AGT and RH blood group polymorphisms affect blood pressure and lipids in Afro-Caribbeans.

Robinson MT, Wilson TW, Nicholson GA, Grell GA, Etienne C, Grim CM, Wilson D, Grim CE.

Department of Psychiatry, UC San Diego, La Jolla, CA, USA.

Population blood pressure variation is most likely due to multiple genes. This is likely the reason why monogenic testing with the angiotensinogen (AGT) gene polymorphisms on chromosome 1 (1q42-43), especially M235T, has met with negative results, especially in those of African descent. The RH blood group system, also on chromosome 1 (1 p36.2-34), has likewise been associated with blood pressure variation in African-Americans and with the rise in blood pressure with age in whites. Using a random sample of the population, we investigated the combined effects of single and combined variation of the AGTN M235T and RH genotypes on blood pressure, lipids, and lipoprotein concentrations in Afro-Caribbeans aged 18-60 years from the island nation of Dominica. In monogenic analysis, AGT M235T was not associated with blood pressure. However, it was associated with HDL (MM 42+/-23, MT 44+/-12, TT 52+/-14 (P=0.002)). RH genotype was significantly associated with systolic blood pressure (P=0.006) and Apo-A (P=0.003). These effects remained after adjustment for age, gender, weight, and BMI. In the polygenetic analysis, AGT M235T and RH were significantly associated with systolic blood pressure (P=0.037; interaction effects, P=0.068). The association of the AGT M235T with blood pressure across RH blood group haplotypes was then tested. Of the five RH haplotypes available for analysis, the AGT M235T was significantly associated with blood pressure within the "D" haplotype (P=0.01). The RH blood group and gender were significantly associated with systolic blood pressure and Apo-A levels (P=0.005 and 0.012, respectively). All interactions were independent of age and weight. In conclusion, we demonstrate a significant association of AGT M235T with blood pressure and cholesterol metabolism in an Afro-Caribbean population in the "genetic context" of the RH blood group system. Further investigation of these interactions may help understand the effects of genetic factors on cardiovascular risk in African-derived and other populations.

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Comparison of simultaneous measurement of mouse systolic arterial blood pressure by radiotelemetry and tail-cuff methods.

Whitesall SE, Hoff JB, Vollmer AP, D'Alecy LG.

Dept. of Molecular and Integrative Physiology, University of Michigan, 7708 Medical Sciences Bldg. II, Ann Arbor, MI 48109-0622, USA.

Radiotelemetry of mouse blood pressure accurately monitors systolic pressure, diastolic pressure, heart rate, and locomotor activity but requires surgical implantation. Noninvasive measurements of indirect systolic blood pressure have long been available for larger rodents and now are being reported more frequently for mice. This study compared mouse systolic arterial blood pressure measurements using implanted radiotelemetry pressure transducer with simultaneous tail-cuff measurements in the same unanesthetized mice. The pressure range for comparison was extended by inducing experimental hypertension or by observations of circadian elevations between 3 AM and 6 AM. Both trained and untrained tail-cuff operators used both instruments. Every effort was made to follow recommended manufacturer's instructions. With the initial flow-based tail-cuff instrument, we made 671 comparisons (89 sessions) and found the slope of the linear regression to be 0.118, suggesting poor agreement. In an independent assessment, 277 comparisons (35 sessions) of radiotelemetry measurements with the pulse based tail-cuff instrument were made. The slope of the linear regression of the simultaneous measurements of systolic pressures was 0.98, suggesting agreement. Bland-Altman analysis also supported our interpretation of the linear regression. Thus although reliable systolic pressure measurements are possible with either tail-cuff or radiotelemetry techniques, in our hands some tail-cuff instruments fail to accurately detect elevated blood pressures. These data, however, do not distinguish whether this instrument-specific tail-cuff failure was due to operator or instrument inadequacies. We strongly advise investigators to obtain an independent and simultaneous validation of tail-cuff determinations of mouse blood pressure before making critical genotyping determinations.

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Cardiovascular effects of intravenous pentazocine and cyclazocine in conscious, curarized-conscious, and anesthetized dogs.

Kucukhuseyin C.

Department of Pharmacology and Clinical Pharmacology, Cerrahpasa Medical Faculty, University of Istanbul, Cerrahpasa-Istanbul, Turkey. tahic istanbul.edu.tr

