[Show abstract][Hide abstract]ABSTRACT: Chronic (21 days) treatment with the selective monoamine oxidase (MAO)-A inhibitor clorgyline, but not with the MAO-B inhibitor deprenyl in pithed rats leads to increased blood pressure responses to sympathetic stimulation and intravenous tyramine, and to elevated unstimulated heart rates. No significant changes are observed in plasma catecholamine responses to sympathetic stimulation, nor in beta-adrenoreceptor numbers in heart ventricles. These findings suggest that the hypotensive effects of MAO inhibitors result from central nervous system rather than peripheral nervous system alterations.
Article · Jun 1982 · European Journal of Pharmacology
[Show abstract][Hide abstract]ABSTRACT: Immobilization stress (2.5 h daily) or repeated injection of isoproterenol (1 mg/kg, 3 times daily) for 1 wk caused a subsensitivity to the chronotropic and pressor effect of epinephrine in pithed rats. Propranolol (1 mg/kg) inhibited, to a greater extent in control than in immobilized rats, the chronotropic effect of epinephrine. The residual heart rates did not differ significantly among control, immobilized, and isoproterenol-treated rats. Practolol (1 mg/kg) but not butoxamine (5 mg/kg) mimicked the effect of propranolol. The subsensitivity in the blood pressure responses was not abolished by injection of either of the beta-adrenoceptor blockers. Butoxamine or propranolol shifted the epinephrine dose-blood pressure response curves to the left. The degree of shift was similar in control and immobilized or isoproterenol-treated rats. Daily injection of quinacrine (16 mg/kg), an antimalarial agent that inhibits phospholipase A2, blocked the subsensitivity to the chronotropic effect of epinephrine, but not that to the pressor effect of epinephrine. These observations suggest that immobilization stress causes desensitization of alpha- and beta 1-receptors but not beta 2-receptors. The mechanism of desensitization of beta 1-receptors by immobilization appears to be similar to that after isoproterenol treatment, possibly due to increased turnover of phospholipids.
Article · Jun 1981 · The American journal of physiology
[Show abstract][Hide abstract]ABSTRACT: Forced immobilization is a severe stress in rats which diminishes levels of epinephrine in specific nuclei in the hypothalamus and brain stem, suggesting that release of epinephrine is stimulated to a rate which exceeds the rate of its replacement. In the pineal gland, frog erythrocytes, C6 astrocytoma cells and rat brain, beta-adrenoceptor agonists appear to regulate the number of their receptors. Exposure to high concentrations of an agonist leads to apparent decrease in receptors reflected by a decrease in maximal specific binding of antagonists. The apparent decreases in receptors have been shown to be attended by decreases in physiologic responsiveness. In C6 astrocytoma cells, beta-agonists stimulate methylation of phosphatidylethanolamine to increase formation of membrane phosphatidylcholine which in turn appears to enhance activation of adenyl cyclase. Interference with the metabolism of phospholipids by exposure to phospholipase A2 inhibitor, mepacrine (quinacrine), prevents agonist-induced desensitization of beta-adrenoceptors in astrocytoma cells. In the present study repeated immobilization stress has been found to decrease significantly the number of beta-adrenoceptors in hypothalamus and brain stem while increasing the number of alpha 2-adrenoceptors. The desensitization of beta-adrenoceptors was prevented by treatment with mepacrine.
[Show abstract][Hide abstract]ABSTRACT: Repeated forced immobilization or repeated administration of isoproterenol reduces the number of beta adrenoceptors in the heart and spleen of rats. Isoproterenol, but not immobilization, reduced the number of beta receptors in the lung. These changes in beta adrenoceptors were prevented by administration of quinacrine, a phospholipase A2 inhibitor, although the drug had no effect on beta adrenoceptors when given alone. Immobilization, but not isoproterenol, reduced the number of alpha-1 adrenoceptors in the heart but had no effect on the lung. Quinacrine treatment decreased the number of alpha-1 receptors in heart and lung but increased alpha-2 receptors in the spleen. The changes in receptor number attending exposure to agonists are usually consistent with the expected changes. The effects of quinacrine on such changes suggest that phospholipids are involved in modulating the changes in number of receptors or their availability to interact with ligands.
