Biomedical subjects

P Devillier

Publications and source records attributed to P Devillier.

At least 37 records · Page 2Linked to original sources

PubMed2001

Increase in neurokinin B expression and in tachykinin NK(3) receptor-mediated response and expression in the rat uterus with age.

We analyzed tachykinin NK(3) receptor (NK(3)R) gene expression by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) in uteri from young (3-month-old) and old (30-month-old) rats. In addition, we characterized the expression of the preprotachykinin-B (TAC-3) gene, which encodes neurokinin B (NKB), the preferred endogenous agonist of NK(3)R. Compared with young rats, NK(3)R messenger RNA (mRNA) levels were about 45-fold higher in uteri from old animals. TAC-3 mRNA was expressed in the rat uterus, and its levels were about 2.5-fold higher in old than in young rats. The contractile effect of the selective tachykinin NK(3)R agonist [MePhe(7)]-NKB in uteri from young and old animals was investigated by using conventional organ bath technique. A marked correlation was observed between the magnitude of the contraction elicited by [MePhe(7)]-NKB and the level of expression determined by RT-PCR for the NK(3)R. These observations are consistent with a role for the NKB/NK(3)R ligand-receptor pair in regulating uterine functions and support the existence of a link between estrogen and the NK(3)R/NKB activation pathway.

Aging↗

PubMed2000

Human internal mammary artery contraction by isoprostaglandin f(2alpha) type-III [8-iso-prostaglandin F(2alpha)].

Isoprostaglandin F(2alpha) type-III (formerly known as 8-iso-prostaglandin F(2alpha)) is produced in large quantities in vivo in clinical situations associated with oxidant stress such as atherosclerosis, hypercholesterolemia, and myocardial reperfusion. Isoprostaglandin F(2alpha) type-III may alter smooth muscle and platelet functions. The aim of this study was to evaluate the effects of isoprostaglandin F(2alpha) type-III on isolated human internal mammary arteries, and to characterise the signalling underlying mechanisms. In organ baths, concentration-dependent contractions of human internal mammary arteries were obtained in response to isoprostaglandin F(2alpha) type-III stimulation. The responses to isoprostaglandin F(2alpha) type-III were inhibited in a concentration-dependent manner by the thromboxane A(2) receptor antagonist, GR 32191 ([1R-[1 alpha(Z), 2beta,3beta,5 alpha(+)-7-[[1, 1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl) cyclo pentyl]-4-4heptanoic acid], hydrochloride), 3x10(-9) to 3x10(-7) M). However, this effect was associated with a decreased maximal contraction. AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid, 10(-6) to 3x10(-5) M), an EP(1)-DP receptor antagonist had no effect on isoprostaglandin F(2alpha) type-III-induced contractions. The maximal responses to isoprostaglandin F(2alpha) type-III were significantly reduced in the presence of the cyclooxygenase inhibitor indomethacin (10(-5) M) (E(max): 147+/-20% vs. 213+/-19% in control group, P<0.05). Isoprostaglandin F(2alpha) type-III stimulated thromboxane B(2) release (5.7-fold increase) from human internal mammary arteries. Baicaleine, a non-specific lipoxygenase inhibitor, (10(-4) M) and AA 861 (2,3,5-trimethyl-6-(12-hydroxy-5, 10-dodecadiynyl)-1,4 benzoquinone), a 5-lipoxygenase inhibitor (10(-5) M) did not affect isoprostaglandin F(2alpha) type-III response. In conclusion, this study shows that (1) isoprostaglandin F(2alpha) type-III is a vasoconstrictor in human internal mammary arteries, with a potency equivalent to prostaglandin F(2alpha), (2) the contractions induced by isoprostaglandin F(2alpha) type-III are mediated by TP receptor but not EP(1)-DP-receptor activation, (3) thromboxane A(2) but not cysteinyl leukotrienes production is involved in the vascular effects of isoprostaglandin F(2alpha) type-III. Isoprostaglandin F(2alpha) type-III, produced at sites of free radical generation, may play an important role in internal mammary artery spasm in situations of oxidant stress such as coronary bypass surgery.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2000

Thromboxane A(2) modulates cyclic AMP relaxation and production in human internal mammary artery.

