摘要:

Abstract—The role of cyclooxygenase-2 (COX-2) in the prolonged regulation of renal function was evaluated during changes in sodium intake and reduction of NO synthesis. It was evaluated in conscious dogs by administering a selective inhibitor (nimesulide) during 8 consecutive days. Nimesulide administration to dogs with normal or high sodium load did not modify glomerular filtration rate but reduced renal blood flow (16%;P<0.05). The vasoconstriction elicited by COX-2 inhibition was greater when NO production was inhibited because glomerular filtration rate decreased by >25% when nimesulide was administered to dogs with a reduced NO synthesis. During low sodium intake, COX-2 inhibition elicited a decrease (P<0.05) of both glomerular filtration rate (34%) and renal blood flow (31%). Sodium excretion only decreased (P<0.05) during the first day of COX-2 inhibition in dogs with normal or high sodium load. The increase in plasma potassium levels elicited by COX-2 inhibition was greater in dogs with low sodium intake and was enhanced when NO production was inhibited. This change in potassium was not secondary to a decrease in plasma aldosterone levels. The results of this study suggest that COX-2–derived metabolites (1) play a more important role in the long-term regulation of renal hemodynamic when sodium intake is low, (2) protect the renal vasculature from the vasoconstriction secondary to a reduction in NO, (3) are only acutely involved in regulating urinary sodium excretion, and (4) play a more important role in regulating plasma potassium concentration when NO synthesis is reduced.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Recent studies have linked fetal exposure to a suboptimal intrauterine environment with adult hypertension. The aims of the present study were to see whether prenatal dexamethasone administered intravenously to the ewe between 26 to 28 days of gestation (1) resulted in high blood pressure in male and female offspring and whether hypertension in males was modulated by testosterone status, and (2) altered gene expression for angiotensinogen and angiotensin type 1 (AT1) receptors in the brain in late gestation and in the adult. Basal mean arterial pressure (MAP) at 2 years of age was significantly higher in wethers exposed to prenatal dexamethasone (group D; 106±5 mm Hg, n=9) compared with the control group (group S; 91±3 mm Hg, n=8;P<0.01). Infusion of testosterone for 3 weeks had no effect on MAP in either treatment group. At 130 days of gestation, dexamethasone administered between 26 to 28 days of gestation (group DF; n=8), resulted in an increased expression of angiotensinogen in hypothalamus (in arbitrary units: 2.5±0.3 versus 1.3±0.3 in the saline group [group SF], n=10;P<0.05). In addition, there was higher expression of the AT1receptors in medulla oblongata in group DF (2.6±0.6 versus 1.1±0.2 in group SF;P<0.01). This effect of prenatal dexamethasone treatment was still evident in females at 7 years of age (group DA; n=5; 2.6±0.5 versus 1.1±0.2 in group SA; n=6,P<0.05). In conclusion, brief prenatal exposure of the pregnant ewe to dexamethasone leads to hypertension in adult animals of both sexes. Most interestingly, the mechanism leading to programming of hypertension might be linked with the brain angiotensin system.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—The aims of this study were to delineate the relative contribution of angiotensin II (ANG II) subtype 1A (AT1A) and 1B (AT1B) receptors to the development of two-kidney, one-clip (2K1C) Goldblatt hypertension in mice, to examine if increased nitric oxide synthase (NOS) activity counteracts the vasoconstrictor influences of ANG II in 2K1C hypertensive mice, and to determine the role of ANG II type 2 (AT2) receptors in 2K1C hypertension in mice. AT1AANG II receptor knockout (AT1A−/−) and wild-type (AT1A+/+) mice underwent clipping of the right renal artery. Systolic blood pressure (SBP) was significantly lower in AT1A−/− compared with AT1A+/+ mice, and neither clip placement nor AT2receptor blockade with PD 123319 (PD) altered SBP in AT1A−/− mice. A significant and sustained rise in SBP from 119±5 to 163±6 mm Hg was observed in the 2K1C AT1A+/+ mice from day 10 to day 26. Chronic PD infusion did not alter the course of hypertension in 2K1C/AT1A+/+. Acute PD infusion did not alter mean arterial pressure (MAP) in AT1A+/+, PD/AT1A+/+, 2K1C/AT1A+/+, PD/2K1C/AT1A+/+, AT1A−/−, PD/AT1A−/−, and PD/2K1C/AT1A−/− mice compared with basal levels. In contrast, acute PD infusion caused significant increases in MAP in 2K1C/AT1A−/− mice. The subsequent acute NOS inhibition caused greater increases in MAP in 2K1C/AT1A+/+ and PD/2K1C/AT1A+/+ mice than in AT1A+/+ and PD/AT1A+/+ mice. These results support the essential role of AT1Areceptors in mediating 2K1C hypertension and support the hypothesis that augmented NO production serves as a counteracting system in this model of hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Exaggerated cardiovascular reactivity to behavioral challenges among otherwise healthy individuals has been associated with carotid atherosclerosis. We evaluated whether a similar relationship exists among hypertensives, who are at a heightened atherosclerotic risk. Untreated, hypertensive men (n=251; age range, 40 to 70 years; 197 white, 54 black) completed a standardized battery of behavioral challenges while their blood pressure responses to the battery were measured. Mean and maximum carotid intima-media thickness and the occurrence of carotid plaques were subsequently determined using B-mode ultrasonography. Although greater systolic and diastolic responses to the battery were associated with greater mean and maximum intima-media thickness in univariate analyses (P<0.01), only diastolic reactivity showed a unique association with mean and maximum carotid intima-media thickness after multivariate adjustment for age, race, socioeconomic status, smoking and alcohol use, body mass index, lipid profile, glucose and insulin concentrations, and resting blood pressure (P<0.05). Carotid plaque occurrence was associated with greater systolic reactivity (P=0.05) and was marginally associated with greater diastolic reactivity (P=0.07) in univariate analyses, but neither systolic nor diastolic reactivity was uniquely associated with the presence of carotid plaques after multivariate risk-factor adjustment. Among hypertensives, exaggerated behaviorally evoked cardiovascular reactivity appears to be uniquely associated with greater carotid intima-media thickness but not with carotid plaque occurrence.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Migration of endothelial cells (EC) is a key event in angiogenesis that contributes to neovascularization in diabetic vasculopathy. Leptin induces angiogenesis and is elevated in obesity and hyperinsulinemia. The antidiabetic thiazolidinediones (TZD) inhibit leptin gene expression and vascular smooth muscle cell migration through activation of the peroxisome proliferator–activated receptor-&ggr; (PPAR&ggr;). This study investigates the role of leptin in EC migration, the chemotactic signaling pathways involved, and the effects of the TZD-PPAR&ggr; ligands troglitazone (TRO) and ciglitazone (CIG) on EC migration. We demonstrate that leptin induces EC migration. Because activation of two signaling pathways, the phosphatidylinositol-3 kinase (PI3K)→Akt→eNOS and the ERK1/2 MAPK pathway, is known to be involved in cell migration, we used the pharmacological inhibitors wortmannin and PD98059 to determine if chemotactic signaling by leptin involves Akt or ERK1/2, respectively. Both wortmannin and PD98059 significantly inhibited leptin-induced migration. Treatment with the TZD-PPAR&ggr;-ligands TRO and CIG significantly inhibited the chemotactic response toward leptin. Both PPAR&ggr;-ligands inhibited leptin-stimulated Akt and eNOS phosphorylation, but neither attenuated ERK 1/2 activation in response to leptin. The inhibition of Akt-phosphorylation was accompanied by a PPAR&ggr;-ligand–mediated upregulation of PTEN, a phosphatase that functions as a negative regulator of PI3K→Akt signaling. These experiments provide the first evidence that activation of Akt and ERK 1/2 are crucial events in leptin-mediated signal transduction leading to EC migration. Moreover, inhibition of leptin-directed migration by the PPAR&ggr;-ligands TRO and CIG through inhibition of Akt underscores their potential in the prevention of diabetes-associated complications.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—The NO/superoxide (O2−) balance is a key regulator of endothelial function. O2−levels are elevated in many forms of cardiovascular disease; therefore, decreasing O2−should improve endothelial function. To explore this hypothesis, internal mammary arteries and saphenous veins, obtained from patients undergoing coronary artery revascularization, and aortic and carotid arteries from Wistar-Kyoto and spontaneously hypertensive stroke-prone rats were incubated with O2−dismutase or NAD(P)H oxidase inhibitors. O2−levels were measured using lucigenin chemiluminescence; NO bioavailability was assessed in organ chambers; and mRNA expression of NAD(P)H oxidase components was quantified by use of a Light Cycler. In rat arteries, phenylarsine oxide, 4-(2-aminoethyl)-benzenesulfanyl fluoride, and apocynin all decreased NADH-stimulated O2−production, but only apocynin increased NO bioavailability. In human internal mammary arteries and saphenous veins, apocynin decreased NAD(P)H-stimulated O2−generation and caused vasorelaxation that was endothelium dependent and reversed on addition of the NO synthase inhibitor NG-nitro-l-arginine methyl ester. In addition, it increased NO production from cultured human endothelial saphenous vein cells. Polyethylene-glycolated O2−dismutase also increased NO bioavailability in rat carotid arteries and human blood vessels, but the effects were smaller than those observed with apocynin. NADH-generated O2−and mRNA expression of p22phox, gp91phox, and nox-1 were comparable between the 2 strains of rat. This is the first study to demonstrate pharmacological effects of apocynin in human blood vessels. The increases in NO bioavailability shown here suggest that the NAD(P)H oxidase pathway may be a novel target for drug intervention in cardiovascular disease.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Sildenafil inhibits cGMP breakdown by phosphodiesterase 5. In vitro, increased cGMP levels inhibit cAMP breakdown by phosphodiesterase 3. It is uncertain, however, whether sildenafil increases biological effects of interventions increasing cAMP levels in vivo. The objective of the present study in 40 healthy male volunteers was to determine the existence and extent of interactions with sildenafil and vasodilators acting via cGMP or cAMP or independently from these mediators on the arterial tone of the human forearm. Forearm blood flow (FBF) responses (plethysmography) to brachial artery infusions of 3 doses each of nitroglycerin, which increases cGMP levels; of isoprenaline and milrinone, which increase cAMP levels; and of verapamil as a control were assessed at baseline and 80 minutes after 50 mg oral sildenafil in 10 volunteers each. Sildenafil increased FBF (2.5±0.1 to 3.5±0.2 mL/min per 100 mL,P<0.001; n=40). At equipotent vasodilator dosages, sildenafil increased FBF from 7.5±1.0 to 9.8±1.2 mL/min per 100 mL for nitroglycerin, from 8.3±1.0 to 10.4±1.4 mL/min per 100 mL for isoprenaline, and from 8.1±1.0 to 10.3±1.2 mL/min per 100 mL for milrinone and slightly decreased FBF from 7.7±1.3 to 7.1±1.2 mL/min per 100 mL for verapamil. ANOVA for repeated measures revealed a significant interaction between sildenafil and the type of vasodilator on FBF (P<0.01). The responses of FBF to nitroglycerin, milrinone, and isoprenaline after sildenafil were similarly increased compared with the response to verapamil (P<0.01). Sildenafil markedly enhanced the arterial vasodilator response to nitroglycerin, milrinone, and isoprenaline. The response to milrinone and isoprenaline is compatible with an interaction between cGMP and phosphodiesterase 3 or an enhancement of the NO component of cAMP-mediated vasodilation, and raises the possibility of enhanced biological effects of interventions leading to increases of cAMP in the presence of sildenafil.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—The objective of this study was to determine the effect of chronic stress exposure on the circadian pattern of cardiovascular responses in mice. Using male C57BL6 mice with carotid arterial catheters, we tested the effect of 7 days of intermittent shaker stress on body weight, food intake, drinking activity, plasma corticosterone, mean arterial pressure (MAP), and heart rate. The stress was delivered automatically for 2-minute periods (150 cycles/min), 45 times/d for 7 days. Plasma corticosterone was significantly increased in acutely and chronically stressed mice, with a partial attenuation in the chronic condition. Stress increased water intake, produced no change in food intake, and significantly decreased body weight (5% change). MAP and heart rate were measured continuously on stress days 1, 3, and 7 and during the basal and recovery periods. Chronic stress did not produce a sustained increase in MAP; however, there was an increase in MAP during the first stress day and a decrease during the recovery period. There was a circadian pattern in the pressor responses, with greater increases seen during the light period (nonactive phase) than in the dark period (+24% versus +11% on stress day 3, light versus dark). The results suggest that a stress delivered during the nonactive phase represents a higher cardiovascular risk.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—It is well established that renin-angiotensin system blockers exert NO/prostacyclin-dependent antithrombotic effects. Because some beneficial effects of these drugs are mediated by angiotensin (Ang)-(1-7), in the present study we examined if their antithrombotic action could be mediated by Ang-(1-7). Intravenous infusion of Ang-(1-7) (1, 10, or 100 pmol/kg per minute for 2 hours) into rats developing venous thrombosis caused 50% to 70% reduction of the thrombus weight. This effect was dose-dependently reversed by cotreatment with A-779 (selective Ang-[1-7] receptor antagonist) or EXP 3174 (angiotensin type 1 receptor antagonist) but not by PD 123,319 (angiotensin type 2 receptor antagonist). Similarly, the antithrombotic effects of captopril (ACE inhibitor) and losartan (angiotensin type 1 receptor blocker) were attenuated by A-779 in a dose-dependent manner. The effect of Ang-(1-7) was completely abolished by concomitant administration of NO synthase inhibitor (NG-nitro-l-arginine methyl ester) and prostacyclin synthesis inhibitor (indomethacin), as has been shown previously for captopril and losartan. Thus, the antithrombotic effect of renin-angiotensin system blockers involves Ang-(1-7)–evoked release of NO and prostacyclin.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID