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Biomedical subjects

A Berdeaux

Publications and source records attributed to A Berdeaux.

At least 37 records · Page 2Linked to original sources
PubMed1998

Endothelium-dependent hyperpolarization in isolated arteries taken from animals treated with NO-synthase inhibitors.

To study the effects of chronic in vivo inhibition of NO synthase on endothelium-dependent hyperpolarization, cell-membrane potential (in individual vascular smooth-muscle cells) and changes in tension (in isolated rings) were recorded from isolated canine coronary arteries and guinea-pig carotid arteries and aortas. In coronary arteries taken from control dogs and contracted with U46619, acetylcholine- and bradykinin-induced endothelium-dependent relaxations, which were unaffected by short-term in vitro exposure to indomethacin but were inhibited partially by L-nitro-arginine (LNA). In coronary arteries taken from dogs treated over the long term in vivo with LNA (30 mg/kg on the first day and 20 mg/kg the 7 following days, i.v.), the response to acetylcholine and bradykinin was inhibited when compared with arteries from control dogs. Short-term in vitro exposure to LNA or indomethacin or both did not influence the effects of either agonist. In these arteries, the hyperpolarizing response to acetylcholine, observed in the presence of LNA and indomethacin, was enhanced, whereas that to bradykinin was partially inhibited. In the guinea pig isolated aorta, the relaxation to bradykinin was abolished by long-term in vivo treatment with L-nitro-arginine-methyl-ester (L-NAME; 1.5 mg/ml, in the drinking water for > or =4 days). In the isolated guinea pig carotid artery studied in the presence of LNA and indomethacin, acetylcholine induced a hyperpolarization that was not significantly affected by long-term in vivo treatment with L-NAME. These findings indicate that endothelium-dependent hyperpolarizations are maintained during long-term inhibition of NO synthase and probably act as a back-up mechanism to elicit endothelium-dependent relaxations.

Animals↗
PubMed1998

Selective large coronary endothelial dysfunction in conscious dogs with chronic coronary pressure overload.

Coronary vascular responses to acetylcholine (ACh, 3 micrograms/kg i.v.), nitroglycerin (NTG, 25 micrograms/kg i.v.), and a 20-s coronary artery occlusion (reactive hyperemia, RH) were investigated in seven conscious dogs with severe left ventricular (LV) hypertrophy and chronic coronary pressure overload (CCPO) due to supravalvular aortic banding and in seven control dogs. All dogs were instrumented for measurement of ultrasonic coronary diameter (CD) and Doppler coronary blood flow (CBF). LV-to-body weight ratio was increased by 82% in CCPO dogs. In control dogs, ACh increased CD (+ 5.9 +/- 1.7%). This response was reduced (P < 0.05) in CCPO dogs (+ 1.9 +/- 0.9%). Similarly, flow-mediated increases in CD after RH were blunted (P < 0.01) in CCPO (+ 2.1 +/- 0.8) vs. control dogs (+ 6.8 +/- 1.8%). In contrast, ACh and RH increased CBF similarly in both groups. Increases in both CD and CBF to NTG were not different between control dogs and CCPO. Peak systolic CBF velocity was greater, P < 0.01, in CCPO (94 +/- 17 cm/s) compared with control (35 +/- 7 cm/s) dogs, most likely secondary to the increased systolic coronary perfusion pressure (215 vs. 130 mmHg). Histological analyses of large coronary arteries in CCPO revealed medial thickening, intimal thickening, and disruption of the internal elastic lamina and endothelium. In contrast, small intramyocardial arterioles failed to show the intimal and endothelial lesions. Thus, in CCPO selective to the coronary arteries, i.e., a model independent from systemic hypertension and enhanced levels of plasma renin activity, endothelial control was impaired for both flow-mediated and receptor-mediated large coronary artery function, which could be accounted for by the major morphological changes in the large coronary arteries sparing the resistance vessels. The mechanism may involve chronically elevated systolic coronary perfusion pressure, CBF velocity, and potential disruption of laminar flow patterns.

Acetylcholine↗
PubMed1997

Prostaglandins reduce the contractile responses to noradrenaline and angiotensin II in canine femoral arteries after but not before chronic inhibition of nitric oxide synthesis.

This study was designed to compare the contractile responses to graded concentrations of noradrenaline (1 nM-100 microM) and angiotensin II (0.1-100 nM) of femoral arteries isolated from normal control dogs and from dogs after long-term inhibition of nitric oxide (NO) by N(omega)-nitro-L-arginine (L-NNA; 20 mg/kg/day for 7 days). Maximal contraction to noradrenaline was similar in rings obtained from control and L-NNA-treated dogs. In the latter, however, sensitivity to noradrenaline was reduced compared with control rings, whether the endothelium was present [50% effective concentration (EC50) = 6.04 +/- 0.06 vs. 6.37 +/- 0.08; p < 0.01] or absent (EC50 = 6.00 +/- 0.11 vs. 6.45 +/- 0.05; p < 0.01). Indomethacin reversed this hyporesponsiveness to noradrenaline in arteries obtained from L-NNA-treated dogs but had no effect in rings isolated from control dogs. An almost complete inhibition of the contractile response to angiotensin II, also reversed by indomethacin, was observed in arteries taken from L-NNA-treated dogs both in the presence and in the absence of endothelium. These results suggest that the cyclooxygenase pathway might be upregulated in the smooth muscle cells of canine femoral arteries after long-term inhibition of NO synthesis and that relaxing prostanoids mediate the hypocontractile response of these arteries to both noradrenaline and angiotensin II.

Angiotensin II↗
PubMed1997

Chronic inhibition of NO synthase enhances the production of prostacyclin in coronary arteries through upregulation of the cyclooxygenase type 1 isoform.

We previously reported that chronic inhibition of NO synthase (NOS) in dogs leads to an upregulation of the cyclooxygenase (COX) pathway in the endothelium of the coronary artery after stimulation by bradykinin (BK) in vitro. The present experiments were designed to identify the nature of the COX isoform involved in this phenomenon. Rings of circumflex (LCX) and left anterior descending (LAD) coronary arteries were isolated from six control dogs and six dogs treated with the NOS-inhibitor, N omega-nitro-L-arginine (L-NNA, 30 mg/kg/d, i.v., during 7 days). Concentration-response curves to BK in U46619-contracted rings from LCX coronary arteries were constructed in the presence and absence of another NOS inhibitor (NG-monomethyl-L-arginine, L-NMMA), of selective inhibitors of the inducible isoform of COX (NS-398 and L-745,337) and of a non selective inhibitor of the inducible and constitutive isoforms of COX (indomethacin). Finally, measurements of 6-keto-prostaglandin F1 alpha, the stable metabolite of prostacyclin, were performed in the incubation medium by enzymo-immuno-assay on rings of isolated LAD coronary arteries in the presence and absence of the same inhibitors of COX, before and after stimulation by BK. In rings taken from control dogs, BK evoked a concentration-dependent relaxation (Emax: 115 +/- 10%; EC50: 8 +/- 4 nM). In the presence of L-NMMA, the concentration-relaxation curve to BK was significantly shifted to the right (Emax: 77 +/- 8%; EC50: 43 +/- 22 nM, P < 0.05). Addition of NS-398, L-745,337 and indomethacin to L-NMMA did not further modify the concentration-relaxation curve to BK. After chronic inhibition of NOS, the concentration-relaxation curve to BK was similar to that observed in rings taken from control dogs in the presence of L-NMMA (Emax: 75 +/- 5%; EC50: 69 +/- 36 nM). Addition of L-NMMA, alone or in combination with NS-398 or L-745,337 did not significantly modify this concentration-relaxation curve to BK. In contrast, the L-NMMA-indomethacin combination blunted the BK-induced relaxation of the coronary artery (Emax: 28 +/- 10%, P < 0.01). Basal release of prostacyclin was not different in rings taken from control and L-NNA treated dogs (56 +/- 16 vs 58 +/- 15 pg.mm-2). BK significantly increased this release but the increment was twofold greater in rings taken from L-NNA treated dogs than in rings taken from control dogs (P < 0.05). In rings taken from control and L-NNA treated dogs, the BK-stimulated production of prostacyclin observed in the presence of the solvent was not significantly modified by L-NMMA or the L-NMMA-L-745,337 combination. In contrast, the L-NMMA-indomethacin combination as well as endothelium removal completely suppressed the BK-stimulated production of prostacyclin. These findings demonstrate that in dogs submitted to chronic inhibition of NO synthesis (1) the residual relaxation to BK of canine isolated coronary arteries is mainly due to production of prostacyclin of endothelial origin, and (2) the enhancement of prostacyclin production by these vessels is mainly due to an upregulation of the endothelial constitutive isoform of COX.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Coronary effects of exogenous and endogenous bradykinin in conscious dogs.

The effects of intravenous (iv) bolus administrations of bradykinin (0.1-1 microgram.kg-1) on large and small coronary arteries were investigated in seven chronically instrumented conscious dogs. Bradykinin dose-dependently increased heart rate, left ventricular dP/dt max, coronary blood flow and coronary artery diameter and decreased aortic pressure. Subchronic inhibition of the nitric oxide synthase (NOS) pathway (N omega-nitro-L-arginine, 20 mg.kg-1.d-1 during 7 days) attenuated the systemic and coronary effects of bradykinin. HOE 140, a specific bradykinin B2 receptor antagonist, administered at a dose (30 micrograms/kg) sufficient to completely inhibit the systemic and coronary effects of exogenous bradykinin (1 microgram/kg, iv bolus), had no effect on baseline systemic and coronary hemodynamic parameters. HOE 140 had also no effect on the flow-dependent increase in large coronary artery diameter and on the relationship between flow debt and flow repayment volumes observed during myocardial reactive hyperemia. This lack of effect of HOE 140 persisted when experiments were repeated after NOS inhibition. We conclude that (a) exogenous bradykinin dilates large and small coronary arteries through a partially NO-mediated mechanism, and (b) endogenous bradykinin plays no role in the control of arterial pressure, heart rate, LV dP/dt max, basal and flow-stimulated coronary hemodynamics, both in control conditions and after subchronic inhibition of NOS in the conscious dog.

Acetylcholine↗
PubMed1996

Effects of mibefradil on large and small coronary arteries in conscious dogs: role of vascular endothelium.

The systemic and coronary hemodynamic effects of mibefradil, a "nondihydropyridine" calcium antagonist acting on both L- and T-type calcium channels, were investigated in chronically instrumented conscious dogs before and after local endothelium removal of the circumflex coronary artery by angioplasty. After intravenous infusion, mibefradil (0.2 mg kg-1 min-1) decreased mean arterial blood pressure (MAP; -15 +/- 1%), increased heart rate (HR; 58 +/- 9%), and coronary blood flow (CBF; 103 +/- 14%) (all p < 0.05). Before endothelium removal, mibefradil increased the diameter of the left circumflex epicardial coronary artery (LCX) by 7.8 +/- 1.2% from 3,006 +/- 219 microns, but this dilatory effect was significantly reduced by 69% (p < 0.001) and 45% (p < 0.01), 3 and 21 days after endothelium removal, respectively. Mibefradil also reduced by 46% (p < 0.01) the potent coronary constrictor effect of ergonovine (300 micrograms intravenous bolus). These results demonstrate that mibefradil is a potent dilator of large and small coronary arteries in conscious dogs and that approximately 30% of its dilatory effect on large coronary artery is endothelium-independent. In addition, mibefradil prevents ergonovine-induced epicardial coronary constriction.

Animals↗
PubMed1996

Coronary and systemic hemodynamic effects of sustained inhibition of nitric oxide synthesis in conscious dogs. Evidence for cross talk between nitric oxide and cyclooxygenase in coronary vessels.

