摘要:

Abstract—Blood pressure is a marker of elevated risk for cardiovascular disease, even within the normotensive range. The present study evaluates cardiorenal modifications observed in normotensive (<140/90 mm Hg) subjects. Using World Health Organization–International Society of Hypertension definitions, 265 normotensive subjects were categorized as having optimal (n=73), normal (n=84), and high-normal (n=108) blood pressure. Renal hemodynamics and function and cardiac morphology were evaluated by isotopic clearance techniques and ultrasonography, respectively. Urinary albumin excretion was measured in 24-hour urine collections. Body mass index and 24-hour urinary sodium (estimate of sodium intake), as well as left ventricular mass index, relative wall thickness, and glomerular filtration rate and filtration fraction, progressively increased in the optimal to high-normal groups. In contrast, effective renal plasma flow remained constant. Albuminuria was similar in all groups. Of interest, the proportion of subjects with concentric pattern of cardiac geometry (relative wall thickness ≥0.44) increased from 7% in optimal to 13% and 20% in normal and high-normal groups, respectively (P<0.05). Within this normotensive range of blood pressure, left ventricular mass index and relative wall thickness but not albuminuria were linearly correlated to systolic blood pressure; however, no correlation with diastolic blood pressure was found. In conclusion, changes in cardiac geometry and renal hemodynamics (increase in glomerular filtration rate and filtration fraction, an approximate index of glomerular pressure) that could predispose to cardiovascular morbidity and renal risk are already present in normotensive subjects with blood pressure higher than 120/80 mm Hg.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—Hypertension is strongly related to cardiovascular disease and all-cause mortality. Exercise reduces blood pressure but the response varies between individuals. The mechanisms by which physical activity energy expenditure (PAEE) modifies blood pressure are not fully defined but include modulation of sympathetic tone. Novel polymorphisms in the G-protein coupled receptor (GPR10) have been linked with high blood pressure. GPR10 may mediate the relationship between PAEE and blood pressure via central nervous mechanisms. We examined whether two GPR10 polymorphisms (G-62A and C914T) modify the association between PAEE and blood pressure in the MRC Ely study (N=687). When stratified by the C914T genotype, there were between-group differences for body mass index (BMI) (P=0.05), diastolic blood pressure (DBP) (P=0.006), and systolic blood pressure (SBP) (P=0.005). No differences were found betweenG-62A genotypes. The previously reported inverse relationship between PAEE and blood pressure was not observed in minor allele carriers for either polymorphism (A62 carriers: DBP &bgr;-1.11,P=0.52; SBP &bgr;-1.66,P=0.52. T914 carriers: SBP &bgr;=3.27;P=0.60) but was in common allele homozygotes (G62G: DBP &bgr;-6.18P=0.00001; SBP &bgr;-8.54P=0.0001. C914C: SBP &bgr;-7.07;P=0.00001). This corresponded to a significant interaction between PAEE and GPR10 polymorphisms on DBP (G-62A:P=0.006) and SBP (G-62A:P=0.008. C914T:P=0.068). Significant interactions were observed between haplotype (derived fromG-62A and C914T), PAEE, and blood pressure (DBP:P=0.08; SBP:P=0.023). The effect of physical activity on blood pressure is highly variable at population level. Knowledge of GPR10 genotype may define those who are least likely to benefit from physical activity. These findings may have relevance in the targeted treatment of hypertensive disease.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—Inflammation may play an important role in the pathogenesis of cardiac fibrosis in heart failure (HF) after myocardial infarction (MI).N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring antifibrotic peptide whose plasma concentration is increased 4- to 5-fold by angiotensin-converting enzyme inhibitors. We tested the hypothesis that in rats with HF after MI, Ac-SDKP acts as an anti-inflammatory cytokine, preventing and also reversing cardiac fibrosis in the noninfarcted area (reactive fibrosis), and thus affording functional improvement. We found that Ac-SDKP significantly decreased total collagen content in the prevention group from 23.7±0.9 to 15.0±0.7 &mgr;g/mg and in the reversal group from 22.6±2.2 to 14.4±1.6 (P<0.01). Interstitial collagen volume fraction and perivascular collagen were likewise significantly reduced. We also found that infiltrating macrophages were reduced from 264.7±8.1 to 170.2±9.2/mm2,P<0.001 (prevention), and from 257.5±9.1 to 153.1±8.5 mm2,P<0.001 (reversal), while transforming growth factor (TGF)-&bgr;-positive cells were decreased from 195.6±8.4 to 129.6±5.7/mm2,P<0.01 (prevention), and from 195.6±8.4 to 130.7±10.8/mm2,P<0.01 (reversal). Ac-SDKP did not alter either blood pressure or left ventricular hypertrophy (LVH); however, it depressed systolic cardiac function in the prevention study while having no significant effect in the reversal group. We concluded that Ac-SDKP has an anti-inflammatory effect in HF that may contribute to its antifibrotic effect; however, this decrease in fibrosis without changes in LVH was not accompanied by an improvement in cardiac function.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—17&bgr;-Estradiol reduces myocardial hypertrophy and left ventricular mass, suggesting that the selective estrogen receptor modulator raloxifene may have similar effects. However, it is not clear whether raloxifene inhibits both cardiac hypertrophy and dysfunction. We used transverse aortic-banded mice to produce pressure-overload cardiac hypertrophy and used neonatal rat ventricular cardiomyocytes to investigate the cellular mechanisms of raloxifene on cardiac hypertrophy. Left ventricular mass and fractional shortening of mice hearts were measured by transthoracic echocardiography. Protein synthesis of cardiomyocytes was evaluated by incorporation of [3H]leucine into cardiomyocytes exposed to angiotensin II. Phosphorylation of mitogen-activated protein (MAP) kinase was also observed in cardiomyocytes. Raloxifene prevented increases in left ventricular mass and decreases of fractional shortening at 4 weeks after aortic banding. Pretreatment with raloxifene before angiotensin II stimulation inhibited the increase in [3H]leucine incorporation into neonatal rat cardiomyocytes in a concentration-dependent manner. This inhibition was partially but not significantly attenuated byNG-nitro-l-arginine methyl ester (l-NAME), an inhibitor of nitric oxide synthase, and completely abolished by ICI182780, an estrogen receptor antagonist. Although the phosphorylation of p38 MAP kinase, c-Jun N-terminal kinase (JNK), or extracellular signal-regulated protein kinase (ERK) in cardiomyocytes was significantly increased by angiotensin II stimulation as compared with the control, pretreatment with raloxifene attenuated p38 MAP kinase phosphorylation, but neither JNK nor ERK phosphorylation. We conclude that raloxifene inhibits cardiac hypertrophy and dysfunction and that the inhibition of p38 MAP kinase phosphorylation after the stimulation of estrogen receptors may be involved in the cellular mechanisms of this agent.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—Lysophosphatidylcholine (LPC) is an endogenous phospholipid released from the cell membrane during ischemia, and it has potent cardiac effects, including inhibition of atrial natriuretic peptide (ANP) release. The aim of this study was to investigate the effects of LPC on hemodynamics and ANP release in hypertrophied atria and to define its mechanism. Isolated, perfused, beating, hypertrophied atria from monocrotaline-treated rats were used. LPC (30 &mgr;mol/L), a mixture of stearoyl-LPC, palmitoyl-LPC, and oleoyl-LPC, caused suppression of ANP release, which was markedly attenuated in hypertrophied atria compared with nonhypertrophied atria. Suppression of ANP release by stearoyl-LPC, palmitoyl-LPC, or oleoyl-LPC was also attenuated in hypertrophied atria. The potency appeared to be dependent on the species of fatty acid residue of LPC. Changes in ANP release by LPC, palmitoyl-LPC, and oleoyl-LPC were positively correlated with the degree of cardiac hypertrophy, but that by stearoyl-LPC was not. Changes in ANP release by LPC also were negatively correlated with changes in pulse pressure. Stearoyl-LPC caused an increase in intracellular Ca2+in single, atrial myocytes in a concentration-dependent manner, which was markedly attenuated in hypertrophied atrial myocytes. These results suggest that attenuation of LPC-induced suppression of ANP release from hypertrophied atria might partly be related to changes in pulse pressure in terms of cardiac hypertrophy and/or disturbance of intracellular Ca2+regulation.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—Recent studies have shown that diets rich in monounsaturated fatty acids (MUFAs) from olive oil, a natural source of oleic acid, have beneficial effects on blood pressure (BP) in hypertensive patients. With this in mind, we investigated whether a synthetic derivative of the MUFA oleic acid, 2-hydroxyoleic acid (2-OHOA), was capable of regulating the BP of Sprague-Dawley rats. Intraperitoneal and oral administration of 2-OHOA to rats induced significant and sustained decreases in BP in a time-dependent manner. Without affecting heart rate, treatments for 7 days provoked reductions in systolic BP of 20 to 26 mm Hg. At the molecular level, the density of G&agr;s, but not G&agr;i2or G&agr;o, increased in membranes from the hearts and aortas of 2-OHOA–treated rats, whereas in heart membranes, the density of G&agr;q/11 and protein kinase C&agr; proteins was also augmented. These molecular alterations were reflected in the increase in cAMP levels after G&agr;s protein and &bgr;-adrenergic receptor stimulation. On the contrary, inhibitory hormones reduced adenylyl cyclase activity to the same extent in 2-OHOA–treated rats as in vehicle-treated ones. Our results indicate that cardiovascular tissues from 2-OHOA–treated rats exhibited increased cAMP production in response to G&agr;s activation, which might be attributed to enhanced expression of G&agr;s proteins. As a result of this change, a significant reduction in systolic BP was observed. Therefore, BP can be lowered by administration of 2-OHOA, which might represent the first member of a new family of antihypertensive drugs.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—Excess production of superoxide anion in response to angiotensin II plays a central role in the transduction of signal molecules and the regulation of vascular tone. We examined the ability of insulin resistance to stimulate superoxide anion production and investigated the identity of the oxidases responsible for its production. Rats were fed diets containing 60% fructose (fructose-fed rats) or 60% starch (control rats) for 8 weeks. In aortic homogenates from fructose-fed rats, the superoxide anion generated in response to NAD(P)H was more than 2-fold higher than that of control rats. Pretreatment of the aorta from fructose-fed rats with inhibitors of NADPH oxidase significantly reduced superoxide anion production. In the isolated aorta, contraction induced by angiotensin II was more potent in fructose-fed rats compared with control rats. Losartan normalized blood pressure, NAD(P)H oxidase activity, endothelial function, and angiotensin II-induced vasoconstriction in fructose-fed rats. To elucidate the molecular mechanisms of the enhanced constrictor response to angiotensin II, expressions of angiotensin II receptor and subunits of NADPH oxidase were examined with the use of angiotensin II type 1a receptor knockout (AT1a KO) mice. Expression of AT1a receptor mRNA was enhanced in fructose-fed mice, whereas expression of either AT1b or AT2 was unaltered. In addition, protein expression of each subunit of NADPH oxidase was increased in fructose-fed mice, whereas the expression was significantly decreased in fructose-fed AT1a KO mice. The novel observation of insulin resistance-induced upregulation of AT1 receptor expression could explain the association of insulin resistance with endothelial dysfunction and hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—The present studies were undertaken to investigate the potential effect of a calcium channel blocker (CCB) to enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker (ARB) on vascular injury and the cellular mechanism of the effect of CCB on vascular remodeling. In polyethylene cuff-induced vascular injury of the mouse femoral artery, proliferation of vascular smooth muscle cells (VSMCs) and neointimal formation associated with activation of extracellular signal-regulated kinase (ERK), and tyrosine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3, inflammatory response assessed by monocyte chemoattractant protein-1 and tumor necrosis factor-&agr; expression, as well as oxidative stress such as expression of NADH/NADPH oxidase p22phoxsubunit and superoxide production, were less in AT1areceptor null mice. Administration of nonhypotensive doses of a CCB, azelnidipine (0.5 or 1 mg/kg per day) attenuated these parameters in wild-type and AT1a receptor null mice. Coadministration of lower doses of an ARB, olmesartan (0.5 mg/kg per day), and azelnidipine (0.1 mg/kg per day), which did not affect vascular remodeling, significantly inhibited these parameters in wild-type mice. Moreover, the effective dose of azelnidipine (1 mg/kg per day) exaggerated the inhibitory action of olmesartan at effective doses of 1 or 3 mg/kg per day on VSMC proliferation in the injured arteries. These results suggest that azelnidipine could inhibit vascular injury at least partly independent of the inhibition of AT1receptor activation and that azelnidipine could exaggerate the vascular protective effects of olmesartan, suggesting clinical possibility that the combination of CCB and ARB could be more effective in the treatment of vascular diseases.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—Hypertension in (mRen2)27 transgenic rats is partly dependent on activation of the sympathetic nervous system, but the role of ganglionic transmission is unknown. We assessed indices of synaptic plasticity (post-tetanic short-term potentiation [PTP] and long-term potentiation [LTP]) and sympathetic ganglionic transmission without tetany in superior cervical ganglia (SCG) of Hannover Sprague-Dawley rats (HnSD) versus (mRen2)27 rats. There were no differences in decay time constants [PTP=9 minutes; LTP=120 to 150 minutes in both (mRen2)27 and HnSD]. However, angiotensin (Ang) II increased PTP and LTP in SCG isolated from (mRen2)27 rats to a greater extent than HnSD. Candesartan (an AT1antagonist) blocked the potentiation in both groups. Without a preceding tetanic pulse, 16-nM Ang II induced similar significant increases in ganglionic transmission of ≈14% in both strains. Assessment of Ang II receptors by125I-[Sar1Thr8]-Ang II binding showed that the AT1-receptor subtype predominates in the ganglia. The density of receptors in the SCG was comparable in (mRen2)27 and HnSD rats, whether measured in tissue from ganglia removed and frozen versus ganglia used in the transmission testing, suggesting that upregulation of receptors in vitro after removal of SCG did not occur. The divergence of effects of Ang II on LTP and PTP [greater in (mRen2)27 than HnSD] and nontetany ganglionic transmission (similar in both strains) may reflect different locations of receptors (pre- versus postsynaptic) or different signaling mechanisms involved in the two responses. We suggest that functional Ang II receptors in SCG mediate physiological actions of Ang II on ganglionic transmission and may play a pivotal role in hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—Angiotensin II is a known stimulus for the expression of vascular endothelial growth factor (VEGF). This action of angiotensin II is mediated by the angiotensin type 1 (AT1) receptor. However, the role of the angiotensin type 2 (AT2) receptor subtype in inducing VEGF expression has been controversial. The aim of the present study was to assess the effects of AT2 receptor blockade on VEGF expression in the retina, initially in experimental diabetic rats induced by injection of streptozotocin. The AT1 receptor antagonist, valsartan, or the AT2 receptor antagonists, PD123319, were administered to diabetic rats for 4 weeks. Increased gene and protein expressions of VEGF, as assessed by real-time reverse transcription-polymerase chain reaction and immunostaining, respectively, were observed in the retina in diabetic rats. Treatment with either valsartan or PD123319 attenuated retinal VEGF expression. To further explore the link between angiotensin receptor subtypes and VEGF expression, valsartan, or PD123319 were administered to rats that were infused with angiotensin II for 2 weeks. VEGF expression was also increased in the retina from angiotensin II infused rats, and this was attenuated by valsartan and PD123319. These findings suggest that VEGF expression is modulated by AT1 and AT2 receptors, thereby implicating angiotensin II receptor subtypes in retinal diseases such as diabetic retinopathy.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID