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Biomedical subjects

C Thuillez

Publications and source records attributed to C Thuillez.

At least 127 records · Page 7Linked to original sources
PubMed1982

Theophylline kinetics and ventilatory flow in bronchial asthma and chronic airflow obstruction: influence of erythromycin.

The kinetics and the effects on the ventilatory function peak expiratory flow rate (PEFR) of a single 600-mg oral dose of theophylline were investigated in 46 adult patients with bronchial asthma (BA) and in 16 adult patients with chronic airflow obstruction (CAO). In the former, theophylline induced an early and potent bronchodilatation (60% rise in PEFR), the kinetics of which correlated with plasma concentration. Theophylline was also effective in patients with CAO, but the magnitude of its bronchodilator effect was less than in those with BA: this was despite plasma concentrations of much the same order. In adult patients with BA (but not with CAO) theophylline plasma levels and bioavailability are higher after simultaneous erythromycin dosing.

Adult↗
PubMed1981

Preload changes modify systolic pressure-diameter relations in the conscious dog.

The behavior of the end-systolic ventricular diameter was examined during control state, atrial pacing, and acute volume loading (VL) followed by methoxamine infusion in conscious dogs instrumented with a left ventricular micromanometer and ultrasonic crystals measuring internal diameter and wall thickness. Heart rate and systolic pressure were markedly increased by maximal VL but for moderate VL were minimally modified. Moderate VL increased end-diastolic diameter by 5% and end-systolic diameter by 2.9% with a significant increase of systolic stress. There was no common final pathway of shortening in the force-velocity-length diagram for different preloads. During methoxamine infusion, the end-systolic pressure-diameter points described a linear regression but points obtained during atrial pacing before VL were significantly shorter. We conclude that VL increases the total loading of the heart producing a lengthening of the end-systolic diameter when end-diastolic diameter is increased. This reduces the expression of the Starling mechanism and suggests caution when interpreting end-systolic pressure-diameter relations and derived indices for significantly different end-diastolic diameters.

Animals↗
PubMed1980

Beta-adrenoceptor blocking effects and pharmacokinetics of betaxolol (SL 75212) in man.

1 The pharmacological effects and the pharmacokinetics of betaxolol (SL 75212), a new beta-adrenoceptor blocking agent, were compared with those of propranolol and a placebo in a double-blind trial involving six healthy volunteers. 2 Heart rate (HR), myocardial contractile force (MCF), systolic blood pressure (SBP) and peak expiratory flow rate (PEFR) were measured at rest and during vigorous exercise before and at intervals up to 25 h after oral administration of the drugs. In addition, plasma renin activity (PRA) at rest and blood levels of betaxolol and propranolol were determined. 3. Betaxolol proved to be a potent and long-lasting beta-adrenoceptor blocking drug, devoid of intrinsic beta-sympathomimetic activity. Its beta-adrenoceptor blocking action was shown to four-fold that of propranolol at the cardiac and renal levels and to last at least 25 h after drug intake. 4 The peak blood level of betaxolol was reached 2 to 4 hr after its administration, the first-pass loss is likely to be low and the half-life is 12.3 h. These pharmacokinetic data are perfectly consistent with the long duration of the pharmacological effects of betaxolol in man.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Lack of impairment of nitric oxide-mediated responses in a rat model of high-renin hypertension.

1. Angiotensin (Ang) II triggers the expression of a pro- oxidant phenotype in the vascular wall, suggesting that activation of the renin-angiotensin system (RAS) causes endothelial dysfunction in various pathological situations, such as hypertension. However, this hypothesis has been mostly tested in a setting of exogenous administration of AngII. 2. We tested the hypothesis of a role for endogenous activation of the RAS leading to oxidant stress and endothelial dysfunction in a high-renin model of hypertension (i.e. two-kidney, one-clip hypertension) in rats. One month after clipping or sham surgery, aorta were isolated from untreated rats or rats treated by the angiotensin AT1 receptor antagonist irbesartan (10 mg/kg per day). Mesenteric artery segments were also isolated from normotensive or hypertensive rats. 3. Hypertension reduced the relaxations to acetylcholine but did not affect the ratio of contractions to phenylephrine in the presence compared with the absence of a nitric oxide (NO) synthase inhibitor, used as an index of basal release of NO. 4. The free radical scavenger tempol reduced the contractions to phenylephrine in the absence, but not in the presence, of an inhibitor of NO synthesis. This index of free radical-mediated degradation of NO was not affected by hypertension. In parallel, hypertension did not affect the expression of p22phox, a component of the free radical generating enzyme reduced nicotinamide adenine dinucleotide phosphate oxidase. 5. Chronic treatment with the AT1 receptor antagonist decreased blood pressure, moderately improved the response to acetylcholine, but did not affect basal NO release in hypertensive rats, although it did increase basal NO release in normotensive rats. 6. Thus, this model of hypertension is characterized by an impaired stimulated NO release but not of basal NO release in isolated arteries. Furthermore, there was no functional evidence of an increased oxidative stress-mediated impairment of NO release. This is not in favour of a direct link between activation of the RAS and development of endothelial dysfunction in experimental hypertension.

