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T Vago

Publications and source records attributed to T Vago.

At least 55 records · Page 3Linked to original sources
PubMed1991

Changes in alpha-1 and beta-2 adrenoceptor density in human hepatocellular carcinoma.

Catecholamines are involved critically in the mechanisms of liver cell proliferation by acting on hepatic alpha-1 and beta-2 adrenoceptors. To identify the role of these receptors in human hepatocellular carcinoma (HCC), the density was examined of alpha-1 and beta-2 adrenoceptors with their affinity and coupling of beta-2 adrenoceptors to adenylate cyclase in HCC tissue and in nonadjacent/nontumor tissue from the same livers. Studies were also done on healthy livers from age-matched and sex-matched patients undergoing abdominal surgery for nonhepatic diseases. Twenty-two HCC had a decrease of about 72% in alpha-1 adrenoceptor density compared with their nonadjacent/nontumor tissue and a decrease of about 40% compared with healthy controls. Nonadjacent/nontumor tissue from HCC patients had a 125% increase in alpha-1 adrenoceptor density compared with healthy livers. Twenty-three of 24 HCC had an increase of about 180% in beta adrenoceptor density compared with their nonadjacent/nontumor tissue and healthy controls. Beta adrenoceptors were coupled to adenylate cyclase, as evidenced by a guanosine triphosphate-mediated right shift in (-)-isoproterenol competition isotherms and by cyclic adenosine monophosphate (cAMP) production after stimulation with (-)-isoproterenol. The HCC tissue yielded a larger increase in cAMP than nonadjacent/nontumor tissue and healthy controls. The authors conclude that a higher density of alpha-1 adrenoceptors in nonadjacent/nontumor tissue from HCC characterizes the "healthy" part of the liver in HCC patients and that an increase in beta-2 and a decrease in alpha-1 adrenoceptor densities characterize the tumor part of the liver in human HCC.

Adenylyl Cyclases↗
PubMed1991

Effect of propionyl-L-carnitine on L-type calcium channels in human heart sarcolemma.

Propionyl-L-carnitine (PC) protects perfused rat hearts against damage by ischemia-reperfusion. Activation of L-type calcium channel play a role on ischemia-reperfusion damage. Therefore, we studied the effect of PC on some properties of L-type calcium channels in an in vitro preparation from human myocardium sarcolemma (from patients with idiopathic dilated cardiomyopathy). Binding of the L-type calcium channel blockers isradipine [3H]-PN 200-110 (PN) to plasma membrane preparations revealed a single population of binding sites (total number: Bmax = 213 +/- 34 fM/mg protein and affinity: Kd = 152 +/- 19 nM; n = 6). The characteristics of these binding sites were evaluated in the presence and in the absence of Ca2+ and of calcium blockers (D-888, a verapamillike drug, and diltiazem). Incubation in a Ca2(+)-containing buffer increased the affinity of PN binding sites. Binding sites for PN were modulated by organic calcium channel blockers; in competition isotherms at 37 degrees C, D-888 (desmethoxyverapamil) decreased the PN binding, whereas diltiazem increased it. These results strongly suggest that the site labelled by PN is the voltage-operated calcium channel of the human myocardium. The addition of PC (1 mM) to plasma membranes labelled with PN at 37 degrees C decreased the affinity of the binding; this effect was counteracted by the addition of Ca2+ to the medium. This result was consistent with a competition between Ca2+ and PC. The effect of PC incubation at 4 degrees C was the opposite; at this temperature PC increased the affinity of the binding sites and the effect was obscured by Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1991

Alpha 1 adrenoceptor subtype mediates noradrenaline induced contraction of the human internal mammary artery: radioligand and functional studies.

