Biomedical subjects

J F Bouchard

Publications and source records attributed to J F Bouchard.

13 recordsLinked to original sources

PubMed2000

Participation of prostaglandin E2 in the endothelial protective effect of ischaemic preconditioning in isolated rat heart.

OBJECTIVE: To assess whether the protective effect of ischaemic preconditioning (IPC) on endothelial function in coronary arteries of the rat involves prostaglandins. METHODS: Isolated rat hearts perfused under constant flow conditions were exposed to 30 min of partial ischaemia (flow-rate 1 ml/min) followed by 20 min of reperfusion, after which coronaries were precontracted with U-46619 0.1 microM, and the coronary response to the endothelium-dependent vasodilator, serotonin (5-HT, 10 microM), was compared to that of the endothelium-independent vasodilator, sodium nitroprusside (SNP, 3 microM). Prostaglandin production was blocked with a perfusion of indomethacin 10 microM started 15 min before IPC or a corresponding sham period and stopped just before the 20-min reperfusion period. RESULTS: In untreated hearts, ischaemia diminished selectively 5-HT-induced vasodilatation, compared to sham hearts. The vasodilatation by SNP was unaffected after ischaemia and reperfusion. IPC (5 min of zero-flow ischaemia followed by 10 min reperfusion before the 30-min partial ischaemia) preserved the vasodilatation produced by 5-HT. Enzymeimmunoassays showed an increased production of PGE2 in the IPC group. Treatment of hearts with indomethacin blocked the protective effect of IPC on the vasodilatation produced by 5-HT and decreased the production of PGE2. A 5-min perfusion with 3 nM PGE2 started 15 min before the partial ischaemia, protected the endothelium. This was blocked by 1 microM chelerythrine, but not by 0.3 microM glibenclamide. CONCLUSIONS: These results suggest that IPC affords protection to endothelial function in coronary arteries of the rat partially via the release of PGE2. Under our experimental conditions, the protective effect of PGE2 is mediated by PKC.

6-Ketoprostaglandin F1 alpha↗

PubMed2000

Heat stress-induced protection of endothelial function against ischaemic injury is abolished by ATP-sensitive potassium channel blockade in the isolated rat heart.

The protection conferred by heat stress (HS) against myocardial ischaemia-reperfusion injury, in terms of mechanical function preservation and infarct size reduction, is well documented and mechanisms underlying these effects have been extensively explored. However, the effect of HS on coronary circulation is less known. The aim of this study was thus to investigate the role of ATP-sensitive potassium (K(ATP)) channels in the protection against ischaemic injury afforded by HS to the coronary endothelial function. Twenty-four hours after whole body hyperthermia (42 degrees C for 15 min, H groups) or sham anaesthesia (Sham groups), isolated perfused rat hearts were subjected to a 15 min stabilization period followed by a 30 min infusion of either 0.3 microM glibenclamide (Gli, a K(ATP) channel blocker) or its vehicle (V). Hearts were then exposed to a low-flow ischaemia (30 min)-reperfusion (20 min) (I/R) or normally perfused (50 min), after which coronaries were precontracted with 0.1 microM U-46619. Finally, the response to the endothelium-dependent vasodilator, 5-hydroxytryptamine (5-HT, 10 microM) was compared to that of the endothelium-independent vasodilator, sodium nitroprusside (SNP, 3 microM). In hearts from Sham-V and Sham-Gli groups, I/R selectively diminished 5-HT-induced vasodilatation without affecting the vasodilatation to SNP. In V-treated groups, prior HS preserved the vasodilatation produced by 5-HT. This HS-induced protection was abolished by Gli treatment. In conclusion, these results suggest that K(ATP) channel activation contributes to the preservation of coronary endothelial function conferred by heat stress against ischaemic insult.

ATP-Binding Cassette Transporters↗

PubMed2000

Effect of antioxidant treatments on nitrate tolerance development in normotensive and hypertensive rats.