Sustained inhibition of NO synthesis (N omega-nitro-L-arginine [L-NNA], 20 mg.kg-1.d-1, 7 days) was investigated at rest and during exercise in conscious dogs. At rest, L-NNA did not alter mean arterial blood pressure but markedly increased total peripheral resistance (+73 +/- 14%, P < .01). Exaggerated hypertension was observed during exercise (+132 +/- 5 mm Hg after L-NNA versus +113 +/- 5 mm Hg before L-NNA, P < .01). L-NNA decreased the resting coronary artery diameter by 6 +/- 1% and suppressed its exercise-induced dilation but had no effect on coronary blood flow and resistance. L-NNA decreased flow repayment volumes during reactive hyperemia, but corresponding flow debt volumes remained unchanged. The cyclooxygenase inhibitor diclofenac (10 mg/kg) had no effect on reactive hyperemia parameters before L-NNA but reduced flow repayment volumes, durations, and corresponding debt-to-repayment ratios in L-NNA-treated dogs (all P < .05). In vitro, indomethacin blunted the residual relaxation to bradykinin of large coronary arteries taken from L-NNA-treated, but not from control, dogs. Bradykinin-induced increase in 6-ketoprostaglandin F1 alpha production was greater in coronary arteries taken from L-NNA-treated dogs (+ 179 +/- 41 pg/mm2) than from control dogs (+ 66 +/- 18 pg/mm2) (P < .05). These results indicate that (1) NO is of major importance in the control of systemic but not coronary resistance vessels at rest and during exercise, and (2) after L-NNA, the cyclooxygenase pathway is involved in myocardial reactive hyperemia and in the residual relaxation to bradykinin of isolated coronary arteries. Thus, in conscious dogs, the cyclooxygenase pathway might act as a protective mechanism of the coronary circulation when endothelial nitric oxide synthesis is altered.

Acetylcholine↗
PubMed1995

Endothelial modulation of beta-adrenergic dilation of large coronary arteries in conscious dogs.

BACKGROUND: Endothelium-derived relaxing factors have been described as important intermediates in beta-adrenergic vasodilation of resistance coronary vessels, but their involvement at the level of large epicardial coronary arteries remains controversial. Therefore, we examined the role of vascular endothelium in the beta-adrenergic-mediated vasodilation of large epicardial coronary arteries in conscious dogs. METHODS AND RESULTS: Nine dogs were instrumented for measurement of left circumflex coronary artery diameter (CD) by sonomicrometry and coronary blood flow velocity (CBFv) with a Doppler technique in response to graded doses of isoproterenol (0.001 to 0.1 microgram/kg IV bolus). Under control conditions, isoproterenol induced dose-dependent increases in CD and CBFv. When CBFv was kept constant at its baseline value by inflation of a cuff occluder, isoproterenol still induced dose-dependent increases in CD, but the latter were of lesser magnitude than those observed under normal CBFv conditions (110 +/- 20 versus 170 +/- 30 microns, respectively, ie, a reduction of 33% of the dilatory response at 0.1 microgram/kg, P < .01). In the same dogs, the coronary endothelium was then mechanically removed at the site of CD measurement by a balloon angioplasty technique. After this procedure, the dose-dependent increases in CD induced by isoproterenol under either normal or controlled CBFv conditions were overimposable, and their magnitude was similar to that of the increases observed in the presence of an intact endothelium when CBFv was kept constant. After beta 1-adrenergic receptor blockade by atenolol (1 mg/kg), isoproterenol-induced increases in CD were abolished either when CBFv was kept constant or after endothelium removal. CONCLUSIONS: In conscious dogs, the direct stimulating effect of isoproterenol on beta 1-adrenergic receptors is endothelium-independent at the level of large coronary arteries. The endothelium reinforces the dilatory response to isoproterenol through an indirect, flow-dependent mechanism.

Adrenergic beta-Agonists↗
PubMed1995

Comparison of the effects of exercise and cold pressor test on the vasomotor response of normal and atherosclerotic coronary arteries and their relation to the flow-mediated mechanism.

This study was designed to assess the vasomotor response of coronary arteries to exercise and the cold pressor test, and its relationships with the endothelium-mediated dependent mechanism. Twenty-two patients were entered in the study. Group I was composed of 12 patients with a total cholesterol level < 200 mg/dl associated with angiographically smooth, normal coronary arteries. Group 2 consisted of 10 patients with both a cholesterol level > 240 mg/dl and angiographic luminal irregularities of the left anterior descending coronary artery. Coronary blood flow was assessed by a 0.018-inch tip guidewire during Doppler ultrasonography, and analysis of the coronary arterial dimension of the midportion of the left anterior descending coronary artery was performed by quantitative coronary angiography. Catecholamine concentrations were assessed at the different stages of the protocol. The rate-pressure product increased during both the cold pressure test and exercise (p < 0.001). Coronary blood flow velocity increased during the cold pressor and exercise tests by 24.5 +/- 10% and 72 +/- 42%, respectively (p < 0.001), and by 127 +/- 62% (p < 0.0001) after administration of papaverine. In group 1, the cold pressor test had a more pronounced vasodilating effect on epicardial coronary arteries (+11.2 +/- 16%) compared with group 2 (-2 +/- 9%, p < 0.05). Similarly, exercise had a vasodilating action in group 1 (11.3 +/- 15%) compared with group 2 (-1.9 +/- 8%, p < 0.05). Both responses were highly correlated (r = 0.92, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Role of the renin-angiotensin system in systemic and regional vascular responses to orthostatic stress in healthy volunteers.