STUDY OBJECTIVE: The aim was to evaluate the characteristics of alpha adrenergic binding sites on human internal mammary arteries and the alpha adrenoceptor mediated vasoconstrictor response to catecholamines. DESIGN: Human internal mammary arteries were cut longitudinally, the intimal layer was scraped, and the arteries homogenised and centrifuged at 50,000 g to obtain a membrane pellet. Saturation isotherms with [3H]-prazosin were done with 50-100 micrograms plasma membranes per tube and increasing concentrations of [3H]-prazosin (non-specific binding: 2.5 mM noradrenaline plus superoxide dismutase and catalase). Kinetic isotherms were done with 100 micrograms plasma membranes and 1-5 nM [3H]-prazosin for time periods ranging from 1 to 90 min; at the equilibrium, dissociation of [3H]-prazosin was achieved by 10 microM prazosin. alpha 2 Adrenoceptor density on internal mammary artery membranes was assessed with [3H]-rauwolscine (non-specific binding: 1 microM yohimbine). Separation of membrane bound radioactivity was achieved by rapid vacuum filtration through Whatman GF/C fibre filters. Saturation isotherms were evaluated by Scatchard plots and kinetic data, and competition isotherms by Enzfitter analysis. Contractility studies were done with helical strips of artery (without adventitial layer) placed in a thermostated perfusion bath. Data were obtained in the presence of different concentrations of agonists and antagonist to obtain Schild plots. Antagonist drugs were employed at only one concentration for each preparation. SUBJECTS: Mammary arteries were collected from 51 patients (age range 42-65 years) undergoing surgery for coronary grafting. MEASUREMENTS AND MAIN RESULTS: The binding of [3H]-prazosin to arterial plasma membrane was rapid and reversible. The K + 1 was 0.13 (SD 0.03) X 10(9) M.min-1 (n = 5) and the Kd, determined as a ratio between k-1/K + 1, was 0.34(0.01) nM (n = 5). [3H]-Prazosin binding, displaceable by 2.5 mM (-)-noradrenaline, was saturable and disclosed an alpha 1 adrenoceptor density of 30(3) fmol.mg-1 protein with a dissociation constant (Kd) of 215(50) pM (n = 18). The adrenergic agonists competed with [3H]-prazosin in the following order of potency: (-)-adrenaline [Ki = 0.6(0.1) microM; n = 5] greater than (-)-noradrenaline [Ki = 1.05(0.015) microM; n = 12] much greater than (-)-isoprenaline [Ki = 150(10) microM; n = 4]. Specific binding of [3H]-rauwolscine to IMA plasma membranes was negligible (about 2 fmol.mg-1 protein) (n = 15) with an unfavourable ratio of non-specific v specific binding. Catecholamines induced a dose dependent contractile response in arterial strips; (-)-noradrenaline: EC50 = 0.48(0.12) microM, n = 20; (-)-adrenaline: EC50 = 0.15(0.16) microM, n = 10; and methoxamine, a selective alpha 1 adrenergic agonist: EC50 0.67(0.15) microM, n = 10. The alpha 2 adrenoceptor agonists BHT-933, BHT-920, and guanabenz did not contract the arterial strips (up to 10 mM). Prazosin (0.03-0.1 microM) produced concentration dependent right shifts of the (-)-noradrenaline [pA2 = 9.83(0.11), n = 19], (-)-adrenaline [pA2 = 9.50(0.31), n = 10], and methoxamine [pA2 = 8.96(0.18), n = 10] concentration-response curve. CONCLUSIONS - Internal mammary artery plasma membranes possess alpha 1 adrenoceptors which are involved in the vasoconstrictor response to catecholamines. alpha 2 Adrenoceptors seem not to be involved.

Adult↗
PubMed1991

Beta-adrenergic receptors and reflex tachycardia after single and repeated felodipine administration in essential hypertension.

To verify the possible contribution of beta-adrenergic receptor down-regulation to the reversal of reflex tachycardia during chronic treatment with a dihydropyridine calcium antagonist, 11 hypertensive patients were studied with noninvasive blood pressure (BP) and heart rate (HR) monitoring after a placebo period, and on the first and seventh day of felodipine administration, 5 mg twice daily. Plasma catecholamines and neutrophil beta-adrenergic receptors were measured on the first and seventh day of treatment, immediately before and 2 h after drug administration. The first administration of felodipine was followed by a significant drop in BP (peak reduction in mean BP 24 +/- 7 mm Hg), lasting 6 h and mirrored by reflex tachycardia (peak increase in HR 14 +/- 9 beats/min). On the morning of the seventh day, 12 h after the previous felodipine administration, mean BP (MBP) was 16 mm Hg lower than on the last placebo day, while HR was unchanged. The next administration of felodipine was followed by a smaller drop in BP (MBP - 15 +/- 7 mm Hg; NS vs. placebo), while reflex tachycardia was the same as after acute felodipine (HR 13 +/- 8 beats/min; p less than 0.05 vs. placebo, NS vs. acute administration). Plasma noradrenaline concentration increased after both acute and chronic administration (p less than 0.0001), and preadministration values were highest on day 7 (p less than 0.05). Neutrophil beta-adrenergic receptor density and affinity did not change either acutely or chronically. This study gives both indirect and direct evidence that beta-adrenoceptor down-regulation does not occur during repeated felodipine administration in hypertension. Reflex tachycardia is not abolished, but is reset to lower BP levels.