The cardiovascular effects of intravenous pentazocine and cyclazocine in dogs were studied under conscious, curarized-conscious (paralyzed by gallamine), and anesthetized states. In the conscious state, blood pressure and heart rate were dose-dependently increased by pentazocine (1, 2, 3 mg/kg) and to a lesser extent by cyclazocine (0.3 mg/kg). In all subsequent experiments on dogs, the results were obtained using 3 mg/kg pentazocine and 0.3 mg/kg cyclazocine. Pentazocine accelerated breathing, peaking at about 10 min, whereas cyclazocine reduced breathing to a minimum in 1 min, followed by a gradual recovery thereafter. In the curarized-conscious state, the blood pressure response to pentazocine was biphasic, namely an initial decrease followed by an increase; chronotrophic activity was stimulated. Pretreatment with either ganglionic or alpha andrenergic blocking agents not only significantly antagonized the pressory responses to the drug but also potentiated the initial decreases in blood pressure and unmasked a bradycardic component, but these parameters were not altered by 0.3 mg/kg naxalone. In open-chest anesthetized dogs, blood pressure, heart rate, contractility, and mean peripheral vascular resistance were simultaneously decreased by both pentazocine and cyclazocine, initially accompanied by increases in aortic blood flow. During the later stages of drug action, only the blood pressure and contractility were increased above control levels (biphasic effect). A comparison of blood pressure and heart rate responses to pentazocine in dogs kept under differing experimental conditions revealed that conscious dogs were more sensitive than curarized conscious and anesthetized animals to pentazocine action. In isolated guinea pig atria, the effect of adrenaline (0.1, 0.3, or 1 mg/mL) on the spontaneous breathing rate was significantly augmented by 10 mg/mL pentazocine (p < 0.02 for 0.3 g/mL; p < 0.01 for 0.1 g/mL adrenaline). In dogs, however, adrenaline (1 mg/kg)-induced increases in heart contractility, aortic blood flow, and blood pressure remained almost unaltered in the presence of pentazocine. We concluded that the abovementioned cardiovascular responses to pentazocine and cyclazocine are a consequence of the sum of the two following opposing effects: (i) an indirect reflex activation of sympathetic neuromediation in the periphery, and (ii) a direct membrane effect on the heart leading to bradycardia and a depression in myocardial contractility.

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Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromso Study.

Svartberg J, von Muhlen D, Schirmer H, Barrett-Connor E, Sundfjord J, Jorde R.

Department of Medicine, University Hospital of North Norway, 9038 Tromso, Norway. johan.svartberg unn.no

OBJECTIVE: To test the hypothesis that lower endogenous testosterone levels are associated with higher blood pressure, left ventricular mass, and left ventricular hypertrophy. DESIGN: Population-based cross-sectional study. METHODS: Sex hormone levels, measured by immunoassay, anthropometric measurements and resting blood pressure were studied in 1548 men aged 25-84 Years; echocardiography was completed in 1264 of these men. Partial correlations and multiple regressions were used to estimate the associations between sex hormones, blood pressure and left ventricular mass by height. Analyses of variance and covariance were used to compare men with categorical hypertension and left ventricular hypertrophy. RESULTS: In age-adjusted partial correlations, total testosterone and sex hormone-binding globulin (SHBG) were each inversely associated with systolic blood pressure (SBP) (P<0.001). Men with categorical hypertension (SBP> or =140 or diastolic blood pressure (DBP)> or =90 mmHg) had lower levels of total and free testosterone and SHBG before (P<0.001, P=0.011 and P<0.001, respectively) and after (P<0.001, P=0.035 and P=0.002, respectively) adjusting for body mass index (BMI). Total testosterone and SHBG were each inversely associated with left ventricular mass (P<0.001), and men with left ventricular hypertrophy had significantly lower levels of total testosterone (P=0.042) and SHBG (P=0.006); these associations were no longer significant after adjusting for BMI. CONCLUSION: The results of the present study are consistent with the hypothesis that lower levels of testosterone in men are associated with higher blood pressure, left ventricular mass, and left ventricular hypertrophy. The reduced associations after adjusting for BMI suggest that the association of low testosterone levels with blood pressure and left ventricular mass is mediated by obesity.

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Hypertension in a dental school patient population.

Kellogg SD, Gobetti JP.

University of Michigan School of Dentistry, 1011 N. University Avenue, Room #G018, Ann Arbor, MI 48109-1070, USA. skellog umich.edu

Patient records were retrospectively reviewed to investigate the incidence of hypertensive patients seen at a U.S. dental school. This research was conducted to create an awareness of the current problems in diagnosing and treating hypertensive patients in the dental environment. Nine hundred and seventy-six records of patients seen between January 1, 1999 and January 1, 2000 were reviewed. Five hundred records that met specific study criteria related to health history, medications used, recorded blood pressure, and other criteria were selected for the study. Factors examined included demographic data consisting of age, sex, and ethnicity; history of hypertension; Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure classification; control of hypertension; and medications used. The data demonstrated that 32 percent of the patients were hypertensive, 49 percent of whom were unaware of their high blood pressure prior to their dental visit. Nearly 9 percent of the hypertensive patients with elevated blood pressure had to be immediately sent for medical consult before they could receive dental treatment. The average blood pressure of the hypertensive patients was systolic 145.6 and diastolic 87.9 with a range of 110 to 240 systolic, 60 to 135 diastolic. Of the diagnosed patients, 41.9 percent were taking antihypertensive medication for their condition, and 13 percent were taking two or more medications. Nearly one third of a sample of 500 dental school clinic patients had high blood pressure in this retrospective study. This study demonstrates that it is crucial that dental providers take blood pressure readings for screening, monitoring of hypertensive patients, and appropriate dental care.

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Role of two angiotensinogen polymorphisms in blood pressure variation.

Robinson M, Williams SM.

Polymorphism Research Laboratory, Department of Psychiatry, Basis Science Building, La Jolla, CA, USA.

Genetic analysis of hypertension has yielded inconsistent results, making it difficult to draw clear conclusions regarding the impact of specific variants on blood pressure regulation. Among the most studied of the candidate genes for blood pressure regulation is angiotensinogen (AGT), but as with other candidate loci associations with blood pressure have been inconsistent. We examined the contributions of two AGT polymorphisms (T174M and M235T) to detect the effects of each on blood pressure variation, using single-site and two-site analyses. We analysed data from a study of 177 subjects from Accra, Ghana. We observed significant single-locus associations of the T174M polymorphism with average systolic (SBP) and diastolic blood pressure (DBP) when age was used as a covariate (P<0.001 and P=0.010, respectively). Also, we observed a significant association of the M235T polymorphism with SBPs and DBPs (P<0.001 and P=0.014, respectively). Finally, we observed a simultaneous significant association of the two polymorphisms with SBP and DBP (P<0.001 and P=0.026, respectively), although the two-loci model is not significantly better than either single-locus model. However, for SBP the two-loci model is marginally better (P=0.08 in comparison to both single-locus models). These results suggest that variants at these two AGT sites together, in conjunction with age, may be significantly associated with elevated SBP, whereas the single-site models are as good models of DBP. It is possible that earlier inconsistent results with these AGT polymorphisms with hypertension in African-derived populations may have resulted from an 'incomplete' model in the different study populations. Given the inconclusive nature of our two-loci results, this possibility requires further investigation.

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Reduced endothelial vasomotor function and enhanced neointimal formation after vascular injury in a rat model of blood pressure lability.

Eto M, Toba K, Akishita M, Kozaki K, Watanabe T, Kim S, Hashimoto M, Sudoh N, Yoshizumi M, Ouchi Y.

Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Increased short-term blood pressure variability is known to be associated with hypertensive target organ damage. Sinoaortic denervation (SAD) induces a marked increase in blood pressure lability without affecting the average blood pressure level. The aim of this study was to investigate the effects of blood pressure lability on endothelial vasomotor function and neointimal formation after balloon injury in SAD rats. Direct longterm measurement of mean arterial pressure showed no significant difference in the average of mean arterial pressure between the SAD group and sham-operated control group. In contrast, the standard deviation of mean arterial pressure, as an index of blood pressure lability, was 3-fold greater in SAD rats. To study endothelial function, isometric tension of aortic rings was measured 4 weeks after SAD or sham operation. Endothelium-dependent vasorelaxation induced by acetylcholine was significantly reduced in the SAD group (20% reduction at maximum relaxation). Endothelium-independent vasorelaxation induced by sodium nitroprusside was similar in each group. Acetylcholine-induced NO release from aortic rings was significantly reduced in the SAD group. Next, we examined neointimal formation in carotid arteries in SAD and sham-operated rats at 2 weeks after balloon injury. The neointimal-to-medial area ratio in the SAD group was 50% higher than that in the sham-operated group. The percentage of proliferating cell nuclear antigen-positive cells in the intima was significantly higher in the SAD group. These findings suggest that increased blood pressure lability, independently of average blood pressure level, impairs endothelial function by inhibiting NO production, enhances neointimal formation after balloon injury, and may thereby contribute to atherogenesis.

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The influence of ambulatory blood pressure profile on left ventricular geometry.

Balci B, Yilmaz O, Yesildag O.

Department of Cardiology, Ondokuz Mayis University, 55060 Samsun, Turkey. bahattinbalci ttnet.net.tr

Besides causing a hypertrophy in the left ventricle, hypertension results in a change in the geometry of the left ventricle. The blood pressure, which does not decrease enough during the night, leads to structural changes in the left ventricle. In this study, the influence of 24-hour blood pressure profile on the left ventricular geometry was examined. Ambulatory blood pressure monitoring was applied to 60 patients with mild to moderate hypertension who had never been treated and standard echocardiographic evaluation was conducted thereafter. The patients were divided into two groups with respect to the ambulatory blood pressure profiles: the patients whose night blood pressure levels decreased by more than 10% compared to their daytime blood pressure levels (dipper) and those whose levels did not decrease that much (nondipper). The left ventricle mass index and the relative wall thickness of the patients were calculated. With respect to the left ventricle geometry, mass index and relative wall thickness of the patients were determined as: having normal geometry, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. Age, gender, systolic, and diastolic blood pressure were similar within the dipper and nondipper groups. Normal geometry, concentric remodeling, and concentric hypertrophy ratios were similar in both groups. Eccentric hypertrophy was higher in the nondipper group compared to the dipper group (42.9% vs 6.3%, P < 0.03). Patients with mild to moderate hypertension, whose blood pressure does not decrease enough, develop eccentric hypertrophy.

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