Alpha and beta adrenergic control of contraction force of perch heart (Perca fluviatilis) in vitro

Noradrenaline showed a negative inotropic effect on the isolated electrically triggered atrium of the perch. The effect was stronger at lower temperature and was antagonized by an alpha adrenergic blocker, phentolamine. The inotropic effect of adrenaline was dependent on incubation temperature. The effect was negative at 15 C but biphasic at 24 C, where with increasing adrenaline concentration a positive inotropic effect was followed by negative inotropy. Phentolamine not only antagonized the negative inotropic effect of adrenaline at 15 degrees C but changed it to positive. This positive inotropic effect was antagonized by a beta adrenergic blocker, propranolol. On the triggered ventricular strip adrenaline had no effect at 6 or 15 C, but increased contraction force at 24 C. It can be suggested that in the perch heart atrium there is an activity balance of alpha and beta receptors, which mediate the negative and positive inotropic control, respectively. As in higher vertebrates, alpha adrenergic activation decreases and beta activation increases by agonists in the following order: noradrenaline, adrenaline and isoprenaline. The balance changes towards increased beta activity when temperature rises.     

Role of endogenous adrenaline in cardiac arrhythmia induced by dichlorodifluoromethane (FC 12) in mammals]

During the inhalation of normally oxygenated gas mixtures containing light or middle concentrations of FC 12, the presence of perfused epinephrine is necessary to induce cardiac arrhythmia in rabbits and dogs. The only inhalation of normally oxygenated gas mixtures containing a very high concentration of FC 12 produces in rabbits and dogs an important decrease in arterial pressure, tachycardia, a fall in respiratory amplitude, an acceleration reflex of respiratory frequency and cardiac arrhythmia. The same experiments in baro and chemodenervated animals show that : respiratory depression due to FC 12 still occurs, but not through the arterial chemoreceptors ; tachycardia has a reflex origin : barodenervation reveals the negative chromotropic effect of FC 12 and increases the fall in arterial pressure, mainly due to the negative inotropic effect of FC 12 ; adrenaline is necessary for FC 12-induced arrhythmia : barodenervation suppresses tachycardia due to the release of endogenous epinephrine and abolishes any arrhythmia.     

Adrenergic responses of the cardiovascular system of the eel, Anguilla australis, in vivo

Heart output, arterial pressures, and heart rate were measured directly in conscious unrestrained eels (Anguilla australis) and responses to intra-arterial injection of adrenaline monitored. Adrenaline increased systemic vascular resistance, heart output, and cardiac stroke volume in all animals. In some cases small transient decreases in stroke volume and hence heart output were seen at the peak of the pressor response: These probably reflect a passive decrease in systolic emptying due to increased afterload on the heart. In most cases, adrenaline produced tachycardia; but two animals showed consistent and profound reflex bradycardia, which was accompanied by a concomitant increase in stroke volume such that heart output was maintained or increased slightly. The interaction of changes in heart output and systemic vascular resistance produced complex and variable changes in arterial pressure. There was no consistent pattern of changes in branchial vascular resistance. Atropine treatment in vivo revealed vagal cardio-inhibitory tone in some animals and always blocked the reflex bradycardia seen during adrenaline induced hypertension. In some animals, adrenaline injection after atropine pretreatment led to the establishment of cyclic changes in arterial pressure with a period of about 1 min (Mayer waves).     

Role of the endothelial glycocalyx in dromotropic, inotropic, and arrythmogenic effects of coronary flow

Coronary flow regulates cardiac functions, and it has been suggested that endothelial membrane glycosylated proteins are the primary shear stress mechanosensors. Our hypothesis was that if these proteins are the sensors for flow, then intracoronary perfusion of lectins or specific antibodies should differentially depress coronary flow-enhanced responses of different parenchymal cell types such as auricular-ventricular (A-V) nodal cells (dromotropic effect), contractile myocytes (inotropic effect), and junctional Purkinje-muscle cells (spontaneous ventricular rhythm). The coronary flow stimulatory effects on A-V delay and spontaneous ventricular rhythm were selectively depressed by six of eight lectins. None of the lectins depressed the coronary flow inotropic effect. Antibodies against endothelial surface proteins, alpha(v)beta(5)-integrin and sialyl-Lewis(b) glycan, depressed the dromotropic but not the inotropic effects of coronary flow, whereas the vascular cell adhesion molecule 1 antibody had no effect on the dromotropic, but enhanced the inotropic, effect. The fact that lectins and antibodies differentially depressed regional coronary flow effects suggests that there is a chemical distinctiveness in their intravascular endothelial cell surfaces. However, nonselective cross-linking of endothelial glycocalyx proteins with 2,000-kDa dextran-aldehyde or vitronectin indistinctively depressed the dromotropic and inotropic effects of coronary flow. These results indicate that coronary flow-induced stress acts on specific structures located in the capillary intravascular membrane glycocalyx.     