OBJECTIVES: To investigate the effect of chronic antioxidant treatments on the development of nitrate tolerance in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats by evaluating (i) coronary vascular reactivity, (ii) lipid peroxidation (malondialdehyde), and (iii) peroxynitrite formation (3-nitrotyrosine). METHODS: Tolerance was induced in 16-week-old male SHR and WKY, by 4 days of continuous treatment with nitroglycerin patches. Two groups were orally pre-treated (2-weeks) with antioxidants: N-acetyl-L-cysteine (NAC) or melatonin. Effects of serotonin (5-HT) and sodium nitroprusside (SNP) perfusion were tested in isolated Langendorff-perfused hearts. 3-Nitrotyrosine levels were measured in coronary sinus effluent and malondialdehyde in plasma. RESULTS: Nitrate tolerance reduced SNP-induced dilation in both strains. This alteration was differently improved by antioxidants: melatonin was effective in SHR, whereas NAC was effective in WKY. Tolerance also reduced 5-HT-mediated vasodilation in WKY, which was reversed by both antioxidants. By contrast, nitrate tolerance enhanced the vasoconstriction to 5-HT in SHR and both antioxidants prevented this response. Furthermore, tolerance was associated with higher malondialdehyde levels in both strains and with higher 3-nitrotyrosine levels in SHR. These changes were reversed by both antioxidants. CONCLUSIONS: A participation of oxidative stress was suggested during nitrate tolerance development, since antioxidants prevented the increase in lipid peroxidation and improved vascular responses to SNP and 5HT. Differential effects of antioxidants on SNP-induced vasodilation in SHR and WKY may suggest distinct mechanisms of tolerance development in hearts from hypertensive and normotensive rats. An increased peroxynitrite generation, expressed by higher 3-nitrotyrosine levels, could contribute to nitrate tolerance in the coronary circulation of SHR.

Acetylcysteine↗

PubMed1999

Identification and characterization of a new growth hormone-releasing peptide receptor in the heart.

Hexarelin, a synthetic hexapeptide of the growth hormone-releasing peptide (GHRP) family with strong growth hormone (GH)-releasing activity, features protecting activity against postischemic ventricular dysfunction in hearts from GH-deficient and senescent rats. To document whether hexarelin action is mediated through specific cardiac receptors, perfusion of Langendorff rat hearts with hexarelin and binding studies were carried out. In the Langendorff rat heart system, hexarelin induced a dose-dependent increase in coronary perfusion pressure. Nifedipine, chelerythrine, and bisindolylmaleimide partially inhibited the vasoconstriction induced by hexarelin, suggesting that this effect was mediated at least in part by L-type Ca(2+) channels and protein kinase C. In contrast, diclofenac and 1-(7-carboxyheptyl)imidazole were without effect, suggesting that prostaglandins and thromboxanes were not involved in the coronary vasoconstriction induced by hexarelin. To characterize the hexarelin binding sites in the rat heart, [(125)I]Tyr-Bpa-Ala-hexarelin was used as photoactivatable radioligand in saturation and competitive binding studies. We specifically labeled a hexarelin receptor with an M(r) of 84 000 in rat cardiac membranes. Saturation binding curves revealed a single class of binding sites with a K(d) of 14.5 nmol/L and a density of 91 fmol/mg of protein. Competition binding studies gave an IC(50) of 2.9 micromol/L for hexarelin; MK-0677 and EP51389, both potent GH secretagogues, did not displace the binding of the photoactivatable derivative from rat cardiac membranes. Interestingly, both compounds were devoid of any vasoconstrictive activity. These results suggest the existence of a new class of hexarelin receptor in the heart, whose role in the regulation of the coronary vascular tone is yet to be determined.

Animals↗

PubMed1999

Mechanisms of protection afforded by cyclooxygenase inhibitors to endothelial function against ischemic injury in rat isolated hearts.

The aim of this study was to assess whether cyclooxygenase (COX) inhibitors protect the endothelial function against the deleterious effect of ischemia and reperfusion. Isolated rat hearts perfused under constant-flow conditions were exposed to 30 min of partial ischemia (flow, 1 ml/min) followed by 20 min of reperfusion, after which coronaries were precontracted with U-46619, and the response to the endothelium-dependent vasodilator, serotonin (5-HT), was compared with that of the endothelium-independent vasodilator, sodium nitroprusside (SNP). In untreated hearts, ischemia diminished selectively 5-HT-induced vasodilation, compared with sham hearts (without ischemia). The vasodilation to SNP was unaffected in all groups. Pretreatment with 6-MNA, 30 microM, a COX-2 inhibitor with some activity on COX 1, diclofenac, 1 microM (COX-1 and -2), or 1-(7-carboxyheptyl) imidazole, 10 microM [thromboxane (TX) synthase inhibitor] but not indomethacin, 10 microM (COX-1 inhibitor) preserved the vasodilation induced by 5-HT after ischemia. Enzyme immunoassays indicated that all COX inhibitors decreased the concentration of TXB2 and 6-keto-PGF1alpha [stable metabolites of TXA2 and prostacyclin (PGI2), respectively] in coronary effluent during ischemia. Furthermore, indomethacin was the only one to abolish the concentration of PGE2 during ischemia and early reperfusion. No clear trend on ventricular postischemic recovery could be observed between treated and untreated groups under our experimental protocols. These data suggest that, under our conditions, 6-MNA, diclofenac, and 1-7-CHI, but not indomethacin, protect the endothelial function via a reduction in TX concentration. Disparities between COX inhibitors may be due to the complete abolition of PGE2 concentration during ischemia and reperfusion in the indomethacin group.

Animals↗

PubMed1999

Modification of vasodilator response in streptozotocin-induced diabetic rat.

Functional dilatory response in streptozotocin-induced diabetic rats was investigated using thoracic aortas, isolated hearts, and mesenteric beds. Dose-response curves to the PGI2 analogue iloprost on phenylephrine-preconstricted rings of diabetic rats and controls were comparable. In contrast, decreased vasodilation in diabetic rats was observed when dose-response curves to iloprost were performed in hearts and on phenylephrine-preconstricted mesenteric beds. Dose-response curves to forskolin, an adenylyl cyclase activator, performed with hearts and phenylephrine-preconstricted aortic rings and isolated mesenteric beds of diabetic rats and controls were comparable. However, a decreased vasodilation to the ATP-sensitive potassium channel (K(ATP)) activator lemakalim was observed in diabetic hearts, but not in aortic rings and mesenteric beds. In conclusion, under our experimental conditions, diabetes mellitus affects the vasodilation to iloprost in both coronary and mesenteric beds, but not in the aorta. In the heart, this modification of vascular reactivity may be due to a decrease in K(ATP) channel mediated response and not to a decreased activity of adenylyl cyclase. At this time, in the isolated mesenteric bed, the mechanism of this modification in vascular reactivity remains unknown.

Adenylyl Cyclases↗

PubMed1998

Protection afforded by preconditioning to the diabetic heart against ischaemic injury.

OBJECTIVE: The aim of this study was to assess whether the cardioprotective effect of ischaemic preconditioning (IPC) on endothelial function in coronary arteries and myocardial function is affected in the streptozotocin-induced diabetic rat heart. METHODS: Isolated hearts, perfused under constant flow conditions, were exposed to 30 min of partial ischaemia (flow rate 1 ml min-1) followed by 20 min of reperfusion. RESULTS: In the diabetic group (without ischaemia or IPC), infusion of 10 microM serotonin (5-HT), an endothelium-dependent, and 3 microM sodium nitroprusside (SNP), an endothelium-independent vasodilator, in the coronary bed preconstricted with 0.1 microM U-46619 induced a marked vasodilation. Ischaemia, either without or with preconditioning with a single 5 min ischaemia and 10 min reperfusion (IPC1) before ischaemia, was accompanied by a reduced 5-HT-induced vasodilation in diabetic hearts. In contrast, IPC1 preserved the response to 5-HT in non-diabetic hearts. A more extensive IPC with 3 periods of 5 min ischaemia followed by 5 min reperfusion (IPC3) preserved the vasodilation produced by 5-HT in both diabetic and non-diabetic hearts. IPC3 increased the recovery of d P/dtmax and d P/dtmin during the 30 min ischaemic period and during reperfusion in all hearts. In contrast, IPC1 had no effect on myocardial recovery in either groups. Adenosine pre-treatment started 30 min before ischaemia mimicked IPC3, preserving the vasodilation to 5-HT and improving myocardium recovery in both groups. When adenosine was started 15 min before ischaemia, vasodilation to 5-HT was preserved in non-diabetic hearts only. CONCLUSIONS: These results suggest that IPC affords protection to endothelial function in resistance coronary arteries of diabetic hearts. To achieve this protection, a more extensive IPC is needed, which may be related to a longer exposure to adenosine.

Adenosine↗

PubMed1998

Binding sites for growth hormone-releasing peptide.

Growth hormone-releasing peptides (GHRPs) are known to release growth hormone (GH) in vivo and in vitro by a direct action on receptors in anterior pituitary cells. Measurement of second messengers released following somatotroph stimulation suggests the existence of more than one GHRP receptor subtype in the hypothalamic-pituitary system. Furthermore, hexarelin, a hexapeptide of the GHRP family and a potent GH secretagogue, is reported to increase left ventricular ejection fraction, suggesting the expression of specific myocardial GHRP binding sites. In order to confirm such a hypothesis, a photoactivatable derivative of hexarelin, Tyr-p-benzoyl phenylalanine-Ala-hexarelin, was developed. A putative GHRP receptor with an apparent relative molecular mass of 57,000 was specifically labelled and characterized in human, bovine and porcine anterior pituitary membranes using this hexarelin derivative. The existence of myocardial binding sites was also demonstrated using the same approach. The differential binding affinity of GHRP analogues to cardiac tissue raises the possibility of the existence of distinct GHRP receptor subtypes in the pituitary and the cardiovascular system, for which physiological roles have yet to be determined.

Animals↗

PubMed1998

Role of kinins in the endothelial protective effect of ischaemic preconditioning.

1. The aim of this study was to assess whether the protective effect of ischaemic preconditioning on endothelial function in coronary arteries of the rat involves kinins. 2. Isolated hearts of the rat were exposed to a 30-min low-flow ischaemia (flow rate of 1 ml min[-1]) followed by 20-min reperfusion, after which coronaries were precontracted with 0.1 microM U-46619, and the response to the endothelium-dependent vasodilator, 5-hydroxytryptamine (5-HT, 10 microM), compared to that of the endothelium-independent vasodilator, sodium nitroprusside (SNP, 3 microM). 3. In untreated hearts, ischaemia-reperfusion diminished selectively 5-HT-induced vasodilatation, compared with time-matched sham hearts. The vasodilatation to SNP was unaffected after ischaemia-reperfusion. Preconditioning (5 min of zero-flow ischaemia followed by 10 min reperfusion) in untreated hearts preserved the vasodilatation produced by 5-HT. 4. Blockade of B1 and B2 receptors with either 3 nM [Lys[0], Leu8, des-Arg9]-bradykinin (LLDBK) or 10 nM Hoe 140 (icatibant), respectively, (started 15 min before ischaemic preconditioning or a corresponding sham period and stopped just before the 20-min reperfusion period) had no effect on the vasodilatation produced by either 5-HT or SNP in sham hearts. Pretreatment with Hoe 140 did not block the protective effect of ischaemic preconditioning on the 5-HT vasodilatation. In contrast, LLDBK halved the protective effect of ischaemic preconditioning on endothelium-dependent vasodilatation. 5. Perfusion with either bradykinin or des-Arg9-bradykinin (1 nM) 30 min before and lasting throughout the ischaemia protected the endothelium. 6. In conclusion, ischaemic preconditioning affords protection to the endothelial function in coronary resistance arteries of the rat partly by activation of B1 receptors. Although exogenous BK perfusion can protect the endothelium, B2 receptors do not play an important role in this protection in the rat isolated heart.

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

PubMed1998

[Role of B1 receptors in the endothelial protective effect of ischaemic preconditioning].

The aim of this study was to assess whether the cardioprotective effect of ischaemic preconditioning (IPC) on endothelial function in resistance coronary arteries of the rat involves activation of kinin receptors. Isolated rat hearts perfused under constant flow conditions were exposed to 30 min of partial ischaemia (flow rate 1 mL/min) followed by 20 min of reperfusion. Preconditioning was performed with 5 min zero-flow ischaemia and 10 min reperfusion before the 30-min ischaemia. After the 20-min reperfusion period, coronaries were precontracted with U-46619 0.1 microM, and the coronary response to the endothelium-dependent vasodilator, serotonin (5-HT, 10 microM), was compared to that of the endothelium-independent vasodilator, sodium nitroprusside (SNP, 3 microM). Kinin B1 and B2 receptors were blocked with perfusion of either [Lys0, Leu8, des-Arg0]-Bradykinin 30nM (LLDBK) or Hoe 140 10 nM (Hoe) respectively, started 15 min before IPC or a corresponding sham period and stopped just before the 20-min reperfusion period. In untreated hearts, ischemia diminished selectively 5-HT-induced vasodilatation, compared to sham hearts (without ischaemia). The vasodilatation by SNP was unaffected after ischaemia and reperfusion. Preconditioning in untreated hearts preserved the vasodilatation produced by 5-HT. Treatment of hearts with either Hoe or LLDBK had no effect on the vasodilatation produced by both 5-HT and SNP in sham hearts. Pre-treatment with Hoe did not block the protective effect of IPC on the 5-HT vasodilatation. LLDBK halved the protective effect of IPC on endothelium-dependent vasodilatation. In addition, the protective effect of BK on the endothelial function in the isolated rat heart was blocked by LLDBK. These results suggest that IPC and exogenous kinin perfusions afford protection to endothelial function in resistance coronary arteries of the rat partially by activation of B1 kinin receptors. B2 receptors do not play any role in that protection.

Animals↗

PubMed1997

[Decrease of vascular response to iloprost in diabetic rats].

The functional dilatory response in the streptozotocin-induced diabetic rat was investigated using thoracic aortas and coronary microcirculation. The aortas were cut in 4 mm intact or denuded rings and mounted into 20-ml organ baths. Coronary microcirculation was evaluated with isolated hearts perfused under constant flow conditions. Firstly, vasodilation to iloprost (Ilo) was examined. Dose-response curves to Ilo (10 pM-10 microM) on phenylephrine (PE, 30 nM for endothelium-denuded, and 0.3 microM for intact) preconstricted rings of diabetics and age-matched controls were comparable (n = 6). Decreased vasodilation in diabetic group was observed when dose-response curves to Ilo (1 nM-0.1 microM) were realized in isolated hearts (-22 +/- 3.3% vs -46 +/- 3.9%, n = 6, p < 0.05). Secondly, dose-response curves to forskolin (FSK), an adenylate-cyclase activator, performed in hearts (1 nM-3 microM), and on PE preconstricted rings (10 pM-10 microM) of diabetics and age-matched controls were comparable. Finally, the effect of an activator of ATP sensitive potassium channels (KATP), cromakalim (CMK), was evaluated in coronary circulation (0.3 nM-3 microM) and in aortas (10 pM-10 microM). Decreased vasodilation to CMK was observed in diabetic hearts (-10.5 +/- 4.3 vs -30.1 +/- 2.8%, n = 6, p < 0.05). In conclusion, under our experimental conditions, diabetes affects selectively the coronary vasodilation to iloprost. This modification of vascular reactivity may be due to a decrease of KATP channels sensitivity but not to a decreased activity of adenylate-cyclase.

Adenosine Triphosphate↗

PubMed1996

Mechanisms of protection afforded by preconditioning to endothelial function against ischemic injury.

The aim of this study was to assess whether the cardioprotective effect of ischemic preconditioning (IPC) on endothelial function in resistance coronary arteries of the rat involves adenosine and/or activation of ATP-sensitive K+ channels (KATP channels). Isolated rat hearts perfused under constant-flow conditions were exposed to 30 min of partial ischemia (flow rate 1 ml/min) followed by 20 min of reperfusion. Preconditioning was performed with 5 min of ischemia and 10 min of reperfusion before the 30-min ischemia. After the 20-min reperfusion period, coronary arteries were precontracted with U-46619 (0.1 microM), and the coronary response to the endothelium-dependent vasodilator serotonin (5-HT; 10 microM) was compared with that of the endothelium-independent vasodilator sodium nitroprusside (SNP; 3 microM). KATP channels or adenosine receptors were blocked with perfusion of either glibenclamide (0.3 microM) or 8-phenyltheophylline (8-PT; 5 microM), respectively, starting 15 min before IPC or a corresponding sham period. In untreated hearts, ischemia selectively diminished 5-HT-induced vasodilation, compared with sham hearts (without ischemia). The vasodilation by SNP was unaffected after ischemia and reperfusion. Preconditioning in untreated hearts preserved the vasodilation produced by 5-HT. Treatment of hearts with either glibenclamide or 8-PT halved the vasodilation produced by both 5-HT and SNP in sham hearts. Glibenclamide reduced by one-half, whereas 8-PT completely blocked, the protective effect of IPC on endothelium-dependent vasodilation. These results suggest that IPC affords protection to endothelial function in resistance coronary arteries of the rat partially by activation of KATP channels. Adenosine plays a major role in that protection.

Adenosine Triphosphate↗

PubMed1994

Evidence that prostaglandins I2, E2, and D2 may activate ATP sensitive potassium channels in the isolated rat heart.

OBJECTIVE: The aim was to study the contribution of ATP sensitive potassium channels (KATP channels) in the coronary vasodilatation produced by prostaglandins I2, E2, and D2 in rats. METHODS: Isolated Langendorff rat hearts, perfused under constant flow conditions, and rat aortic rings were used. Dose-response curves to PGE2, PGD2, and iloprost, a PGI2 analogue, were performed before and during KATP channel blockade with glibenclamide. Arachidonic acid was used to increase the formation of endogenous PGI2. RESULTS: Infusions of PGE2, PGD2, and iloprost in isolated hearts induced marked vasodilatation, as reflected by the reduction in coronary perfusion pressure of 27(SEM 7), 30(6), and 43(6)%, for 0.1 microM PGE2, PGD2, and iloprost, respectively. Infusion of glibenclamide (0.3 microM) was accompanied by a 23(3)% increase in coronary perfusion pressure. The vasodilatation induced by levcromakalim (0.1 microM) was completely inhibited in the presence of glibenclamide, whereas that of papaverine (30 microM) was unaffected. Glibenclamide significantly reduced the vasodilatation induced by iloprost (at 3 to 100 nM), PGE2 (30 and 100 nM), and PGD2 (30 and 100 nM), at all concentrations studied. In contrast, glibenclamide (1 microM) had no effect on iloprost induced relaxation of aortic rings. Arachidonic acid infusion (from 0.1 to 3 microM) in isolated hearts induced a pronounced vasodilatation and a significant release of 6-keto-PGF1 alpha into the coronary effluent in a dose dependent fashion. Both responses to arachidonic acid were significantly reduced in the presence of the cyclo-oxygenase inhibitor diclofenac (1 microM). In an additional experimental series, the vasodilatation induced by arachidonic acid infusions was found to be significantly reduced in the presence of glibenclamide. CONCLUSIONS: Glibenclamide is a potent inhibitor of the coronary dilator action of prostaglandins I2, E2, and D2. This observation suggests that these prostaglandins may cause vasodilatation by opening KATP channels.

Adenosine Triphosphate↗