The effects of a single oral dose (5 mg) of the angiotensin-converting enzyme (ACE) inhibitor, ramipril, on the systemic and regional vascular responses to simulated orthostatic stress by the lower body negative pressure (LBNP) technique were investigated in eight healthy volunteers, in a double-blind, placebo-controlled crossover study. Arterial blood pressure remained unchanged throughout the study. Ramipril increased significantly forearm (venous occlusion plethysmography, + 37% +/- 4% from 1.98 ml.min-1.100 ml-1) and renal (PAH clearance, + 6 +/- 2% from 1.20 1.min-1) blood flows and decreased corresponding vascular resistances, 150 minutes after its administration and before LBNP. It also significantly reduced calculated filtration fraction and inhibited by approximately 86% plasma ACE activity. Lower body negative pressure at -10 and -20 mmHg induced a progressive and significant decrease in central venous pressure and significant increases in forearm, splanchnic (indocyanine green clearance) and total peripheral vascular resistances which were of the same magnitude after ramipril and placebo administrations. Ramipril blunted the LBNP-induced increase in renal vascular resistance observed at -20 mmHg after placebo but a similar increase in glomerular filtration rate (inulin clearance) was observed at LBNP-10 and -20 mmHg after ramipril and placebo. Calculated filtration fraction increased after placebo (LBNP-10 mmHg) and ramipril (LBNP-20 mmHg). Finally, LBNP-induced changes in biological parameters were similar after ramipril and placebo at all levels of LBNP. Thus, ramipril does not interfere with the adaptive forearm and splanchnic vascular responses and preserves renal hemodynamics during orthostatic stress simulated by LBNP in healthy volunteers.

Adult↗
PubMed1995

Comparisons of the effects of nicorandil, pinacidil, nicardipine and nitroglycerin on coronary vessels in the conscious dog: role of the endothelium.

1. The vasodilator properties of nicorandil on large and small coronary arteries were compared to those of nicardipine, pinacidil, nitroglycerin and acetylcholine in six conscious dogs. 2. Intravenous bolus injections of acetylcholine (0.1 micrograms kg-1), nitroglycerin (0.3-3 micrograms kg-1), pinacidil (10-100 micrograms kg-1), nicardipine (3-30 micrograms kg-1) and nicorandil (10-100 micrograms kg-1) dose-dependently increased circumflex coronary artery diameter and decreased coronary vascular resistance, indicating vasodilator effects on both conduit and resistance coronary arteries. 3. Three days after removal of the endothelium of the circumflex coronary artery (balloon angioplasty), pinacidil- and nicardipine-induced dilation of large coronary arteries was greatly reduced (both -76%, P < 0.01) whereas that produced by nitroglycerin and nicorandil was decreased only slightly and to a similar extent for both drugs (-19%, P < 0.01 and -28%, P < 0.05, respectively). 4. Thus in conscious dogs, nicardipine- and pinacidil-induced dilatation of large coronary arteries is endothelium-dependent. In contrast, the vasodilator effects of nitroglycerin and nicorandil on conduit vessels are endothelium-independent. 5. Finally, our results demonstrate that nicorandil dilates the large coronary arteries through its nitrate-like action and that the ATP-potassium channel opening properties of the drug are not involved in this effect in the conscious dog.

Acetylcholine↗
PubMed1995

Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs.

The effects of (7,8-dimethoxy 3-[3-([(1S)-(4,5-dimethoxybenzocyclobutan-1-yl)methyl]methylamino) - propyl]1,3,4,5-tetrahydro-2H-benzapin 2-one hydrochloride) (S 16257), a new bradycardic agent acting through inhibition of the hyperpolarization-activated I(f) current in the sino-atrial node, on arterial blood pressure, cardiac output, left ventricular pressure and dP/dt, epicardial coronary artery diameter and coronary blood flow velocity were investigated at graded doses (0.1 to 1 mg/kg) and compared to those of propranolol (1 mg/kg) and saline in chronically instrumented conscious dogs. At rest, S 16257 induced a dose-dependent bradycardia that was significant at 0.5 (-16% +/- 3%) and 1 mg/kg (-23% +/- 3%). At 0.5 mg/kg, S 16257 decreased both resting HR and treadmill exercise-induced tachycardia to a similar extent as propranolol. However, in contrast to propranolol, S 16257 (0.5 mg/kg) did not affect the increase in mean coronary blood flow velocity and the decrease in coronary vascular resistance observed during a control exercise performed under saline. In addition, S 16257 did not affect resting epicardial coronary artery diameter and only attenuated its increase during exercise, whereas propranolol reduced it at rest and maintained a significant constriction of these large vessels throughout the exercise period. Propranolol, but not S 16257, decreased left ventricular dP/dt at each stage of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

[Hemodynamic effects of sub-chronic NO synthase inhibition in conscious dogs: role of EDRF/NO in muscular exertion].

Acute and chronic administration of nitric oxide (NO) synthase (NOS) inhibitors increase mean arterial blood pressure (MAP) in rats but their hemodynamic effects in other species remain unknown. Moreover, the role of NO in the control of exercise-induced vasodilation is still debated. To answer these questions, six dogs were instrumented for the continuous measurement of cardiac output (CO, electromagnetic flow probe on the aorta), MAP (aortic catheter) and left ventricular pressure (Konigsberg gauge). Total peripheral resistance (TPR) was calculated as MAP/CO ratio and dP/dt was used as an index of cardiac inotropism. The dogs were treated from day 0 (D0) to 7 (D7) by the NOS inhibitor, N omega-nitro-L-arginine (L-NNA), 20 mg/kg/day (IV). Such a dose regimen resulted in NOS inhibition evidenced (a) in vivo by a reduction of the hypotensive responses to graded doses of acetylcholine and bradykinin, (b) ex vivo by a decrease in the relaxation of the femoral artery to acetylcholine (EC 50 = 2.2 +/- 0.6 10(-7) M after L-NNA vs 2.2 +/- 0.8 10(-8) M in controls). One month after instrumentation, the dogs being conscious, MAP measured at rest remained unchanged following one week L-NNA treatment (from 90 +/- 2 at D0 to 91 +/- 5 mmHg at D7). However, TPR increased (from 3,600 +/- 290 at D0 to 6,300 +/- 510 dyn.s.cm-5 at D7) and CO decreased (from 2.1 +/- 0.2 at D0 to 1.2 +/- 0.1 l/min at D7) (all p < 0.01), partly as the result of a marked bradycardia (from 100 +/- 7 at D0 to 60 +/- 7 beats/min at D7). L-NNA induced-increase in TPR was completely reversed by a bolus injection of nitroglycerin (10 micrograms/kg). During treadmill exercise (12 km/h), heart rate (251 +/- 9 at D0 vs 226 +/- 11 beats/min at D7), CO (6.3 +/- 0.9 at D0 vs 4.3 +/- 0.7 l/min at D7) and stroke volume remained significantly lower, and TPR significantly higher (1,662 +/- 278 at D0 vs 2,621 +/- 489 dyn.s.cm-5 at D7) after L-NNA than in the control state. Thus, NOS inhibition in resting conscious dogs by L-NNA markedly increases peripheral resistance but does not increase arterial pressure. In addition, L-NNA blunts both exercise-induced peripheral vasodilation and increase in cardiac output, despite metabolic vasodilation.

Acetylcholine↗
PubMed1995

Effects of the angiotensin type I receptor antagonist, losartan, on systemic and regional vascular responses to lower body negative pressure in healthy volunteers.

1. The effects of a single oral dose (50 mg) of the angiotensin II AT1-receptor antagonist, losartan, on the systemic and regional vascular responses to simulated orthostatic stress by the lower body negative pressure (LBNP) technique were investigated in nine healthy volunteers, in a double-blind, placebo-controlled crossover study. 2. Arterial blood pressure remained unchanged throughout the study. Three hours after its administration and before LBNP, losartan selectively increased renal blood flow (PAH clearance) by 8.3% (3.5 to 13.1%, 95% CI) from 1.25 +/- 0.08 l min-1 (P < 0.05) and decreased plasma aldosterone levels by 58% (29 to 87%, 95% CI) from 22 +/- 3 ng 100 ml-1 (P < 0.05). 3. LBNP at -10 and -20 mm Hg induced a progressive and significant decrease in central venous pressure and increases in forearm (plethysmography) and splanchnic (indocyanine green clearance) vascular resistances which were similar after losartan and placebo administrations. Losartan blunted the LBNP-induced increase in renal vascular resistance observed at -20 mm Hg after placebo but a similar increase in glomerular filtration rate (inulin clearance) was observed at LBNP -10 and -20 mm Hg after losartan and placebo. Calculated filtration fraction increased after placebo (LBNP -10 mm Hg) and losartan (LBNP -20 mm Hg). Finally, LBNP-induced changes in biological parameters were similar after losartan and placebo at all levels of LBNP. 4. Thus, losartan does not interfere with the adaptive forearm and splanchnic vascular responses and preserves renal haemodynamics during orthostatic stress simulated by LBNP in healthy volunteers.

Adult↗
PubMed1995

ITF 296, a new endothelium-independent vasodilator: comparison with nitroglycerin and isosorbide dinitrate.

The effects of a new nitrate ester derivative, ITF 296, on large conductance and small resistance coronary arteries were investigated and compared with those of nitroglycerin and isosorbide dinitrate in chronically instrumented conscious dogs with an intact or with a deendothelialized large coronary artery. In a wide range of doses, ITF 296 (0.3-3 micrograms/kg), nitroglycerin (0.1-0.3 micrograms/kg), and isosorbide dinitrate (0.3-10 micrograms/kg) induced a highly selective dilatation of the large conductance vessels, an effect that was dose-dependent. At 30-fold higher doses, the three drugs also dilated coronary arterioles, an effect that preceded dilatation of large arteries but was transient. Qualitatively, ITF 296 therefore exhibits the same pattern of coronary effects as nitroglycerin and isosorbide dinitrate. Quantitatively, ITF 296 was 6.6-fold less potent than nitroglycerin at dilating large coronary arteries, but its effects on these vessels were of longer duration. Three days after endothelium removal, the vasodilation observed during reactive hyperemia or induced by acetylcholine were almost completely abolished. In contrast, the vasodilating effects of ITF 296 (30-100 micrograms/kg) and nitroglycerin (1 microgram/kg) were not significantly different from those observed before endothelium removal, thus indicating that these two drugs dilate the large conductance coronary arteries through an endothelium-independent mechanism.

Animals↗
PubMed1994

Heterogeneous regional vascular responses to simulated transient hypovolemia in man.

OBJECTIVE: To describe the evolution of systemic and regional blood flows during and after hypovolemia in humans. DESIGN: Simulation of hypovolemia by a prolonged application of lower body negative pressure (LBNP). SETTING: Laboratory of Clinical Research, Surgical Intensive Care Unit of an University Hospital. PARTICIPANTS: 8 healthy male volunteers. INTERVENTIONS: 3 successive and increasing 15 min-levels of LBNP were followed by a progressive return (10 min) to atmospheric pressure, then a 60 min-recovery period. MEASUREMENTS AND MAIN RESULTS: Simulated hypovolemia induced a parallel one-third decrease in cardiac output (bioimpedance), musculocutaneous (venous plethysmography) and splanchnic (ICG clearance) blood flows. Adrenergic-mediated peripheral vasoconstriction prevented any change in mean arterial pressure. The decrease in renal blood flow (PAH clearance) was limited, glomerular filtration rate (inulin clearance) unchanged and thus filtration fraction increased. All the cardiovascular and biological variables returned to pre-LBNP values during the recovery period except for splanchnic blood flow which remained below control values 60 min after the return to atmospheric pressure. CONCLUSIONS: Since a sustained splanchnic vasoconstriction follows a transient normotensive hypovolemia in healthy men despite adequate treatment considering arterial pressure and cardiac output, the therapeutic goals of fluid resuscitation after hypovolemic shock might be revisited and a supranormal value of cardiac output proposed.

Adult↗