摘要:

Abstract—Ischemic damage to the subcortical white matter of the brain, referred to as leukoaraiosis, is a frequent complication of hypertension-related microvascular disease and contributes to the risk of stroke and vascular dementia. A large genetic contribution to this late-life form of target organ damage was suggested by a study of elderly male twins. As part of the Genetic Epidemiology Network of Arteriopathy (GENOA), 483 non-Hispanic white subjects were recruited to undergo MRI for determination of the brain volume of leukoaraiosis (291 women and 192 men from 210 sibships providing 434 sibling pairs; mean age±SD=65.2±7.3 years). The GENOA–Rochester sibships contain 2 or more siblings with essential hypertension diagnosed before age 60. The frequency distribution of the volume of leukoaraiosis was positively skewed, with a median value of 6.61 cm3(interquartile range: 4.77 to 9 0.83 cm3). Variance component models were used to estimate the heritability (ie, the proportion of phenotypic variation caused by additive genetic factors). After logarithm transformation of the volume of leukoaraiosis, the estimated heritability (±SE) was 0.802±0.102 (P<0.0001). Adjustments for sex, age, systolic blood pressure, and brain volume reduced the heritability estimate to 0.671±0.110 (P<0.0001). This evidence of strong genetic influence on the susceptibility to leukoaraiosis justifies efforts to localize the responsible genes and characterize the predisposing genetic polymorphisms.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—To investigate the mediators of bradykinin-induced vasorelaxation in human coronary microarteries (HCMAs), HCMAs (diameter ≈300 &mgr;m) obtained from 42 heart valve donors (20 men and 22 women; age range, 3 to 65 years; mean age, 46 years) were mounted in Mulvany myographs. In the presence of the cyclooxygenase inhibitor indomethacin, bradykinin relaxed preconstricted HCMAs in a concentration-dependent manner.NG-nitro-l-arginine methyl ester and ODQ (inhibitors of nitric oxide [NO] synthase and guanylyl cyclase, respectively) and the NO scavenger hydroxocobalamin, either alone or in combination, shifted the bradykinin concentration-response curve to the right. Removal of H2O2(with catalase), inhibition of cytochrome P450 epoxygenase (with sulfaphenazole or clotrimazole) or gap junctions (with 18&agr;-glycyrrhetinic acid or carbenoxolone), and blockade of large- (BKCa) and small- (SKCa) conductance Ca2+-dependent K+channels (with iberiotoxin and apamin), either alone or in addition to hydroxocobalamin, did not affect bradykinin. In contrast, complete blockade of bradykinin-induced relaxation was obtained when we combined the nonselective BKCaand intermediate-conductance (IKCa) Ca2+-dependent K+channel blocker charybdotoxin and apamin with hydroxocobalamin. Charybdotoxin plus apamin alone were without effect. Inhibition of inwardly rectifying K+channels (KIR) and Na+/K+-ATPase (with BaCl2and ouabain, respectively) shifted the bradykinin concentration-response curve 10-fold to the right but did not exert an additional effect in the presence of hydroxocobalamin. In conclusion, bradykinin-induced relaxation in HCMAs depends on (1) the activation of guanylyl cyclase, KIR, and Na+/K+-ATPase by NO and (2) IKCaand SKCachannels. The latter are activated by a factor other than NO. This factor is not a cytochrome P450 epoxygenase product or H2O2, nor does it depend on gap junctions or BKCachannels.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—Hypertension increases oxidative stress, which can impair myocardial microvascular function and integrity. However, it is yet unclear whether long-term antioxidant intervention in early hypertension would preserve myocardial perfusion and vascular permeability responses to challenge. Pigs were studied after 12 weeks of renovascular hypertension without (n=8) or with daily supplementation of antioxidants (100 IU/kg vitamin E and 1 g vitamin C, n=6), and compared with normal controls (n=7). Myocardial perfusion and microvascular permeability were measured in vivo by electron beam computed tomography before and after 2 cardiac challenges (intravenous adenosine and dobutamine). Basal left ventricular muscle mass was also obtained. Mean arterial pressure was significantly increased in both groups of hypertensive animals (without and with antioxidants, 123±9 and 126±4 mm Hg, respectively, versus normal, 101±4 mm Hg; bothP<0.05), but muscle mass was not different among the groups. The impaired myocardial perfusion response to adenosine observed in hypertensives (normal, +51±14%;P<0.05 versus baseline; hypertension, +14±15%;P=0.3 versus baseline) was preserved in hypertensive pigs that received antioxidants (+44±15%;P=0.01 compared with baseline). Long-term antioxidant intervention also preserved subendocardial microvascular permeability responses in hypertension. On the other hand, antioxidant intervention had little effect on the hypertension-induced myocardial vascular dysfunction observed in response to dobutamine. This study demonstrates that the impaired myocardial perfusion and permeability responses to increased cardiac demand in early hypertension are significantly improved by long-term antioxidant intervention. These results support the involvement of oxidative stress in myocardial vascular dysfunction in hypertension and suggest a role for antioxidant strategies to preserve the myocardial microvasculature.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—Angiotensin II (Ang II) is implicated in the proinflammatory process in various disease situations. Thus, we sought to determine the role of Ang II in early inflammation-induced fibrosis of pressure-overloaded (PO) hearts. PO was induced by suprarenal aortic constriction (AC) at day 0 in male Wistar rats, and they were orally administered 0.1 mg/kg per day candesartan every day from day −7. This was the maximum dose of candesartan that did not change arterial pressure in hypertensive rats with AC (AC rats). In AC rats, cardiac angiotensin-converting enzyme (ACE) activity was transiently enhanced after day 1 and peaked at day 3, declining to lower levels by day 14, whereas serum ACE activity was not changed. In AC rats, PO induced early fibroinflammatory changes (monocyte chemoattractant factor [MCP]-1 and transforming growth factor [TGF]-&bgr; expression, perivascular macrophage accumulation, and fibroblast proliferation), and thereafter, left ventricular hypertrophy developed, featuring myocyte hypertrophy, intramyocardial arterial wall thickening, and perivascular and interstitial fibroses. Candesartan suppressed the induction of MCP-1 and TGF-&bgr; and reduced macrophage accumulation and fibroblast proliferation in PO hearts. Candesartan significantly prevented perivascular and interstitial fibrosis. However, candesartan did not affect myocyte hypertrophy and arterial wall thickening. In conclusion, a subdepressor dose of candesartan prevented the MCP-1–mediated inflammatory process and reactive myocardial fibrosis in PO hearts. Ang II might play a key role in reactive fibrosis in hypertensive hearts, independent of arterial pressure changes.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID