Biomedical subjects

M Thibonnier

Publications and source records attributed to M Thibonnier.

At least 55 records · Page 3Linked to original sources

PubMed1987

Binding characteristics of atrial natriuretic factor and the production of cyclic GMP in kidneys of Dahl salt-sensitive and salt-resistant rats.

The binding of atrial natriuretic factor (ANF) was studied in kidney membranes of inbred salt-sensitive (S) and inbred salt-resistant (R) rats on high or low salt diet. Important differences between strains were seen in the rate of dissociation of ANF from its renal receptor(s) and this was dependent on salt (NaCl) intake. On low salt diet ANF dissociation rates were similar between strains. R rats responded to high salt diet with a decrease in the rate of ANF dissociation from its renal receptor, but ANF dissociation in S rats was not altered by dietary salt. Receptor density was similar between strains. Basal cGMP production was slightly higher for renal membranes of S rats, but ANF stimulation of cGMP production was similar between strains and was not influenced by salt intake in either strain. Since strain-related salt-induced changes in ANF-receptor binding kinetics were not reflected in any strain-related salt-induced changes in ANF stimulated cGMP production, it is tentatively concluded that the ANF receptor likely to be different between S and R strains is the ANF receptor not linked to cGMP production.

Animals↗

PubMed1987

[Vasopressin, the antidiuretic hormone].

Vasopressin is actively involved in the regulation of blood pressure to the same degree as catecholamines and the renin angiotensin aldosterone system are, especially in stressful situations. Vasopressin induces and increase in blood pressure when mechanisms buffering its potent vasoconstrictor effect are altered. Vasopressin binds to specific membrane receptors classified into two main types. The V1 receptors found in blood vessels, platelets and hepatocytes are linked to two intra-cellular messengers, namely 1,2 diacylglycerol and 1,4,5 inositol triphosphate which stimulate protein kinase C and calcium-calmodulin kinase in the presence of calcium. V2-renal receptors stimulate the production of cyclic AMP which activates protein kinase A. Subsequently, the actin network is altered and particles containing pores agregate at the cell surface to produce water molecules reabsorption. Vasopressin modifies human hemostasis via platelet aggregation, stimulation of the three fractions of factor VIII, of factor XII and of fibrinopeptide A. These properties were used to treat hemostasis abnormalities seen in Von Willebrand's disease and hemophilia. There is a feed-back loop between vasopressin and the atrial natriuretic factor: vasopressin stimulates atrial natriuretic factor release via a V1 action whereas the atrial natriuretic factor reduces vasopressin release and inhibits vasopressin antidiuretic action.

Atrial Natriuretic Factor↗

PubMed1987

Solubilization of human platelet vasopressin receptors.

The human platelet membrane receptor for vasopressin (AVP) has been solubilized with the cholic acid derivative detergent 3-( [3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate. Rapid and simple separation of free tritiated AVP ( [3H]AVP) from the solubilized receptor-hormone complex was done by filtration through polyethylenimine-treated filters. [3H]AVP binds to this soluble receptor with an equilibrium dissociation constant of 11.03 +/- 1.86 nM and a maximal number of binding sites = 288 +/- 66 fmol/mg protein while the corresponding values of the membrane-bound receptor are 1.62 +/- 0.21 nM and 237 +/- 38 fmol/mg of protein, respectively. The Ki value for native AVP derived from competition experiments is 11.02 +/- 2.05 nM for the soluble receptor. Competition experiments with specific vascular and renal antagonists confirm that the solubilized receptor belongs to the V1-vascular subtype.

Arginine Vasopressin↗

PubMed1987

The human platelet vasopressin receptor and its intracellular messengers: key role of divalent cations.

The effects of divalent cations on human platelet vasopressin receptor binding characteristics and effects of receptor occupancy on endogenous protein phosphorylation were investigated. Binding of vasopressin to its receptor is modulated by both the nature and the concentration of ions. Whatever the cation present, guanosine 5'-triphosphate or 5' guanylylimidodiphosphate do not alter the receptor binding characteristics. In the presence of extracellular calcium, vasopressin stimulates the phosphorylation of a 45,000-dalton protein and to a lesser degree of a 20,000-dalton protein following a pattern observed with thrombin and 12-O-tetradecanoylphorbol-13-acetate, a phorbol ester. Phosphorylation is also stimulated by a V1 vascular agonist, but not V2 renal agonists, and is more potently blocked by a V1 vascular antagonist than by a V2 renal antagonist. These results suggest that human platelets bear typical V1 vascular vasopressin receptors which stimulate the phosphorylation of specific substrates of protein kinase C and myosin light-chain kinase.

Arginine Vasopressin↗

PubMed1986

Characterization of vasopressin receptors of rat urinary bladder and spleen.

By use of tritiated arginine-8-vasopressin (AVP), vasopressin specific binding sites were detected on Sprague-Dawley rat urinary bladder and spleen. In both tissues, one class of high-affinity binding sites was characterized with an equilibrium dissociation constant of 1.61 +/- 0.22 and 1.91 +/- 0.16 nM and a maximal binding capacity of 155 +/- 5 and 110 +/- 11 fmol/mg of protein, for bladder and spleen, respectively. In both tissues, several experimental arguments suggest that these receptors belong to the V1-vascular type: Highly significant correlations were found between the relative agonistic vasopressor activities of eight AVP agonists and their relative abilities to inhibit [3H]AVP binding to the receptors, whereas no such relationship existed when antidiuretic activities were considered. The same profile was also observed with the antagonistic activities of five AVP antagonists. Moreover, AVP (10(-12)-10(-5) M) did not modify the basal cyclic AMP production in either tissue. As cyclic AMP is known to respond to V2 stimulation, the data suggest that the receptors measured are the V1 type. In Dahl rats the receptor characteristics were modulated by salt diet. More interestingly, the number of spleen vasopressin binding sites was always lower in Dahl salt-resistant animals than in the Dahl salt-sensitive animals receiving either a sodium deficient or a 1% NaCl or an 8% NaCl-containing diet. The exploration of vasopressin receptors regulation should facilitate the comprehension of the role played by AVP in different models of experimental hypertension.

Animals↗

PubMed1986

[Regulation of V1-vasopressinergic receptors in the rat].

Using tritiated vasopressin, specific binding sites for vasopressin were identified on splenic membranes of Sprague-Dawley rats. One class of high affinity receptors was characterized with an equilibrium dissociation constant of 1.91 +/- 0.16 nM and a maximal binding capacity of 110 +/- 11 fmol/mg of protein. Several experimental evidences suggest that these receptors belong to the V1-vascular type: The affinity of 8 vasopressin agonists for the receptor is correlated to their vasopressor activity in vivo whereas no such relationship exists when their antidiuretic activity is considered. The affinity of 5 vasopressin antagonists for the receptor is correlated to their antivasopressor activity in vivo whereas no such relationship exists when their antidiuretic activity is considered. Vasopressin does not stimulate cyclic AMP production of splenic membranes. The regulation of these receptors was studied in sodium-sensitive (S) and sodium-resistant animals (R) of Dahl receiving a special diet (0.1 or 8% NaCl) for two weeks. In both strains of animals, the number of receptors is smaller in R animals than in S animals, whatever the diet ingested. Splenic membranes of rat bear easily accessible V1-vasopressinergic receptors. These receptors are modulated by sodium intake and the difference in receptor number between S and R rats could explain the increased vascular reactivity of S animals to vasopressin.

Animals↗

PubMed1985

[Treatment of human arterial hypertension. Role of calcium channel inhibitors].

The vasoconstrictor effects of several hormonal systems, including catecholamines, the renin-angiotensin-aldosterone system and vasopressin, are mediated by calcium. Calcium channel inhibitors acting on smooth muscle therefore exert a potent vasodilator effect which can be of benefit for the treatment of human arterial hypertension. Single doses of nifedipine or verapamil induce a rapid and pronounced fall in blood pressure and can be used as emergency treatments of acute, severe hypertension. Blood pressure response to these drugs can be predicted from a variety of parameters, such as peripheral arterial resistance, age and activation of the renin-angiotensin system. The anti-hypertensive activity of calcium channel inhibitors is maintained in long-term treatments, whether they are administered alone or associated with one or two other drugs, as in hypertensions difficult to control. The advent of new compounds with long-lasting effects should encourage the development of this new category of anti-hypertensive agents.

