Search PubMed⌕ Search

Biomedical subjects

G Tsujimoto

Publications and source records attributed to G Tsujimoto.

139 records · Page 8Linked to original sources
PubMed1985

Effects of pheochromocytoma on cardiovascular alpha adrenergic receptor system.

We have examined the in vivo consequences of prolonged stimulation of the cardiovascular alpha-adrenergic receptor system in a rat model harboring pheochromocytoma. New England Deaconess Hospital rats with transplanted pheochromocytomas developed systolic hypertension and their plasma norepinephrine concentrations were approximately 60-fold greater than controls. Alpha 1-adrenergic receptors were quantitated in hearts from controls and rats with transplanted pheochromocytoma using the alpha 1-receptor selective antagonist [3H]prazosin. Down-regulation of alpha 1-receptors was found in the hearts of pheochromocytoma rats (33.0 vs. 23.0 fmol/mg protein) without any significant change in the affinities of these receptors for the circulating catecholamine, norepinephrine. Furthermore, the responsiveness of the blood vessel to the alpha-adrenergic stimulation was assessed using in vitro contractile experiments. Aortic rings from pheochromocytoma animals showed an eight fold decrease in sensitivity (EC50) and a 74% decrease in maximal contractility (Emax) to norepinephrine as compared with controls. Similarly, mesenteric artery rings prepared from the same animals showed a five fold loss of EC50 but no decrease in Emax to phenylephrine as compared with controls. In addition, serotonin EC50 and Emax of these mesentery preparations remained unaltered. Coupled with our previous findings [9], the present study suggests that rats with pheochromocytoma secreting large amounts of norepinephrine provide a valuable model system for studying in vivo desensitization of the cardiovascular alpha-receptor systems as well as the beta-adrenergic receptor system.

Animals↗
PubMed1985

Direct measurement of vascular alpha 1-adrenoceptors.

alpha-Adrenoceptors play an important role in regulating vascular tone. [125I]BE2254, a high affinity antagonist, has been utilized to label alpha 1-receptors in membrane preparations from rabbit aorta. [125I]BE2254 specifically labels a single class of binding sites with the characteristics of alpha 1-receptors. Catecholamines compete for [125I]BE2254 binding stereospecifically and with the characteristic alpha-adrenergic potency series (-)-adrenaline greater than or equal to (-)-noradrenaline much greater than (-)-isoprenaline. The alpha 1-adrenoceptor selective antagonist prazosin is much more potent than yohimbine in competing for the [125I]BE2254 binding sites, which suggests that the alpha-adrenoceptor identified is predominantly of the alpha 1 subtype. The extension of radioligand binding techniques to individual rabbit aortas should simplify the study of vascular alpha-adrenoceptor regulation.

Adrenergic alpha-Antagonists↗
PubMed1985

Desensitization of beta-adrenergic receptor-mediated vascular smooth muscle relaxation.

Responsiveness to catecholamines may be blunted after prolonged exposure to an agonist; this phenomenon, termed desensitization, is often mediated by receptor down-regulation. beta-Adrenergic receptors mediate relaxation of vascular smooth muscle. We have examined the possibility that this response may be desensitized after prolonged exposure to increased concentrations of epinephrine. Rats were treated with epinephrine infusions (300 micrograms/kg/hr from a minipump) for 7 days and had levels of plasma epinephrine 70-fold greater than those of controls. The mesenteric artery rings from the epinephrine-treated rats contracted normally when exposed to serotonin; however, the extent of relaxation promoted by the beta-adrenergic agonist isoproterenol was blunted (86 +/- 4 vs. 43 +/- 9%; p less than 0.05). Acetylcholine and nitroglycerine, which may act through a cyclic GMP mechanism, caused virtually identical relaxation responses in both control and epinephrine-treated groups. To determine the mechanism for the loss in responsiveness to isoproterenol, we measured adrenergic receptors in individual mesenteric arteries using [125I]cyanopindolol. Specific binding of [125I]cyanopindolol was found to have the expected characteristics of interaction with beta receptors. There was no difference in the number of beta-adrenergic receptors between control and epinephrine-treated animals (24 +/- 5 vs. 26 +/- 6 fmol/mg of protein), although there was significantly marked down-regulation of beta-adrenergic receptors in hearts (23 +/- 2 vs. 10 +/- 1 fmol/mg of protein; p less than 0.001) and lungs (172 +/- 29 vs. 76 +/- 7 fmol/mg of protein; p less than 0.01) in the same rats. The ability of isoproterenol to stimulate cyclic AMP production in the mesenteric arteries from the two groups was not significantly different (20.3 +/- 3.5 vs. 23.8 +/- 4.7 pmol of cAMP/mg of protein/2 min). Furthermore, mesenteric artery relaxation was found to be decreased in response to the cyclic AMP analogue dibutyryl cyclic AMP (45 +/- 2.0 vs. 28 +/- 2.0%; p less than 0.001) in the epinephrine-infused rats. These data suggest that the desensitization of beta-adrenergic receptor-mediated smooth muscle relaxation may be caused by a mechanism distal to cyclic AMP production.

