The inotropic and chronotropic effects of catecholamines on the dog heart

1. The chronotropic and inotropic responses of the denervated dog heart to intravenous infusions of noradrenaline, adrenaline and isoprenaline were studied.

2. The maximum rate of rise of pressure in the left ventricle of the heart, (dP/dt max) measured at a constant heart rate and mean systemic arterial pressure during each series of infusions, was used as an index of inotropic changes (Furnival, Linden & Snow, 1970).

3. The order of potency of the catecholamines in producing both chronotropic and inotropic effects was isoprenaline > adrenaline > noradrenaline.

4. For the same increase in heart rate produced by an infusion of a catecholamine, noradrenaline caused a greater inotropic effect than adrenaline, which in turn caused a greater increase than isoprenaline.

5. The chronotropic and inotropic effects of noradrenaline were potentiated by an intravenous injection of cocaine HCl (5 mg/kg), whereas those of isoprenaline were unchanged.

6. The relative difference between the responses to noradrenaline and isoprenaline was abolished by an intravenous injection of cocaine HCl.

7. It is concluded that the different relative chronotropic and inotropic effects of isoprenaline and noradrenaline are due to the greater uptake of noradrenaline by sympathetic nerve endings in the sinu-atrial node than in the muscle of the left ventricle.

     

Relaxing effect of pharmacologic interventions increasing cAMP in rat heart

The relationship between cAMP and relaxation was studied in the isolated rat heart beating at constant rate and perfused at constant coronary flow. After treatment during 1 min with different positive inotropic interventions, cyclic nucleotide levels (cAMP and cGMP) and cAMP-dependent protein kinase activity were determined in heart homogenates. Glucagon, norepinephrine, and isoproterenol increased cAMP from 0.503 +/- 0.025 pmol/mg wet wt to 1.051 +/- 0.099, 0.900 +/- 0.064, and 0.982 +/- 0.138, respectively. Simultaneously glucagon, norepinephrine, and isoproterenol increased cAMP-dependent protein kinase activity ratio from 0.21 +/- 0.02 to 0.45 +/- 0.04, 0.33 +/- 0.02, and 0.34 +/- 0.02, respectively. The ratio between maximal velocities of contraction and relaxation (+T/-T) was significantly decreased by these interventions, whereas time to peak tension (TTP) was shortened by norepinephrine and isoproterenol. High calcium, ouabain, and paired stimulation did not affect cAMP levels, TTP, or +T/-T. A striking correlation was found between cAMP-dependent protein kinase activity and relaxation induces, i.e., TTP, -T, or +T/-T (r = +/- 0.7 to -0.9). Results suggest that inotropic interventions increasing cAMP levels might be primarily affecting intracellular mechanisms causing relaxation.     

Lymphatic vessels of the mammalian heart

An in situ heart lung preparation was developed to label lymphatics of the actively beating dog heart with subsequent fixation by vascular perfusion. Immediately after interstitial injections of trypan blue and colloidal carbon, a rich plexus of lymphatic vessels was visualized in the epicardium of the actively beating heart. With this method of fixation, tissue preservation is generally excellent and uniform throughout the heart. In thin sections examined with the electron microscope, lymphatic vessels are easily recognized by the content of plasma proteins which is preserved as an electron dense precipitate that is evenly dispersed throughout the lumen. An extensive plexus of thin walled lymphatic vessels is observed throughout the epicardial, myocardial and subendocardial regions. Numerous anchoring filaments are observed closely apposed to the abluminal endothelial surface which extend into the surrounding connective tissue. The distribution and ultrastructure of the cardiac lymphatic vessels are discussed in relation to their role in the removal of interstitial fluid from the heart.     

Adenosine as inhibitor of myocardial effects of catecholamines

Summary Infusion of adenosine into the coronary arteries of isolated guinea pig hearts produced a dosedependent inhibition of dP/dt_max caused by bolus injections of isoproterenol (4×10^–11 moles). Threshold concentration of adenosine was 10^–7 M and maximal inhibition (90%) occurred at 10^–5 M. Coronary dilation induced by, papaverine did not influence the contractile response to catecholamines. In addition to its influence on cardiac performance, adenosine (10^–5 M) effectively inhibited the isoproterenol (10^–7 M) induced initial rise in myocardial levels of cyclic 35-AMP, glucose-1-phosphate and glucose-6-phosphate. Adenosine also antagonized the effect of isoproterenol on adenylate cyclase activity in a crude membrane preparation from guinea pig ventricles; it was without effect on the activity of the membrane phosphodiesterase. Theophylline inhibited the actions of adenosine both on adenylate cyclase activity and on contractile force development.-Upon infusion of isoproterenol (3×10^–7 M) into the coronary arteries of the isolated heart (perfusion at constant pressure), the adenosine concentration in the effluent perfusate increased within 45 s from 10^–8 M to about 10^–6 M. It thus appears conceivable that in ventricular myocardium endogenously formed adenosine may serve 2 functions: dilation of the coronary arteries and limitation of the inotropic and metabolic effects of catecholamines.A preliminary report of these studies was presented at the 47th Meeting of the German Physiological Society in Regensburg, Germany [Pflügers Arch.365, R4 (1976)]     

Direct effects of various catecholamines on liver circulation in dogs.