Adult↗
PubMed1990

Respiratory-burst stimulants desensitize beta-2 adrenoceptors on human polymorphonuclear leukocytes.

We investigated the effect of respiratory-burst stimulants on beta-2 adrenoceptors in human polymorphonuclear leukocytes (PMNL). Pre-incubation of PMNL with these substances did not affect the number or affinity of the receptors but desensitized them, as shown by the "right-shift" in (-)-isoproterenol competition isotherms. H-7, an established protein kinase C inhibitor, and nimesulide, a new putative inhibitor of this enzyme, blunted both superoxide anion production and beta-2 adrenoceptor desensitization. A positive correlation was found between superoxide anion generation and the "right-shift" in isoproterenol competition isotherm (r = 0.92; p less than 0.01). Desensitization of beta-2 adrenoceptors was not due to superoxide anions per se since incubation of PMNL with superoxide anion scavengers (superoxide dismutase and catalase) did not modify the results.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

Interaction of selected vasodilating beta-blockers with adrenergic receptors in human cardiovascular tissues.

beta- And alpha 1-adrenoceptor antagonist properties of bufuralol, carvedilol, celiprolol, dilevalol, labetalol, and pindolol were investigated in human myocardium and mammary artery using binding techniques and functional studies. In myocardial membranes, beta-adrenoceptor antagonists showed monophasic competition isotherms for [125I]pindolol binding with high affinity (Ki from 1-100 nM), except for celiprolol which displayed a biphasic competition isotherm (pKi = 6.4 +/- 0.06 for beta 1- and 4.8 +/- 0.07 for beta 2-adrenoceptors). Drug interactions with alpha 1-adrenoceptors were evaluated in human mammary artery by [3H]prazosin binding and by measuring contractile responses to norepinephrine (NE). Labetalol and carvedilol showed a moderate affinity for alpha 1-adrenoceptors (pKi = 6.2 +/- 0.01 and 6.1 +/- 0.06, respectively), and inhibited NE-induced contractions (pA2 = 6.93 +/- 0.23 and 8.64 +/- 0.24, respectively). Dilevalol, bufuralol, and pindolol displayed weak effect both in binding (Ki in micromolar range) and functional experiments (pA2 = 5.98, 5.54, and 6.23, respectively). Celiprolol did not show antagonist properties up to 100 microM in functional studies, but displayed a slight affinity for alpha 1-adrenoceptors in binding studies. The data indicate that the vasodilating activity of these beta-adrenoceptor antagonists is caused in some instances by an alpha 1-adrenoceptor antagonism (labetalol, carvedilol), whereas for the others alternative mechanisms should be considered.

Adrenergic beta-Antagonists↗
PubMed1989

Identification of alpha 1-adrenergic receptors on sarcolemma from normal subjects and patients with idiopathic dilated cardiomyopathy: characteristics and linkage to GTP-binding protein.

Discontinuous density sucrose gradient centrifugation was used to isolate membrane vesicles from the left ventricle of three normal subjects (one prospective organ donor and two traffic victims whose hearts were obtained 1 hour after death) and nine patients undergoing cardiac transplantation as a consequence of idiopathic dilated cardiomyopathy. Sarcolemma-enriched subcellular fractions, detected in the interface between 8.55% and 25% sucrose, were identified by the increased activity of Na+,K+-ATPase and by enrichment in beta-adrenergic receptor density. The density of beta-adrenergic receptors was lower in vesicles from diseased hearts (610 +/- 71 fmol/mg protein) than in vesicles from normal hearts (1,410 +/- 226 fmol/mg protein; p less than 0.01). alpha 1-Adrenergic receptors were identified in these membrane vesicles by [3H]prazosin binding. Specific binding of [3H]prazosin was about 50% of the total binding at 1 nM, and alpha 1-adrenergic binding sites were saturable at approximately 3 nM. Scatchard analysis revealed 58 +/- 5 fmol/mg protein (KD = 0.90 +/- 0.08 nM) in pathological hearts and 30 +/- 5 fmol/mg protein (KD = 0.90 +/- 0.03 nM) in normal hearts (p less than 0.01). The displacement curve of (-)-norepinephrine in membrane vesicles from normal hearts delineated one subpopulation of alpha 1-adrenergic receptors; the addition of 0.1 mM GTP did not cause right shift. In membrane vesicles from diseased heart, the displacement curve of (-)-norepinephrine disclosed two subpopulations of alpha 1-adrenergic receptors. A right shift that occurred after addition of GTP showed that in this case alpha 1-adrenergic receptors were functionally coupled with GTP-binding protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Identification and characterization of alpha 1- and beta 2-adrenergic receptors in human liver.

