ISSN:0194-911X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

We conducted a genome-wide scan for quantitative trait loci influencing the systolic blood pressure, diastolic blood pressure, and pulse responses to a postural challenge in 498 white sibling-pairs from the Hypertension Genetic Epidemiology Network, a multicenter study of the genetic susceptibility to hypertension. All participants were hypertensive (systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or on antihypertensive medications) with diagnosis before age 60. Blood pressure and pulse were measured by an oscillometric method after a 5-minute rest in a supine position and again immediately on standing. The genome scan included a total of 387 autosomal short-tandem-repeat polymorphisms typed by the National Heart, Lung, and Blood Institute Mammalian Genotyping Service at Marshfield. We used multipoint variance-components linkage analysis to identify possible quantitative trait loci influencing postural change phenotypes after adjusting for sex, age, and use of antihypertensive medications. There was suggestive evidence for linkage on chromosome 18q for the postural systolic blood pressure response (maximum logarithm of the odds score=2.6 at 80 centiMorgans). We also observed a maximum logarithm of the odds score of 1.9 for the systolic blood pressure response and 1.7 for the diastolic blood pressure response on chromosome 6p. The marker that demonstrated the strongest evidence for linkage for the systolic blood pressure response (D18S858) lies within 20 centiMorgans of a marker previously linked to rare familial orthostatic hypotensive syndrome. Our findings indicate that there may be 1 or more genes on chromosome 18q that regulate systolic blood pressure during the physiological recovery period after a postural stressor.

ISSN:0194-911X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Hypertension is a leading cause of morbidity and mortality. Efforts to identify hypertension genes have focused on 3 approaches: mendelian disorders, candidate genes, and genome-wide scans. Thus far, these efforts have not identified genes that contribute substantively to overall blood pressure (BP) variation in the community. A 10-centiMorgan (cM) density genome-wide scan was performed in the largest families from 2 generations of Framingham Heart Study participants. Heritability and linkage for long-term mean systolic and diastolic BP phenotypes were analyzed by use of solar software. Heritability estimates were based on BP measurements in 1593 families. Genotyping was performed on 1702 subjects from 332 large families, and BP data were available for 1585 (93%) genotyped subjects who contributed 12 588 longitudinal BP observations. The mean age was 47 years, and mean BP was 127/80 (systolic/diastolic) mm Hg. Long-term systolic and diastolic BP phenotypes had high heritability estimates, 0.57 and 0.56, respectively. For systolic BP, multipoint log-of-the-odds (LOD) scores >2.0 were located on chromosome 17 at 67 cM (LOD 4.7,P=0.0000016) and 94 cM (LOD 2.2). For diastolic BP, LOD scores >2.0 were identified on chromosome 17 (74 cM, LOD 2.1) and chromosome 18 (7 cM, LOD 2.1). Using a genome-wide scan, we found strong evidence for a BP quantitative trait locus on chromosome 17. Follow-up studies are warranted to identify the gene or genes in this quantitative trait locus that influence BP. Such knowledge could extend our understanding of the genetic basis of essential hypertension and have implications for the evaluation and treatment of patients with high BP.

ISSN:0194-911X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Oscillometric blood pressure devices tend to overestimate systolic blood pressure and underestimate diastolic blood pressure compared with sphygmomanometers. Recent studies indicate that discrepancies in performance between these devices may differ between healthy and diabetic subjects. Arterial stiffness in diabetics could be the underlying factor explaining these differences. We studied differences between a Dinamap oscillometric blood pressure monitor and a random-zero sphygmomanometer in relation to arterial stiffness in 1808 healthy elderly subjects. The study was conducted within the Rotterdam Study, a population-based cohort study of subjects aged 55 years and older. Systolic and diastolic blood pressure differences between a Dinamap and a random-zero sphygmomanometer were related to arterial stiffness, as measured by carotid-femoral pulse wave velocity. Increased arterial stiffness was associated with higher systolic and diastolic blood pressure readings by the Dinamap compared with the random-zero sphygmomanometer, independent of age, gender, and average mean blood pressure level of both devices. The &bgr;-coefficient (95% CI) was 0.25 (0.00 to 0.50) mm Hg/(m/s) for the systolic blood pressure difference and 0.35 (0.20 to 0.50) mm Hg/(m/s) for the diastolic blood pressure difference. The results indicate that a Dinamap oscillometric blood pressure device, in comparison to a random-zero sphygmomanometer, overestimates systolic and diastolic blood pressure readings in subjects with stiff arteries.

ISSN:0194-911X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Aging of the vasculature results in arterial stiffening and an increase in systolic and pulse pressures. Although pressure load is a stimulus for left ventricular hypertrophy, the extent to which vascular stiffening per se, independent of blood pressure, influences left ventricular structure is uncertain. Two hundred seventy-six subjects (79 normotensive and 197 otherwise healthy hypertensive individuals) underwent echocardiography to assess left ventricular structure. Arterial stiffness was estimated by the pressure-independent stiffness index, &bgr;, and the pressure-dependent elastic modulus derived from simultaneous carotid ultrasound and applanation tonometry. Systemic arterial compliance (the inverse of stiffness) was estimated by the arterial compliance index. In multivariate analysis, &bgr; was related to age (P<0.001) and smoking history (P<0.01) but not mean pressure, whereas elastic modulus was related to age and mean pressure (bothP<0.001). The arterial compliance index was only related to age. Whereas systolic and diastolic pressures and the elastic modulus were positively associated with left ventricular mass (allP<0.001), primarily because of increases in wall thicknesses, &bgr; and the arterial compliance index bore no relation to left ventricular mass. &bgr; was inversely related to chamber diameter and directly related to left ventricular relative wall thickness, the ratio of wall thickness to chamber radius. Younger and older hypertensive subjects had comparable left ventricular mass, despite higher systolic and pulse pressures in the older group, whereas older hypertensives had higher mean relative wall thickness, associated with a significant increase in arterial stiffness (&bgr;, 7.06 versus 5.17; elastic modulus, 595 versus 437 dyne/cm2×10−6) and reduction in the arterial compliance index (0.87 versus 1.05 mL/mm Hg per square meter) (allP<0.001). Thus, the extent to which arterial stiffness relates to left ventricular hypertrophy is dependent on the method by which arterial stiffness is estimated. Pressure-dependent methods show an association with left ventricular hypertrophy, whereas the pressure-independent stiffness index, &bgr;, and the arterial compliance index are most strongly associated with aging and left ventricular concentric remodeling but not hypertrophy.

ISSN:0194-911X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Aldosterone is synthesized in extra-adrenal tissues, both blood vessels and brain. We undertook the present study to determine whether the rat heart produces aldosterone and to investigate the effects of adrenalectomy, ACE inhibition, and angiotensin II on aldosterone synthesis in the heart. To clarify the pathophysiological role of cardiac aldosterone in the hypertensive heart, we compared the synthesis of aldosterone in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) with that in Wistar-Kyoto rats. The effects of the aldosterone antagonist spironolactone on myocardial hypertrophy in adrenalectomized SHRSP were also studied. Isolated rat hearts were perfused for 2 hours, and the perfusate was analyzed with HPLC and mass spectrometry. The activity of aldosterone synthase was estimated on the basis of the conversion of [14C]deoxycorticosterone to [14C]aldosterone. The levels of aldosterone synthase gene (CYP11B2) mRNA were determined with competitive polymerase chain reaction. Aldosterone production, the activity of aldosterone synthase, and the expression of CYP11B2 mRNA were increased in hearts from adrenalectomized rats and rats treated with angiotensin II. ACE inhibitors decreased cardiac aldosterone synthesis. Cardiac aldosterone, aldosterone synthase activity, and CYP11B2 mRNA levels in hearts from 2- and 4-week-old SHRSP were significantly greater than those of age-matched Wistar-Kyoto rats. Spironolactone prevented cardiac hypertrophy in adrenalectomized SHRSP. These results suggest that the rat heart produces aldosterone and that endogenous cardiac aldosterone may affect cardiac function and hypertrophy in hypertension in rats.

ISSN:0194-911X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Obesity is commonly associated with impaired myocardial contractile function. However, a direct link between these 2 states has not yet been established. There has been an indication that leptin, the product of the human obesity gene, may play a role in obesity-related metabolic and cardiovascular dysfunctions. The purpose of this study was to determine whether leptin exerts any direct cardiac contractile action that may contribute to altered myocardial function. Ventricular myocytes were isolated from adult male Sprague-Dawley rats. Contractile responses were evaluated by use of video-based edge detection. Contractile properties analyzed in cells electrically stimulated at 0.5 Hz included peak shortening, time to 90% peak shortening, time to 90% relengthening, and fluorescence intensity change. Leptin exhibited a dose-dependent inhibition in myocyte shortening and intracellular Ca2+change, with maximal inhibitions of 22.4% and 26.2%, respectively. Pretreatment with the NO synthase inhibitorN&ohgr;-nitro-l-arginine methyl ester (L-NAME, 100 &mgr;mol/L) blocked leptin-induced inhibition of both peak shortening and fluorescence intensity change. Leptin also stimulated NO synthase activity in a time- and concentration-dependent manner, as reflected in the dose-related increase in NO accumulation in these cells. Addition of an NO donor (S-nitroso-N-acetyl-penicillamine [SNAP]) to the medium mimicked the effects of leptin administration. In summary, this study demonstrated a direct action of leptin on cardiomyocyte contraction, possibly through an increased NO production. These data suggest that leptin may play a role in obesity-related cardiac contractile dysfunction.

ISSN:0194-911X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

We hypothesized that the cardioprotective effect of angiotensin II type 2 receptor (AT2R) blockade with PD 123,319 (PD) on the recovery of left ventricular (LV) mechanical function after ischemia/reperfusion (IR) in the isolated working rat heart is associated with the enhanced expression of AT2R protein and mRNA as well as an increase in inositol 1,4,5-trisphosphate type 2 receptor (IP3R) and protein kinase C&egr; (PKC&egr;) proteins. We assessed AT2R, angiotensin II type 1 receptor (AT1R), IP3R, and PKC&egr; protein expression (Western blots) and AT2R mRNA levels (Northern blots) in myocardium from isolated working rat hearts that were subjected to global ischemia (30 minutes) followed by reperfusion (30 minutes). Groups of adult rat hearts (n=6) were exposed to no IR, no IR+PD (0.3 &mgr;mol/L), IR, and IR+PD. Compared with no IR and no IR+PD, IR decreased (P<0.05) functional recovery and AT2R mRNA and protein, as well as AT1R mRNA (not protein) and IP3R and PKC&egr; proteins. Compared with IR, PD+IR improved LV functional recovery (P<0.05) and markedly increased AT2R mRNA and protein (P<0.001). However, PD did not change AT1R mRNA or protein. More importantly, PD+IR markedly increased IP3R and PKC&egr; proteins. The downregulation of AT2R mRNA and protein with IR and their upregulation with PD indicate that the effects of PD are AT2R specific. The overall results suggest that the cardioprotective effect of acute PD treatment on LV functional recovery after IR in the isolated working rat heart is specifically due to AT2R blockade and is associated with enhanced downstream IP3R and PKC&egr; signaling.

ISSN:0194-911X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

In vitro studies on the role of the mitogen-activated protein (MAP) kinase family (extracellular signal-regulated kinase [ERK], c-Jun NH2-terminal kinase [JNK], and p38) in cardiac hypertrophic response have produced confusing and contradictory results. We examined the in vivo role of the angiotensin II type 1 (AT1) receptor in cardiac MAP kinase activities during both the onset and development of cardiac hypertrophy in stroke-prone spontaneously hypertensive rats (SHRSP). In both the acute and chronic phases of cardiac hypertrophy in SHRSP, cardiac JNK activities were significantly increased compared with those in normotensive rats, whereas there was no prominent increase in cardiac ERK or p38 activities in SHRSP. Losartan, an AT1receptor antagonist, prevented the onset of cardiac hypertrophy and regressed the progression of cardiac hypertrophy in SHRSP, being accompanied by the reduction of JNK activity and activator protein-1 (AP-1) activity in SHRSP. However, in spite of the normalization of blood pressure, hydralazine did not prevent or regress cardiac hypertrophy and did not decrease JNK or AP-1 activity in SHRSP. Inversely, hydralazine significantly increased the cardiac ERK activity in SHRSP by enhancing its phosphorylation. In conclusion, we have obtained the first evidence that the AT1receptor is involved in the enhanced cardiac JNK activity in both the onset and development of cardiac hypertrophy of hypertensive rats. We propose that JNK is involved in AT1receptor–mediated cardiac hypertrophy in vivo, in part mediated by the activation of AP-1.

ISSN:0194-911X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

We investigated whether a relationship exists between circulating transforming growth factor &bgr; -1 (TGF-&bgr;1), collagen type I metabolism, microalbuminuria, and left ventricular hypertrophy in essential hypertension and whether the ability of the angiotensin II type 1 receptor antagonist losartan to correct microalbuminuria and regress left ventricular hypertrophy in hypertensives is related to changes in TGF-&bgr;1and collagen type I metabolism. The study was performed in 30 normotensive healthy controls and 30 patients with never-treated essential hypertension classified into 2 groups: those with microalbuminuria (urinary albumin excretion >30 and <300 mg/24 h) associated with left ventricular hypertrophy (left ventricular mass index >116 g/m2for men and >104 g/m2for women) (group B; n=17) and those without microalbuminuria or left ventricular hypertrophy (group A; n=13). The measurements were repeated in all patients after 6 months of treatment with losartan (50 mg once daily). The serum concentration of TGF-&bgr;1was measured by a 2-site ELISA method, and the serum concentrations of carboxy-terminal propeptide of procollagen type I (a marker of collagen type I synthesis) and carboxy-terminal telopeptide of collagen type I (a marker of collagen type I degradation) were measured by specific radioimmunoassays. The duration of hypertension and baseline values of blood pressure were similar in the 2 groups of patients. No differences in serum TGF-&bgr;1, carboxy-terminal propeptide of procollagen type I, and carboxy-terminal telopeptide of collagen type I were found between normotensives and group A of hypertensives. Serum TGF-&bgr;1, carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I were increased (P<0.05) in group B of hypertensives compared with group A of hypertensives and normotensives. No differences in carboxy-terminal telopeptide of collagen type I were found among the 3 groups of subjects. After treatment with losartan, microalbuminuria and left ventricular hypertrophy persisted in 6 patients (then considered nonresponders) and disappeared in 11 patients (then considered responders) from group B. Compared with nonresponders, responders exhibited similar control of blood pressure and higher (P<0.05) blockade of angiotensin II type 1 receptors (as assessed by a higher increase in plasma levels of angiotensin II). Whereas TGF-&bgr;1, carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I decreased (P<0.05) in responders, no changes in these parameters were observed in nonresponders. These findings show that an association exists between an excess of TGF-&bgr;1, stimulation of collagen type I synthesis, inhibition of collagen type I degradation, and cardiorenal damage in a group of patients with essential hypertension. In addition, our results suggest that the ability of losartan to blunt the synthesis of TGF-&bgr;1and normalize collagen type I metabolism may contribute to protect the heart and the kidney in a fraction of patients with essential hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2000

数据来源: OVID