Biomedical subjects

C Thuillez

Publications and source records attributed to C Thuillez.

At least 73 records · Page 4Linked to original sources

PubMed1995

Infarct size-limiting properties of Ro 40-5967, a novel nondihydropyridine calcium channel, in anesthetized rats: comparison with verapamil.

We assessed the hemodynamic and infarct size (IS)-limiting effects of the new calcium antagonist Ro 40-5967 in a rat model of ischemia/reperfusion and compared the effects of Ro 40-5967 with those of verapamil. Open-chest rats underwent 20-min coronary occlusion followed by 2-h reperfusion. We determined area at risk (AAR) and IS at the end of reperfusion by India ink injection and triphenyltetrazolium chloride (TTC) staining, using computerized analysis of enlarged sections after color video acquisition. Ro 40-5967 [0.3 mg/kg intravenous (i.v.) bolus 15 min before ischemia + 0.3 mg/kg/h i.v. infusion] and verapamil (0.3 mg/kg followed by 0.3 mg/kg/h) induced significant and similar limitations of IS (percentage of AAR: controls, 61.2 +/- 3.5%; Ro 40-5967, 41.0 +/- 4.0%; verapamil, 43 +/- 4.8%; both p < 0.01 versus controls). The IS-limiting effect of Ro 40-5967 was not accompanied by any changes in heart rate (HR) or rate-pressure product (RPP), whereas verapamil decreased both HR and RPP throughout ischemia/reperfusion. In contrast, verapamil administered at a lower dose (0.03 mg/kg followed by 0.03 mg/kg/h), which induced hemodynamic effects similar to those of Ro 40-5967, had no effect on IS (57.1 +/- 5.2, p = NS). Furthermore, additional hemodynamic studies performed in noninfarcted rats showed that Ro 40-5967 exerted negative inotropic effects that were less marked than those induced by verapamil. Therefore, Ro 40-5967 exerts myocardial protective effects that appear to be independent of changes in systemic hemodynamics or myocardial contractility.

Anesthesia↗

PubMed1995

Myocardial and coronary endothelial protective effects of acetylcholine after myocardial ischaemia and reperfusion in rats: role of nitric oxide.

1. Recent experiments suggest that acetylcholine (ACh) may exert myocardial protective effects during ischaemia (I) and reperfusion (R). The present study was designed (i) to assess whether ACh limits infarct size and protects coronary endothelial cells in a rat model of I and R, (ii) to evaluate the role of ATP-sensitive potassium (KATP) channels and nitric oxide (NO) in the beneficial effect of ACh (iii) to evaluate whether the protective effect of ACh also extends to coronary endothelial cells and (iv) to assess whether ACh contributes to the beneficial effect of preconditioning. 2. Anaesthetized rats were subjected to 20 min I (left coronary artery occlusion) and 2 h of R. Infarct size was assessed by triphenyltetrazolium (TTC) staining and expressed as a % of the area at risk (India ink injection). Vascular studies were performed on 1.5-2 mm coronary segments (internal diameter 250-300 micros) removed distal to the site of occlusion and mounted in wire myographs. 3. ACh limited infarct size (from 59 +/- 3 to 26 +/- 5%, P < 0.01), and this was prevented by atropine (46 +/- 7%; P < 0.05 vs ACh), but not by the inhibitor of KATP channels, glibenclamide (29 +/- 8%). The inhibitor of NO synthesis NG-nitro L-arginine did not affect infarct size (54 +/- 5%) but abolished the beneficial effect of ACh (59 +/- 8%; P < 0.05 vs ACh), whereas the NO donor 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1 limited infarct size to the same extent as ACh (28 +/- 6%). Preconditioning also limited infarct size (5 +/- 2%, P< 0.01 vs control), and this was not affected by atropine (6 +/- 2%). I and R induced a significant decrease in the endothelium-dependent relaxations of isolated coronary arteries toACh (maximal response: sham: 58+/-4; I/R: 25+/-5%; P<0.01) and this dysfunction was prevented by prior in vivo treatment with ACh (55+/-7%; P<0.01 vs I/R) or (SIN-1 50+/-5%; P<0.05 vs I/R).4 Thus, in the rat model, ACh is able to stimulate potent endogenous protective mechanisms during I and R, which are evident both at the level of myocardial and coronary endothelial cells, and appear entirely mediated through the production of NO. Pharmacological stimulation of this endogenous protective mechanism may constitute a new approach in the treatment of acute myocaridal ischaemia.

Acetylcholine↗

PubMed1995

Influence of sympathetic tone on mechanical properties of muscular arteries in humans.

Although smooth muscle tone is a key determinant of mechanical properties of arteries in animal experiments, it has not yet been studied in humans because of technical limitations. To assess the influence of tone on arterial properties in humans and to emphasize the interest of calculation at specific stress, we used echo tracking and photoplethysmographic measurement of arterial pressure to study radial arterial mechanics during a cold pressor test (CPT) in 12 healthy volunteers (28 +/- 2 yr). During CPT, mean arterial pressure rose from 83 +/- 3 to 106 +/- 5 mmHg (P < 0.05), internal diameter decreased from 2.75 +/- 0.15 to 2.54 +/- 0.14 mm (P < 0.05), and wall thickness increased from 0.576 +/- 0.027 to 0.634 +/- 0.029 mm (P < 0.05). At a specific pressure (105 mmHg), midwall stress and incremental modulus decreased whereas arterial compliance increased. The incremental modulus of elasticity and compliance were fitted as functions of pressure and of midwall stress. CPT decreased the modulus about equally at all wall stresses measured. The modulus decreased and the compliance increased at every level of pressure measured. At all levels of midwall stress, the compliance was decreased. Thus acute sympathetic stimulation induced by CPT decreases the wall stiffness of human arteries in vivo. This may be explained by an unloading of stiffer wall components during active arterial constriction.

Adult↗

PubMed1995

Role of basal and stimulated release of nitric oxide in the regulation of radial artery caliber in humans.

Although it is well established that nitric oxide contributes to the regulation of resistance arterial tone in humans, its role at the level of large arteries is less clear. Therefore, we assessed in healthy volunteers the effect of local administration of the inhibitor of nitric oxide synthesis NG-monomethyl-L-arginine (L-NMMA) on basal radial artery diameter (transcutaneous A-mode echotracking) and radial blood flow (Doppler) as well as on the radial response to acetylcholine and the nitric oxide donor sodium nitroprusside. A catheter was inserted into the brachial artery for measurement of arterial pressure and infusion of L-NMMA (2, 4 and 8 mumol/min for 5 minutes, n = 11), acetylcholine (3, 30, 300 and 900 nmol/min for 3 minutes, n = 8), and nitroprusside (2.5, 5, 10, and 20 nmol/min for 3 minutes, n = 6). None of the treatments affected arterial blood pressure or heart rate. L-NMMA dose-dependently decreased radial blood flow (from 31 +/- 6 to 17 +/- 3 10(-3) L/min after 8 mumol/min, P < .01) but did not affect radial artery diameter (from 2.93 +/- 0.11 to 2.90 +/- 0.14 mm). Acetylcholine dose-dependently increased radial blood flow (154 +/- 43% after 900 nmol/min) and radial artery diameter (16 +/- 4%), and both effects were markedly reduced after L-NMMA (increase in radial blood flow and radial artery diameter: 22 +/- 20% and 3 +/- 2%, respectively; both P < .01 versus controls). Nitroprusside also dose-dependently increased radial artery diameter (14 +/- 4% after 20 nmol/min) but only moderately affected radial blood flow (47 +/- 21%).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1995

[Calcium antagonists in cardiovascular diseases].

By blocking the inward transmembrane calcium current and opposing the effects of increased intracellular ionised calcium, calcium antagonists exert vascular and myocardial effects which are useful therapeutic tools. Coronary and peripheral vascular relaxation results in an increase in coronary flow and a reduction of the afterload and, therefore, of myocardial oxygen consumption. In some cases, negative myocardial inotropic and chronotropic effects also reduce myocardial oxygen requirements. Spastic angina is the indication of choice of all calcium antagonists whereas, to date, verapamil and diltiazem have been shown to be effective in stable angina and, in the post-infarction situation, diltiazem and verapamil decrease the number of cardiovascular events, and verapamil alone has been shown to reduce mortality. All calcium antagonists have been shown to be effective in hypertension and most have a protective effect on the target organs. The main fields of research concern atherosclerosis, the primary prevention of myocardial infarction and the study of molecules which can be used in heart failure.

Animals↗

PubMed1995

[Action of Buflomedil on the cutaneous microcirculation studies by a cold provocation test. Multicenter, double-blind, placebo controlled trial].

The aim of this multicentre trial involving 136 cardiologists was to evaluate, in double-blind versus placebo design, the vasoactive effect of Buflomedil in out-patients with a very simple cooling-test from a practical standpoint and previously described (1). The authors have selected patients having a basal pulpar temperature below 30 degrees C by cutaneous thermometer and falling after immersion of the contralateral hand in water at 4 degrees C, with out complete recovery during 10 minutes following withdrawal. This study carried out 408 eligible patients with 398 finally included in double-blind period (200 in the Buflomedil group, 198 in the placebo group). After a run-in period of 7 days with placebo in single blind, to evaluate the stability of measures, the patients were then treated with either Buflomedil 600 mg a day or placebo at the same dosage, for 14 days. The patients in both groups had a Raynaud's phenomenon and were heavy smokers (> or = 20 packs/year), having either acrocyanosis or lower limbs arterial occlusive disease. The results have shown, after 14 days of oral treatment an increase of basal temperature of 2.01 degrees C in Buflomedil group, versus only 0.82 degrees C in placebo group. This warming-up give evidence of microcirculatory blood flux increasing. This significant difference between the both groups was the same each measurement time after immersion during the recovery phase. There also was a good parallelism between the cutaneous temperature and the global clinical improvement by visual analogic scale filled out by the investigator (p < or = 0.0001) and the patients (p < or = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

[Cutaneous pulpar temperature and cold test. Predictive specificity and sensitivity in pharmaco-clinical studies].

The aim of this study was to measure the cutaneous pulpar temperature of the fingers and assess its evolution after one minute of controlateral hand immersion in a water bath at 4 degrees C and during 10 minutes after cooling. This test was carried out in 347 subjects (120 M, 227 F) divided in 5 groups: 117 healthy volunteers (49 M, 68 F) without any vascular diseases, 46 patients (5 M, 41 F) with acrocyanosis, 87 patients (19 M, 68 F) with Raynaud's phenomenon, 31 patients (24 M, 7 F) with peripheral arterial occlusive disease and 66 patients (23 M, 43 F) with other vascular diseases (high blood pressure and coronary disease). The mean initial temperature (TO) analysis in each group, showed that 2 groups, acrocyanosis and especially Raynaud's group, had a finger temperature significantly lower than the control group (27.4 +/- 4.8 degrees C 25.3 +/- 4.9 degrees C versus 30.5 +/- 4.9, p < 0.02). The cooling test showed 3 different cutaneous temperature reactions: subjects without any modification during and after immersion, subjects with a temperature decreasing after immersion and a normal rewarming after 10 minutes and subjects with a decreasing without any total recovery after 10 minutes. In the subjects with cold hands (initial temperature < 30 degrees C), this cooling test can isolate all patients with a temperature decreasing without any rewarming after 10 minutes with a specificity at 100% (no normal subject with cold hands were abnormal to this test).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

[Role of nitric oxide in the regulation of the mechanical properties of peripheral muscular arteries in man].

Although several experiments have demonstrated the existence of a basal NO-dependent vasodilatory tone at the arteriolar level, the contribution of NO to the mechanical properties of large arteries has not been investigated in humans. To evaluate the effect of NO-synthase inhibition on these mechanical properties, radial artery internal diameter (d, mm) and wall thickness (h, mm) were measured continuously in 11 healthy volunteers (age: 24 +/- 1 years), using an A-mode echo-tracking system coupled to a Doppler device for the measurement of radial blood flow (RBF, ml/min). A catheter was inserted in the brachial artery for measurement of arterial pressure (AP, mmHg), and infusion of the inhibitor of NO synthesis NG-monomethyl L-arginine (L-NMMA: 4 mumol/min for 5 min, infusion rate 0.8 ml/min). Arterial compliance C, 10(-3) mm2/mmHg), distensibility (D, 10(-3)/mmHg), mid-wall stress (sigma, 10(5) dynes/mm2) and incremental modulus (Ei, 10(7) dynes/mm2) were calculated before and after L-NMMA. After L-NMMA, RBF decreased from 31 +/- 6 to 23 +/- 4 (p < 0.05), radial vascular resistance increased from 2.70 +/- 0.35 to 3.77 +/- 0.55 (p < 0.05), without changes in AP or heart rate. Table shows mechanical parameters, assessed at fixed AP (80 mmHg) (*: p < 0.05 vs baseline): [table: see text] Thus, the L-NMMA-induced decrease in radial arterial wall stiffness (Ei) without changes in arterial diameter or stress demonstrates that NO-synthase inhibition induces an isometric relaxation of vascular muscle cells, which explains the increase of arterial compliance at constant mid-wall stress. These results demonstrate that NO contributes to the regulation of peripheral muscular arterial mechanics in humans. At the level of large arteries, the isometric relaxation observed after NO-synthase inhibition is probably the consequence of compensatory vasodilator mechanisms.

Adult↗

PubMed1995

[Demonstration of a vasopressor role of endogenous endothelin after inhibition of nitric oxide synthesis in rats].

Although it is clear that vascular endothelial cells synthesize and release endothelin (ET), the contribution of this vasconstrictor peptide to the regulation of vascular tone appears limited in normal conditions. One possibility to explain this moderate effect is that continuous production of nitric oxide (NO) may permanently inhibit the release and the vasoconstrictor effects of ET. In these conditions, inhibition of NO synthesis might unmask a vasopressor response to ET. Thus, we tested whether bosentan (3 mg/kg i.v.), a non-peptide antagonist of ETA and ETB receptors, or BQ-123 (3 mg/kg), an antagonist of ETA receptors, affected the hypertensive response induced by the NO synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME 3 mg/kg) or NG-nitro L-arginine (3 mg/kg) in anesthetized, normotensive rats. Bosentan or BQ-123 did not affect blood pressure. L-NAME significantly increased mean arterial pressure (% increase from baseline: 25 +/- 5%), and this was reduced by bosentan (13 +/- 3%; p < 0.05) or by BQ-123 (14 +/- 5%; p < 0.01). In contrast, bosentan did not affect the pressor response to phenylephrine. The response to L-NAME (3 mg/kg) was also reduced by bosentan in ganglion-blocked (chlorisondamine: 2.5 mg/kg; controls 89 +/- 10; bosentan: 45 +/- 7%) or pithed rats (controls: 165 +/- 9; bosentan 85 +/- 12%; p < 0.01). Bosentan also inhibited the pressor response to NG-nitro L-arginine (3 mg/kg-1) in normal (controls 24 +/- 5, bosentan 10 +/- 3%; p < 0.01) or ganglion-blocked rats (controls 86 +/- 13; bosentan 25 +/- 8; p < 0.01). Finally, L-NAME induced a modest increase in plasma levels of ET-1 (controls: 26.8 +/- 4.1; L-NAME: 38.5 +/- 3.3 pg/ml; p < 0.05). Thus, acute inhibition of NO synthesis unmasks a tonic vasopressor influence of ET.

Animals↗

PubMed1994

Comparison of the effects of dilevalol and propranolol on systemic and regional haemodynamics in healthy volunteers at rest and during exercise.

