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1.
Respir Physiol Neurobiol ; 150(2-3): 278-86, 2006 Feb 28.
Article in English | MEDLINE | ID: mdl-15979951

ABSTRACT

We recently developed a model of chronic intermittent hypoxia (CIH) (FiO2 5%, 8 h/day, 35 days) in the rat that was associated with an increased infarction in isolated heart. The aim of the present study was to characterize its functional consequences on vasoreactivity. Aorta and carotid artery were studied using organ bath technique while mesenteric vascular bed was perfused. In the three vascular beds, relaxation to acetylcholine was similar in CIH and control normoxic (NX) rats. Contractions to noradrenaline and angiotensin II were similar between CIH and NX rats. In contrast, contraction to endothelin-1 was increased by 17% (P < 0.05) in carotid artery from CIH rats. Indomethacin pre-treatment reduced by 24% (P < 0.001) contraction to endothelin-1 in carotid artery from CIH rats only. These data suggested that 35-day CIH-exposure induced no change in endothelial function of aorta, carotid artery and mesenteric bed. In contrast, CIH-exposure induced an increased contractile response to endothelin-1 in carotid artery, presumably owing to the release of constrictor cyclooxygenase-derived products.


Subject(s)
Aorta/physiopathology , Carotid Arteries/physiopathology , Hypoxia, Brain/physiopathology , Vasoconstriction/physiology , Analysis of Variance , Animals , Aorta/drug effects , Carotid Arteries/drug effects , Chronic Disease , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Endothelin-1/pharmacology , In Vitro Techniques , Male , Mesenteric Arteries/drug effects , Mesenteric Arteries/physiopathology , Potassium Chloride/pharmacology , Rats , Rats, Wistar , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacology
2.
J Hypertens ; 24(1): 85-93, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16331105

ABSTRACT

OBJECTIVE: Cysteinyl leukotrienes (cysLT) are pro-inflammatory and vasoactive products suspected to be involved in the regulation of vascular tone and blood pressure in hypertension. DESIGN: We investigated, in spontaneously hypertensive rats (SHR), the involvement of cysLT in the in-vivo regulation of blood pressure and the in-vitro endothelium-dependent contraction to acetylcholine in isolated aorta. METHODS: SHR and Wistar-Kyoto rats (WKY) were orally treated for 3 weeks with either the cysLT biosynthesis inhibitor MK-886 (0.1 mg/ml) or vehicle. After mean arterial blood pressure (MABP) measurement, aortic ring preparations were removed from all groups of animals, and contractions and relaxations were monitored subsequent to stimulation with acetylcholine. RESULTS: MABP was higher in SHR. Chronic treatment with MK-886 did not alter MABP in either SHR or WKY. In the presence of the N-nitro-L-arginine (L-NA, 100 micromol/l), and on prostaglandin F2alpha (PGF2alpha)-induced tone, acetylcholine evoked concentration-dependent contractions in intact aortic rings from SHR only. Pretreatment with either MK-886 (10 micromol/l), the 5-lipoxygenase (5-LO) inhibitor AA861 (10 micromol/l), or the cysLT1 receptor antagonist MK571 (1 micromol/l) reduced (P < 0.05) acetylcholine-induced contractions in intact aortic rings from SHR only. Acetylcholine-induced contractions were weaker (P < 0.01) in SHR chronically treated with MK-886 than in SHR. In the presence of L-NA, leukotriene (LT) D4 induced greater (P < 0.05) concentration-dependent contractions in aortic rings from SHR than from WKY. MK571 abolished LTD4-evoked contractions. CONCLUSION: These data suggested that 5-LO-derived products, through the activation of cysLT1 receptors, could be involved in the endothelium-dependent contraction to acetylcholine in aorta from SHR but not in the regulation of MABP in SHR.


Subject(s)
Aorta, Thoracic/physiopathology , Blood Pressure/physiology , Endothelium, Vascular/physiopathology , Hypertension/physiopathology , Indoles/pharmacology , Lipoxygenase Inhibitors , Vasoconstriction/physiology , Acetylcholine/pharmacology , Animals , Aorta, Thoracic/drug effects , Arachidonate 5-Lipoxygenase/physiology , Benzoquinones/pharmacology , Biopterins/analogs & derivatives , Biopterins/pharmacology , Blood Pressure/drug effects , Body Weight/drug effects , Body Weight/physiology , Dinoprost/pharmacology , Endothelium, Vascular/drug effects , Leukotriene D4/pharmacology , Lipoxygenase Inhibitors/pharmacology , Male , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/physiology , Nitroarginine/pharmacology , Propionates/pharmacology , Quinolines/pharmacology , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Receptors, Leukotriene/physiology , Vasoconstriction/drug effects
3.
Cardiovasc Res ; 63(1): 155-60, 2004 Jul 01.
Article in English | MEDLINE | ID: mdl-15194472

ABSTRACT

OBJECTIVES: Endocannabinoids have been shown to play a role in the regulation of vascular tone. The effects of 2-arachidonoyl glycerol (2-AG) on induced-tone were examined in rat aortic rings in vitro. METHODS: Aortic rings from Wistar Kyoto (WKY) rats were suspended in organ chambers for recording isometric tension development in response to 2-AG. The production of TXA2 in response to 2-AG was also assessed by enzyme immunoassay. RESULTS: In endothelium-intact rings pre-contracted to PGF(2alpha), 2-AG (10 nM-30 microM) induced a biphasic effect: a weak relaxation from 10 nM to 0.1 microM, which turned into a concentration-dependent contraction from 3 to 30 microM. Endothelium-denudation did not change 2-AG-mediated vascular effects. 2-AG-induced contraction was unaffected by both the cannabinoid CB1 receptor antagonist SR141716A (3 microM) and the CB2 receptor antagonist SR144528 (1 microM). In contrast, the anandamine transport inhibitor (AM404, 100 microM) and the amino hydrolase inhibitor (PMSF, 30 microM) attenuated (P<0.05) the contractile response evoked by 2-AG in endothelium-intact and rubbed aortic rings. In addition, the cyclooxygenase inhibitor (indomethacin, 10 microM) and the thromboxane A2 (TXA2) receptor (TP receptor) antagonist GR32191 (0.3 microM) totally abolished the contraction elicited by 2-AG in endothelium-intact and rubbed aortic rings. Challenge of isolated aortic rings with 2-AG (10 microM) evoked a significant increase in TXA2 level (measured as TXB2 level) in endothelium-intact and rubbed aortic rings. CONCLUSION: These data suggested that the contraction elicited by 2-AG resulted from the vascular smooth muscle cell uptake and conversion of 2-AG to constrictor prostanoid TXA2, which in turn caused vasoconstriction through the stimulation of TP receptor.


Subject(s)
Aorta , Arachidonic Acids/pharmacology , Cannabinoid Receptor Modulators/pharmacology , Glycerides/pharmacology , Muscle, Smooth, Vascular/drug effects , Vasoconstrictor Agents/pharmacology , Animals , Dinoprost/metabolism , Dinoprostone/metabolism , Endocannabinoids , In Vitro Techniques , Male , Muscle, Smooth, Vascular/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Rats , Rats, Inbred WKY , Thromboxane A2/metabolism
4.
Br J Pharmacol ; 140(1): 186-94, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12967948

ABSTRACT

(1) Long-term treatment of rats with Nomega-nitro-l-arginine methyl ester (l-NAME) induces hypertension associated with inflammatory and vascular changes. Leukotrienes are proinflammatory vasoactive products that are suspected to be involved in the pathogenesis of hypertension. We investigated, in rats chronically treated with l-NAME, the involvement of leukotrienes in the in vivo regulation of blood pressure and the in vitro contraction elicited by noradrenaline in isolated aorta. (2) Rats were randomly assigned to four groups and orally treated for 3 weeks with l-NAME (1 mg ml-1), l-NAME (1 mg ml-1) plus the leukotriene biosynthesis inhibitor MK-886 (0.1 mg ml-1), MK-886 (0.1 mg ml-1) alone or vehicle (Methocel, 0.1%). All the drugs were added to the drinking fluid. (3) The mean arterial blood pressure (MABP) increased significantly in l-NAME-treated rats (173.3+/-9.4 mmHg (n=25)) vs Methocel-treated rats (110.7+/-4.8 mmHg (n=11), P<0.001). Chronic treatment with MK-886 prevented this rise in MABP. (4) Aortic rings with or without endothelium were suspended in organ baths for recording isometric changes in response to noradrenaline. Pretreatment with either MK-886 (10 microm), the CysLT1 receptor antagonist MK571 (1 microm) or the dual CysLT1/CysLT2 receptor antagonist BAY-u9773 (0.1 microm) reduced (P<0.05) noradrenaline-induced contractions in intact aortic rings from l-NAME-treated rats only. (5) Noradrenaline (0.3 microm) induced a two-fold increase in cysteinyl leukotriene (CysLT) release (measured by enzyme immunoassay) in intact aortic rings from l-NAME-treated rats only. (6) These data suggested (1) a role for the 5-lipoxygenase pathway in the regulation of blood pressure in l-NAME-treated rats and (2) the involvement of endothelial CysLTs in noradrenaline-induced contraction in aorta from l-NAME-treated rats.


Subject(s)
Blood Pressure/drug effects , Indoles/pharmacology , Leukotrienes/biosynthesis , NG-Nitroarginine Methyl Ester/pharmacology , Vasoconstriction/drug effects , Animals , Aorta/drug effects , Aorta/metabolism , Blood Pressure/physiology , Dose-Response Relationship, Drug , In Vitro Techniques , Male , Norepinephrine/pharmacology , Rats , Rats, Wistar , Vasoconstriction/physiology
5.
J Cardiovasc Pharmacol ; 42(1): 42-7, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12827025

ABSTRACT

We previously described on human vascular preparations that, in addition to its antagonistic properties on Angiotensin II type 1 (AT1) receptor, losartan could also inhibit the contraction elicited by the stable thromboxane A2 mimetic U46619. The present study was designed (1) to investigate, in human vascular preparations (the saphenous veins) whether these antagonistic properties on thromboxane A2/prostaglandin H2 (TP) receptor were shared by some other AT1 receptor antagonists (irbesartan and valsartan) and the active metabolite of losartan EXP3174, and (2) to compare their antagonistic properties on TP receptors to their antagonistic properties on AT1 receptors. In the presence of indomethacin (10 microM) and Nomega-nitro-L-arginine (100 microM), irbesartan, valsartan, and EXP3174 induced a rightward shift of U46619- and angiotensin II-induced contraction. The inhibitory effect of irbesartan, valsartan, and EXP3174 on U46619-induced contraction was significant from 100 microM while their inhibitory effect on the contraction elicited by angiotensin II was significant from 1 nM. With regard to the plasma therapeutic concentrations of irbesartan, valsartan, and EXP3174, these data suggest that TP receptor blockade does not account for the antihypertensive effects of these AT1 receptor blockers.


Subject(s)
Angiotensin II Type 1 Receptor Blockers , Angiotensin II/pharmacology , Muscle Contraction/drug effects , Muscle, Smooth, Vascular , Receptors, Thromboxane A2, Prostaglandin H2/antagonists & inhibitors , Saphenous Vein , Valine/analogs & derivatives , 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology , Biphenyl Compounds/pharmacology , Drug Antagonism , Humans , Imidazoles/pharmacology , In Vitro Techniques , Irbesartan , Losartan , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Saphenous Vein/drug effects , Saphenous Vein/metabolism , Tetrazoles/pharmacology , Valine/pharmacology , Valsartan
6.
J Hypertens ; 20(2): 263-72, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11821711

ABSTRACT

OBJECTIVES: We have previously reported that 5-lipoxygenase-derived products, and particularly the cysteinyl leukotrienes (CysLTs), were involved in angiotensin II (Ang II)-induced contractions in isolated aortas from spontaneously hypertensive rats. DESIGN: The aim of this study was to assess the role of CysLTs in the vascular response to Ang II in an Ang II-dependent model of hypertension, the (mRen-2)27 transgenic rats (TGs). METHODS: Intact aortic rings from TG and normotensive Sprague-Dawley rats (SDs) were suspended in organ chambers for isometric tension development in response to Ang II. In addition, the release of CysLTs in response to Ang II (0.3 micromol/l) was measured by enzyme immunoassay. RESULTS: In isolated aortas from TG rats, pretreatment with the 5-lipoxygenase inhibitor (AA861, 10 micromol/l) or the CysLT1 receptor antagonist (MK571, 1 micromol/l) significantly (P < 0.05) reduced Ang II-induced contractions by 52 and 42%, respectively. In addition, Ang II induced a 2.6-fold increase in CysLT release (pg/mg dry weight tissue: 58.3 +/- 17.9 (Ang II, n = 7) versus 22.5 +/- 5.9 (basal, n = 7) P < 0.05), which was inhibited by the AT1 receptor antagonist losartan (1 micromol/l). In contrast, in aortas from SD rats, pretreatment with AA861 or MK571 did not alter Ang II-induced contraction and CysLT production remained unchanged after exposure to Ang II. CONCLUSION: These data suggest that CysLTs are involved in the contractile responses to Ang II in isolated aortas from TG but not from SD rats.


Subject(s)
Angiotensin II/pharmacology , Animals, Genetically Modified/physiology , Aorta/drug effects , Aorta/physiology , Leukotriene Antagonists , Membrane Proteins , Vasoconstrictor Agents/pharmacology , Animals , Arachidonate 5-Lipoxygenase/immunology , Benzoquinones/pharmacology , Blood Pressure/physiology , Blotting, Western , Body Weight/physiology , Dose-Response Relationship, Drug , Endothelium, Vascular/enzymology , Endothelium, Vascular/immunology , Lipoxygenase Inhibitors/pharmacology , Models, Animal , Models, Cardiovascular , Muscle Contraction/drug effects , Muscle Contraction/physiology , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/enzymology , Muscle, Smooth, Vascular/immunology , Muscle, Smooth, Vascular/physiology , Rats , Rats, Inbred SHR/genetics , Rats, Sprague-Dawley/genetics , Receptors, Leukotriene/biosynthesis , Vascular Patency/drug effects , Vascular Patency/physiology
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