As measured by electromagnetic blood flow transducers, direct infusion of epinephrine, norepinephrine, and dopamine into the portal vein (PV) produced a 40-50% decrease in hepatic arterial (HA) blood flow; isoproterenol increased HA flow by about 69%. No changes in PV flow or pressure were observed. Direct HA infusion of the vasoconstrictors decreased HA flow by amounts comparable to those occurring after PV infusion. However, HA infusion of isoproterenol increased HA flow only 15% suggesting a difference in beta-receptor population in the two vessels. When infused directly into the superior mesenteric artery (SMA), epinephrine and norepinephrine reduced SMA flow by about 45% and PV flow by 20-25%; HA flow increased 6-8%. Infusion of isoproterenol and dopamine into SMA increased SMA flow by 115% and 206% and PV flow by 60% and 70%, respectively, whereas HA flow decreased by 25% and 50%. Portal vein pressure increased less than 3 mmHg. Alpha- and beta-receptor blockade of the liver did not change significantly the alterations in hepatic arterial blood flow that were secondary to changes in portal venous blood flow. It is likely that regulation of hepatic arterial flow resides in mechanisms located within the liver sinusoids.     

Kinetics of heart rate and catecholamines during exercise in humans

Summary To elucidate the role of factors other than the nervous system in heart rate (f _c) control during exercise, the kinetics off _c and plasma catecholamine concentrations were studied in ten heart transplant recipients during and after 10-min cycle ergometer exercise at 50 W. Thef _c did not increase at the beginning of the exercise for about 60 s. Then in the eight subjects who completed the exercise it increased following an exponential kinetic with a mean time constant of 210 (SEM 22) s. The two other subjects were exhausted after 5 and 8 min of exercise during whichf _c increased linearly. At the cessation of the exercise,f _c remained unchanged for about 50 s and then decreased exponentially with a time constant which was unchanged from that at the beginning of exercise. In the group of eight subjects plasma noradrenaline concentration ([NA]) increased after 30 s to a mean value above resting of 547 (SEM 124) pg · ml^–1, showing a tendency to a plateau, while adrenaline concentration ([A]) did not increase significantly. In the two subjects who became exhausted an almost linear increase in [NA] occurred up to about 1,300 pg · ml^–1 coupled with a significant increase in [A]. During recovery an immediate decrease in [NA] was observed towards resting values. The values of thef _c increase above resting levels determined at the time of blood collection were linearly related with [NA] increments both at the beginning and end of exercise with a similar slope, i.e. about 2.5 beats · min^–1 per 100 pg · ml^–1 of [NA] change. These findings would seem to suggest that in the absence of heart innervation the increase inf _c depends on plasma [NA].     

Chromaffin tissue and sources of catecholamines in the vertebrate heart

Summary The myocardium of all the classes of vertebrate animals, excluding the cyclostomata, contains no chromaffin tissue. Muscular fibers of the cyclostomata heart are slightly chromaffin reactive. No chromaffin elements are contained in the anervous heart of chick embryos.In the authors' opinion one of the sources of catecholamines in the heart is the muscular tissue itself.Presented by Active Member AMN SSSR D. A. Biryukov Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 59, No. 1, pp. 98–100, January, 1965     

The heart rate response to exercise and circulating catecholamines in heart transplant recipients

The plasma concentration of noradrenaline ([NA]) is higher than that of adrenaline ([A]) both in normal subjects and in heart transplant recipients (HTR). Since in both groups the myocardial density of beta1-adrenergenic receptors is much greater than that of beta2-adrenergenic receptors, the chronotropic response of a denervated heart to changes in plasma [NA] and [A] in the absence of reinnervation should be similar to that of agonist stimulation of beta1-receptors. To test this hypothesis, 17 HTR and 9 healthy subjects (CTL) performed incremental exercise on a cycle ergometer to voluntary exhaustion. Heart rate (HR) was recorded by electrocardiography. [NA] and [A] were measured by high-pressure liquid chromatography at rest and at increasing workloads (w). In both groups, HR and [NA+A] increased with w, and HR with [NA+A]. Normalized HR values, plotted against the logarithm of [NA+A], fitted significantly logistic curves. The affinity constants were different, i.e. 2599+/-350 and 487+/-37 ng.l(-1), for HTR and CTL, respectively. The chronotropic effect of changes in [NA+A] in HTR was similar to that of combined beta1- and beta2-adrenergic activation evoked by applying isoprenaline to isolated heart myocytes (Brodde OE, Pharmacol Ther 60:405-430, 1993). These findings suggest that over time sympathetic reinnervation and the modulation of beta-receptors may take place in HTR, ruling out the hypothesis of persistent heart denervation.     

The effects of ultracentrifugation on the mammalian erythrocyte

Pieces of rat spleen were subjected in an air turbine ultracentrifuge to a force of approximately 400,000 times gravity for periods varying from one-half to one hour. They were immediately fixed for study with both the light and electron microscopes. Stained preparations show a displacement and stratification of materials within the erythrocytes. The stratified layers are probably components of the stroma which differ in their relative specific gravities and staining reactions. The chemical nature of the different layers has not been determined, but their relative volumes are indicated by the dimensions of the layers. Electron micrographs show some effects of the ultracentrifugation such as stretching and the concentration of more dense material in the centrifugal halves of the cells, but a clear cut demonstration of the three stratified layers observed in Mallory's triple stained preparations is not evident. Except for the plasma membrane and a finely granular interior of the erythrocyte, little other structure is revealed within it, especially concerning the nature and distribution of the stroma.