Angiotensin Receptor Antagonists↗
PubMedDate not supplied

Differential effects of verapamil and diltiazem on regional blood flow and function in the canine normal and ischemic myocardium.

We studied the effects of verapamil and diltiazem on regional myocardial blood flow (RMBF, tracer microspheres) and function during ischemia in 18 open-chest dogs. Instrumentation included left ventricular and aortic pressure transducers, an electromagnetic flowmeter, and a hydraulic occluder on the circumflex coronary artery; sonocardiometry measured shortening of severely ischemic, moderately ischemic, and nonischemic subendocardial segments (% delta L). Measurements were made in the control state, 10 min after subtotal coronary stenosis, and 10 min later in control (n = 6, group I), verapamil-treated (0.3 mg/kg i.v.) (n = 6, group II), and diltiazem-treated (0.3 mg/kg i.v.) (n = 6, group III) dogs. The effects of coronary stenosis were similar in all three groups and after 20 min of coronary stenosis there were no further modifications of any parameter in group I. Verapamil and diltiazem produced similar reductions in heart rate and mean aortic pressure. In severely ischemic zones, RMBF was similarly decreased [0.22 +/- 0.03-0.12 +/- 0.04 ml/min/g, p less than 0.01 (verapamil) and 0.21 +/- 0.02-0.12 +/- 0.02 ml/min/g, p less than 0.01 (diltiazem)] without any change in function. In moderately ischemic zones, verapamil did not modify RMBF and function while diltiazem increased RMBF from 0.43 +/- 0.05 to 0.96 +/- 0.18 ml/min/g (p less than 0.05) and % delta L from 3.5 +/- 1.2 to 6.2 +/- 1.2 (p less than 0.05). In nonischemic zones, although RMBF was increased by 42.9 +/- 13.6% (p less than 0.05) with verapamil and 156.9 +/- 33.8% (p less than 0.01) with diltiazem, % delta L remained unchanged. Thus, (a) diltiazem and verapamil, although increasing flow, do not affect function in nonischemic areas; (b) diltiazem and verapamil exert almost no effects either on flow or on function in severely ischemic areas; and (c) while verapamil shows no effects on flow and function, diltiazem increases both parameters in marginal areas demonstrating its ability to preserve the viability of this zone.

Animals↗
PubMedDate not supplied

Chronic decrease in flow contributes to heart failure-induced endothelial dysfunction in rats.

Chronic heart failure (CHF) impairs endothelium-dependent, nitric oxide (NO)-mediated dilation. This decreased dilation may be partly secondary to the chronic decrease in blood flow, but this hypothesis has not yet been tested. Thus, we assessed whether a localized, chronic increase in blood flow in vivo reverses endothelial dysfunction of small arteries in rats with CHF. Two months after coronary artery ligation or sham surgery, second-order side branches of the superior mesenteric artery were ligated in order to obtain persistently elevated blood flow (HF) in the adjacent first-order side branch compared with normal vessels (NF). One month later, responses to acetylcholine and flow-mediated vasodilatation (FMD) were assessed in vitro in an arteriograph. Chronic heart failure induced a decrease in mesenteric blood flow (374 +/- 25 and 305 +/- 27 micro L/min for sham and CHF, respectively; P < 0.05). Neither CHF nor the chronic increase in flow affected the responses to acetylcholine. Chronic heart failure decreased FMD (maximal response in sham and control 34 +/- 6 and 13 +/- 4%, respectively; P < 0.05). Chronic increases in blood flow did not modify FMD in sham, but restored FMD in CHF rats (28 +/- 4%; P < 0.05 vs CHF NF). The restored response was abolished by an inhibitor of NO synthesis (N(G)-nitro-l-arginine). Chronic heart failure did not affect the abundance of mesenteric endothelial NO synthase (eNOS) mRNA. A chronic increase in flow significantly increased the abundance of eNOS mRNA in sham rats, but only moderately and non-significantly in CHF rats. Thus, endothelial dysfunction of small arteries in CHF appears to be largely the consequence of the chronic decrease in flow.

Acetylcholine↗
PubMedDate not supplied

Angiotensin II receptor blockade unmasks a depressor response to endothelin antagonists in rats.

Endothelin (ET) antagonists do not decrease blood pressure in normal rats. Since angiotensin II (AII) and ET both induce smooth muscle cell contraction through the same transduction pathways we designed experiments to assess whether blockade of the renin angiotensin system would unmask a vasodilatory response to ET receptor antagonists in rats. For this purpose, we tested the effect on arterial blood pressure of the mixed ETA-ETB receptor antagonist bosentan or of the ETA antagonist BQ-123 in the absence or the presence of the AII receptor antagonist losartan. In control conditions bosentan did not affect arterial blood pressure. In contrast, in losartan-pretreated rats, bosentan induced a marked, dose-dependent decrease in arterial pressure (% change after bosentan 10 mg/kg: control -3 +/- 3, losartan -32 +/- 6; cilazapril -28 +/- 3). Similarly, BQ-123 decreased blood pressure in losartan-pretreated but not in control rats. Bosentan also increased the hypotensive effect of losartan in conscious, normotensive rats. The hypotensive effect of the combination of bosentan and losartan was not associated with any changes in cardiac output or heart rate, and thus was entirely due to a decrease in total peripheral resistance. We conclude that blockade of angiotensin II, AT1 receptors unmasks a vasodilator response to ET antagonists. This suggests that endogenous ET plays an active role in the maintenance of arterial blood pressure in rats which can be unmasked by a concomitant inhibition of the renin angiotensin system.

Anesthesia↗
PubMedDate not supplied

Evaluation of the determinants of flow-mediated radial artery vasodilatation in humans.

The relative importance of the early peak response during hyperaemia and of the duration of the hyperaemic phase (t1/2: blood flow velocity half time and AUCt1/2: area under the curve of flow velocity at t1/2) in the magnitude of the flow-dependent vasodilatation of the radial artery was determined in humans. Radial artery diameter was measured continuously in 18 healthy volunteers using an echo-tracking system coupled to a Doppler device for the measurement of the radial blood flow. In 9 subjects, arterial parameters were measured at baseline and during 3 hyperaemic tests performed after 2, 5 or 10 minutes of ischaemia. Reproducibility of the measured parameters was studied in 9 other subjects. Radial artery diameter, AUCt1/2 and t1/2 increased proportionally with the duration of ischaemia. In contrast, the peak flow response was already maximal after 5 minutes of ischaemia. The regression analysis showed that the best fit model after stepwise analysis only included t1/2 (r = 0.85, p < 0.001). There was no correlation between the peak flow values and the duration of hyperaemia (r = 0.29, p = 0.14). These results demonstrate that conduit arteries postischaemic flow-dependent vasodilatation in humans is both determined by the peak value and by the duration of the hyperaemic phase and suggest that these two components must be considered when comparing this index of NO release between different groups of subjects.

Adult↗
PubMedDate not supplied

[Oxidative stress and endothelial dysfunction in heart failure].

Chronic heart failure is characterized by increased vascular systemic resistances secondary to activation of various vasoconstrictor systems and to decreased endothelium-dependent vasodilatation. Endothelial dysfunction, described both in animals and in humans, may be caused by an increased inactivation of nitric oxide (NO) by reactive oxygen species, leading to decreased NO bioavailability and impaired vasodilatation. Increased levels of free radicals in heart failure may result either from increased production or a decrease in the cellular antioxidant reserves. Free radicals are produced by three enzymatic systems: NADH/NADPH oxidase (after stimulation by angiotensin II or TNF-alpha), xanthine oxidase or endothelial NO-synthase (NOS) itself. However, oxidative stress alone cannot explain endothelial dysfunction. Other mechanisms involved in the regulation of the production of NO (e.g. decreased expression and/or activity of the NOS) and/or changes in production of vasoconstrictors may participate in this impaired endothelium-dependent vasodilatation in heart failure.

Animals↗
PubMedDate not supplied

[Coronary endothelial dysfunction after ischemia-reperfusion: mechanisms and possibilities for protection].

Although cardiac ischaemia-reperfusion is well known as a disease of the myocytes, it is now clear that its consequences also extend to the vascular wall and especially to the endothelial cells. Using a rat model of ischaemia-reperfusion in vivo, we evidenced an impairment of the NO-dependent relaxation to acetylcholine of coronary artery segments. Moreover, we showed that cultured endothelial cells submitted to anoxia/reoxygenation displayed an increased neutrophil adhesion, associated with an increased expression of adhesion molecules, probably responsible for the endothelial injury. In this context, we focused on the concept of endogenous protection against ischaemia, i.e. preconditioning, and demonstrated that endothelial dysfunction could be reversed by both the early and the delayed phase of preconditioning. The delayed endothelial preconditioning mechanism appears to involve complex interactions between NO and free radicals, leading to delayed improvement of NO production and decreased neutrophil adhesion to the endothelium. Identification of these mechanisms may lead to the development of new endothelial protective agents in pathophysiological situations associated with endothelial dysfunction.

