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J F Giudicelli

Publications and source records attributed to J F Giudicelli.

At least 37 records · Page 2Linked to original sources
PubMed1999

Influence of the endothelium, nitric oxide and serotonergic receptors on coronary vasomotor responses evoked by ergonovine in conscious dogs.

1. The respective contributions of coronary vascular endothelium, nitric oxide (NO) and serotonergic receptors to the effects of ergonovine on large and small coronary arteries were investigated in conscious dogs. 2. In seven dogs with an endothelium intact, ergonovine (30 - 1000 microg, i.v.) induced a biphasic response on large coronary artery with an early and transient vasodilatation (up to +2.9+/-0.5% from 3310+/-160 microm, P<0.01) followed by a sustained vasoconstriction (down to -4.9+/-0.5%, P<0.001) which occurred simultaneously with a sustained increase in coronary blood flow (CBF) (up to +100+/-26% from 28+/-4 ml min(-1), P<0.001). After endothelium removal (balloon angioplasty), the ergonovine-induced vasodilatation was abolished and vasoconstriction potentiated (-6.4+/-0.9% after vs -4.9+/-0.5% before endothelium removal, P<0.01). 3. After blockade of NO synthesis by Nomega-nitro-L-arginine (30 mg kg(-1)) in four other dogs, the early vasodilatation induced by ergonovine was abolished but the delayed vasoconstriction as well as the increase in CBF remained unchanged. 4. Both ketanserin and methiothepin (0.3 mg kg(-1)) abolished the early vasodilatation and reduced the delayed vasoconstriction induced by ergonovine. Ketanserin decreased and methiothepin abolished the reduction in coronary resistance induced by ergonovine. 5. Thus, the complex interactions between vascular endothelium and serotonergic receptors to ergonovine-induced constriction of large coronary arteries might explain the induction of coronary spasms in patients with endothelial dysfunction.

Animals↗
PubMed1999

Pharmacokinetic-pharmacodynamic model for fantofarone cardiac and brachial haemodynamic effects in healthy volunteers.

AIMS: To investigate the pharmacokinetics of SR 33671, the main active metabolite of the calcium antagonist fantofarone, and the relationships between its concentrations and pharmacodynamic effects after a single oral administration of two doses (100 and 300 mg) of fantofarone. METHODS: A placebo-controlled, randomized, double-blind and crossover study was performed in six healthy volunteers. SR 33671 plasma concentrations (C, ng ml-1 ) and effects (E) on heart rate (HR, beats min-1 ), PR interval duration (ms), brachial artery flow (BAF, ml min-1 ) and brachial vascular resistance (BVR, mmHg s ml-1 ) were determined repeatedly after drug intake. Haemodynamic effects were expressed as percent changes from initial values. Bi-exponential (pharmacokinetics), and linear [E=S.C+E0, for cardiac effects] or sigmoid [E=Emax.Cgamma/(CEgamma50+Cgamma ), for haemodynamic effects] models were fitted to individual data. RESULTS: Peak plasma concentrations and areas under the curve up to 24 h were (mean+/-s.d.) 16+/-10 ng ml-1 and 157.50+/-89.13 ng ml-1 h, and 63+/-11 ng ml-1 and 535.50+/-135.11 ng ml-1 h, after 100 and 300 mg, respectively. Terminal half-life was approximately 4 h. For pharmacodynamics, we obtained: S=-0.201+/-0.057 beats min-1/ng ml-1 for HR, S=0.526+/-0.114 ms/ng ml-1 for PR interval duration, Emax=42+/-6%, CE50=8.8+/-7.2 ng ml-1 and gamma=2.2+/-1.5 for BAF, and Emax=-28+/-4%, CE50=5.8+/-5.1 ng ml-1 and gamma=3.4+/-1.8 for BVR. At a SR 33671 concentration of 15 ng ml-1, BVR is decreased by 27% whereas HR is reduced by less than 3 beats min-1 and PR interval duration is increased by less than 8 ms. CONCLUSIONS: Fantofarone is able to induce submaximal peripheral vasodilating effects at doses that are devoid of any clinically significant cardiac effect.

Adult↗
PubMed1999

Effects of antiaggregant and antiinflammatory doses of aspirin on coronary hemodynamics and myocardial reactive hyperemia in conscious dogs.

Clinical studies have shown that low doses of aspirin (<300 mg/day) inhibit thromboxane A2 production and platelet aggregation but preserve prostacyclin synthesis. In contrast, high doses of aspirin (>1,000 mg/day) suppress the synthesis of both eicosanoids. Because the consequences of aspirin administration have never been investigated on coronary vasomotor tone in vivo, we investigated the effects of low and high doses of aspirin on systemic and coronary hemodynamics under basal conditions and after myocardial reactive hyperemia in conscious dogs. Dogs were instrumented with a Doppler flow probe and a hydraulic occluder. Coronary blood flow was measured in the conscious state at baseline and during myocardial reactive hyperemia after 10, 20, and 30 s of coronary occlusion. Thromboxane B2 serum concentrations, an index of platelet aggregation, decreased by >90% after long-term i.v. administration of aspirin, 100 mg/day for 7 days (low dose). Neither systemic and coronary hemodynamics nor reactive hyperemia were affected by the drug. After combined administration of this low dose of aspirin and of the nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine (L-NNA, 30 mg/kg/day/7 days), reactive hyperemia decreased to the same extent as when L-NNA was administered alone. After administration of a unique high-dose aspirin (1,000 mg, i.v.), myocardial reactive hyperemia was markedly reduced, and this effect was still observed after previous blockade of NOS and cyclooxygenase by L-NNA and diclofenac, respectively. Thus long-term treatment with a low antiaggregant dose of aspirin does not alter the ability of coronary vessels to dilate during myocardial reactive hyperemia in conscious dogs. In contrast, short-term administration of a high antiinflammatory dose of aspirin severely blunts myocardial reactive hyperemia through a mechanism that is independent of both cyclooxygenase and nitric oxide metabolic pathways.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Systemic and regional hemodynamics assessment in rats with fluorescent microspheres.

The aim of this study was to validate in rats an alternative to the radioactive microspheres (RM) reference technique, the fluorescent microspheres (FM), for the simultaneous determination of cardiac index (CI) and regional blood flows (RBF). Validation of the FM method was performed in three steps: (a) comparison of CI and RBF values obtained simultaneously by FM and RM, (b) determination of the repeatability of the measurements by using two successive injections of FM, and (c) evaluation of the ability of the FM method to assess vasodilating effects (by using dipyridamole). CI values (range, 242-513 ml/min x kg; n = 20) obtained with FM correlated with those obtained with RM (r = 0.82: p<0.001), and agreement was found between FM and RM (error 95% confidence interval for one pair, +/-125 ml/min x kg). FM RBF values, although smaller than corresponding RM RBF values, were correlated with the latter (range, 0.1-7 ml/min x g; n = 71; r = 0.99; p< 0.001). Agreement was dependent on RBF values, e.g., error 95% confidence intervals for one pair were 0.08-0.13 and 3.86-6.48 for 0.1 and 5 ml/min x g, respectively. Two successive FM injections at a 10-min interval (conscious rats) provided similar values (n = 14) for CI (306+/-24 vs. 346+/- 18 ml/min x kg), and renal (5.1+/-0.2 vs. 6.2+/-0.3 ml/min x g), left (6.1+/-0.3 vs. 5.8+/-0.4 ml/min x g) and right (4.8+/-0.4 vs. 4.7+/-0.3 ml/min x g) myocardial RBF. Corresponding error 95% confidence intervals were +/-187 ml/min x kg, +/-2.8, +/-2.2, and +/-2.0 ml/min x g, respectively. Dipyridamole (2, 4, 6, and 8 mg/kg x min for 10 min, i.v.; n = 9-13 per group, conscious rats) significantly and dose dependently increased left and right myocardial blood flows, whereas renal blood flow was not affected. We conclude that the FM technique (a) is reliable and in agreement with the RM method, (b) provides repeatable measurements of systemic and regional hemodynamics, and (c) allows detection and quantification of vasodilating effects in rats.

Animals↗
PubMed1999

Combined selective angiotensin II AT1-receptor blockade and angiotensin I-converting enzyme inhibition on coronary flow reserve in postischemic heart failure in rats.

We investigated whether angiotensin I-converting enzyme inhibition (ACEI) and angiotensin II AT1-receptor blockade (AT1-) would exert beneficial additive effects on coronary hemodynamics and on cardiac remodeling in post-myocardial infarction (MI) heart failure in rats. Wistar rats with MI were treated daily for 6 weeks with either trandolapril (0.1 mg/kg), losartan (3 mg/kg), or their combination, after which coronary hemodynamics (basal and at maximal vasodilation, fluospheres), systemic hemodynamics, and cardiac remodeling were investigated. Neither trandolapril nor losartan (both in nonantihypertensive doses) nor their combination (which significantly decreased blood pressure) proved to be effective at improving MI-induced impairments of basal coronary hemodynamics and of coronary flow reserve, and at preventing cardiac fibrosis development. In contrast, both trandolapril and losartan significantly improved the hemodynamic status [e.g., left ventricular end diastolic pressure: -27% and -39%, urinary cyclic guanosine monophosphate (GMP): -37%, and -26%, respectively] and slightly limited cardiac hypertrophy (-5% and -3%, respectively), and, in their combination, tended to exert additive effects on these three parameters (-49, -42, and -10%, respectively). Thus whereas the ACEI/AT1- combination tended to exert additive effects on systemic hemodynamics and cardiac hypertrophy in post-MI heart failure rats, no such effect was found for coronary hemodynamics, probably in relation to the lack of prevention of cardiac fibrosis. We conclude that an early (6 weeks) drug-induced improvement in coronary hemodynamics does not contribute to the long-term survival prolongation observed in this experimental model after either ACEI or AT1-.

Angiotensin Receptor Antagonists↗
PubMed1999

Valsartan and coronary haemodynamics in early post-myocardial infarction in rats.

Angiotensin II AT1 receptor blockade (AT1-) has been shown to prolong survival in post-myocardial infarction (MI) heart failure in rats. In this study, we investigated whether an early AT1-induced improvement in coronary vasodilatation reserve (CVR) might be involved in this beneficial effect. Wistar rats with MI were treated daily and orally for 6 weeks with valsartan, 5 (MI-V5) or 50 mg/kg (MI-V50). MI-controls and sham-operated rats (S-controls) received no treatment. Subsequently, systemic and coronary haemodynamics (at baseline and at maximal vasodilatation, CVR fluospheres) were investigated in the conscious state, and cardiac remodelling (hypertrophy and fibrosis) was assessed. As compared to MI-controls. valsartan (5 mg/kg), had no effect on systemic haemodynamics or myocardial hypertrophy and fibrosis development, gave slightly improved basal left and right ventricular coronary flow and resistance values, but decreased left and right CVR values. Valsartan (50 mg/kg), decreased blood pressure (-11%) and left ventricular end diastolic pressure (-32%), limited the development of cardiac hypertrophy (19%) but not that of fibrosis, slightly improved basal left ventricular flow and resistance values but only the right ventricular CVR value was increased. We conclude that in rats with post-MI. an early AT1-induced improvement in coronary haemodynamics is not responsible for the long-term survival prolongation observed. Furthermore. that cardiac hypertrophy was prevented whereas fibrosis was not, suggests that the latter is a pivotal determinant of CVR.

Administration, Oral↗
PubMed1998

Influence of beta-adrenoceptor agonists on the pulmonary circulation. Effects of a beta3-adrenoceptor antagonist, SR 59230A.

The aims of this study were (a) to compare in the rat isolated perfused lung preparation, the effects of isoprenaline and of three beta3-adrenoceptors agonists, SR 59104A, (N-[(6hydroxy-1,2,3,4-tetrahydronaphtalen-(2 R)-2yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride), SR 59119A (N[(7-methoxy-1,2,3,4-tetrahydronaphtalen-(2R)-2yl)methyl]-( 2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride) and SR 58611A (ethyl¿(7S)-7-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7, 8-tetrahydronaphtalen-2-yloxy¿acetate hydrochloride) on hypoxia-induced pulmonary vasoconstriction, and (b) to investigate the potential existence of atypical beta-adrenoceptors in these effects. Propranolol (0.1 microM) was used to antagonize beta1- and beta2-adrenoceptors whereas SR 59230A, 3-(2-ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronapht-1-ylam ino]-(2S)-2-propanol oxalate) (0.3 microM) was used to block beta3-adrenoceptors. Isoprenaline and the three beta3-adrenoceptors agonists caused concentration-dependent relaxations during the pulmonary pressure response. Propranolol and SR 59230A inhibited the relaxant effects of isoprenaline. SR 59230A but not propranolol inhibited those of SR 59104A. Finally, propranolol and SR 59230A failed to oppose SR 59119A- and SR 58611A-induced relaxant effects. In concentrations > or = 1 microM, SR 59230A caused per se a relaxation of the hypoxic vasoconstricted lung. These results suggest the existence of atypical beta-adrenoceptors in the rat pulmonary vessels.

Adrenergic beta-Agonists↗
PubMed1998

Pre-ejectional left ventricular wall motions studied on conscious dogs using Doppler myocardial imaging: relationships with indices of left ventricular function.

Duration of the pre-ejection period is a sensitive index of myocardial function. Our purpose was to document normal pre-ejectional left ventricular (LV) wall motions at rest and under dobutamine using Doppler myocardial imaging (DMI), and to correlate posterior wall velocities with indices of LV systolic function. M-mode recordings of both walls were imaged on eight conscious dogs chronically instrumented. Subendocardial pre-ejectional velocities were digitized and measured every 3.8 ms. DMI analysis consisted of sign recognition, velocity measurement, duration and timing from the Q wave of the electrocardiogram. Isovolumic contraction time (Ict) was represented by the time interval from onset to peak of the first derivative of LV pressure. Conventional Doppler labelling of velocity signs, positive toward and negative away from the transducer, was applied to the direction of encoded wall motions. For physiological understanding, wall motions of both walls were also labelled inward and outward with respect to the left ventricular cavity center. In each wall, PEP was shown as several colored strips, each strip representing the period of time that the wall was moving in one direction. Changes in velocity sign corresponding to changes in direction of motion were opposed in each wall (p < 0.001), featuring successive inward and outward wall motions. There was a markedly sustained inward motion during Ict. Its velocity amplitude increased with dobutamine. There was a positive correlation between velocities of the inward motion contemporaneous of Ict and ejection fraction (r = 0.72, p < 0.003). Values of Ict respectively drawn from DMI and from hemodynamics were also significantly correlated (r = 0.85, p < 0.007). Thus, the inward motion evidenced by DMI during Ict appears promising to assess myocardial function and effect of drugs.

Animals↗
PubMed1998

Pharmacokinetic-pharmacodynamic model relating zabiciprilat plasma concentrations to brachial and femoral haemodynamic effects in normotensive volunteers.

AIMS: To investigate, in healthy volunteers, the relationships between the plasma concentrations (C, ng ml(-1)) of zabiciprilat, the active metabolite of the angiotensin I-converting enzyme inhibitor (ACEI) zabicipril, and the effects (E) induced on plasma converting enzyme activity (PCEA, nmol ml(-1) min(-1)), brachial and femoral artery flows (BAF, FAF, ml min(-1)), and brachial and femoral vascular resistances (BVR, FVR, mmHg x s ml(-1)) after a single oral administration of two doses (0.5 and 2.5 mg) of zabicipril. METHODS: The study was placebo-controlled, randomized, double-blind and crossover. E was related to C by the Hill model, E = Emax x Cgamma/(CE50gamma + Cgamma), fitted to the data of both doses simultaneously. RESULTS: We obtained (mean +/- s.d.) Emax = -99 +/- 1%, CE50 = 2.2 +/- 1.0 ng ml(-1) and gamma = 1.0 +/- 0.4 for PCEA, Emax = 55 +/- 26 ml min(-1), CE50 = 5.1 +/- 4.0 ng ml(-1) and gamma = 2.4 +/- 1.6 for BAF, and Emax = -45 +/- 10%, CE50 = 2.0 +/- 1.3 ng ml(-1) and gamma = 2.3 +/- 1.4 for BVR. The parameters obtained for FAF and FVR were similar to those obtained for BAF and BVR, respectively. The CE95 (C required to induce 95% of Emax) varies from 7 to 17 ng ml(-1) for haemodynamic effects. CONCLUSIONS: As zabiciprilat peak plasma concentrations average 20 ng ml(-1) after the 2.5 mg dose of zabicipril, this dose of the drug should be sufficient to induce optimal haemodynamic effects.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Additive effects of enalapril and losartan in (mREN-2)27 transgenic rats.