Role of NO-mediated mechanisms in post-irradiation changes of neurohormonal regulation of the heart function

Investigations on isolated Langendorff-perfused rat heart have shown that after the impact of ionizing radiation in 1 Gy dose the myocardial contractility and relaxation are decreased. The inhibition of NO synthesis attenuates chrono- and inotropic responses of the heart and reaction of coronary vessels to norepinephrine (NE), increases negative inotropic and vasoconstrictor effects of carbamylcholine (CCh). In the irradiated animals the reaction of isolated heart to NE and CCh is decreased. The post-irradiation changes in adreno- and cholinoreactivity caused not only by changes in receptor sensitivity and density, but also by impairment of NO-mediated regulation of coronary flow and biomechanical heart function.     

Pathophysiological plasma ET-1 levels antagonize beta-adrenergic dilation of coronary resistance vessels in conscious dogs

On the basis of in vitro experiments showing that endothelin (ET)-1 interferes with smooth muscle ATP-sensitive K(+) (K(ATP)) channel opening, which is pivotal in beta-adrenergic coronary dilation, we hypothesized that pathophysiological plasma ET-1 levels impair beta-adrenergic dilation of resistance coronary vessels. In conscious instrumented dogs, graded intravenous doses of dobutamine caused the expected inotropic responses. As myocardial O(2) consumption (MVo(2)) increased, the disproportionate rise in coronary sinus (CS) Po(2) indicates that increases in coronary blood flow (CBF) exceeded metabolic requirements, consistent with beta-adrenergic dilation. ET-1 intravenous infusions, to reach pathophysiological plasma levels, reduced slopes of the Po(2)-MVo(2) and CBF-MVo(2) relations. In contrast, the first derivative of left ventricular pressure over time responses to dobutamine were not impaired during ET-1 delivery. Clazosentan, an ET(A) receptor blocker, prevented reduction of the slope of Po(2)-MVo(2) and CBF-MVo(2) relations. After ganglionic blockade to exclude reflex influences, ET-1 still reduced slopes of Po(2)-MVo(2) and CBF-MVo(2) relations. To assess effects of ET-1 on endothelium-dependent and -independent coronary vascular responses, intracoronary ACh and nitroglycerin were given to directly target coronary vessels. CBF responses to ACh and nitroglycerin were maintained during ET-1 delivery. In contrast, responses to intracoronary K(ATP) channel-dependent dilators adenosine and lemakalim were impaired by ET-1. In conclusion, pathophysiological levels of ET-1 impaired beta-adrenergic dilation of resistance coronary vessels through an ET(A) receptor-dependent process. In contrast, left ventricular inotropic responses to dobutamine were not impaired during ET-1 delivery. Our data suggest that ET-1 may interfere with smooth muscle K(ATP) channels to impair beta-adrenergic coronary dilation.     

Effects of hypoxaemia and hyperoxaemia on some cardiovascular responses of rats to adrenaline

Systemic blood pressure and pulse rate responses to intravenously administered adrenaline during hypoxaemia or hyperoxaemia were studied in urethane-anaesthetized rats. Hypoxaemia or hyperoxaemia was induced by ventilating the animals with 15% O2/85% N2 or with 100% O2, respectively. Hypoxaemia significantly decreased the diastolic blood pressure and elevated the pulse rate; the reflex falls in pulse rate in response to adrenaline were significantly reduced. Hyperoxaemia, on the other hand, did not cause remarkable changes in blood pressure or pulse rate, but significantly depressed diastolic blood pressure to adrenaline. It is suggested that the compensatory cardiovascular reflexes may be impaired by hypoxaemia, and that hyperoxaemia reduces vasoconstrictor response to catecholamine possibly by lessening or enhancing the sensitivities of the vascular alpha 1- or beta 2-adrenoceptors, respectively.     