Animals↗
PubMedDate not supplied

[Endothelin. A new class of vasoactive peptides].

Endothelin (ET) is a novel vasoactive peptide occurring in 3 isoforms (ET1, ET2, ET3) in humans. Derived from vascular endothelium cells, ET arises from a precursor peptide and exerts diverse actions through specific receptors. ET possess a wide spectrum of activities: a potent vasoconstrictor activity but also contraction of nonvascular smooth muscles (air-way, intestinal, urinary) or mitogenic actions, renal and endocrine effects. The physiological and/or physiopathological roles of endothelin is still unclear, but ET may play a part in the genesis of some vascular diseases as atherosclerosis, forms of hypertension or may be implicated in the pathogenesis of vasospasm.

Animals↗
PubMedDate not supplied

[Hand skin heating: a new method for the evaluation of conduit artery endothelial function in insulin-dependent diabetic patients].

The presence of an altered endothelium-mediated flow-dependent dilatation (FDD) of peripheral conduit arteries in insulin-dependent diabetic patients without microangiopathy is still controversial. We studied 10 normotensive and non atherosclerotic insulin-dependent diabetic patients (D group) without complication (neuropathy, microalbuminuria or neuropathy) and 10 control subjects (C group) matched for age, sex and BMI. Radial artery diameter (RAD, echotracking) and flow (RAF, Doppler) were measured at baseline and during FDD in response to distal hand skin heating (from 34 to 44 degrees C). a method developed to increase RAF by stable steps by decreasing gradually hand skin vascular resistance. Endothelium-independent dilatation was evaluated by administration of glyceryl trinitrate (GTN: 0.3 mg spray). At baseline, there was no difference between group for RAF (C: 18 +/- 5 vs D: 18 +/- 2 mL/min; NS) and RAD (C: 2.51 +/- 0.12 vs D: 2.54 +/- 0.07 mm; NS). Heating induced in the diabetic group a smaller increase in RAF (C: 473 +/- 126% vs D: 262 +/- 63%; p<0.05) and RAD (C: 22.6 +/- 2.6% vs D: 16.1 +/- 1.8%; p<0.01). This last result remains significant when the increase in RAF was included into the analysis of RAD variation during heating (p<0.05). GTN-induced dilatation was similar in the 2 groups. Our results obtained by use of the hand skin heating method demonstrate the presence of an abnormal arteriolar skin reactivity and an altered peripheral conduit artery endothelium-dependent dilatation in uncomplicated insulin-dependent diabetic patients. The early identification of these anomalies, with negative prognostic value, could contribute to the management of these patients.

Adult↗
PubMedDate not supplied

[Role of vascular calcium-activated potassium channels in the regulation of human peripheral conduit artery diameter].

The role of an endothelium-derived hyperpolarizing factor (EDHF), acting through the opening of vascular calcium-activated potassium (K(Ca)) channels, in the regulation of the basal diameter of human peripheral conduit arteries has never been investigated in vivo. We measured in 7 healthy subjects the effect of the local infusion of an inhibitor of K(Ca) channels, tetraethylammonium chloride (TEA, 9 micromol/min, 8 min), on radial artery diameter (echotracking) and flow (Doppler). Endothelium-independent dilatation was assessed before and after TEA using sodium nitroprusside (SNP: 5, 10 and 15 nmol/min, 3 min each). TEA induced a decrease in radial artery diameter (2.65 +/- 0.09 to 2.52 +/- 0.09 mm: p < 0.05) and flow (9.4 +/- 1.2 to 7.4 +/- 1.1 ml/min; p < 0.01) without modification in the radial artery dilatation in response to SNP (NS). The decrease in radial artery diameter was still significant even when the decrease in flow was taken as covariate into analysis (p < 0.05). These results demonstrate the role of vascular K(Ca) channels in the regulation of basal peripheral conduit artery diameter and arteriolar tone in human strongly suggesting the involvement of an EDHF a these two levels.

Adult↗
PubMedDate not supplied

Cimetidine does not alter free unchanged captopril pharmacokinetics and biological effects in healthy volunteer.

The effects of cimetidine (single or repeated administration) on free unchanged captopril plasma levels, pharmacokinetic parameters and plasma converting enzyme inhibitory effects have been investigated in normal healthy volunteers. Cimetidine affected neither captopril pharmacokinetic parameters nor its biological effects, suggesting that no change in captopril dosing is necessary when cimetidine is co-administered.

Adult↗