Mechanism of self-regulation and the inotropic reaction of the rat myocardium during aging

The experiments on rat papillary muscles revealed that in ageing rats myocardium has a decreased distension ability. The curves of shortening value/length and force/velocity for the myocardium of old animals are shifted downwards. The alterations in isotonic contraction parameters had a distinct age differentiation, while the age did not affect the inotropic effects of increased frequency, paired stimulation and external calcium. It is suggested that changes in biomechanical properties of ageing myocardium are associated with alterations in calcium transport in sarcoplasmic reticulum.     

Pharmacokinetic analysis of alpha- and beta-adrenoreceptors in the chick embryo amnion

Following a stimulation with acetylcholine, the beta-adrenergic agonists adrenaline (A), noradrenaline (NA), isoproterenol (Iso) and salbutamol (Sal) induced a concentration-dependent decrease in the tone and (or) rate of amnion contraction with EC50 ISO < NA < A < Sal. Metaprolol, a specific beta 1-antagonist, induced a rightward shift in the dose-response curves of Iso, NA and A, whereas beta-antagonist butoxamine was ineffective. pA2 values for beta-antagonists were propranolol 8.3, metoprolol 7.0, butoxamine 5.6. EC50 values of alpha-adrenergic agonists form a sequence: clonidine < NA < methoxamine < phenylephrine. Specific alpha-antagonists yohimbine and idazoxan were found to antagonise competitively the effects of NA. The data obtained characterize the adrenergic receptors mediating stimulation of amniotic contractile activity as alpha 2-adrenergic receptors. Inhibition of contractile receptors in amnion is mainly mediated by beta 1-adrenergic receptor activation.     

The combained effects of the long-term gamma-irradiation and heavy metall ions on the haematopoietic system of rats

The combiened effects of different dose rates (0.625 microGy/s - 1.1 mGy/s) of gamma-irradiation and of cuprum and of cadmium ions on the haematopoietic system of rats were studied. It was found that only low dose rates (0.625-10 microGy/s, summary doses 0.5-2.0 Gy) of gamma-irradiation yields in the increasing proliferative activity of bone marrow. The number of myelocariocytos in S-phase was increased at 1.5-1.8 times. In case of the treatment with both cadmium chloride and radiation the changes in proliferative activity of bone marrow are completely due to the radiation factor. Combination of cuprum acetate and ionizing radiation induce opposite effects providing formal normalization of the haematopoietic characteristic of bone marrow up to 3, 6 and 12 months after the end of the radiation and the chemical exposure of the animal.     

The inotropic memory of amphibian myocardium.

(1) Experimentally observed changes of contractile force induced by changes in the pattern of stimulation of frog ventricular myocardium were compared with predictions computed on the basis of a model for the contractile conditioning, proposed in a previous paper. (2) For this purpose, two functions (Potentiation and Inhibition) which describe in the model the effect of previous contractions, were determined experimentally. (3) It is shown that the model adequately predicts : force-frequency curve Inotropic Effect Curves at different basal frequencies, effect of the suppression of a contraction in a sequence of definite frequency, frequency-staircases, and strength-interval curves. (4) The formal characteristics of the model are discussed, and it is suggested that the potentiation mechanism results from the recirculation of activator calcium in two types of compartments, from which calcium passes to the myofilaments during the contractions or is lost to the exterior with first order kinetics during the rest period. Possible locations for these compartments are proposed. Various hypothesis on the nature of the inhibitory mechanism are considered.     

Modification of the chronotropic-inotropic relations in the atrial and ventricular myocardium during external gamma-irradiation

It has been shown of isolated muscle preparations of rat heart that external gamma-irradiation with a dose of 6 Gy reduces the contractile capacity of myocardium and changes the chronoinotropic relationships: in the auricle, the rate/power relationship and the potentiating effect of the passive interval increase, and in the ventricles, the potentiating effect decreases. Modification of the chronoinotropic relationships may be associated with changes in the calcium ion transport in the heart cells.     

Mechanism of the negative inotropic effects of alpha 1-adrenoceptor agonists on mouse myocardium

This study was done to identify the mechanism of the alpha1-adrenoceptor (AR) mediated negative inotropic effects of phenylephrine (PE) on adult mouse myocardium. As reported by others, we also found that the nonselective alpha1AR agonist PE produced a negative inotropic effect on ventricular strips from adult mice that was inhibited by the alpha1AAR antagonist 5-methylurapidil (5MU) but not by the alpha1BAR antagonist chloroethylclonidine (CEC) or the alpha1DAR antagonist BMY 7378. The selective alpha1AAR agonist A61603 also produced a negative inotropic effect, which was antagonized by 5MU. Phorbol 12,13-dibutyrate (activator of all PKC isoforms) mimicked the negative inotropic responses to PE and A61603. The negative inotropic effects of PE were inhibited by bisindolylmaleimide (inhibitor of all PKC isoforms) but not by G? 6976 (inhibitor of Ca2+-dependent PKC). Rottlerin, an inhibitor of Ca2+-independent PKCdelta, antagonized the negative inotropic effects of PE and A61603. PE and A61603 increased the translocation of PKCdelta, which was prevented by rottlerin. These data suggest that the alpha1AR-mediated negative inotropy on adult mouse myocardium is signaled by Ca2+-independent PKCdelta.     

Age-related changes in inotropic effects of noradrenaline and acetylcholine on the myocardium of guinea pigs]

The inotropic effects of noradrenaline (10(-7)-10(-5) M) and acetylcholine (10(-8)-10(-6) M) were studied in experiments carried out on preparations of the right atria and on papillary muscles of the right ventricle in adult (4-5 months) and old (18-24 months) guinea pigs. An age-related decrease in inotropic noradrenaline effects and the displacement of dose-effect relationships to the right was revealed. Similar changes of the dose-related effects of acetylcholine superfused against the background of noradrenaline action were observed. The direct inotropic action of the acetylcholine did not change with ageing. A lack of the essential atrial-ventricular differences in age-related changes in myocardial reactivity is apparently very significant for support of effective functional coupling of cardiac chambers in ageing.     

Mitotic activity of regenerating rat liver following stimulation with alpha- and beta-adrenoreceptors

A study was made of the effect of stimulating alpha- and beta-adrenoreceptors on the mitotic activity of the rat regenerating liver following resection. Mesaton, a stimulator of alpha-adrenoreceptors, and isadrin, a stimulator of beta-adrenoreceptors, in a dose of 0.2 mg/kg were injected one hour before liver resection or 30 min, 8 and 24 h after operation. In all experimental groups, mesaton gave rise to an increase in the mitotic index without lowering the coefficient of the mitotic phases. The least pronounced stimulating effect was attained when mesaton was injected 9 hours after partial hepatectomy. Isadrin reduced the mitotic activity as judged from the decrease of the coefficient of the phases and augmentation of the number of binuclear cells. The experiments confirmed a previously advanced assumption that stimulation of alpha-adrenoreceptors favours while that of beta-adrenoreceptors reduces cell proliferation.     

The effects of short-term hypoxia on motor cortex excitability and neuromuscular activation.

The effects of acute hypoxia on motor cortex excitability, force production, and voluntary activation were studied using single- and double-pulse transcranial magnetic stimulation techniques in 14 healthy male subjects. Electrical supramaximal stimulations of the right ulnar nerve were performed, and transcranial magnetic stimulations were delivered to the first dorsal interosseus motor cortex area during short-term hypoxic (HX) and normoxic (NX) condition. M waves, voluntary activation, F waves, resting motor threshold (rMT), recruitment curves (100-140% of rMT), and short-interval intracortical inhibition and intracortical facilitation were measured. Moreover, motor-evoked potentials (MEPs) and cortical silent periods were determined during brief isometric maximum right index finger abductions. Hypoxia was induced by breathing a fraction of inspired oxygen of 12% via a face mask. M waves, voluntary activation, and F waves did not differ between NX and HX. The rMT was significantly lower in HX (55.79 +/- 9.40%) than in NX (57.50 +/- 10.48%) (P < 0.01), whereas MEP recruitment curve, short-interval intracortical inhibition, intracortical facilitation, maximum right index finger abduction, and MEPs were unaffected by HX. In contrast, the cortical silent periods in HX (158.21 +/- 33.96 ms) was significantly shortened compared with NX (169.42 +/- 39.69 ms) (P < 0.05). These data demonstrate that acute hypoxia results in increased cortical excitability and suggest that acute hypoxia alters motor cortical ion-channel function and GABAergic transmission.     

