The influence of pertussis toxin on the effects of adenosine, the adenosine receptor agonist (-)-N6-phenylisopropyladenosine (PIA) and the m-cholinoceptor agonist carbachol on heart rate and atrioventricular (AV) conduction was investigated in spontaneously beating isolated perfused guinea-pig hearts. In addition, the effects of the agents on the electrocardiogram recorded from anesthetized guinea pigs were studied. Adenosine (0.1-100 mumol/l) and PIA (0.001-100 mumol/l) had concentration-dependent negative chronotropic and negative dromotropic effects. These effects were prevented by pretreatment of the animals with pertussis toxin (150 micrograms/kg; i.v.). Carbachol (0.001-100 mumol/l) had similar cardiac depressant effects. These effects were also abolished by pertussis toxin. In contrast, the negative chronotropic and negative dromotropic effects of the calcium antagonist verapamil which was investigated for comparison were not influenced by pretreatment with pertussis toxin. Since the cardiac depressant effects mediated via adenosine receptors or via m-cholinoceptors are most probably due to an activation of a K+ conductance, it is concluded that both receptors in the sinus node and in the AV node may be coupled via a common pertussis toxin-sensitive guanine nucleotide-binding protein to the K+ channel. It remains to be elucidated whether an additional inhibitory coupling to Ca2+ channels also plays a role.

Animals↗

PubMedDate not supplied

Protein phosphorylation in isolated trabeculae from nonfailing and failing human hearts.

Disturbances in the cAMP production during beta-adrenergic stimulation and alterations of Ca2+ transport controlling proteins and their regulation in the sarcoplasmic reticulum might be involved in the pathogenesis of the failing human heart. Thus, we investigated the cAMP-mediated phosphorylation of phospholamban, troponin I and C-protein in electrically driven, intact isolated trabeculae carneae from nonfailing and failing (NYHA IV) human hearts in parallel to contractile properties on the same tissue samples. The increase in force of contraction induced by isoproterenol (0.2 microM) or pimobendan (100 microM), a phosphodiesterase inhibitor, was diminished in the failing human hearts compared to nonfailing hearts by 49% and 36%, respectively. Concomitantly the isoproterenol-induced phosphorylation (pmol P/mg homogenate protein) of phospholamban, troponin I and C-protein was reduced from 13.0 +/- 2.4 (n = 4), 30.5 +/- 1.5 (n = 5) and 11.0 +/- 1.3 (n = 5) in the nonfailing heart to 5.2 +/- 0.6 (n = 13), 14.6 +/- 2.2 (n = 16) and 7.1 +/- 1.0 (n = 6) in the failing human heart, respectively. Pimobendan changed the phosphorylation state of these proteins similar to isoproterenol. The fact that combined addition of both agents or dibuturyl cAMP (1 mM) alone restored the phosphorylation capacity as observed in the control groups indicates that i) a reduced cAMP generation is related to the reduced phosphorylation of regulatory phosphoproteins located in the sarcoplasmic reticulum and contractile apparatus e.g. phospholamban, troponin I and C-protein, that ii) there is a relationship between protein phosphorylation state and contractile activity and that iii) no changes in the respective content of phosphoproteins are involved in the limitation of cAMP-mediated inotopic activity in the failing human heart.

Adolescent↗

PubMedDate not supplied

Adrenergic and muscarinic receptor regulation and therapeutic implications in heart failure.

In end-stage heart failure the expression of different myocardial regulatory proteins involved in the beta-adrenergic cAMP signalling pathway is altered. The downregulation of beta 1-adrenoceptors and their uncoupling from the effector as well as an increased expression of the inhibitory GTP-binding protein seem to be the most important alterations. Since catecholamine levels are elevated in these patients and since some alterations can be 'restored' after treatment with beta-adrenoceptor antagonists it was hypothesized that excessive beta-adrenergic stimulation could be involved in these alterations. In this article the changes of beta-adrenergic receptors, GTP-binding proteins, sarcoplasmic reticulum Ca(2+)-ATPase and of phospholamban found in heart failure are addressed with its possible therapeutic implications.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

[Experimental visualization of the ventricular conduction system of the heart intra vitam (author's transl)].

The in-vivo tolerability of an in vitro in cow, calf and sheep hearts developed method for radiologic visualization of the left ventricular conduction system is tested in four animal experiments. The clinical in-vivo tolerability could be demonstrated on principle; however, it is to accent that hypertonic X-ray contrast dyes may be the cause of morphological changes in the micro- and ultrastructures of the specialised musculature of unknown dignity.

Animals↗

PubMedDate not supplied

Effect of vanadate on myocardial force of contraction.

Ammonium vanadate (NH4VO3; 50-1000 microM) increases the force of contraction of isolated electrically driven cat papillary muscles in a concentration-dependent manner. The positive inotropic effect (PIE) of NH4VO3 became significant at 50 microM and was maximal at 500 to 1000 microM. It was accompanied by an increase in the rate of force development, in the rate of relaxation and in relaxation time of the isometric contraction. Similar results as with NH4VO3 were also observed in the presence of 1 microM propranolol, 5 microM phentolamine or after reserpine-pretreatment (5 mg/kg i.p.). These results indicate that vanadate produces a direct PIT in ventricular cardiac muscle which is unlikely to be mediated by alpha- or beta-adrenoceptor stimulation. In cat left atrial strips, however, vanadate ions produced a negative inotropic effect through a hitherto unknown mechanism. Vanadate effects similar to those observed in the cat heart were obtained in ventricular and atrial preparations from bovine hearts.

Animals↗

PubMedDate not supplied

Effects of vanadate on the c-AMP system of the heart.

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Adenylyl Cyclases↗

PubMedDate not supplied

New positive inotropic agents acting by phosphodiesterase inhibition or alpha 1-adrenergic stimulation.

New knowledge and insight into cardiac muscle physiology and pharmacology together with the development of novel drugs may change the treatment of congestive heart failure in the future. This article reviews two newer inotropic mechanisms currently under investigation. It will place special emphasis on the mechanisms of action of selective cardiac phosphodiesterase inhibition and of alpha 1-adrenoceptor mediated stimulation of the phosphoinositide pathway.

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Effect of dacron wool filtration on microembolism in extracorporeal circulation.

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Autopsy↗