Effect of Phenoxybenzamine on Myocardial Cell Necroses and Blood Levels of Catecholamines in Pigs Subjected to Stress (original) (raw)
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Acta Pharmacologica et Toxicologica, 2009
The degree of myocardial cell necroses in pigs exposed to stress induced by a myorelaxant (succinylcholine) for about 12 min. was investigated. The P-adrenoceptor blocker propranolol was given in varying doses prior to the induced stress. The degree of necroses in these pigs was evaluated according to a point scale, ranging from 0 to 6 points, and compared with the changes found in untreatedcontrols following stress. The blood levels of noradrenaline and adrenaline were assayed before, during, and immediately after the period of stress. N O protective effect of propranolol on the cardiac lesions was found when the drug was administered intravenously in a single dose of either 1 mg or 3 mg per kg. During the period of stress the blood levels of noradrenaline were high, indicating a high degree of activity in the sympatho-adrenal system. Propranolol in a single dose of 10 mg per kg intravenously reduced the number and size of heart lesions, while the blood levels of the catecholamines were lower under stress than after administration of 1 and 3 mg propranolol. After oral treatment with propranolol, 120 mg three times a day for 6 or 7 days, an almost complete absence of heart cell necrosis after the stress was obtained. The activity of the sympatho-adrenal system was elevated, as reflected by the high blood levels of catecholamines. The results indicate that stress-induced heart cell necrosis is mediated via the activity of the sympatho-adrenal system. The difference between a single and repeated doses of propranolol in protecting the heart suggests a complex ation of the adrenergic P-receptor blocker.
Effect of phenoxybenzamine on the turnover rate of heart norepinephrine
Biochemical Pharmacology, 1969
CHANGES in the turnover rate of norepinephrine (NE) are a much better index of sympathetic tone than are changes in the tissue concentration of the amine, which might remain constant or even decline despite an increased rate of synthesis. Recent reviews from this laboratory have emphasized
Naunyn-schmiedebergs Archives of Pharmacology, 1982
The positive inotropic effects of catecholamines were studied on samples of ventricular myocardium taken from patients undergoing open heart surgery. The adenylyl cyclase and binding of 3H-(−)-bupranolol were examined in membrane particles prepared from similarly obtained samples. The equilibrium dissociation constant (K D ) for (−)-bupranolol was estimated in 4 ways: blockade of the positive inotropic effects of catecholamines, blockade of the stimulation of the adenylyl cyclase by catecholamines, saturation binding of 3H-(−)-bupranolol, inhibition of the binding of 3H-(−)-bupranolol by its unlabeled stereoisomers. The estimates of K D fall in the range 0.5–1.4 nmol/l. The stereo-selectivity ratio (K D (+)-isomer/K D (−)-isomer) is 73. Both values for bupranolol are very similar in cat and man. The inotropic potency of (−)-noradrenaline is nearly 2 orders of magnitude higher in cat heart tissues than in tissues from human hearts. The difference in inotropic potencies between species is only partially accounted for by the five-fold lower potency of (−)-noradrenaline for the human heart adenylyl cyclase as compared to the cat enzyme.
In vivo recovery of α1-adrenoceptors in rat myocardial tissue after alkylation with phenoxybenzamine
European Journal of Pharmacology: Molecular Pharmacology, 1994
The rate of recovery of rat myocardial al-adrenoceptor density and responsiveness after in vivo block with phenoxybenzamine (1 mg/kg, i.p.) have been investigated by measuring [3H]prazosin binding, and noradrenaline-stimulated [3H]inositol phosphate production. Repopulation of al-adrenoceptors was monoexponential, with a tl/2 of 33 h; functional recovery was also monoexponential, with tl/2 of 28 h. Furthermore, our results clearly demonstrate the absence of a receptor reserve for al-adrenoceptors mediating noradrenaline-stimulated phosphoinositide breakdown in rat myocardial tissue. These observations indicate a close relationship between the density of [3H]prazosin binding sites and the ability of al-adrenoceptors to respond to noradrenaline. Moreover, based on competition curves for inhibition of specific [3H]prazosin by WB-4101 to rat myocardial membranes 48 h and 7 days after the administration of phenoxybenzamine, the results suggest that rat myocardial membranes contain both al-adrenoceptors subtypes, i.e., alA and alB, in an approximate ratio of 20: 80, and this relative ratio does not seem to be altered during the recovery process.