Two forms of thromboxane A(2) (TP) receptors, TPalpha and TPbeta receptors, have recently been cloned. These receptors regulate adenylate cyclase activity in two opposite ways: TPalpha receptors activate, whereas TPbeta receptors inhibit adenylate cyclase and cAMP generation. The aim of this study was to examine the effects of the thromboxane A(2) analogue, U46619 (9,11-dideoxy-9alpha,11 alpha-methanoepoxy-prostaglandin F(2alpha)), on forskolin-induced relaxation and cAMP accumulation in human internal mammary artery (IMA) and saphenous vein (SV). In organ baths, IMA rings precontracted with U46619 (3.10(-9) and 3.10(-8) M) were less sensitive to forskolin than rings precontracted with methoxamine (3. 10(-6) M). In contrast, the sensitivity to forskolin was similar in SV rings contracted with the same concentrations of these agonists. U46619 reduced significantly the ten-fold increase in cAMP induced by forskolin in IMA but not in SV rings. Sensitivity and maximal relaxation in response to sodium nitroprusside were not altered in either IMA or SV. In summary, stimulation of TP receptors with the thromboxane A(2) analogue, U46619, inhibited the cAMP pathway of relaxation through the inhibition of cAMP synthesis in human IMA but not in SV. It is suggested that thromboxane A(2) may play a role in the control of muscle tone in IMA both by its potent contractile effect and by its inhibitory effect on the cAMP pathway of relaxation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2000

Inhibition by SR 59119A of isoprenaline-, forskolin- and VIP-induced relaxation of human isolated bronchi.

In the human isolated bronchus (HIB) it has been shown that beta(3)-adrenoceptor stimulation fails to induce relaxation of airway smooth muscle. It has however been reported in human ventricular endomyocardial biopsies that beta(3)-adrenoceptor stimulation induced a marked negative inotropic effect which could be linked to Gi protein activation. The aims of this study were: (1) to determine in HIB (internal diameter 1-2 mm) whether the selective beta(3)-adrenoceptor agonist SR 59119A (N[7-methoxy-1,2,3, 4-tetrahydronaphthalen-(2R)methyl]-(2R)-2-hydroxy-2-(3-chloroph eny l)e thanamine hydrochloride) was able to inhibit adenylate-cyclase-mediated airway smooth muscle relaxation induced by isoprenaline, forskolin or vasoactive intestinal peptide (VIP) and (2) to investigate the role of the Gi protein in this interaction. SR 59119A (0.1 microM and 1 microM) induced a shift to the right of concentration response curve for isoprenaline (-0. 15+/-0.06 and -0.54+/-0.21 log unit, P<0.05 and P<0.01 respectively), forskolin (-0.12+/-0.02 and -0.30+/-0.05 log unit, P<0.001), and VIP (-0.42+/-0.12 log unit, P<0.01 with SR59119A 10(-6)M). The inhibitory effect of SR 59119A was (1) abolished by an incubation of HIB with pertussis toxin (1 microg/ml, during 15 h in Krebs-Henseleit solution, at 21 degrees C), which is known to inactivate the Gi protein and (2) increased after an incubation of HIB with the pro-inflammatory cytokine IL-1beta (10 ng/ml, during 15 h in Krebs-Henseleit solution, at 21 degrees C), which is known to up-regulate Gi protein expression. Our results suggest that the selective beta(3)-adrenoceptor agonist SR59119A might inhibit the cAMP-dependent relaxation of human isolated bronchus through Gi protein-mediated inhibition of adenylate cyclase.

Adenosine Monophosphate↗

PubMed2000

Angiotensin II-induced contractions in human internal mammary artery: effects of cyclooxygenase and lipoxygenase inhibition.

OBJECTIVE: This study investigated, in isolated human internal mammary artery, the involvement of the cyclooxygenase and the lipoxygenase pathways of arachidonic acid metabolism in the contraction induced by angiotensin II. METHODS: Rings of human internal mammary arteries were suspended in organ baths for recording of isometric tension. In addition, the release of eicosanoids in response to angiotensin II (0.3 microM) was measured by enzyme immunoassay. RESULTS: In human arterial rings without endothelial dependent relaxation in response to substance P or acetylcholine, the angiotensin II-induced contractions were significantly (P<0.05) reduced by 27% in the presence of GR32191 0.3 microM (thromboxane A(2) (TXA(2)) receptor antagonist) but remained unchanged in the presence of dazoxiben 100 microM (thromboxane synthase inhibitor). In addition, angiotensin II failed to modify TXB(2) and 6-keto-PGF(1alpha) production. These results suggest the contribution of a TXA(2)/PGH(2) agonist other than TXA(2) in angiotensin II-induced contractions. However, indomethacin increased (P<0.05) angiotensin II-mediated contractile response and cysteinyl leukotriene production, suggesting a redirection of arachidonic acid metabolism from the cyclooxygenase pathway to the lipoxygenase pathway. Indeed, the contractions induced by angiotensin II were inhibited (P<0.05) by phenidone 100 microM (cyclooxygenase and lipoxygenase inhibitor), baicalein 100 microM (5-, 12- and 15-lipoxygenases inhibitor), AA861 10 microM (5-lipoxygenase inhibitor) and MK571 1 microM (CysLT(1) receptor antagonist). Cysteinyl leukotrienes were released in response to angiotensin II (pg/mg dry weight tissue: 32+/-9 (basal, n=6) vs. 49+/-9 (angiotensin II 0.3 microM, n=6), P<0.05). LTD(4), and at a lesser degree LTC(4), induced contractions of internal mammary artery and MK571 1 microM abolished the contraction to LTD(4). CONCLUSIONS: This study suggests that the in vitro vasoconstrictor effects of angiotensin II in human internal mammary artery are enhanced at least in part by eicosanoids produced by the cyclooxygenase pathway, probably PGH(2), acting on TXA(2)/PGH(2) receptors, and by lipoxygenase-derived products, particularly cysteinyl leukotrienes acting on CysLT(1) receptors.

6-Ketoprostaglandin F1 alpha↗

PubMed2000

Effects of 7-hydroxycoumarin (umbelliferone) on isolated perfused and ischemic-reperfused rat heart

7-Hydroxycoumarin (CAS 93-35-6, 7-HC) is the main coumarin (1,2-benzopyrone) metabolite and the therapeutic active molecule. It exhibits antioxidant properties in vitro and may share with other coumarin derivatives vasodilator effects. The aim of the study was to assess the effects of 7-HC on isolated perfused and ischemic-reperfused rat heart. After a 10-min perfusion, an increase in the coronary flow was observed with 7-HC at 10(-4) mol/l (p = 0.002) as well as an increase in left ventricular developed pressure with 7-HC at 10(-5) mol/l (p = 0.038). The increase in coronary flow is not solely explained by the increase in inotropism. It appears to be also induced through a direct vasodilator effect which, however, does not involve the release of vasodilator prostaglandins since it was not inhibited by indometacin. After the 30-min global ischemia and the 45-min reperfusion period, 7-HC at 10(-5) mol/l induced an increase in left ventricular developed pressure (p = 0.042) and in the ratio of heart rate x left ventricular developed pressure over oxygen consumption (p = 0.036).

Journal Article↗

PubMed2000

Furosemide inhibits thromboxane A2-induced contraction in isolated human internal mammary artery and saphenous vein.