Adrenergic receptors were identified in healthy human hepatic tissue from thirty-nine subjects undergoing elective abdominal surgery by using the specific alpha 1-antagonist [3H]-prazosin and the beta adrenergic antagonist [3H]-dihydroalprenolol ([3H]-DHA). [3H]-prazosin binding to plasma membranes was rapid, of high affinity, saturable and stereospecific with a maximal binding capacity (Bmax) of 74.1 +/- 5.5 fmol mg-1 of protein. The displacement curve for (-)-norepinephrine was better explained by a one-site binding and after addition of GTP 0.1 mM the curve was not right-shifted, suggesting the majority of alpha receptors in healthy human liver are of the alpha 1 subtype and not linked to a GTP-binding protein. [3H]-DHA binding to liver plasma membranes was also rapid, of high affinity, saturable and stereospecific with a Bmax 96.5 +/- 10.3 fmol mg-1 of protein of receptors. Computer aided analysis of the displacement curve of ICI 118,551, a subtype selective beta 2-antagonist (IC50 = 62 +/- 2 nM), indicated a one-site binding, thus, showing that beta adrenergic receptors are of the beta 2 subtype. The displacement curve of [3H]-DHA for (-)-isoproterenol was right shifted by GTP indicating that beta 2 adrenergic receptors are linked to a GTP-binding protein in human liver. These results indicate that alpha 1- and beta 2-receptors co-exist in human liver but only beta 2-receptors are linked to a GTP-binding protein.

Cell Membrane↗
PubMed1986

Alterations in norepinephrine content and beta adrenoceptor regulation in myocardium bordering aneurysm in human heart: their possible role in the genesis of ventricular tachycardia.

On the assumption that alterations in the adrenergic system may play a role in generating ventricular tachycardia in patients with myocardial post-infarction apical aneurysm, we evaluated norepinephrine concentration, number and affinity of both beta 1 and beta 2 adrenoceptors in perianeurysmatic tissue in twelve patients operated upon for congestive heart failure and recurrent sustained ventricular tachycardia. Concentration of norepinephrine in perianeurysmatic tissue was 0.1 +/- 0.05 micrograms g-1 tissue (n = 8), this value being much lower than that found in papillary muscle (n = 10) from patients with mitral valve stenosis (0.8 +/- 0.02 micrograms g-1 tissue) (P less than 0.01). The total number of beta adrenoceptors (71.4 +/- 7.8 v. 48.0 +/- 5.1 fmol mg-1 protein; P less than 0.01) and the percentage of beta 1 subtype were found to be higher in perianeurysmatic tissue (approximately 90%) than in papillary muscle (approximately 68%). Out of twelve patients with aneurysm, beta 2 adrenoceptors had considerably decreased in three patients and were absent in the remaining nine. Decrease in the neuronally released norepinephrine associated with contrasting behaviours of beta 1 and beta 2 adrenoceptors suggests the presence of a profound alteration in the sympathetic innervation of the perianeurysmatic myocardial tissue that may contribute to the genesis of sustained ventricular tachycardia in patients with postinfarction apical aneurysm.

Adult↗
PubMed1985

Characterization of alpha 2-adrenoceptor binding properties of imidazoline-like drugs, azoloazepine derivatives and beta-phenethylamine-like drugs in human platelet membranes.

To characterize the agonist profile of alpha 2-adrenoceptor agonists (imidazoline-like drugs, azoloazepine derivatives, beta-phenethylamines-like drugs) on human platelets, the characteristics of alpha 2-adrenoceptors (KD, Bmax) have been evaluated and the affinity constants measured by displacement technique and computer-assisted analysis of the curves. Furthermore, since alpha 2-adrenoceptor agonists interact with the post-synaptic receptors in a calcium-operated channel, whether the effect of calcium-entry inhibitors (verapamil, nifedipine, diltiazem) is related to a competition with alpha 2-receptors has also been examined. By Scatchard analysis, it was calculated that in human platelets alpha 2-adrenoceptors have KD = 3.45 nM and Bmax = 247 fmol (mg protein)-1. As far as the potency is concerned, imidazoline-like drugs were the most potent agonists in human platelet alpha 2-adrenoceptors (guanabenz IC50 = 8.6 +/- 0.8 X 10(-8), B-HT 920 IC50 = 2.9 +/- 0.3 X 10(-7), (-)-adrenaline IC50 = 3.4 +/- 0.5 X 10(-7)). Among the calcium-entry inhibitors only verapamil antagonized [3H]rauwolscine binding: the effect was stereospecific, (-)-D 600 being more potent than (+)-D 600. Nifedipine and diltiazem did not affect alpha 2-receptor binding. It is concluded that human platelets alpha 2-receptors share the agonist potency profile of other tissues containing alpha 2-receptors (brain, pre-synaptic junction), and that among calcium-entry blockers only verapamil can antagonize alpha 2-agonists. Nifedipine and diltiazem do not appear to interact stereospecifically with alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1984

