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G Tsujimoto

Publications and source records attributed to G Tsujimoto.

At least 127 records · Page 7Linked to original sources
PubMed1989

Pharmacokinetic and pharmacodynamic principles of drug therapy in old age. Part 2.

In this Part 2, pharmacodynamic studies which have examined the possibility of true changes in drug "sensitivity" in old age are reviewed. In a variety of organ systems, age-related physiological changes are reflected in altered drug responsiveness in the elderly. Also, a better understanding of different pathophysiological background of disease in this age group leads to a more rational pharmacotherapeutic approach, which is exemplified in the recent drug therapy of hypertension in the elderly.

Aging↗
PubMed1989

Pharmacokinetic and pharmacodynamic principles of drug therapy in old age. Part 1.

Changes in pharmacokinetics and pharmacodynamics which occur with aging are reviewed. In Part 1, age-related alterations in pharmacokinetics, which deals with absorption, distribution, metabolism and elimination of drugs, are summarized. Special emphasis is placed on "drug clearance" which conceptual importance for the evaluation of drug elimination has only been recently recognized. Age-related physiological alterations and their influence on major determinants for each organ clearance are discussed.

Aged↗
PubMed1988

Simultaneous determination of metoprolol and alpha-hydroxymetoprolol in human plasma and urine by liquid chromatography with a preliminary observation on metoprolol oxidation in Japanese subjects.

A simple, sensitive, and highly reliable liquid chromatographic method using fluorescence detection is described for the simultaneous determination of metoprolol and alpha-hydroxymetoprolol in plasma and urine. This method involves a single extraction of the compounds with the internal standard pindolol from alkalinized plasma or urine into dichloromethane. A reconstituted aliquot with a mobile phase is injected onto a reversed-phase, Zorbax ODS column, and the detection is achieved by the excitation and emission wavelengths at 230 and 300 nm, respectively. The assay is reproducible and precise for metoprolol and alpha-hydroxymetoprolol in both plasma and urine samples, as judged by a coefficient of variation of less than 9.2% at all concentrations examined. The standard curves for metoprolol and alpha-hydroxymetoprolol are linear over 10-200 ng/ml in plasma and over 0.5-10 micrograms/ml in urine. The lower detection limit is 2 ng/ml for each of the compounds in plasma using a 0.5-ml sample. Preliminary data on the oxidation polymorphism of metoprolol in Japanese subjects are reported using the current assay method. In 183 Japanese subjects no poor metabolizer of metoprolol has been identified so far.

Chromatography, Liquid↗
PubMed1988

In vivo desensitization of glycogenolysis to Ca2+-mobilizing hormones in rat liver cells.

Rat hepatocytes contain several types of Ca2+-linked receptors, all of which stimulate glycogen breakdown by increasing cytosolic free Ca2+ concentration [( Ca2+]c). In vivo desensitization of this Ca2+ messenger system was studied in hepatocytes isolated from either pheochromocytoma (PHEO)-harboring and chronically norepinephrine (NE)-infused rats. Homologous desensitization for alpha 1-adrenergic receptor-mediated phosphorylase activation developed in the early stage of PHEO rats (3-4 wk after implantation), whereas, in the later stage of tumor development or in the NE-infused rats, phosphorylase responses to all Ca2+-mobilizing stimulations were subsensitive (heterologous desensitization). In the homologous desensitization, the [Ca2+]c response to alpha 1-adrenergic stimulation was selectively reduced. We found, using the phenoxybenzamine inactivation method, that there was a linear relationship between alpha 1 receptor density and the [Ca2+]c response; consequently, the blunted [Ca2+]c response to alpha 1-adrenergic stimulation could not be explained by the 34% downregulation of alpha 1 receptors seen in these rats. These results indicated that uncoupling at a step proximal to alpha 1 receptor-stimulated [Ca2+]c increase is also of primary importance in homologous desensitization of phosphorylase activation. On the other hand, heterologous desensitization also involved alteration(s) at steps distal to the rise in [Ca2+]c. Our data demonstrate that prolonged exposure to catecholamines results in desensitization of the [Ca2+]c mobilization pathway and may involve multiple mechanisms.

Adrenal Gland Neoplasms↗
PubMed1988

Beta adrenoceptors in the canine large coronary arteries: beta-1 adrenoceptors predominate in vasodilation.

Beta adrenoceptors of the canine large coronary artery were characterized by observing the effects of the subtype selective antagonists, metoprolol (beta-1) and ICI 118,551 (beta-2), on the vasodilator responses of isolated and perfused preparations to beta adrenoceptor agonists and in the radioligand binding assay. The integrity of the endothelium was checked by acetylcholine-induced vasodilations. Without any precontraction, isoproterenol, norepinephrine, epinephrine and procaterol (selective beta-2 agonist) dilated the canine large coronary artery pretreated with phentolamine (10(-5) M). The rank order of agonist potency was isoproterenol greater than norepinephrine greater than epinephrine greater than procaterol. The pA2 values for metoprolol and ICI 118,551 were determined by the antagonisms of the vasodilator responses to isoproterenol and procaterol. The slopes of Schild plots for metoprolol and ICI 118,551 against isoproterenol and the value for ICI 118,551 against procaterol were not significantly different from unity, but the value for metoprolol against procaterol was significantly less than unity. The pA2 value for metoprolol against isoproterenol was 7.48 and those values for ICI 118,551 against isoproterenol and procaterol was 7.19 and 7.25, respectively. These pA2 values are typical for beta-1 adrenoceptors. The beta adrenoceptors of the canine large coronary artery were examined further using an antagonist [125I]iodocyanopindolol as a ligand for the binding of beta adrenoceptors. The [125I]iodocyanopindolol binding to the canine coronary artery smooth muscle membrane was saturable with a KD of 63.7 pM and a total number of radioligand binding sites of 44 fmol/mg of protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1988

Cardiomyopathy in a rat model of pheochromocytoma. Morphological and functional alterations.

To investigate the cardiac muscle damage observed in pheochromocytoma, New England Deaconness Hospital rats were implanted subcutaneously with a transplantable pheochromocytoma. The tumor was evident 4 weeks after transplantation. Approximately 5-6 weeks after transplant, systolic blood pressure was significantly increased in tumor-bearing animals (183 +/- 13 vs 119 +/- 7 in controls). At this time a cardiomyopathy with the following features was apparent in the tumor-bearing animals: multifocal lesions of enhanced interstitial and replacement fibrosis; granularity of the cytoplasm and contraction band necrosis; and mixed inflammatory infiltrates. Using a morphological scoring system from 0 (no cardiac damage) to 3 (complete involvement of the ventricular cross section studied), the pheochromocytoma animals had a cardiomyopathy score of 1.8 +/- 0.1, which is significantly greater than that found in age- and sex-matched controls: 0.4 +/- 0.1, p less than .001. A significant increase in the wet heart weights (1.28 +/- 0.07 vs. 1.12 +/- 0.04 in controls) was also observed in these animals, indicating the possibility of cardiac hypertrophy in the pheochromocytoma rats. There was a marked decrease in sensitivity to isoproterenol in isolated, electrically driven left atrial strips from pheochromocytoma rats. Isoproterenol's EC50 increased eightfold from 1.5 +/- 0.6 x 10(-8) M in controls to 1.3 +/- 0.4 x 10(-7) M in left atrial strips from the pheochromocytoma rats. However, there was no difference in maximal contractile response to isoproterenol in either the left atrial strips or in right or left ventricular papillary muscle strips. Also, there was no change in responsiveness of either left atrial or right ventricular muscle strips from pheochromocytoma hearts to contraction induced by 3.75 mM calcium chloride. However, the contractile response to calcium was enhanced in left ventricular papillary muscle from tumor-bearing animals (808 +/- 195 vs 372 +/- 101 mg tension in controls, p less than 0.05). These results demonstrate a catecholamine-induced cardiomyopathy in hearts from pheochromocytoma-bearing rats. Furthermore, the results demonstrate a functional beta-adrenergic receptor desensitization in isolated left atrial strips from tumor-bearing rats, whereas maximal contraction of heart muscle, induced by either isoproterenol or calcium chloride, remains intact.

Animals↗
PubMed1987

Effects of thyroid hormone on beta-adrenergic responsiveness of aging cardiovascular systems.

We have compared the effects of beta-adrenergic stimulation on the heart and peripheral vasculature of young (2-mo-old) and older (12-mo-old) rats both in the presence and absence of triiodothyronine (T3)-induced hyperthyroidism. The hemodynamic consequences of T3 treatment were less prominent in the aged hyperthyroid rats compared with young hyperthyroid rats (both in intact and pithed rats). There was a decrease in sensitivity of chronotropic responsiveness to isoproterenol in older pithed rats, which was apparently reversed by T3 treatment. The number and affinity of myocardial beta-adrenergic receptor sites measured by [125I]cyanopindolol were not significantly different in young and older control rats; also, beta-receptor density increased to a similar extent in both young and older T3-treated rats. The ability of isoproterenol to relax mesenteric arterial rings, markedly blunted in older rats, was partially restored by T3 treatment without their being any change in isoproterenol-mediated relaxation in the arterial preparations from young rats. The number and affinity of the beta-adrenergic receptors measured in the mesenteric arteries was unaffected by either aging or T3 treatment. The data suggest that effects of thyroid hormone and age-related alterations of cardiovascular responsiveness to beta-adrenergic stimulation are interrelated in a complex fashion with a net result that the hyperkinetic cardiovascular manifestations in hyperthyroidism are attenuated in the older animals.

Aging↗
PubMed1987

Desensitization of postjunctional alpha 1- and alpha 2-adrenergic receptor-mediated vasopressor responses in rat harboring pheochromocytoma.

Prolonged stimulation of tissues by adrenergic agonists may lead to diminished responsiveness of the tissues to subsequent activation by catecholamines; this phenomenon has been termed desensitization or tachyphylaxis. We have examined the in vivo consequences of prolonged stimulation of vascular alpha-adrenergic receptors in rats harboring pheochromocytoma, a tumor that secretes catecholamines. In both early (3-4 weeks after implantation) and late (6-7 weeks after implantation) stages of tumor development, New England Deaconess Hospital rats with transplanted pheochromocytomas developed hypertension and tachycardia and had plasma dopamine and norepinephrine concentrations markedly greater than controls. In both these stages of pheochromocytoma, pressor responses to several vasoconstrictors were examined after pithing. Rats with the tumor were found to become progressively subsensitive to alpha-adrenergic agonists. In the early phase of pheochromocytoma, loss in sensitivity was found for both alpha 1- and alpha 2-adrenergic agonists, whereas responsiveness to the nonadrenergic vasoconstrictors Arg-vasopressin and angiotensin-II was intact (homologous desensitization). However, in the later stage of pheochromocytoma, pressor responses to all these vasoconstrictive agents and also to stimulation of the complex sympathetic outflow were found to be subsensitive (heterologous desensitization). In plasma membranes prepared from mesenteric arteries of early stage tumor-bearing rats, [3H]prazosin binding sites were significantly decreased to 150 +/- 12 fmol/mg vs. 234 +/- 19 fmol/mg in controls. [3H]Yohimbine binding sites were not significantly altered. Our results show that both postjunctional alpha 1- and alpha 2-adrenergic receptor-mediated vasopressor responses can be specifically attenuated in the presence of chronically elevated endogenous catecholamine levels produced by pheochromocytoma and that each alpha-receptor subtype may be differently regulated in the development of desensitization.

Angiotensins↗
PubMed1987

Effects of triiodo-L-thyronine (T3)-induced hyperthyroidism on the cardiovascular alpha-adrenoceptor system in young and older rats.

We have compared the vasopressor response of alpha-adrenoceptor agonists in young (2 month-old) and older (12 month-old) pithed rats both in the presence and absence of triiodo-L-thyronine (T3)-induced hyperthyroidism. There was no age-related changes in the pressor response to either the alpha 1-selective agonist phenylephrine or the alpha 2-selective agonists clonidine and UK-14,304. However, T3-induced hyperthyroidism caused a selective reduction in postjunctional alpha 2-adrenoceptor-mediated pressor responses but not alpha 1-adrenoceptor-mediated ones in both age groups. In contrast to vascular alpha-adrenoceptors, there was an age-related decrease in the number of myocardial alpha 1-adrenoceptor sites measured by specific binding of [3H]prazosin. With thyroid hormone treatment, the density of ventricular alpha 1 receptors was found to be further reduced even in the older rats. These results suggest that thyroid hormone and aging have different influences on the cardiovascular alpha-adrenoceptor system and that these two physiological variables are independently interrelated.

Aging↗
PubMed1987

Characterization of vasopressor response to sympathetic stimulation in the pithed rat: differential regulation of neuronally stimulated and blood-borne catecholamine-stimulated pressor responses in rats harboring pheochromocytoma.

The vasopressor response to sympathetic stimulation in the pithed rat was characterized both by analyzing the effects of chemical sympathectomy, adrenalectomy and selective antagonists on the vasopressor response and by measurement of changes in plasma concentrations of catecholamines. Stimulation of the spinal sympathetic outflow evoked a biphasic pressor response: an initial transient component was caused mainly by postganglionic sympathetic nerve stimulation (the direct response); a slowly developing secondary component was mediated predominantly by circulating catecholamines released from the adrenal medulla (the adrenal response). Parallel analysis of plasma catecholamines showed that the rise in epinephrine appeared to be closely related to this adrenal component. The pressor response in adrenalectomized rats was selectively blocked by prazosin but not by yohimbine; however, in sympathectomized rats, the pressor response was abolished by prazosin and yohimbine together but not by either drug given alone. These results suggest that the direct, neurogenic component is mediated mainly by alpha-1 adrenoceptors whereas the secondary, adrenally mediated response occurs by activation of both alpha-1 and alpha-2 adrenoceptors. Furthermore, the in vivo regulation of each component of the pressor response was studied in rats harboring pheochromocytoma (PHEO), a tumor causing marked elevations in endogenous catecholamine concentrations. In PHEO rats, the direct pressor response was found to be relatively intact but the adrenal response was blunted. Inasmuch as there was normal rise in plasma epinephrine to electrical stimulation in PHEO rats, the results suggest a differential regulation of neuronally stimulated and blood-borne catecholamine-mediated pressor responses in PHEO rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗
PubMed1986

A unique pressor response to isoprenaline in the pithed rat during triiodo-L-thyronine(T3)-induced hyperthyroidism.

Thyroid hormone appears to be involved in the regulation of beta-adrenoceptors affecting cardiovascular performance. In the present study, the influence of hyperthyroidism on beta-adrenoceptor-mediated response of the cardiovascular system was investigated in vivo using the pithed rat preparation. Hyperthyroidism was induced by triiodothyronine injections (500 micrograms/kg, i.p.) for 6 days. A markedly accelerated basal heart rate and a wider pulse pressure with a significantly elevated systolic blood pressure were observed in hyperthyroid pithed rats. Although the basal and the maximal heart rates were increased in hyperthyroid rats, EC50 of the heart rate response to isoprenaline did not significantly differ between euthyroid and hyperthyroid pithed animals. Markedly different responses of blood pressure to isoprenaline were obtained in the two groups; isoprenaline caused a dose-dependent decrease in diastolic pressure in euthyroid pithed rats, whereas it produced pressor response in hyperthyroid pithed rats. This unique pressor response to isoprenaline observed in hyperthyroid pithed rats was abolished by the beta 1-adrenoceptor selective antagonist metoprolol but not by the alpha-adrenoceptor antagonist phenoxybenzamine. The density of myocardial binding sites of the beta-type was markedly increased after T3 treatment (65%), whereas that of the mesenteric artery was not altered. The results indicate that thyroid hormone exerts different effects on cardiac and vascular beta-adrenoceptors, and this different susceptibility to thyroid hormone may in part be responsible for the altered response of blood pressure to isoprenaline seen in hyperthyroid pithed rats.

Animals↗
PubMed1986

Age-related change in adrenergic regulation of glycogen phosphorylase in rat hepatocytes.

The effects of development on adrenergic regulation of glycogenolysis were studied in rat liver. In isolated hepatocytes, the activation of glycogen phosphorylase by alpha-adrenergic stimulation decreased moderately with advancing age. However, activation by beta-adrenergic receptors more markedly declined and almost disappeared in isolated hepatocytes from 6-month-old rats. Furthermore, the ability to glucagon to stimulate phosphorylase activity and cAMP generation was found to decrease with increasing age. The age-related changes in the pattern of stimulation of glycogen phosphorylase by catecholamines in isolated hepatocytes were accompanied by parallels changes in the numbers of alpha 1- and beta-adrenoceptors in membranes prepared from the isolated hepatocytes. A progressive decrease in the total number of alpha 1-receptors measured with [3H]-prazosin and beta-receptors measured with [125I]cyanopindolol (CYP) was found with increasing age. The loss of beta-adrenergic receptors was much more dramatic. Our results suggest that age-related alterations of hepatic glycogen phosphorylase activation by catecholamines may in part be explained by the changes in the expression adrenergic receptors.

Aging↗
PubMed1986

Developmental alteration in adrenergic regulation of hepatic glycogen phosphorylase.

The effects of development upon adrenergic regulation of glycogenolysis were characterized using isolated hepatocytes from 3 different age groups of male rats (6 week-old, 8 week-old and 30 week-old). The phosphorylase a response in isolated hepatocytes to alpha-adrenergic stimulation decreased moderately with advancing age; whereas, that to beta-adrenergic stimulation declined more rapidly and almost disappeared at the age of 30 weeks. This developmental alteration in relative contribution of alpha- and beta-adrenergic regulation of phosphorylase was further confirmed by the experiments with specific antagonists. Also, the dramatic decrease of beta-adrenergic response on glycogen phosphorylase activity was found to be closely associated with a similar change of cAMP generation. In addition, the glucagon effect on cAMP production was found to be declined with advancing animal age. These results demonstrate that the glycogenolytic response of isolated rat hepatocytes to catecholamines can be mediated by different pathways according to the age of the animal; thus, juvenile male rats exhibit both the alpha- and beta-adrenergic mechanism for activation of phosphorylase and the maturation is associated with a modest decline of alpha receptor-mediated effect and a dramatic attenuation of a beta-adrenergic/cAMP response.

Aging↗
PubMed1986

Age-related decrease in beta adrenergic receptor-mediated vascular smooth muscle relaxation.

Beta adrenergic receptor-mediated vascular smooth muscle relaxation decreases with increasing age. We have examined the mechanism responsible for this phenomenon using rat mesenteric arteries from young (5-6 weeks) and older (10-12 months) rats. The beta adrenergic agonist isoproterenol produced a dose-dependent relaxation of serotonin-constricted mesenteric artery rings from young rats, whereas the maximal ability of isoproterenol to relax arterial rings from the older rats was found to be reduced markedly (92.7 vs. 27.6%, P less than .0001). The relaxation responses caused by acetylcholine and nitroglycerin, which appear to act independently of cyclic AMP (cAMP), are similar in the two groups. The loss in responsiveness of the mesenteric artery to isoproterenol was not explained by a change in beta receptor number in the vessels (29 +/- 4 in young rats vs. 31 +/- 7 fmol/mg of protein in the older rats). The maximal stimulation of cAMP accumulation by isoproterenol was lower in the older vessels; forskolin activated cAMP accumulation equally in the two groups. However, the vessels from the older rats were less sensitive to forskolin-induced vascular relaxation. Also, the ability of dibutyryl cAMP to promote vascular relaxation was diminished in the older vessels. These data suggest that the diminished cAMP accumulation in older vessels in response to isoproterenol might not necessarily in itself explain completely the reduced physiological response and that an additional defect in the beta adrenergic-mediated relaxation in the vascular smooth muscle of older rats may lie at the level of cAMP-dependent protein kinase activation or more distally.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Alpha adrenergic receptors in the rabbit bladder base smooth muscle: alpha-1 adrenergic receptors mediate contractile responses.

Alpha adrenergic receptors in rabbit bladder base smooth muscle were investigated by in vitro responses of smooth muscle strips to exogenous alpha agonist stimulation and in radioligand binding assays. Norepinephrine and phenylephrine caused significantly greater maximal contractile responses than did clonidine. Also, the contractile response was only inhibited weakly by the alpha-2 selective antagonist yohimbine but was potently inhibited by alpha-1 selective antagonists prazosin and BE2254, suggesting that the response is mediated predominantly by alpha-1 adrenergic receptors. The alpha-1 selective antagonist [125I]BE2254 was used to specifically label a single class of binding sites with a dissociation constant of 131.0 +/- 5.9 pM and a maximal binding capacity of 17.6 +/- 1.9 fmol/mg of protein. Catecholamines compete for [125I]BE2254 binding stereospecifically and with the characteristic alpha adrenergic potency series of (-)-epinephrine greater than (-)-norepinephrine much greater than (-)-isoproterenol. The alpha-1 selective antagonist prazosin (Kd = 2.4 nM) is much more potent in competing for [125I]BE2254 binding than is the alpha-2 selective antagonist yohimbine (Kd = 2900 nM). Also, this dissociation constant of prazosin of [125I]BE2254 binding for bladder base smooth muscle membranes was similar to prazosin's pA2 value of 8.23 to 8.58 in the contraction experiments. The results suggest that alpha-1 rather than alpha-2 receptors predominantly mediate catecholamine-induced contraction in the rabbit bladder base. Also, these receptor sites can be measured directly with the specific antagonist radioligand, [125I]BE2254.

Adrenergic alpha-Agonists↗
PubMed1985

Epinephrine infusion induces hyporesponsiveness of vascular smooth muscle.

Exposure to vasoactive drugs may lead to desensitization of vascular smooth muscle responsiveness. We have explored this phenomenon by infusing epinephrine into awake rabbits for 2h and then assessing smooth muscle contraction, both in vivo and ex vivo. Epinephrine was infused at a rate of 1 microgram X min-1 which resulted in a 15-fold increase in the plasma epinephrine concentration. The dose of phenylephrine required to cause a 25 mmHg increase in mean arterial pressure significantly increased from 109 +/- 56 micrograms prior to the infusion to 261 +/- 143 at the end of the 2h infusion (p less than 0.01). The sensitivity to phenylephrine remained decreased when reassessed 2h later. Untreated rabbits displayed no change in alpha-adrenergic responsiveness when assessed at 2 hourly intervals over the time-course of the experiment. Contraction of aortic rings removed from both epinephrine-treated and control rabbits was determined in vitro in tissue baths. The EC50 of norepinephrine-induced contraction increased from 31 +/- 6 to 210 +/- 20 nM while there was also a 30% decrease in the maximal force of contraction (EMax) in treated vessels. The EC50 only partially recovered after 4h of incubation ex vivo, while the EMax was restored to the control value. The EC50 for histamine in the aortic rings from epinephrine-treated rabbits was not different from controls although there was a 25% reduction in the EMax at 2h. We conclude that desensitization of alpha-adrenergic mediated vascular contractility develops rapidly in vivo and is only slowly reversible after removal of the agonist.

Animals↗
PubMed1985

Differential effects of adrenergic agonists and phorbol esters on the alpha 1-adrenoceptors of hepatocytes and aorta.

Epinephrine, norepinephrine and phenylephrine stimulate phosphatidylinositol labeling with [32P]Pi in both rat hepatocytes and rabbit aorta. Methoxamine was a full agonist for this effect in rabbit aorta whereas cirazoline and oxymetazoline were partial agonists. In contrast, these three agents (methoxamine, cirazoline and oxymetazoline) were unable to stimulate phosphatidylinositol labeling in rat hepatocytes. Furthermore, cirazoline and oxymetazoline were able to displace the dose-response curve to epinephrine in rat hepatocytes, i.e., they behaved as antagonists. Binding competition curves of these agents with labeled adrenergic ligands indicate that the affinity of alpha 1-adrenergic receptors in these two tissues (aorta and liver) for the different agents tested was very similar. In addition it was observed that phorbol myristate-acetate inhibited in a dose-dependent fashion the epinephrine-mediated stimulation of phosphatidylinositol labeling in hepatocytes but was without effect on the action of the amine in aorta. Our data suggest that stereochemical differences for alpha 1-adrenergic activation in liver and aorta may exist and indicate that the ability of phorbol esters to inhibit alpha 1-adrenergic effects is not universal.

Adrenergic alpha-Agonists↗