Evidence suggests that, in addition to its diuretic property, furosemide also may exert direct vascular effects. Because thromboxane A2 (TXA2) has a role in the control of vascular tone, we investigated the effect of furosemide on the contraction induced by U46619 (a stable TXA2 mimetic) on isolated human internal mammary artery (IMA) and saphenous vein (SV). Concentration-response curves to U46619 were performed in the absence (vehicle) or the presence of furosemide (0.1-1 mM) on rings of IMA and SV. In addition, the relaxant effect of furosemide (0.1 microM-1 mM) also was evaluated on U46619-precontracted IMA and SV. The participation of cyclooxygenase derivatives was studied by pretreatment with indomethacin. Furosemide (0.1-1.0 mM) caused parallel rightward shifts of U46619 concentration-response curves without affecting the maximal responses in both IMA and SV. Treatment with indomethacin (1 microM) modified neither the inhibitory effect of furosemide on U46619-induced contractions, nor the relaxant effect of furosemide on U46619-induced contractions, nor the relaxant effect of furosemide on U46619-precontracted IMA and SV. In conclusion, furosemide at high concentrations inhibited U46619-induced contraction in human isolated IMA and SV and relaxed U46619-precontracted IMA and SV by mechanisms independent of the release of relaxant prostaglandins. These results suggest that blockade of TXA2 receptors by furosemide may contribute to explaining the therapeutic effects of furosemide in the treatment of severe heart failure.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2000

Vasoconstrictor effects of iso-prostaglandin F2alpha type-III (8-iso-prostaglandin F2alpha) on human saphenous veins.

Free radical generation can initiate the peroxidation of arachidonic acid, resulting in a non-cyclooxygenase-dependent production of bioactive prostaglandin F2-like compounds. We have investigated the effects of iso-prostaglandin F2alpha type III, (iPF2alpha-III, formerly named 8-iso prostaglandin F2alpha) on human saphenous veins, and characterized the underlying mechanisms. In organ baths, the contractile effects of iPF2alpha-III were tested on saphenous vein rings coming from 22 patients. iPF2alpha-III induced concentration-dependent contractions of isolated human saphenous veins. The maximal contraction did not differ significantly from that of prostaglandin F2alpha (PGF2alpha). The pD2 values for iPF2alpha-III, PGF2alpha, endothelin-1 (ET-1), and U46619 (a stable thromboxane A2 mimetic) were 6.31+/-0.12, 5.66+/-0.13, 7.37+/-0.08, and 7.99+/-0.31, respectively (p < 0.001 for U46619 vs. iPF2alpha-III and PGF2alpha; and ET-1 vs. PGF2alpha). Emax values of iPF2alpha-III, PGF2alpha, ET-1, and U46619 were 137.7+/-24.3%, 145.9+/-7.5%, 92.9+/-16.8%, and 238.7+/-23.7%, respectively (p < 0.001 for U46619 vs. iPF2alpha-III, PGF2alpha and ET-1; and for PGF2alpha vs. ET-1). The responses to iPF2alpha-III were inhibited by GR 32191 10(-7) M, a TP-receptor antagonist, without affecting the maximal response (pD2 values were 5.98+/-0.06 in the absence, and 5.22+/-0.05 in the presence of GR32191; p < 0.001). Concentration-effect curves to iPF2alpha-III were not affected by phosphoramidon 10(-5) M (an endothelin converting enzyme inhibitor), BQ123 10(-6) M (a selective ET(A)-receptor antagonist), BQ788 10(-6) M (a selective ET(B)-receptor antagonist), and indomethacin 10(-5) M (a cyclooxygenase inhibitor). Finally, the contractile response of iPF2alpha-III did not involve the release of thromboxane B2 and ET-1, measured using enzyme immunoassays. This study demonstrates that iPF2alpha-III is a vasoconstrictor of human saphenous veins, with a potency fourfold greater than that of PGF2alpha, and 50 times less than that of the thromboxane A2 mimetic, U46619. These effects are mediated at least in part by TP-receptor stimulation, but do not involve thromboxane A2 or ET-1 release.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2000

Cyclosporine A and cremophor EL induce contractions of human saphenous vein: involvement of thromboxane A2 receptor-dependent pathway.