Antihypertensive Agents↗

PubMed1985

Effect of postoperative extradural morphine on ADH secretion.

The effect of extradural morphine on antidiuretic hormone (ADH) secretion was assessed for the first 6 h after surgery in three groups of patients. Surgery was conducted under extradural bupivacaine: thereafter patients in group I (n = 6) received further injections of bupivacaine, patients in group II (n = 6) received an extradural injection of morphine and in patients in group III (n = 5) both bupivacaine and morphine, were administered extradurally. In group I, plasma ADH values remained unchanged throughout the study. In contrast, in the two groups of patients receiving extradural morphine a delayed and stepwise increase in plasma ADH concentration was documented. These results indicate that extradural morphine induces ADH secretion and suggest that this effect is the consequence of the migration of morphine to the brainstem.

Adult↗

PubMed1985

Characterization of human platelet vasopressin receptors.

Using tritiated arginine-8-vasopressin [3H]AVP, vasopressin-specific binding sites were detected on human platelet membranes. One class of high-affinity binding sites was characterized with an equilibrium dissociation constant of 1.01 +/- 0.06 nM and a maximal binding capacity of 100 +/- 10 fmol/mg of protein (n = 12). Highly significant correlations were found between the relative agonistic (r = 0.87, P = 0.002) or antagonistic (r = 0.99, P = 0.007) vasopressor activities of a series of 13 AVP structural analogues and their relative abilities to inhibit [3H]AVP binding to platelet receptors whereas no such relationship existed when antidiuretic activities were considered (r = 0.28, P = 0.47). AVP did not stimulate cyclic AMP production of human platelets; on the contrary, high AVP concentrations (10(-6) M) inhibited cyclic AMP production measured in basal and prostaglandin E1-stimulated conditions. AVP caused intact platelet aggregation with a half-maximal aggregation (EC50) of 28 +/- 2 nM. This effect was more potently reversed by the specific vascular antagonist d(CH2)5Tyr(Me)AVP (pA2 = 8.10 +/- 0.23) than by the specific renal antagonist d(CH2)5IleuAlaAVP (pA2 = 6.67 +/- 0.12). The pA2 values of these two antagonists in platelets are in close agreement with the pKi values obtained in competition experiments (respectively 8.59 and 6.93) and with pA2 values reported in the literature for their in vivo antivasopressor activity (respectively 8.62 and 6.03). The observation that human platelets bear AVP receptors belonging to the vascular class suggests that platelet receptors can be used to further explore the role of vasopressin in cardiovascular homeostasis.

Adenylyl Cyclases↗

PubMed1985

Acute inhibition of the renin-angiotensin system: interest and limits to detect surgically curable hypertension.

The acute blockade of the renin-angiotensin system has been made it possible to investigate its role in the maintenance of blood pressure and aldosterone secretion in normotensive and hypertensive subjects. The administration of saralasin or captopril and, in the near future, of renin inhibitors induces a fall in blood pressure that is variable from one subject to the other according to the sodium balance and the level of activation of the system. These blockers also decrease the angiotensin II-dependent aldosterone production and increase renin secretion according to the circulating level of angiotensin II and the functional state of adrenal and juxtaglomerular receptors. In practice the definition of an abnormal response to renin-angiotensin blockade is difficult to define precisely, but the hypotensive effect has been tentatively used for the diagnosis of renin-dependent hypertension, especially renovascular hypertension and primary hyperaldosteronism. In renal artery stenosis the most convincing results mainly concern the lateralization of an abnormal unilateral renin secretion, which is potentiated by an acute blockade of the renin-angiotensin system. The acute administration of converting enzyme inhibitor is also useful to detect the absence of decrease in plasma aldosterone, which is characteristic of a solitary tumor or of other anatomical and functional disorders of the adrenal glands.

Aldosterone↗

PubMed1985

[Evaluation of the antihypertensive effect of capsule and tablet forms of nifedipine in moderate hypertension].

The antihypertensive effect of nifedipine which has a preferential antagonistic action in the calcium channels of vascular smooth muscle was studied in several series of patients. A preliminary double-blind placebo study in 7 moderate hypertensive patients showed that a 10 mg capsule of nifedipine induced a significant fall in systolic and diastolic pressures (max. - 14%) which persisted for 3 hours in ambulatory patients. A crossover trial against captopril (1 mg/kg) in 12 moderately hypertensive patients illustrated the antihypertensive effects of 2 capsules (20 mg) of nifedipine. The onset of action was faster and the effects, which were more intense than those of captopril, lasted several hours. A double-blind crossover trial against placebo was performed with 3 doses (20, 40, 60 mg) of a tablet form of nifedipine in 8 hypertensive patients. The degree and duration of the fall in blood pressure depended on the dosage: - 11% and 7 hours with 20 mg; - 14% and 10 hours with 40 mg and - 18% and 12 hours with 60 mg. This study demonstrated a direct relationship between the plasma concentration of nifedipine and the associated fall in mean blood pressure. Finally, in a chronic study of 20 hypertensive patients receiving 2 X 20 mg daily of the tablet form of nifedipine alone for 3 weeks, an 8% fall in blood pressure was observed, normalising the values in 50% of cases. Patients who remained hypertensive were given 2 X 40 mg of the nifedipine tablets for another 3 weeks and an additional 7% fall in blood pressure was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗

PubMed1984

Improved diagnosis of unilateral renal artery lesions after captopril administration.

Captopril was administered (1 mg/kg of body weight) to 37 unselected hypertensive patients undergoing bilateral renal vein catheterization to determine its safety and efficacy in diagnosing hypertension related to unilateral renal artery lesions. In the 18 patients who had a unilateral renal artery lesion demonstrated by angiography, the ratio of plasma renin activity of the involved to uninvolved renal vein rose significantly after administration of captopril, whether or not patients were taking antihypertensive medication. This postcaptopril ratio differentiated cases of unilateral lesions from cases of bilateral lesions or absence of lesions without any overlap. The test was well tolerated despite occasional large drops in blood pressure. These data show that converting enzyme inhibition increases the diagnostic accuracy of renal vein catheterization by increasing the difference between the amount of plasma renin secreted by the two kidneys in cases of unilateral renal artery lesions.

Adult↗

PubMed1984

Pharmacokinetic-pharmacodynamic analysis of unbound disopyramide directly measured in serial plasma samples in man.

The pharmacokinetics and pharmacodynamics of the antiarrhythmic drug, disopyramide, were investigated in 12 volunteers who took 300 mg doses of 3 different capsule preparations and an aqueous oral solution of the drug at 1-week intervals. Concentrations of drug unbound to plasma proteins were measured by a sensitive immunoenzyme assay after ultrafiltration of plasma samples taken serially after dosing. QT interval was measured on serial ECG recordings with correction for changes in heart rate. Unbound concentrations of disopyramide were modelled by an open one-compartment pharmacokinetic model with a zero-order absorption rate and a lag time. There was no significant difference in parameter estimates between the four preparations, except for the lag time, which was significantly shorter for the solution preparation. The saturable protein binding of disopyramide was described by a hyperbolic model including a specific binding site and additional nonspecific binding. The pharmacodynamic relationship between unbound drug concentration and QT prolongation was fit by a simple linear model. This fit was better using unbound concentration of the drug than using total concentrations.

Adult↗

PubMed1984

Osmoregulation and renal effects of vasopressin in normal and mildly hypertensive subjects.

A 2-hr 0.85 M hypertonic saline infusion was administered to ten normotensive volunteers and ten mildly hypertensive subjects to compare in these two groups the osmoregulation of vasopressin and the effect of this hormone on BP. No significant alteration in BP was observed in either group, despite markedly enhanced vasopressin levels. Significant positive correlations between plasma vasopressin (AVP) and plasma osmolality (POsm) were demonstrated in the controls (AVP = -70 + 0.25 POsm, r = 0.68, P less than 0.0001) and in the hypertensive group (AVP = -46 + 0.16 POsm, r = 0.59, P less than 0.0001). However, the vasopressin response to the osmotic stimulus was buffered in the hypertensive subjects; the slope of the regression line between plasma vasopressin and plasma osmolality was less steep in hypertensive subjects than in normotensive subjects (0.16 vs. 0.25, P less than 0.018). During the saline infusion the renal parameters were identical in the two groups. Finally, in mild hypertension, the osmoregulation of vasopressin was preserved but buffered and renal sensitivity to this hormone was normal. An osmotically induced physiological increase in vasopressin did not raise BP in either normotensive or mildly hypertensive subjects.