Cardiac Stress Test Induced By Dobutamine And Monitored By Cardiac Catheterization In Mice
Journal of Visualized Experiments, 2013
Dobutamine is a β-adrenergic agonist with an affinity higher for receptor expressed in the heart (β 1) than for receptors expressed in the arteries (β 2). When systemically administered, it increases cardiac demand. Thus, dobutamine unmasks abnormal rhythm or ischemic areas potentially at risk of infarction. Monitoring of heart function during a cardiac stress test can be performed by either ecocardiography or cardiac catheterization. The latter is an invasive but more accurate and informative technique that the former. Cardiac stress test induced by dobutamine and monitored by cardiac catheterization accomplished as described here allows, in a single experiment, the measurement of the following hemodynamic parameters: heart rate (HR), systolic pressure, diastolic pressure, end-diastolic pressure, maximal positive pressure development (dP/dtmax) and maximal negative pressure development (dP/dt min), at baseline conditions and under increasing doses of dobutamine. As expected, in normal mice we observed a dobutamine dose-related increase in HR, dP/dt max and dP/dt min. Moreover, at the highest dose tested (12 ng/g/min) the cardiac decompensation of high fat diet-induced obese mice was unmasked.
Reduction of β-adrenoceptor function In the heart by oxidative stress
European Journal of Pharmacology, 1990
The effect of oxidative stress on 13-adrenoceptor function in the heart was determined. To this end ventricle membranes, field-stimulated rat left atria and field-stimulated rat right ventricle strips were exposed to 0.1 mM cumene hydroperoxide for 20 min. It was found that oxidative stress increased 13-adrenoceptor number and reduced c-AMP formation in the ventricle membranes. In the rat left atria and rat right ventricle strips the efficacy of I~-adrenoceptor agonists was reduced to approximately 30% of the control value, whereas maximal 13-adrenoceptor-mediated response was reduced to 50%. Using membranes from control atria and from atria exposed to oxidative stress, it was found that oxidative stress had no effect on 13-adrenoceptor density, nor on the affinity of ( -)isoproterenol for the receptor, c-AMP production in membranes prepared from atria exposed to oxidative stress was reduced to approximately 30% of the c-AMP production in membranes prepared of control atria. In addition, it was found that the shape of the function that transduces the stimulus which is generated by receptor activation into an effect, is not altered by oxidative stress. It was concluded that the reduction of the efficacy of 13-adrenoceptor agonists by oxidative stress is probably caused by the reduction of c-AMP formation. Because the efficacy of forskolin and of dibutyryl c-AMP was not affected by oxidative stress, the reduced c-AMP formation is probably caused by an impaired coupling between the receptor and adenylate cyclase. The reduction of maximal [3-adrenoceptor-mediated response might be the result of cytotoxic aldehydes that are produced during oxidative stress.
Adrenoceptors and adaptive mechanisms in the heart during stress
Annals of the New York Academy of Sciences, 2008
Several cardiovascular disorders have been related to alterations in beta-adrenoceptor (beta-AR) signaling at or beyond the receptor level. During the stress reaction, the sympathetic-adrenal medullary system and the hypothalamus-pituitary-adrenal cortex axis are activated, causing beta-AR overstimulation and remodeling of the beta(1)/beta(2)/beta(3)-AR ratio in cardiomyocytes. In a model of foot-shock stress, we described decreased beta(1)-AR signaling occurring simultaneously with increased beta(2)-AR signaling, whereas the response to the nonconventional agonist, CGP12177, was not altered. These alterations may play an adaptive role to the increased sympathetic drive to the heart, protecting the cardiac tissue from the cardiotoxic effects mediated by beta(1)-ARs overstimulation without altering cardiac output, since this would be sustained by the beta(2)-AR, which would also protect myocytes from apoptosis. Moreover, the selective enhancement of the beta(2)-AR population might he...