Chronic treatment with Sandimmune (cyclosporine A [CsA] dissolved in Cremophor EL [CrEL]) is often associated with hypertension and nephrotoxicity. The aims of the present study were to assess the effect of Sandimmune and its two main components (CsA and CrEL) on human saphenous veins and to study the underlying mechanism of their contractile responses. In organ bath, concentration-response curves for Sandimmune (36 ng/ml-120 microg/ml of CsA). CsA (36 ng/ml-120 microg/ml), or CrEL (2.4 microg/ml-8 mg/ml) were elicited in the presence of a thromboxane A2 (TXA2) receptor antagonist (GR32191, 0.3 microM), a cyclooxygenase inhibitor (indomethacin, 1 microM), a 5-lipoxygenase inhibitor (AA861, 10 microM), or their respective vehicles. In addition, the production of TXA2 after CsA challenge was assessed by enzyme immunoassay. Sandimmune, CsA, and CrEL induced concentration-dependent contractions on human saphenous veins. In terms of potency, CsA was a more potent vasoconstrictor agent than CrEL (EC50 values: 11.9+/-3.7 microg/ml (CsA, n = 12) vs. 1.2+/-0.4 mg/ml (CrEL, n = 16), p < 0.05). In contrast, in terms of efficacy, CrEL induced greater contractions than CsA (Emax (% of KCl 90 mM-induced contraction): 98.1+/-16.1% (CrEL, n = 16) vs. 17.0+/-4.3% (CsA, n = 12) p < 0.05). Pretreatment with GR32191 significantly reduced by 85% and 56% the contractions elicited by CsA and CrEL, respectively, whereas indomethacin had no effect. Finally, CsA (12 and 120 microg/ml) failed to stimulate TXA2 production. These in vitro data suggest that Sandimmune-induced contractions on human vascular smooth muscle appear to be mediated by CsA in the therapeutic ranges of doses and by both CsA and CrEL, which, in supratherapeutic doses, acted through a TXA2 receptor-dependent pathway.

Biphenyl Compounds↗

PubMed1999

Leukotrienes, leukotriene receptor antagonists and leukotriene synthesis inhibitors in asthma: an update. Part I: synthesis, receptors and role of leukotrienes in asthma.

Asthma is a chronic inflammatory disease associated with airflow obstruction. Airflow obstruction results from contraction of airway smooth muscle, mucosal oedema, increased secretion of mucus and infiltration of the airway wall by inflammatory cells, particularly eosinophils. Leukotrienes are thought to contribute to the pathophysiology of asthma. Leukotrienes are synthesised from arachidonic acid by a specific synthesis pathway whose key enzyme is 5-lipoxygenase. Cysteinyl leukotrienes (leukotrienes C4, D4 and E4) have been shown to mimic all the pathologic changes that are characteristic of asthma, whereas leukotriene B4 does not appear to exert biological properties relevant to asthma. Cysteinyl leukotrienes bind to two receptor subtypes: CysLT1 and CysLT2. Most of the biological properties of cysteinyl leukotrienes relevant to asthma are mediated through CysLT1 receptor stimulation.

Anti-Asthmatic Agents↗

PubMed1999

Leukotrienes, leukotriene receptor antagonists and leukotriene synthesis inhibitors in asthma: an update. Part II: clinical studies with leukotriene receptor antagonists and leukotriene synthesis inhibitors in asthma.

The demonstration that leukotrienes, mainly cysteinyl leukotrienes, have biological properties relevant to the pathogenesis of asthma has stimulated the development of many therapeutic compounds to block these deleterious effects. Two main classes of leukotriene modulators have been developed: CysLT1 receptor antagonists and leukotriene synthesis inhibitors. This article reviews the pharmacodynamics, the effects on baseline airway function, the protective effects in airway challenges as well as the results in chronic asthma of the different leukotriene modulators. In addition, the complementary anti-inflammatory effect of leukotriene modulators to that of corticosteroids and H1-histamine receptor antagonists is reviewed. Finally, a concise overview of the clinical responsiveness to this new class of drug, the safety and the drug interactions as well as the place in the strategies of treatment for asthmatic patients of the leukotriene modulators is also provided.