Adult↗

PubMed1983

[A simple diagnostic test for primary hyperaldosteronism].

Plasma aldosterone levels were measured as part of two suppression tests in 31 hypertensive patients on normal sodium diet and without recent treatment. Thirteen patients had essential hypertension, 6 had probable bilateral adrenal hyperplasia and 12 had confirmed Conn's adenoma. In the first test, aldosterone levels were measured in the supine patients, then after infusion of 2 litres of isotonic saline over 2 hours. In the second test, aldosterone levels were measured before and 3 hours after oral administration of Captopril 1 mg/kg. Plasma aldosterone values superior to 360 pmol.l-1 after sodium load or to 665 pmol.l-1 after Captopril were characteristic of primary hyperaldosteronism due to adenoma. The test using Captopril has the advantages of being rapid, of avoiding acute blood volume expansion and of being applicable to all forms of hypertension, including severe ones.

Adrenal Glands↗

PubMed1983

Acute antihypertensive effect and pharmacokinetics of a tablet preparation of nifedipine.

A tablet formulation of nifedipine was given to 8 hospitalized hypertensive men, W.H.O. stage I or II, mean age 45 years. After an initial placebo test, nifedipine 20, 40 or 60 mg was given in random order at 72-h intervals, in a single administration crossover study. The placebo and the active drug were given at 8 a.m. Blood pressure and heart rate were measured twice by the same observer, every 20 min from 7 to 8 a.m., and then hourly until 8 p.m., first in recumbency and again after 1 min of standing upright. Plasma nifedipine was assayed in samples taken hourly from 8 a.m. to noon, every 2 h from noon to 8 p.m., and 24 and 48 h after drug administration. All 3 doses significantly lowered blood pressure; the fall during recumbency was significantly larger (-18%) and lasted longer (12 h) after 60 mg than after 20 mg (-11% and 7 h). All 3 doses caused a similar increase in heart rate (+29 to +38%), which reached its maximum after 2 h and lasted for 5 h. The maximum plasma concentration and the area under the plasma concentration--time curve were dose-dependent despite large inter-subject variation. Absorption, bioavailability and elimination were linear between the 20 and 60 mg doses. Plasma nifedipine levels were strongly correlated with the concomitant decrease in mean arterial blood pressure (r = 0.61, p less than 0.001). Four patients experienced mild side effects (headaches, flushes, drowsiness or weakness). This tablet form of nifedipine has a potent antihypertensive action which lasts longer than that of the capsule presentation.

Adult↗

PubMed1983

[A new diagnostic test for primary tumoral hyperaldosteronism].

Plasma aldosterone levels were measured during two tests of inhibition in 31 hypertensive patients (13 essential hypertension, 6 bilateral adrenal hyperplasia and 12 documented Conn adenomas) on normal salt diets after withdrawal of all therapy: 1--before and after intravenous infusion of 2 I normal saline in two hours; 2--before and three hours after administration of 1 mg/kg of Captopril. Plasma aldosterone levels greater than 360 pmol/I after salt loading, or greater than 748 pmol/I after Captopril is characteristic of primary tumoral hyperaldosteronism. Apart from the rapidity of the test, Captopril is well-tolerated, does not require acute volume expansion and can be carried out in all forms of hypertension, even in severe cases.

Adenoma↗

PubMed1983

[Primary hyperaldosteronism: diagnostic value of the administration of a single dose of captopril].

The diagnosis of primary tumoral hyperaldosteronism is based on a series of hormonal parameters, measured under resting conditions and after stimulation. The results of the administration of a single dose of a converting enzyme inhibitor, Captopril (1 mg/kg body weight per os), can support this diagnosis. In contrast to essential hypertension and hyperaldosteronism due to bilateral adrenal hyperplasia, plasma aldosterone levels remain unchanged in tumoral hyperaldosteronism after administrating Captopril. This is a simple test which can be performed in a morning which clearly differentiated 8 cases of primary tumoral hyperaldosteronism from 6 cases of adrenal hyperplasia.

Adenoma↗