Development of long-term radiation effects in rats after whole-body fractionated gamma-irradiation

Albino male rats were divided into four groups and exposed to gamma-radiation (137Cs) for 80, 40, 20 and 10 days at dose rates of 0.25, 0.5, 1.0 and 2.0 Gy/day, respectively. The development of lesions and remote aftereffects was shown to depend upon conditions of formation of the absorbed dose. With fractionated irradiation at dose rates above 1.0 Gy/day the dose-rate played a major role in producing the effect.     

Thiol reactivity and the molecular individuality of alpha- and beta-adrenoreceptors in rat liver plasma membranes.

Whether or not alpha- and beta-adrenoreceptors are non-identical binding sites on the same protein is still an open question. We investigated the effects of sulfhydryl reagents and dithiothreitol on the binding of [3H]dihydroalprenolol and [3H]dihydroergocryptine to beta- and alpha-adrenoreceptors of rat liver plasma membranes. Dithiothreitol inhibited the binding of [3H]dihydroalprenolol to the beta-adrenoreceptor, whereas it had no effect on the specific binding of [3H]dihydroergocryptine to the alpha-adrenoreceptor. In contrast, mersalyl, a mercurial SH reagent, readily blocked the alpha-adrenoreceptor and, although to a lesser extent the beta-adrenoreceptor. The interaction of mersalyl with the alpha-adrenoreceptors was almost instantaneous. In contrast, under the same experimental conditions, the inactivation of the beta-adrenoreceptors was much slower (t 1/2 : 7 min). Finally, a marked difference in the accessibility of the SH groups to mersalyl was observed between the alpha- and beta-adrenoreceptors. The presence of 15 microM (-)-epinephrine or 1.5 microM phentolamine was sufficient to prevent the blockade of the alpha-adrenoreceptor by mersalyl, but inactivation of the beta-adrenoreceptor by mersalyl was not modified by 500 microM (-)-epinephrine and was only slightly decreased by 50 microM (-)-propranolol. Thus, the alpha- and beta-adrenoreceptors from rat liver plasma membranes exhibited biochemical differences which may be interpreted in favor of their molecular individuality.     

Effect of preliminary blockade of alpha- and beta-adrenoreceptors on stress-induced disorders of myocardial relaxation and contractile functions

Effect of preliminary administration of the alpha-adrenoblocker phentolamine and the beta-adrenoblocker inderal on stress-induced disturbances of myocardial extensibility, contractile function and myocardial resistance to hypoxia and excess Ca2+ was studied on an isometrically contracting isolated right atrium of the rat. Inderal substantially prevented the post-stress decrease in atrial extensibility and almost completely prevented the stress-induced decline in the developed tension and the Frank-Starling mechanism efficiency. At the same time inderal prevented the post-stress increase in hypoxic and hypercalcium contracture of the atrium. Phentolamine did not produce any such protective effects. It is suggested that the damaging action of catecholamine excess occurring under stress is mediated via beta-adrenoreceptors but not via alpha-adrenoreceptors of the heart.     

The effects of glycoprotein modification on beta-adrenoreceptors binding ability in rat cardiac membranes

The present study was designed to test the effects of neuraminidase and some proteolytic enzymes on the binding of 125I-HYP (hydroxybenzylpindolol) to beta-adrenoreceptors of rat cardiac membranes. The influence of some S-S and -SH active agents on the ligand binding used was also examined. The decrease in membrane sialic acid content did not alter the binding of ligand used. The degradation of membrane protein by proteases resulted in a time and enzyme type dependent decrease in the binding of 125I-HYP. It was found that the dithiotreitol pretreatment produced more profound decrease in ligand binding than reduced glutathione. Cysteine and mercaptoethanol were ineffective. The effect of dithiotreitol was dependent on the time of preincubation and on the agent concentration used. The decrease in ligand binding was also observed after the alkylation of -SH groups by iodoacetamide and N-ethylmaleimide.