Anti-Asthmatic Agents↗

PubMed1999

Reactivity of the Human Internal Mammary Artery and the Gastroepiploic Artery to Constrictor Substances.

The internal mammary artery (IMA) and the gastroepiploic artery (GEA) are frequently used to construct coronary artery bypass grafts. In order to determine and to compare their contractile properties, we studied the effects of constricting agents which are liberated or infused during coronary bypass surgery. IMA and GEA were arranged as ring segments and suspended in organ baths at optimal stretch using a normalization procedure. Concentration-contraction curves to angiotensin II, norepinephrine, U-46619, endothelin-1, leukotriene C(4) and KCl were performed. The sensitivity (pD(2)) of GEA and IMA to all the agents did not differ. However, GEA developed stronger maximal contraction force than IMA to angiotensin II (P < 0.001), norepinephrine (P < 0.05), U-46619 (P = 0.06), endothelin-1 (P < 0.01), and KCl (P < 0.01), whereas leukotriene C(4) did not induce a significant contraction on GEA and IMA. The higher contractility of GEA may explain that it is more prone to spasm than IMA in the clinical setting. This study reinforces IMA as a first-choice conduit for coronary artery bypass and emphasizes the need for antispastic drugs particularly when GEA is used as bypass vessel.http://link.springer-ny.com/link/service/journals/00547/bibs/8n4p187.html</hea

Journal Article↗

PubMed1999

Effects of amifostine on perfused isolated rat heart and on acute doxorubicin-induced cardiotoxicity.

PURPOSE: To determine the effects of amifostine on an isolated perfused rat-heart model and its protective activity with regard to cardiotoxic doxorubicin perfusion. METHODS: Langendorff constant-pressure isolated rat-heart preparations were used to analyze the effects of the drugs during a 40-min period of perfusion after a 20-min stabilization interval. The first study was conducted with amifostine alone (controls and 10(-6), 10(-5), and 10(-4) M amifostine; n=6 in each group). The second study was conducted with amifostine and doxorubicin (controls, 2.5 x 10(-5) M doxorubicin, 2.5 x 10(-5) M doxorubicin and 10(-5) M amifostine, and 2.5 x 10(-5) M doxorubicin and 10(-4) M amifostine; n=4 in each group). RESULTS: Amifostine had no significant effect on hemodynamic parameters at 10(-6), 10(-5), and 10(-4) M concentrations. However. amifostine increased the coronary flow expressed as a percentage+/-SEM of the baseline flow as follows: 82+/-4% for controls, 95+/-6% for 10(-6) M amifostine, (P=0.13), 111+/-4% for 10(-5) M amifostine (P < 0.01), and 104+/-3% for 10(-6) M amifostine (P < 0.01). When we commenced an amifostine perfusion 20 min in advance of and then during a 40-min perfusion with doxorubicin, at a cardiotoxic concentration of 2.5 x 10(-5) M the left ventricular pressures (LVDP, expressed as percentages +/-SEM of the baseline LVDP before doxorubicin) were 55+/-3% for the doxorubicin controls, 68+/-2% for doxorubicin with 10(-5) M amifostine (P=0.05), and 80+/-3% for doxorubicin with 10(-4) M amifostine (P < 0.01). Whether this protective effect might be related to the known free-radical-scavenging activity of amifostine remains to be determined. CONCLUSION: On a Langendorff-type model of rat heart, 10(-5) and 10(-4) M amifostine alone induced a coronary dilation and, when associated with a cardiotoxic concentration of 2.5 x 10(-5) M doxorubicin, 10(-5) and 10(-4) M amifostine displayed a cardioprotective effect.