The effects of single oral doses of dilevalol 400 mg and propranolol 80 mg on systemic and regional haemodynamics at rest and after sub-maximal exercise, were compared, in a placebo-controlled, randomised, double-blind, crossover study in 6 healthy male volunteers. At rest, as compared to placebo, neither dilevalol nor propranolol significantly affected arterial pressure and heart rate but, whereas propranolol decreased cardiac output (-27% at 2 h) and tended to increase total peripheral resistance, dilevalol tended to increase cardiac output and decreased total peripheral resistance (-7% at 2 h). Neither dilevalol nor propranolol affected brachial artery diameter. Propranolol tended to decrease brachial artery flow (-20% at 2 h) and to increase brachial vascular resistance (+25% at 2 h), but dilevalol did not and the brachial irrigation ratios did not change. Neither of the drugs affected carotid haemodynamics or plasma atrial natriuretic factor. Both drugs tended to decrease plasma renin activity, and dilevalol (+82% at 2 h) increased norepinephrine more than propranolol (+19% at 2 h). After exercise, dilevalol and propranolol produced similar falls in the induced increases in arterial pressure, heart rate and cardiac output, and had the same effects on regional haemodynamics, plasma renin activity and atrial natriuretic factor. Finally, dilevalol greatly increased plasma norepinephrine. We conclude that the beta 2-adrenoceptor agonist activity of dilevalol was clearly expressed at rest, thus inducing vasodilation and counteracting the beta-adrenoceptor blockade-induced negative chronotropic and inotropic effects. However, during sub-maximal exercise, only the beta-adrenoceptor antagonist activity of dilevalol was apparent.

Adult↗

PubMed1994

Plasma 5-fluorouracil and alpha-fluoro-beta-alanin accumulation in lung cancer patients treated with continuous infusion of cisplatin and 5-fluorouracil.

This study was undertaken to investigate the day-to-day pharmacokinetic variability of 5-fluorouracil (5FU) given as a continuous i.v. infusion concomitantly with cisplatin. Ten lung cancer patients were investigated during the first course of chemotherapy. All patients had advanced, previously untreated, inoperable non-small-cell lung cancer. They received continuous infusions of cisplatin given at 100 mg/m2 over 5 days and of 5FU given at 1 g/m2 daily from day 2 to day 5. Both drugs were infused i.v. for 24 h/day at a constant rate with a volumetric pump. Blood samples were drawn from day 2 to day 5, every 4 h from 8 a.m. to 8 p.m. and every 2 h during the night (8 p.m. to 8 a.m.). Plasma 5FU and FBAL concentrations were determined simultaneously by gas chromatography-mass spectrometry. Plasma 5FU concentrations varied widely over the 4-day treatment course for each patient. Despite continuous constant-rate 5FU administration, plasma 5FU concentrations were significantly lower between 8 a.m. and 8 p.m. than during the night. Mean plasma concentrations of 5FU and FBAL increased significantly from the 1st day (0.42 and 1.19 micrograms/ml for 5FU and FBAL, respectively) to the 4th day of 5FU infusion (0.67 and 1.78 micrograms/ml for 5FU and FBAL, respectively). Further study is warranted to elucidate the mechanisms of the observed increase in plasma 5FU concentrations as well as its relationship with cisplatin coadministration and to assess the clinical relevance of this plasma 5FU accumulation.

Aged↗

PubMed1994

Is guanidino succinate a precursor for nitric oxide synthesis in rat vascular tissue?