Blockade of angiotensin II AT1 receptors combined with angiotensin I-converting enzyme inhibition might amplify the potency of the renin-angiotensin system blockade. We studied whether chronic and simultaneous administration of enalapril and losartan would result in additive or synergistic effects in the (mREN-2)27 transgenic rat (TGR), the investigated targets being blood pressure, cardiac hypertrophy, renin-angiotensin system blockade achieved, and plasma active renin concentration. In addition, the origin (renal or extrarenal, rat or mouse) of the induced renin release was determined. Adult TGRs were treated orally and daily for 5 to 7 weeks with 1 mg/kg (E1) or 3 mg/kg (E3) enalapril or 1 mg/kg (L1) or 3 mg/kg (L3) losartan, or their combinations (E1L1 and E3L3). At the end of the treatment period, enalapril and losartan exerted dose-dependent and, when combined, additive effects in terms of blood pressure fall and cardiac hypertrophy limitation, and synergistic effects in terms of plasma active renin stimulation and blockade of exogenous angiotensin I pressor effects, with E3L3>E3>L3, E1L1>E1> or =L1, and E1L1=E3>L3). This indicates that in the TGR, (1) the greater the renin-angiotensin system blockade achieved, the greater are the reduction in blood pressure, the limitation of cardiac hypertrophy, and the reactive rise in plasma renin concentration elicited, and (2) the enalapril-losartan combinations are more potent at achieving these goals than any of their constituents individually. In contrast, there was no interaction between the two drugs regarding aldosteronuria reduction. Measurement of plasma renin concentration and renal renin at pH 6.5 and 8.5, ie, the optimal pH values for rat and mouse renin activities, respectively, indicates that in TGRs the counterregulatory process for renin release elicited by enalapril, losartan, or their combination involves primarily rat renin of renal origin, a finding supported further by the observed increase in the rat renal renin hybridization index.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Role of potassium channels and nitric oxide in the effects of iloprost and prostaglandin E1 on hypoxic vasoconstriction in the isolated perfused lung of the rat.

1. The aims of this study were to compare in the rat isolated perfused lung preparation, the antagonist effects of iloprost, a stable analogue of prostacyclin, and prostaglandin E1 (PGE1) on the hypoxic pulmonary pressure response, and to investigate the possible involvement of KATP and KCa channels and of EDRF (NO) in the effects. In addition, iloprost and PGE1 effects were compared to those of adenosine and forskolin. 2. Isolated lungs from male Wistar rats (260-320 g) were ventilated with 21% O2 + 5% CO2 + 74% N2 (normoxia) or 5% CO2 + 95% N2 (hypoxia) and perfused with a salt solution supplemented with ficoll. Glibenclamide (1 microM), charybdotoxin (0.1 microM), NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) were used to block KATP, KCa channels and NO synthesis, respectively. 3. Iloprost, PGE1, adenosine and forskolin caused relaxation during the hypoxic pressure response. The order of potency was: iloprost > PGE1 = forskolin > adenosine. EC50 values were 1.91 +/- 0.52 10(-9) M, 3.31 +/- 0.58 10(-7) M, 3.24 +/- 0.78 10(-7) M and 7.70 +/- 1.68 10(-5) M, respectively. Glibenclamide, charybdotoxin and L-NAME inhibited partially the relaxant effects of iloprost and forskolin but not those of PGE1. 4. It is concluded that in the rat isolated lung preparation, iloprost and forskolin but not PGE1 dilate pulmonary vessels partly through KATP channels, KCa and nitric oxide release. Furthermore our results suggest that the role of cycli AMP in these effects is not unequivocal.

Adenosine↗
PubMed1997

Pharmacokinetic-pharmacodynamic model relating spiraprilat plasma concentrations to systemic and regional hemodynamic effects in congestive heart failure.

The aim of this study was to investigate the relations between the plasma concentrations of spiraprilat (the active metabolite of the angiotensin-converting enzyme inhibitor spirapril) and its effects on plasma converting enzyme activity (PCEA), pulmonary capillary wedge pressure (PCWP), and brachial blood flow (BBF), after a single oral administration of 6 mg of spirapril in eight patients with severe congestive heart failure (CHF). Concentrations and effects were determined before and repeatedly during 48 h after drug intake. A sigmoid model was fitted to individual observations. Maximal effects, concentrations inducing half-maximal effects, and Hill coefficients were -99 +/- 2%, 3.9 +/- 1.9 ng/ml, and 2.4 +/- 0.7 for PCEA inhibition, -15 +/- 8 mm Hg, 11.8 +/- 9.2 ng/ml, and 2.6 +/- 1.3 for PCWP decrease, and 36 +/- 19 ml/min, 13.8 +/- 7.6 ng/ml, and 3.3 +/- 1.0 for BBF increase. In severe CHF, although a 14 ng/ml plasma concentration of spiraprilat may induce a 95% inhibition of PCEA, a 30 ng/ml plasma concentration is mandatory to normalize PCWP and BBF. This concentration corresponds to the peak achieved after a 6-mg oral dose of spirapril.

Angiotensin-Converting Enzyme Inhibitors↗
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

Placebo-controlled, randomized, double-blind study of intravenous enalaprilat efficacy and safety in acute cardiogenic pulmonary edema.

BACKGROUND: Converting enzyme inhibitors meet most of the criteria required to be used in acute pulmonary edema. However, they could also induce deleterious effects on renal function and electrolytes. The purpose of this study was to evaluate the efficacy and safety of a single intravenous 2-hour infusion of enalaprilat (1 mg) after an acute pulmonary edema. METHODS AND RESULTS: This was a placebo-controlled, randomized, double-blind study performed in 20 congestive heart failure patients (New York Heart Association class III or IV). Systemic and regional hemodynamic parameters, biological parameters, and blood gases were measured before and repeatedly after the onset of infusion. Compared with placebo, enalaprilat decreased pulmonary capillary wedge pressure (-37% versus -10%, P = .001), diastolic and mean systemic blood pressures (-21% versus 0%, P = .009, and -18% versus -1%, P = .026, respectively), diastolic and mean pulmonary blood pressures (-21% versus -8%, P = .040; -18% versus -9%, P = .046), and brachial and renal resistances (-44% versus -14%, P = .017, and -22% versus -2%, P = .014, respectively); increased brachial and renal blood flows (+77% versus +8%, P = .036, and +12% versus 0%, P = .043, respectively), arterial oxygen tension (+2% versus -16%, P = .041), and arterial oxygen saturation (+1% versus -2%, P = .045); and tended to decrease rate-pressure product (-19% versus -7%, P = .076), increase brachial artery diameter (+13% versus 0%, P = .081), and improve intrapulmonary shunt (-18% versus +16%, P = .080). Enalaprilat did not affect cardiac output or carotid or hepatosplanchnic hemodynamics. CONCLUSIONS: Early administration of enalaprilat is effective and well tolerated in acute pulmonary edema.

Acute Disease↗
PubMed1996

Effects of losartan on cerebral arteries in stroke-prone spontaneously hypertensive rats.

OBJECTIVE: To investigate in young salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SP) the effects of a long-term administration of the angiotensin II AT1 receptor antagonist losartan [1 mg/kg (L1) and 10 mg/kg (L10) per day, from 5 to 20 weeks of age] on the structural and functional characteristics of the middle cerebral artery. METHODS: Morphological measurements and isometric tension recordings (myograph, contractile responses to potassium chloride and serotonin, relaxant responses to bradykinin and sodium nitroprusside) were performed on isolated vessels from randomly selected control and losartan-treated SHR-SP and age-matched Wistar-Kyoto (WKY) rats killed at ages 6-7, 10-11 and 16-17 weeks. RESULTS: Whereas all control SHR-SP had died within 18 weeks of being born, losartan at both doses afforded full protection against stroke and mortality. Losartan limited malignant hypertension development dose-dependently. Age-related increases in cerebral arterial wall thickness and wall:lumen ratio were not affected (L1) or limited slightly (L10) by losartan. In control SHR-SP, contractile responses of cerebral arteries to agonists decreased with ageing and stroke occurrence and were significantly smaller than those of age-matched WKY rat arteries. Losartan limited the cerebrovascular contractility impairment dose-dependently in SHR-SP but did not affect the WKY rat cerebral artery contractility. In addition, losartan limited the age-related alteration of the endothelium-dependent relaxation of cerebral arteries observed in control SHR-SP dose-dependently. CONCLUSIONS: In SHR-SP, losartan prevented stroke and improved the cerebral artery's smooth muscle and endothelial cell functions, which are altered during ageing and impaired even more dramatically by stroke occurrence.

Angiotensin II↗