Amifostine↗

PubMed1999

New calcium antagonists: synthesis, X-ray analysis, and smooth muscle relaxing effect of 3-[O-(benzyl-substituted)-oximino-ethers]-hexahydroazepin-2,3- diones.

A series of new Z and E 3-[O-(benzyl-substituted)-oximino-ether]-hexahydroazepin-2,3 -diones was prepared from the corresponding hexahydroazepin-2,3-diones and examined as smooth muscle relaxants. E and Z structures were assigned by NMR analysis and confirmed for 16 (E and Z) by an X-ray diffraction using synchrotron radiations. The nitrobenzyl derivative 16 was the most potent in vitro as relaxant of rat trachea precontracted with acetylcholine. The E isomer 16b was more potent than the Z isomer 16a. E isomer 16b is more potent than aminophylline to relax both rat trachea and human bronchus. This derivative acts mainly by inhibiting cellular influx of extracellular calcium since it inhibits potently and dose-dependently the contractions of rat trachea to high concentrations of KCI and to CaCl2 in a depolarizing medium. It appears to act weakly by inducing cGMP and cAMP synthesis. Moreover, its relaxing activity is not related to an inhibition of phosphodiesterases, to opening of potassium channels or to induction of prostaglandin synthesis. Therefore, 16b appears to work mainly as a potent calcium antagonist.

Animals↗

PubMed1999

Antagonistic effects of losartan on thromboxane A2-receptors in human isolated gastroepiploic artery and saphenous vein.

In addition to its AT1-receptor antagonist activity, losartan has been shown to antagonize thromboxane A2 (TXA2)-induced contraction of animal vessels. We investigated for the first time in human isolated gastroepiploic artery (GEA) and saphenous vein (SV) the TXA2/PGH2-receptor antagonist activity of losartan in the presence of indomethacin (1 microM) and N(omega)-nitro-L-arginine (100 microg). Losartan at concentrations of > or =1 microM on GEA and from 10 microM on SV significantly shifted U46619-induced contractions to the right. In addition, 100 microM losartan decreased by 34% the amplitude of the contraction to U46619 on both GEA and SV. The potency of losartan for the TXA2 receptor was 50- and 80-fold lower than that for the AT1 receptor on human GEA and SV, respectively. This inhibitory effect of losartan appeared selective for angiotensin II and TXA2-induced contractions because 100 microM losartan did not modify either endothelin-1- or KCl-induced contraction in human SV, although a reduction of norepinephrine- and 5-hydroxytryptamine-induced contraction was observed in human GEA and SV, respectively. In conclusion, losartan is an antagonist of TXA2 receptor on human GEA and SV. However, this antagonist activity occurred for a relative high dose of losartan, suggesting that it contributes at a low level, if any, to its antihypertensive effect.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1999

Vasorelaxant actions of enoximone, dobutamine, and the combination on human arterial coronary bypass grafts.

Enoximone (a type III-selective phosphodiesterase inhibitor) and dobutamine (a beta-receptor agonist) are positive inotropic drugs frequently used in the postoperative management of coronary bypass surgery. The purpose of this study was to characterize their relaxant effects on the human internal mammary artery (IMA) and the gastroepiploic artery (GEA) and to test the hypothesis that their combination may have greater than additive relaxant effects. In organ baths, the relaxant effects of enoximone and dobutamine were tested on rings of IMA (n = 86) precontracted with U46619 (a thromboxane A2 mimetic), norepinephrine (NE), or KCl. The relaxant effects of dobutamine and enoximone also were tested on rings of GEA (n = 42) precontracted with U46619 and NE. The effect of the combination of enoximone and dobutamine were tested on rings of IMA (n = 24) precontracted with U46619 or NE. With respect to maximal relaxations induced by papaverine (10(-4) M), enoximone (< or =10(-3) M) caused full relaxations of IMA precontracted with NE, U46619, or KCI. Dobutamine (< or =10(-3) M) caused full relaxations of IMA precontracted with NE or KCI but only 46% (95% CI, 27-65) relaxation in the rings precontracted with U46619. Similar patterns of relaxation were observed in GEA rings, with dobutamine inducing partial relaxation in GEA precontracted with U46619. The pD2 values of enoximone and dobutamine were both significantly lower in segments precontracted with U46619. The in vitro threshold relaxant concentrations were in the upper limits or over the range of therapeutic plasma concentrations. The relaxant effect of the combination was significantly more important than the theoretic additive effect in IMA contracted with U46619 or NE. Enoximone and dobutamine are potent in vitro vasodilators but exert weak relaxant effects in IMA and GEA at concentrations in the therapeutic range. There is, however, a greater than additive vasorelaxant effect of the combination, suggesting that the vasorelaxant effect of the combination, in addition to the additive inotropic effect, may be beneficial to patients undergoing coronary bypass grafting.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1999

Functional assessment of rat aorta after cold storage in different media.

Cold storage is frequently used to store isolated blood vessels for a limited period of time. However preservation of vascular smooth muscle and endothelial functions is time and medium-dependent. The present study was designed to compare the reactivity of rat aorta before and after cold storage for 24 and 48 h in one of four different solutions consisting of Hepes-buffered Krebs solution, Belzer solution, Krebs solution, and Eurocollins solution. Smooth muscle and endothelial functions of the rat aorta were assessed using in vitro isometric tension measurement. The results obtained for vessels preserved for 24 and 48 h were compared with those for vessels studied immediately after harvesting. Sensitivity and maximum contraction to KCl and norepinephrine were not altered in rat aorta preserved up to 48 h in Hepes-Krebs and Belzer solutions. In contrast, the amplitude of contraction elicited by KCl was significantly reduced by 50% and 77% in aorta stored for 24 and 48 h in Krebs solution and by 77% and 96% in those stored in Eurocollins solutions. Similarly, the maximal contraction elicited by norepinephrine was significantly reduced by 60% and 45% in arteries stored for 24 and 48 h in Krebs solution and by 34% and 86% in those stored in Eurocollins solution. In contrast, cold storage in the different media did not alter the relaxations elicited by sodium nitroprusside and forskolin. The endothelium-dependent relaxations in response to acetylcholine were not statistically modified after preservation up to 48 h in Hepes-Krebs solution. In contrast, the maximal relaxations to acetylcholine were significantly decreased after storage for 24 and 48 h in Belzer, Krebs and Eurocollins solutions. These results suggest that among the four media studied, Hepes-Krebs solution is the most suitable medium for the storage of blood vessels under hypothermic conditions.

Animals↗

PubMed1999

Functional comparison of the human isolated femoral artery, internal mammary artery, gastroepiploic artery, and saphenous vein.

Human femoral, internal mammary, and gastroepiploic arteries and saphenous veins are used as bypass grafts for coronary surgery or for reconstruction in arterial occlusive disease. We have characterized the contractile responses of these vessels to various agents that are liberated during cardiac or vascular surgery. In organ baths, U46619 (a stable thromboxane A2 mimetic), norepinephrine, endothelin-1, angiotensin II, and KCl caused concentration-dependent contractions in all vessels tested. Leukotriene C4 did not induce any contraction in the arteries, whereas a contraction was obtained in the saphenous vein rings. U46619 induced the most powerful contraction in all vessels tested. The pD2 values for each agent did not differ among the different vessels. When responses were expressed as a percentage of KCl-induced contraction, the contraction of endothelin-1 (151+/-5%) and leukotriene C4 (43+/-5%) was more significant on saphenous veins than on arteries. In conclusion, thromboxane A2 appears to be the most potent endogenous constricting agent on different human vascular beds. Our second finding is that saphenous veins are more sensitive to contract to leukotriene C4 and endothelin-1 than arteries. These properties may influence early and (or) long-term vein graft patency.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