone by 1.7 +/- 0.2 mN and 2.7 +/- 0.3 mN, respectively. The combined inotropic effect of milrinone with either ouabain of 4.2 +/- 0.3 mN or calcium of 5.6 +/- 0.4 mN was not different from that with calcium or ouabain alone. We conclude that further positive inotropic effects should be expected when digitalis is given to patients with congestive heart failure who are already optimally treated with milrinone.

Adult↗

PubMed1986

The positive inotropic response to milrinone in isolated human and guinea pig myocardium.

The bipyridine derivative, milrinone, produced positive inotropic effects in isolated, contracting right ventricular papillary muscles and left atria from guinea pigs as well as in human papillary muscle strips. The inotropic effect was biphasic in guinea pig papillary muscles (EC50, high affinity, 1.5 X 10(-6) mol/l, about 35% of maximal effect; apparent EC50, 3 X 10(-5) mol/l with a maximal effect at 2 X 10(-4) mol/l) but monophasic in guinea pig left atria (EC50, 6 X 10(-5) mol/l) and in human papillary muscle strips (EC50, 5.8 X 10(-5) mol/l). In guinea pig papillary muscles, reserpine pretreatment or l-practolol preincubation reduced the low concentration effect only. In the presence of l-practolol, carbachol reduced the low concentration effect only. In the presence of l-practolol, carbachol reduced but not abolished the inotropic effects of milrinone (3 X 10(-6) mol/l, 1 X 10(-4) mol/l) in both guinea pig and human myocardium. This antagonism was prevented by atropine preincubation. The maximum inotropic effect of milrinone was similar to that of ouabain and calcium in guinea pig myocardium but markedly less than either calcium or ouabain in human myocardium. Milrinone inhibited crude guinea pig and human cardiac phosphodiesterase activity in vitro but did not inhibit 3H-ouabain binding to partially purified human cardiac (Na+ + K+)-ATPase-containing membranes. We conclude that the primary mode of action of milrinone in both guinea pig and human myocardium is through inhibition of phosphodiesterase.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