Although L-Arginine (L-Arg) is considered the physiological precursor of nitric oxide (NO) synthesis in endothelial cells, recent experiments suggested that another guanidino derivative, guanidino succinate, may also serve as a major source of NO in this tissue. We tested this hypothesis in rat aortas, using two experimental situations in which L-Arg had previously shown significant activity, i.e., the ability to counteract contractile responses to the L-Arg analogue NG-nitro-L-arginine methyl ester (L-NAME) and the relaxation observed after prolonged incubation in physiologic buffer. Rat aortic rings, with or without endothelium, were suspended in organ chambers for recording of isometric tension and were contracted by phenylephrine (PE). After a brief incubation period (0.5 h), L-Arg, D-Arg, or guanidino succinate induced only minor relaxations in rings with or without endothelium. In the presence of L-NAME, L-Arg (but not the D-enantiomer), induced concentration-dependent relaxations of rings with endothelium (relaxation to L-Arg 10(-3) M 52 +/- 13%), reflecting a reversal by L-Arg of the L-NAME-induced potentiation of the contraction to PE. In contrast to L-Arg, guanidino succinate was less effective in the presence than in the absence of L-NAME (relaxation to guanidino succinate 10(-3) M before L-NAME 37 +/- 8% and after L-NAME 14 +/- 3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Noninvasive assessment of regional arteriolar and arterial dilating properties of lisinopril in healthy volunteers.

The effects of single oral doses of lisinopril (5 and 20 mg) on systemic and regional hemodynamics were investigated noninvasively in a placebo-controlled, randomized, double-blind, cross-over study of 6 healthy male volunteers. Lisinopril induced a dose-dependent (significant after 20 mg) and long-lasting (< or = 8 h) decrease in mean arterial pressure (MAP, approximately 11% after 20 mg) that was related to a decrease in total peripheral resistance (TPR), because simultaneously heart rate (HR) and cardiac output (CO) were unchanged. Brachial artery flow (+42 and +47% after 5 and 20 mg, respectively) and diameter (+8 and +9%) increased significantly, whereas brachial vascular resistance (-31 and -38%) decreased significantly from 2 to 8 h after drug intake. Common carotid artery flow (+20 and +24%) also increased significantly, whereas corresponding resistance (-18 and -26%) decreased significantly during the same period. Finally, CO was significantly redistributed toward the brachial and, to a lesser extent, the carotid vascular beds after both doses of lisinopril. We conclude that in healthy subjects lisinopril, at non- or slightly hypotensive doses, dilates both arterioles and large arteries and that this vasodilation is not homogeneous, affecting preferentially the brachial rather than the carotid vascular bed.

Administration, Oral↗

PubMed1994

Pharmacokinetic-pharmacodynamic modeling between pinacidil or pinacidil-N-oxide plasma levels and systemic and regional hemodynamic effects in healthy volunteers.

Pinacidil (P) lowers blood pressure through peripheral vasodilation, but also induces dose-dependent side-effects. In a previous placebo-controlled, randomized, double-blind and crossover study, performed in six healthy male volunteers, we investigated the systemic and regional hemodynamic effects of a single oral administration of 25 mg of P (sustained-release form) and measured the plasma concentrations of P and of its active metabolite, pinacidil-N-oxide (PO). In the present study, our goal has been to investigate the relationships between P and/or PO plasma concentrations and P administration effects on systolic, diastolic and mean arterial pressures (SAP, DAP, MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), brachial and carotid arteries' diameters (BAD, CAD), flows (BAF, CAF) and vascular resistances (BVR, CVR) which were assessed before and at different time intervals after drug intake. Concentration-effect relationships were investigated using both linear and log-linear multiple regression models with P, PO or both P and PO as independent variables (six models). Significant linear relationships were observed between P and/or PO and SAP, DAP, MAP, TPR, BAD, BAF, BVR, CAD and CVR. For example, TPR (dynes.s/cm5) = 1308-3.031 x P (ng/ml), R = 0.57, P = 0.0037; BVR (mmHg.s/ml) = 58-0.261 x P (ng/ml), R = 0.56, P = 0.0042. Almost similar R values were obtained using P, PO, or both P and PO. The use of log-linear models did not improve the fittings.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Role of endogenous endothelin in myocardial and coronary endothelial injury after ischaemia and reperfusion in rats: studies with bosentan, a mixed ETA-ETB antagonist.

1. Previous studies suggested that endothelin-1 (ET-1) may play a role in myocardial ischaemia and reperfusion. This study was designed to test the effect of a new nonpeptide antagonist of endothelin ETA and ETB receptors, bosentan, on myocardial infarct size, ventricular arrhythmias, and coronary endothelial dysfunction after ischaemia and reperfusion. 2. Anaesthetized male Wistar rats were subjected to 20 min ischaemia (left coronary artery occlusion) followed by 1 h (for the evaluation of coronary endothelial dysfunction) or 2 h (for the evaluation of infarct size) reperfusion, or 5 min ischaemia followed by 15 min reperfusion (for the evaluation of reperfusion arrhythmias). Vascular studies were performed on 1.5-2 mm coronary segments (internal diameter 250-300 microns) removed distal to the site of occlusion and mounted in wire myographs for isometric tension recording. Area at risk and infarct size were determined by Indian ink injection and triphenyl tetrazolium staining, using computerized analysis of enlarged sections after colour video acquisition. 3. Bosentan, administered at a dose which virtually abolished the pressor response to big ET-1 (3 mg kg-1, i.v. before ischaemia) did not affect heart rate, arterial pressure or the rate pressure product before ischaemia, during ischaemia and during reperfusion. Bosentan did not affect the incidence of reperfusion-induced ventricular fibrillation (controls: 86%, n = 14; bosentan: 93%, n = 15), and did not modify infarct size (% of area at risk: controls: 63 +/- 4, n = 10; bosentan: 60 +/- 6, n = 8). Ischaemia followed by reperfusion markedly reduced the endothelium-dependent relaxations to acetylcholine(maximal response: sham: 59 +/- 4%, n = 9; ischaemia-reperfusion: 26+/- 6%, n = 8; P<0.01), characteristic of reperfusion-induced endothelial dysfunction, and this dysfunction was not prevented by bosentan (maximal response to acetylcholine: 25 +/-5%, n = 9; P<0.01 vs sham; P = NS vs ischaemia/reperfusion).4. These experiments suggest that endogenous endothelin does not contribute to myocyte or coronary endothelial injury in this rat model of ischaemia and reperfusion.

Animals↗

PubMed1994

Ischemic preconditioning protects against coronary endothelial dysfunction induced by ischemia and reperfusion.

BACKGROUND: Repetitive, brief periods of ischemia and reperfusion ("preconditioning") increase the resistance of myocardial tissue to subsequent prolonged ischemic episodes and limit infarct size. We investigated whether preconditioning also protects against coronary endothelial dysfunction induced by ischemia and reperfusion. METHODS AND RESULTS: Experiments were performed in four groups of rats (n = 8 in each group): group 1 rats underwent sham surgery, group 2 rats were subjected to 20 minutes of left coronary artery occlusion without reperfusion, group 3 rats underwent 20 minutes of occlusion followed by 1 hour of reperfusion, and group 4 rats (preconditioning group) underwent the same protocol as group 3 rats, preceded by three cycles of 5 minutes of ischemia and 5 minutes of reperfusion. At the end of the experiments, coronary segments (internal diameter, 250 to 300 microns) were removed distal to the occlusion site and mounted in wire myographs for isometric tension recording. Relaxations induced by increasing concentrations of acetylcholine, the calcium ionophore A23187, or the nitric oxide (NO) donor SIN-1 were determined in arteries precontracted by serotonin. Basal NO release was estimated by measuring contractions to NG-nitro L-arginine methyl ester (L-NAME). In addition, we determined the effect of preconditioning on infarct size in two additional groups that were subjected to the same protocols as those of groups 3 and 4. In those animals, area at risk (India ink injection) and infarct size (triphenyltetrazolium stain) were determined by computerized analysis of enlarged sections after video acquisition. Preconditioning markedly limited infarct size (percent of area at risk: controls, 57 +/- 2; preconditioning, 2.2 +/- 0.6; P < .01). Ischemia (without or with reperfusion) or preconditioning did not affect the coronary responses to L-NAME, serotonin, A23187, or SIN-1. Ischemia without reperfusion did not modify the relaxations to acetylcholine (maximal relaxation: sham, 58 +/- 4%; ischemia, 56 +/- 7%; P = NS). In contrast, ischemia followed by reperfusion markedly impaired the response to acetylcholine (26 +/- 6%; P < .01 versus sham). This impaired response was restored by preconditioning (maximal relaxation: 59 +/- 9%; P = NS versus sham; P < .01 versus ischemia/reperfusion). CONCLUSIONS: In addition to protecting myocardial cells, preconditioning also protects coronary endothelial cells against ischemia/reperfusion injury.

Acetylcholine↗

PubMed1994

Endothelins. A potential target for pharmacological intervention in diseases of the elderly.

The existence of vasoconstrictive factors originating from the endothelium was confirmed by the description of endothelin, a 21-amino-acid peptide derived from a series of precursors, preproendothelin and a 38-amino-acid big endothelin. Three isoforms of endothelin, endothelin-1, -2 and -3, and 3 receptors (ETA, ETB and ETC) have been described and cloned. The cellular mode of action of endothelin seems to involve the modulation of intracellular calcium (through inositol trisphosphate, diacylglycerol and phospholipase C) and activation of calcium channels. The effects of endothelin are predominantly on the cardiovascular system. Its major effect is vasoconstriction, both systemic and pulmonary, with additional positive chronotropic and inotropic effects on the heart. It has also been implicated in homeostatic regulation of kidney microcirculation, and has powerful mitogenic effects on fibroblasts and smooth muscle cells. Many additional effects have been described on the endocrine system and on other systems. However, the clinical relevance of such effects is uncertain. Increased plasma endothelin levels have been reported in many diseases, but as yet it is not certain whether they are a cause or a consequence of the pathology. Pathologies most probably related to endothelin dysfunction are the vasospastic diseases, especially vasospasm after subarachnoid haemorrhage. Endothelin could be implicated to a lesser measure in diseases typical of the elderly population, such as hypertension or atherosclerosis. Drugs are being developed which act on endothelin metabolism, the most promising of which appear to be the inhibitors of endothelin converting enzyme and endothelin receptor antagonists. Some already existing drugs, such as calcium channel blockers or angiotensin converting enzyme inhibitors, probably act at least in part by interfering with endothelin metabolism or effects.

Aged↗

PubMed1994

[Changes in the mechanical properties of the arterial wall evaluated in vivo in the spontaneously hypertensive rat].

Recent experiments demonstrated increased isobaric arterial compliance and distensibility in hypertensive patients, which could be explained by a decrease in arterial wall stress, when assessed at constant pressure. We investigated the effect of hypertension on the mechanical properties of the carotid arterial wall, and especially wall stress, assessed in vivo in spontaneously hypertensive rats (SHR). Right carotid artery internal diameter (ID) and wall thickness (WT) were continuously monitored in 30 week old anesthetized SHR (n = 8) or their normotensive controls (WKY, n = 7), using a high resolution (1 micron) transcutaneous A-mode echo-tracking system (NIUS 2), coupled to a measurement of left carotid arterial pressure (micromanometer). Mean arterial pressure was 123 +/- 6 in WKY and 202 +/- 2 mmHg in SHR (p < 0.01). Mechanical parameters were calculated at mean pressure from ID and WT-pressure curves (*: p < 0.01 vs WKY). There was no difference between the groups for ID (WKY: 1.13 +/- 0.07; SHR: 1.20 +/- 0.06 mm, NS) and mid-wall stress (WKY: 10.5 +/- 1.2; SHR: 10.5 +/- 0.7 10(5) dynes/cm2, NS) while WT was increased in SHR (WKY: 105 +/- 8; SHR: 191 +/- 16 microns, p < 0.01). In SHR, incremental modulus (wall rigidity) was increased (WKY: 0.86 +/- 0.09; SHR: 1.96 +/- 0.25 10(7) dynes/cm2, p < 0.01) while distensibility (WKY: 1.77 +/- 0.16; SHR: 0.54 +/- 0.06 10(-3) mmHg-1, p < 0.01) and compliance (WKY: 1.84 +/- 0.30; SHR: 0.61 +/- 0.07 10(-3) mm2/mmHg, p < 0.01) were decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