Hind limb blood flow in the brush possum (Trichosurus vulpecula)

1. In the possum (T. vulpecula) sympathetic stimulation, the baroreceptor reflex, exogenous noradrenaline and adrenaline (large dose) produce vasoconstriction in hind limb skeletal muscle. These responses are blocked by α-adrenoceptor blocking agents.2. Exogenous isoprenaline and adrenaline (small dose) produce vasodilatation which is blocked by propranolol.3. Sympathetic cholinergic vasodilator fibres do not appear to exist in the possum.4. At supramaximal frequencies of sympathetic stimulation of the hind limb vascular bed, there is less than maximal response.     

Organization of Efferent Sympathetic Influences Related to Cardiogenic Depressor Reflexes

In acute experiments on anesthetized dogs under open chest conditions, we studied characteristics of the efferent sympathetic influences on the heart and vessels related to realization of cardiogenic depressor vagus-mediated reflexes. Catheterization of the heart cavities and parallel recording of the mass efferent spike activities in the cardiac and vertebral sympathetic nerves and of the pressure in the aortic ventricle of the heart were used. We found that reflex shifts in the spike activity in the cardiac and vertebral nerves elicited by pharmacological stimulation of the left heart (intracoronary injections of veratrine or adrenaline) and by its nidal immune impairment resulting from injection of a cytotoxic serum demonstrate similar direction (a drop in the frequency of the efferent sympathetic activity). Yet, the dynamics of such inhibitory responses to the influence of the same stimulus and their intensity in one nerve or another and those in one and the same nerve under the influence of different stimuli are considerably dissimilar. Thus, realization of vagus-mediated cardiogenic reflexes is characterized by clear heterogeneity of the efferent sympathetic control of different regions of the cardiovascular system. Such a specificity can provide differential regulation of the heart function and functions of the vascular bed related to different cardiogenic influences (both in the norm and under conditions of formation of an injury nidus in the heart).     

The effects of endogenous opioids on tension development of isolated, electrically stimulated rat atria

The possible inotropic effects of all three classes of endogenous opioids were tested alone or in combination with noradrenaline, adrenaline, or carbachol on electrically stimulated atria isolated from male Sprague-Dawley rats. Noradrenaline (6.0 and 12 microM) and adrenaline (4.0 and 8.0 microM) injections caused marked but transient (5 min) dose-related increases in atrial tension compared with preinjection control values, whereas carbachol (0.14 and 1.4 microM) caused a more potent and prolonged (over 15 min) dose-related decrease in atrial tension development. Adrenal enkephalins (0.3-4.0 microM) of methionine enkephalin, leucine enkephalin, Met-enkephalin-Arg6-Phe7, and Met-enkephalin-Arg6-Gly7-Leu8, beta-endorphin (0.2-2.0 microM), or dynorphin A(1-13) (0.2-2.0 microM) did not change atrial tension for a 15-min postadministration test period. In addition, these opioids did not affect the positive inotropic effects of noradrenaline (12 microM) or adrenaline (8.0 microM) or the negative inotropic actions of carbachol (1.4 microM) when the same doses of noradrenaline, adrenaline, or carbachol were given alone. These data indicate that endogenous opioids given in micromolar concentrations tested did not affect atrial tension development of electrically stimulated rat atria. Comparing these data with those of past literature, it is suggested that circulating endogenous opioids probably do not have any direct effects on the rat myocardium to affect myocardial contractility.     

Inotropic effects of adrenaline on the anoxic or hypercapnic myocardium of rainbow trout and eel

Summary The effects of adrenaline on the development of force under anoxia and hypercapnic acidosis (13% CO₂ in 30 mM HCO ₃ ^– ) were examined in isolated, electrically stimulated cardiac ventricle strips of rainbow trout and eel.During anoxia or acidosis applied 15 min in advance, the adrenaline concentration of the bathing solution was increased in 5 steps from 0 to 10^–4 M with 5 min at each step. Before levelling off the contractile tension increased by 145±42% (mean±SE) in the anoxic, 80±14% in the acidotic and 152±41% in the control trout cardiac strips. Except for the acidotic strips the corresponding values tended to be lower for the eel strips being 46±9%, 57±17% and 57±9%, respectively. The inotropic affinity for adrenaline was lower in the trout than in the eel myocardium. For the trout myocardium it remained unchanged, while it decreased somewhat for the eel myocardium under anoxia or acidosis.Adding to the muscle bath 10^–5 M adrenaline resulted in an increase in force development by about 90% for the trout myocardium and 50% for the eel myocardium. 5 min later anoxia or hypercapnic acidosis was applied for 30 min followed by 30 min at control conditions. Relative to the force values recorded just before anoxia or acidosis was applied, the changes in contractile force during these periods were the same with and without adrenaline. Thus adrenaline appears to have a persistent positive inotropic effect in the fish myocardium during and after oxygen lack or acidosis.     

Cardiovascular response to glucagon in hypovolemic dogs.

Glucagon in a dose of 50 mug/kg body weight was studied for its cardiovascular effects in hypovolemic dogs in which coronary blood flow was reduced to an average 40% of its control value and cardiac depression was evident. Myocardial contractility, as judged mainly by dP/dt and acceleration of aortic blood flow, was brought to a normal level for a short time. Systemic and coronary vascular resistances were markedly reduced. These effects were similar in normovolemic dogs. The inotropic, chronotropic, and peripheral vascular effects of glucagon can be evoked also in hypovolemic dogs in which coronary blood flow is less than normal and myocardial metabolism is impaired.     

Histamine receptors in the human heart

Histamine receptor subtypes in $\text{in vitro}$ isolated human coronary arteries and in $\text{in vitro}$ human atrial and ventricular myocardium were studied. The H₁ receptor mediates contraction of coronary vascular smooth muscle but has no effect on atrial or ventricular tissue. The H₂ receptor mediates relaxation of human coronary artery vascular smooth muscle and mediates a positive inotropic response in atrial and ventricular myocardium.     

Early stages of experimental atheromatosis

In female Wistar rats, fed an atherogenic diet, the early changes of serum lipids and the deviation of the vasomotor response to adrenaline and acetylcholine were compared with morphological manifestations. It has been found that the first sign may be detected as the shift in serum lipoproteins and lipids just in a few days. Merging and decrease of alpha-lipoproteins and an increase of the beta-lipoprotein fraction proved as the most sensitive indicator. In the course of several weeks, an alteration of hemodynamic response to adrenaline and acetylcholine occured. The animals revealed a diminished depressoric response to acetylcholie, whereas their blood pressure response to adrenaline in the pressoric phase was decreased but the depressoric phase was markedly expressed. The morphological impairment of the vascular system followed with a delay of several months, although a lipoid infiltration of the liver appeared after 6 weeks of the atherogenic dietary regimen.     

Influence of desoxycorticosterone on the response of coronary artery segments to adrenaline in the presence of pyrogallol

The effect of desoxycorticosterone on the adrenaline-induced relaxation of coronary arteries was studied in vitro, after a known inhibitor of COMT, pyrogallol. Relaxation induced by adrenaline was enhanced by desoxycorticosterone. Relaxation in response to adrenaline was increased by desoxycorticosterone. Pyrogallol potentiated the responses of coronary strips to adrenaline and also reduced or abolished the enhancing effects of desoxycorticosterone. It is concluded that desoxycorticosterone enhances the response of coronary smooth muscle to adrenaline by inhibiting an enzymatic pathway for the inactivation of catecholamines.     

Inhibition of the cardiac inotropic effect of phenylephrine by a tetramine disulfide with irreversible alpha-adrenoceptor blocking activity.

The newly synthesized alpha-adrenoceptor blocking drug BHC (N,N'-bis[6-(10-methoxybenzyl-amino)-a-hexyl]cystamine) was found to block irreversibly the positive inotropic effect of the sympathomimetic drug phenylephrine on the isolated rat left atrium. BHC was used to test the adrenoceptor interconversion hypothesis which claims that low temperature converts inotropic beta-adrenoceptors in rat atrium and frog ventricle to alpha-adrenoceptors. There was no evidence of adrenoceptor 'interconversion.' In the rat atrium low temperature did not increase the BHC antagonism of phenylephrine and did not cause BHC to inhibit the inotropic effect of noradrenaline or isoprenaline. In the perfused frog heart low temperature did not lead BHC to inhibit the inotropic effect of phenylephrine, adrenaline, or isoprenaline.     