Article · Mar 1981 · Journal of Pharmacology and Experimental Therapeutics
[Show abstract][Hide abstract]ABSTRACT: Injection of muscimol (4 mg/kg, i.a.) to unanesthetized SHR rats reduced the arterial blood pressure and heart rate more than in WKY rats. These cardiovascular responses were accompanied by a moderate increase in plasma norepinephrine level and a marked increase in plasma epinephrine level, in the SHR rats. In the WKY rats, only a moderate increase in plasma epinephrine level was seen. Injection of subconvulsive doses of picrotoxin (2 mg/kg, i.a.) or bicuculline (1 mg/kg, i.a.) to SHR rats, elicited a higher and a more prolonged increase of the arterial blood pressure than in WKY rats. Plasma norepinephrine and epinephrine levels increased to the same extent in both the SHR and WKY rats following picrotoxin injection. These results suggest that the SHR rats differ from the WKY rats in the reactivity of GABAergic responses in cardiovascular centers which also modulate the peripheral sympathetic tone.
Article · Feb 1981 · Clinical and experimental hypertension
[Show abstract][Hide abstract]ABSTRACT: The relative potencies of alpha adrenoceptor antagonists at pre- and postsynaptic receptors were assessed by comparing their effects on increments in plasma norepinephrine levels and blood pressure during stimulation of the sympathetic outflow from the spinal cord of pithed rats. Since increments in blood pressure are related to the logarithms of increases in plasma norepinephrine, the latter appear to reflect levels of the catecholamine at vascular alpha receptors. Phenoxybenzamine, dibenamine and chlorpromazine were found to block preferentially postsynaptic alpha receptors, phentolamine and tolazoline were nearly equipotent at pre- and postsynaptic receptors and mianserin and piperoxan were more potent inhibitors of presynaptic alpha receptors. Phenoxybenzamine and dibenamine were much more effective in blocking the pressor responses to sympathetic stimulation than administered norepinephrine. The opposite was true of mianserin and piperoxan, whereas phentolamine appeared to be about equipotent in blocking the pressor response to stimulation and norepinephrine. These results suggest that the pressor effects of administered norepinephrine is mediated by different receptors (alpha-2-type) than is the pressor response to stimulation of the sympathetic outflow which appears to be mediated by alpha-1-type adrenoceptors.
Article · Sep 1980 · Journal of Pharmacology and Experimental Therapeutics
[Show abstract][Hide abstract]ABSTRACT: After destruction, by pithing, of the central nervous system, the blood pressure (BP) of the spontaneously hypertensive (SHR) rat falls, but remains higher than in the pithed normotensive (WKY) rat. At all ages examined, stimulation of the sympathetic outflow evoked greater increases in BP of pithed SHR rats, but the increases in plasma catecholamines were similar in the two strains. The BP increase evoked by administered norepinephrine was greater in old SHR than in old WKY rats, but this increased response was not found in young animals. Both young and old SHR rats, however, were more sensitive than WKY rats to the pressor effects of epinephrine. Results of selective pharmacologic blockade of cardiac or vascular beta-adrenoceptors suggest that a smaller vasodilator response in young SHR rats to the beta-adrenergic effects of epinephrine is responsible for the greater pressor response than in WKY rats. This factor diminishes in older SHR rats in which, as suggested by Folkow, structural changes in the resistance blood vessel diameter may account for the enhanced pressor responsivity of SHR rats.
Article · Apr 1980 · The American journal of physiology
[Show abstract][Hide abstract]ABSTRACT: Plasma levels of norepinephrine reflect the rate of its release from sympathetic nerves. In patients with hypertension and in spontaneously hypertensive (SHR) rats basal plasma NE levels are normal. SHR rats are abnormally reactive to stress, as are the normotensive (WKY) strain from which they were derived. The amounts of NE released by sympathetic stimulation are similar in pithed SHR and WKY rats, but SHR rats have greater blood pressure responses. This may be due to diminished beta-adrenoceptor-mediated vasodilation in young SHR rats and structural changes in arterioles of older SHR rats. It is concluded that in SHR rats separate abnormalities of centrally-mediated responses to stress and of peripheral sensitivity to catecholamines contribute to the development and maintenance of elevated blood pressure.
Article · Feb 1980 · Clinical and experimental hypertension
[Show abstract][Hide abstract]ABSTRACT: Sympathetic stimulation in pithed rats elicits increases in blood pressure (BP) and plasma levels of catecholamines. The BP is proportional to the logarithm of the plasma norepinephrine (NE) concentration. Adrenal medullectomy diminishes slightly only the initial phase of the BP responses, whereas bretylium blocks completely the BP response and diminishes by about 70% the increase in plasma NE. Adrenal medullectomy completely prevents the increase in plasma epinephrine (Epi) and diminishes by 30% plasma NE. Plasma levels of NE appear to reflect sympathetic neuronal activity, but the NE at sympathetic nerve endings is responsible for the increase in BP. Epi released from the adrenal medulla may enhance and accelerate the initial BP response, but plays only a minor role after the first 15 s.
Article · Oct 1979 · The American journal of physiology