1-Methyl-3-isobutylxanthine↗
PubMed1985

Prolonged hyporesponsiveness of vascular smooth muscle contraction after halothane anesthesia in rabbits.

Halothane diminishes smooth muscle contractility in vascular tissue. In order to further characterize this phenomenon we undertook a series of in vivo and ex vivo experiments. Pressor dose-response curves to the selective alpha 1-adrenergic agonist, phenylephrine, were constructed in groups of rabbits before, during and 2 hr after halothane anesthesia and the dose of phenylephrine that induced a 25 torr increase in mean arterial pressure (ED25) was derived by polynomial regression analysis. ED25 torr increased significantly during halothane anesthesia, and rabbits remained in this insensitive state when the ED25 was assessed 2 hr after anesthesia. The halothane-induced loss of responsiveness was corroborated by ex vivo experiments utilizing aortic rings from halothane-anesthetized rabbits. The maximal contraction to norepinephrine (NE) was significantly lower in halothane-treated aortic rings and only slowly returned to normal by 4 hr. The EC50 (the dose causing a 50% maximal contraction) for NE was significantly greater in aortic rings from halothane-anesthetized rabbits. This loss of sensitivity, reflected by the higher EC50 was not restored by 4 hr of ex vivo incubation in a halothane-free medium. We conclude that halothane induces loss of sensitivity to adrenergic agonists that persists for several hours after termination of the halothane anesthetic.

Anesthesia↗
PubMed1985

Desensitization of alpha-1 adrenergic receptor-mediated vascular smooth muscle contraction.

Desensitization of alpha-1 receptor-mediated smooth muscle contraction was studied in rabbit aorta. Incubation of rabbit aorta ring segments with epinephrine (10(-6) M) for 7 hr resulted in a 10-fold loss in sensitivity of the tissue to alpha-1 adrenergic receptor-mediated contraction with no change in maximal force of contraction. This loss in sensitivity was specific for alpha-1 receptor-mediated contraction because responses to histamine and serotonin were unchanged in these aortas. Conversely, prolonged exposure of vessels to histamine (10(-5) M) led to desensitization of histamine-mediated contraction without altering responses to alpha-1 receptor stimulation. Using [125I] BE2254, a potent alpha-1 receptor antagonist, the loss in sensitivity to catecholamines was found not to be mediated by down-regulation of alpha-1 receptors nor by a loss in their affinity for epinephrine. However, desensitization was associated with a blunting of alpha-1 receptor stimulation of phosphatidylinositol turnover. These results suggest that desensitization of alpha-1 receptor-mediated contraction in rabbit aorta does not appear to be mediated by changes in receptor number or affinity but may involve alterations in receptor coupling.

Adenylyl Cyclases↗
PubMed1984

Identification of alpha 1 adrenergic receptors in rabbit aorta with [125I] BE2254.

Alpha-adrenergic receptors may play an important role in regulating vascular tone and reactivity. To study alpha-adrenergic receptors in blood vessels, we have developed a method to characterize and quantitate alpha-adrenergic receptors in a particulate fraction of individual rabbit aortas using the high specific activity alpha antagonist [125I] BE2254. [125I] BE2254 specifically labels a single class of binding sites with a dissociation constant of 286 pM and a maximal binding capacity of 16.7 fmoles/mg protein. Catecholamines compete for [125I] BE2254 binding stereospecifically and with the characteristic alpha-adrenergic potency series of (-)epinephrine greater than or equal to (-)norepinephrine much greater than (-)isoproterenol. The alpha 1-selective antagonist prazosin (KD = 0.7 nM) is much more potent in competing for [125I] BE2254 binding than is the alpha 2-selective antagonist yohimbine (KD = 1000 nM), which suggests that the alpha adrenergic receptor identified is predominantly of the alpha 1 subtype. Also, the dissociation constants from these binding studies were in good agreement with those reported in rabbit aorta from classical pharmacological experiments where contraction was found to be mediated via alpha 1 receptors. This extension of radioligand binding techniques to individual rabbit aortas should simplify the study of vascular alpha adrenergic receptor regulation, and provide a basis for broadening the understanding of vascular alpha adrenergic receptors.

Animals↗
PubMed1984

Desensitization of beta-adrenergic receptors by pheochromocytoma.

Prolonged stimulation of cells by beta-adrenergic receptor agonists may lead to diminished responsiveness of the cells to subsequent activation by catecholamines. This phenomenon has been termed desensitization; the mechanism(s) for desensitization may involve an apparent loss in the number of beta-adrenergic receptors or an alteration in receptor-effector coupling. We have examined the consequences of prolonged stimulation of beta-adrenergic receptors in an interesting rat model harboring pheochromocytoma. New England Deaconess Hospital rats with transplanted pheochromocytomas developed systolic hypertension and plasma norepinephrine concentrations approximately 40-fold greater than controls. beta-Adrenergic receptors were quantitated in several tissues from controls and rats with transplanted pheochromocytoma using the beta-adrenergic receptor antagonist [125I]iodocyanopindolol. Down-regulation of beta 1-receptors was found in heart tissue (22.8 vs. 13.6 fmol/mg protein; P less than 0.001) and adipocytes (29,400 vs. 2,800 sites/cell; P less than 0.001). Also, maximal isoproterenol-stimulated cAMP accumulation in isolated adipocytes was diminished in pheochromocytomic animals (13.1 vs. 4.9 pmol cAMP/10(5) cells/min; P less than 0.05). Interestingly, there was no change in beta-receptors in lung and mesenteric artery, which predominantly contain beta 2-receptors. Furthermore, the competition curves of isoproterenol in the heart membranes from control and pheochromocytomic rats in the absence and presence of guanylylimidodiphosphate indicated uncoupling of the beta-adrenergic receptors in pheochromocytomic animals. Rats with pheochromocytoma secreting large amounts of norepinephrine provide a valuable model system for studying the in vivo development of desensitization.

Adipose Tissue↗
PubMed1982

Re-examination of digoxin dosage regimen: comparison of the proposed nomograms or formulae in elderly patients.

1 Comparison of measured trough serum digoxin concentrations (SDC) with those predicted at steady-state by forty sets of previously described pharmacokinetic equations in conjunction with either measured or estimated creatinine clearance (Clcr) was made in an elderly group of patients with varying Clcr (25-89 ml/min) who received maintenance digoxin therapy. 2 Mean values of day-to-day variation (% coefficient of variation) for serum creatine and measured Clcr examined three times within a week in 7 of 40 elderly patients were 6.42 and 8.36% respectively, while this value for SDC was 12.46%. 3 There was a statistically significant correlation (r = 0.72 to 0.79, P less than 0.001, n = 40) between measured Clcr and that estimated from three different methods. Siersbaek-Nielsen's nomogram approach gave the best correlation. 4 The calculated correlation coefficient values between measured and predicted SDC lay within a relatively narrow range but were weak (r = 0.443-0.628). Prediction error analysis, however, allowed us to determine the best set of pharmacokinetic equations for a first approximation to appropriate digoxin maintenance dosage requirements, namely Gault-estimated elimination rate constant, measured Clcr, and Jusko-estimated volume of distribution.

Aged↗
PubMed1982

Toxic haloperidol reactions with observation of serum haloperidol concentration in two children.

In 2 children who accidentally received haloperidol (0.26 mg/kg in one and 0.10 mg/kg in another) from a prescription error, haloperidol concentrations in serum in both cases and in cerebrospinal fluid in one case were measured with the radioimmunoassay method during the development of the toxic drug reactions. The serum haloperidol concentrations in both cases were far beyond the proposed therapeutic range in children. Our cases are generally compatible with previous findings of others and indicate that the intensity and/or incidence of toxic reactions of haloperidol may be related to plasma concentrations.

Basal Ganglia Diseases↗