Comparison of rat and human left ventricle beta-adrenergic receptors: subtype heterogeneity delineated by direct radioligand binding.

Beta adrenergic receptors were identified in rat myocardial left ventricle and human papillary muscle by using the antagonist radioligand 3H-dihydroalprenolol. The number (37.3 and 44.5 fmol/mg of protein, respectively in rat and man), and the KD (1.6 and 2.8 nM, respectively in rat and man) of beta receptors were not significantly different. Adrenergic receptors of both beta 1 and beta 2 subtypes were found to coexist in the left ventricle. The relative proportions of the two beta receptor subtypes were determined by the use of competition radioligand selective binding and computer modelling techniques employing the subtype selective antagonists ICI 118,551 (beta 2 selective) and atenolol (beta 1 selective) in rat or metoprolol (beta 1 selective) in man. The rat left ventricle contained about 74% beta 1 and 26% beta 2 adrenergic receptors, human left ventricle papillary muscles contained about 69% beta 1 and 31% beta 2. Human and rat left ventricles contain both beta 1 and beta 2 adrenergic receptors with similar affinities. Rat might be a model for the study of human myocardial beta adrenergic receptors.

Adult↗
PubMed1984

Evidence for a role of a serum factor stimulated by metoclopramide in regulating aldosterone secretion.

The stimulatory effect of metoclopramide upon aldosterone secretion is independent of the known aldosterone-regulating mechanisms (renin, potassium, adrenocorticotropic hormone), is unrelated to its effect on prolactin and is absent when metoclopramide is directly added to isolated adrenal zona glomerulosa cells. To examine the possibility of a "humoral" mediation of aldosterone stimulation by metoclopramide, we evaluated the effect of serum of 10 normal subjects injected with metoclopramide (10 mg i.v.) on aldosterone production by collagenase-dispersed calf adrenal zona glomerulosa cells. Whereas no effect was observed with serum collected before the injection, serum collected from 5 to 30 min after the injection stimulated aldosterone production. The effect was seen 2.5 min after the injection, was significant at 5 min (P 0.05), 10, 15, 20 and 30 min (P 0.01). The effect disappeared 40 min after the injection, when plasma aldosterone in subjects was still elevated (P 0.01). The biological half-life of the factor (t1/2) is about 12.5 min. A significant correlation was found between the maximal aldosterone response to metoclopramide in vivo and the maximal effect of serum in vitro (r2=0.69;P 0.01). We suggest that metoclopramide stimulates aldosterone production in vivo by the increase in serum of a factor which, in turn, stimulates aldosterone and whose physiological significance remains to be evaluated.

Adrenal Glands↗
PubMed1984

Effects of potassium supplementation on insulin binding and insulin action in human obesity: protein-modified fast and refeeding.

To investigate the role of potassium deficiency in the development of glucose intolerance during caloric deprivation, potassium balance was maintained within normality with oral potassium supplementation in a group of obese subjects who underwent protein-modified fast and the results of the study of carbohydrate metabolism (oral glucose test, insulin receptors on monocytes and peripheral glucose utilization as assessed by euglycaemic clamp) were compared with those obtained in a group of obese subjects admitted to protein-modified fast without potassium supplementation. Caloric deprivation without oral potassium supplementation was followed by a negative potassium balance and a decrease of serum potassium levels; a decrease of the peripheral levels of insulin along with an increase in insulin receptors and a striking reduction of peripheral glucose utilization were also observed. The maintenance of normal potassium balance and normal serum potassium levels with oral potassium-chloride supplementation was associated with higher peripheral levels of insulin (P less than 0.01) and improvement of peripheral glucose utilization (P less than 0.01) whereas the binding of insulin to monocytes was unchanged. The data suggest that potassium depletion during protein-modified fast causes a decrease of the peripheral levels of insulin and a resistance to insulin action at the postreceptors sites which is reversed by potassium supply.

Adult↗