Altered effect of BAY K 8644 after exposure of the rat aorta to IBMX or Db cAMP.

The development of isometric tension of aortic rings from rats was tested after cumulative administration of BAY K 8644 before and after exposure of the aortic preparations for 15 or 60 minutes to IBMX (10(-4) M) or Db cAMP (3.10(-4) M). BAY K 8644 exhibits dose-dependent contractions of those aortic rings which have not been exposed or have been exposed for only 15 minutes to IBMX or Db cAMP. BAY K 8644 application, after an exposure time of 60 minutes of the aortic rings to either IBMX or Db cAMP, resulted in a dose-dependent relaxation. This relaxing effect is counteracted by elevation of KCl (15 mM) in bath solution but was not changed by norepinephrine. The results indicate that long time exposure of the aortic rings to compounds capable of elevating intracellular cAMP level might induce changes of Ca channel gating.

Decreased contractile response after exposure of the rat aorta to Db cAMP or IBMX.

Isometric tension developed by different receptor agonists was found to be decreased after pretreatment of rat aortic rings with IBMX or Db cAMP and only partially restored by CaCl2 and A 23187. The contraction produced by Bay k 8644 was converted into dose-dependent relaxation after pretreatment of the aorta rings with Db cAMP or IBMX. An alteration of the calcium channel is assumed to play a common role in the cAMP-dependent inhibition of the smooth muscle contraction.

Signal transfer in cardiac muscle. Alteration of the beta-adrenoceptor adenylate cyclase system in the hypertrophied myocardium.

The beta-adrenoceptor adenylate cyclase complex (beta ACR), located in the sarcolemmal membrane, is one of the most effective signal transduction systems regulating function and metabolism of heart muscle primarily via cyclic AMP. It is thought to play an important role in adaptive mechanisms of the heart as to pressure load and stressful stimuli. Present knowledge about composition and function of beta ARC enable us to clear up which of the single components of this system contributes to pathophysiological alterations of heart function. Cardiac beta ARC was investigated in three experimental groups: I) adult rats of WKY strain (WKY), II) adult rats of WKY strain cardiac hypertrophy in which was induced by aortic constriction (WKYAC), and III) adult spontaneously hypertensive rats (SHR). Quantitative assessment of beta-adrenoceptor number (beta AR) as revealed by [3H]dihydroalprenolol binding studies showed a significant reduction to 30% and 35% of control beta AR in membrane preparations of WKYAC and SHR, respectively. The diminished density of myocardial beta AR was accompanied by a reduction of the maximum stimulatory effect of 1(-)adrenaline on adenylate cyclase (AC). Evidence was obtained for a close correlation between the diminished response of beta ARC to beta AR-mediated stimuli and the heart index as measure of cardiac hypertrophy. No correlation between graduated states of hypertrophy and activation of AC has been observed by NaF and Gpp(NH)p. The results indicate that in rat hearts severe hypertrophy of which was induced by pressure-load, mainly the beta AR component of the beta ARC complex contributes to the reduction of beta ARC-mediated responsiveness of the hypertrophied myocardium.

Oscillation of cyclic AMP with the heart cycle of the canine myocardium in situ.

Oscillations of cyclic AMP with the cardiac cycle were demonstrated in the canine heart in situ. For tissue sampling an ECG(R-wave)-triggered, automatically working push-freeze-drill apparatus was employed which allowed intraventricular cryobiopsies from the left ventricular muscle of anaesthetized open-chest dogs. The nucleotide cyclic AMP oscillated with the cardiac cycle during normal working conditions, the higher cyclic AMP values occurring during systole. Cyclic GMP was assayed to be without oscillatory changes during the contraction-relaxation cycle of the heart.

Time parameters of contraction of inotropically responding cultured heart cells in relation to cellular cyclic AMP levels.

Television video microscopy combined with photoelectric recording was used to determine the influence of a number of positive inotropic agents on the amplitude (peak height) and the course of the contraction of electrically paced myocytes in 4-day monolayer cultures derived from the heart ventricles of 1 to 2-day old rats. Cyclic AMP was determined in parallel cultures of the same cell population. Reductions in time to 90% of peak height, 90% of relaxation time, and duration of contraction caused by peak height-augmenting concentrations of isoproterenol, epinephrine, dibutyryl cyclic AMP, and 1-methyl-3-isobutylxanthine, but not of theophylline, correlated with rises in cellular cyclic AMP levels. Ouabain, a rise in extracellular CaCl2, and, in some experiments, phenylephrine in the presence of propranolol increased peak height, but did not change time to 90% of peak height, 90% of relaxation time, duration of contraction, and cyclic AMP content. These responses are compared to those observed by other authors in intact cardiac muscle and are discussed in the light of evidence linking increased myocardial cyclic AMP levels with an abbreviation of systole.

Antagonism by guanosine 3',5'-cyclic monophosphate derivatives against the action of adrenaline on the automaticity of isolated rat heart muscle cells in culture.

Spontaneously and rhythmically beating single cells from the ventricles of new-born rats were cultured on coverslips for 3 to 4 days and transferred to a small perfusion chamber for photoelectric recording of their contractions. The cells responded to 3 - 10(-7) M adrenaline with a pronounced increase and to 1.7 - 10(-5) M carbamylcholine with a mode-rate decrease in the rate of beat. Carbamylcholine nearly abolished the beat-accelerating effect of adrenaline. 8-Bromo cyclic GMP and N2-2'-O-'DIBUTYRYL CYCLIC GMP, in concentrations of 4.2 to 8.4 - 10(-4) M, exerted only very slight depressant effects on the basal rate of beat, but strongly antagonized, and in the majority of experiments with 8-bromo cyclic GMP completely suppressed, the positive chronotropic action of adrenaline. Cyclic GMP, 5'-GMP, and 5'-guanylylimidodiphosphate were without effect. 8-Bromo cyclic AMP caused a marked acceleration of beating. In view of the mediator roles that cyclic AMP and cyclic GMP have been assigned in the cardiac actions of beta-adrenergic and of cholinergic agents, respectively, the present results may be interpreted as being indicative of an adrenergic-cholinergic antagonism at the level of these two cyclic nucleotides.

[Restoration of the automatic contractile activity of K+-arrested heart muscle cells in culture by means of dibutyryl-3', 5'-adenosine monophosphate]. / Wiederherstellung der automatischen kontraktilen Tätigkeit K+-gelähmter Herzmuskelzellen in Kultur durch Dibutyryl-3', 5'-adenosinmonophosphat

Cultured myocardial cells of new-born rats which were arrested by 17.6-37.6 mM KCl regained their ability to contract spontaneously after perfusion with 8-10(-4)-4-10(-3) M dibutyryl cyclic AMP. This adrenaline-like action of DbcAMP is compatible with the notion that cyclic AMP is involved as a second messenger in the action of cyclic AMP-raising adrenergic agents on cardiac activity.