Redox agents modulate a(K+)0 changes evoked by acetylcholine and adrenaline in frog heart

It was observed earlier, that in the presence of oxidizing agents the acetylcholine exerted a positive ino- and chronotropic effect, while the positive ino- and chronotropic action of adrenaline was decreased. In the presence of reducing agents both the negative inotropic effect of acetylcholine and the positive inotropic action of adrenaline was increased. Analyzing the ionic mechanism background of these correlations, the changes of extracellular K(+)-activity (a(K+)0) were followed and it was established that; In relation to slow transient changes (in min time ranges) an oxidant decreased the a(K+)0 following acetylcholine, while it increased the a(K+)0 after adrenaline application. A reductant increased the a(K+)0 with acetylcholine, but decreased a(K+)0 in the presence of adrenaline. Because of the inverse character of redox modulation on a(K+)0 levels, a reverse change in a(K+)0 should be (at least one of) the site of action of the opposite effects of oxidants or reductants exerted on ino- and chronotropism of acetylcholine or adrenaline.     

Acidosis counteracts the negative inotropic effect of K+ on ventricular muscle strips from the toad Bufo marinus

Strenuous activity is associated with acidosis, increased extracellular potassium concentration ([K+]o), and elevated levels of circulating catecholamines. Acidosis and elevated [K+]o are normally considered harmful to cardiac function, and a high sympathetic tone on the heart may lead to arrhythmia. During activity, however, the heart must be able to increase rate and strength of contraction. While the individual effects of [K+]o, acidosis, and adrenaline on contractile properties of cardiac muscle have been characterized for some ectothermic species, less information is available on their interactions. Here we examine the isolated and combined effects of [K+]o, acidosis, and adrenaline on ventricular muscle strips from the toad Bufo marinus. This study showed that increased [K+]o significantly reduced twitch force, while lactic acid significantly increased twitch force and more than counteracted the negative inotropic effects of elevated [K+]o. There was no inotropic effect of Na-lactate (neutralized lactic acid), which suggests that lactic acid stimulated twitch force through reduced pH and not by serving as a substrate. Adrenaline had a positive effect on twitch force in all preparations. Irrespective of treatment, twitch force decreased as stimulation rate increased. During high [K+]o, there was a severe reduction in maximal frequency of toad ventricular strips that was not alleviated by lactic acidosis and/or adrenaline, which suggests that high [K+]o influences twitch force and maximal rate by different mechanisms. In vivo levels of lactic acid, [K+]o, adrenaline, and heart rate previously observed during forced activity in Bufo did not significantly affect the contractile properties of heart muscle strips in vitro. Thus, although [K+]o significantly decreased twitch force, this detrimental effect was more than counteracted by the positive inotropic effect of lactic acid and adrenaline.     

Interaction of inotropic effects on acetylcholine, adrenaline and increase of atrium stimulation frequency in rats adapted and non-adapted to physical exercise]

It is shown in experiments carried out on the isolated strips of the left and right atria of the rat that adrenaline decreases the inotropic effect of acetylcholine while interatrial differences of chrono-inotropy are elevated by acetylcholine and adrenaline. Training of animals changes interaction of regulatory effects in such a way that an increase of the negative chrono-inotropy is compensated and efficiency of the cardiac muscle regulation grows.     

Cardio- and hemodynamics of dogs in exposure of the heart to immune complexes

The cardiovascular effects induced by in-vitro obtained immune complexes (horse serum antigens--rabbit specific antibodies) were studied in dogs. Intracoronary administration of immune complexes was followed by the development of a hypotensive reaction, with a marked decrease in the cardiac output, left ventricle performance, and impairment of pump heart function. After administering immune complexes no marked injuries to the myocardium or depression of its contractility were recorded in the acute period of the reaction. A substantial decrease of venous blood return to the heart caused by blood pooling in the venous peripheral vascular bed underlies pump heart function impairment and the decreased cardiac output.