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Objective:To more precisely and comprehensively estimate the genetic and environmental correlations between various indices of obesity and BP.Methods:We estimated heritability and genetic correlations of obesity indices with BP in the Oman family study (n=1231). Ambulatory and office beat-to-beat BP was measured and mean values for SBP and DBP during daytime, sleep, 24-h and 10min at rest were calculated. Different indices were used to quantify obesity and fat distribution: BMI, percentage of body fat (%BF), waist circumference and waist-to-height ratio (WHtR). SOLAR software was used to perform univariate and bivariate quantitative genetic analyses adjusting for age, age2, sex, age-sex and age2- sex interactions.Results:Heritabilities of BP ranged from 30.2 to 38.2% for ambulatory daytime, 16.8 - 21.4% for sleeping time, 32.1 - 40.4% for 24-h and 22 - 24.4% for office beat-to-beat measurements. Heritabilities for obesity indices were 67.8% for BMI, 52.2% for %BF, 37.3% for waist circumference and 37.9% for WHtR. All obesity measures had consistently positive phenotypic correlations with ambulatory and office beat-to-beat SBP and DBP (r-range: 0.14 - 0.32). Genetic correlations of obesity indices with SBP and DBP were higher than environmental correlations (rG: 0.16 - 0.50; rE: 0.01 - 0.31).Conclusion:The considerable genetic overlap between a variety of obesity indices and both ambulatory and office beat-to-beat BP highlights the relevance of pleiotropic genes. Future GWAS analyses should discover the specific genes both influencing obesity indices and BP to help unravel their shared genetic background.

Objective:Several studies have reported a small yet significant decrease in blood pressure (BP) with continuous positive airway pressure (CPAP) application in patients with obstructive sleep apnea (OSA). We investigated the long-term efficiency of CPAP in the management of hypertensive patients with

To determine, in sedentary normotensive postmenopausal women, the after-effects of exercise on systemic and regional hemodynamics, and whether changes in total peripheral conductance after exercise relate to changes in brachial artery flow-mediated vasodilation (FMD).In 13 sedentary postmenopausal women, the blood pressure (BP), cardiac output, total peripheral resistance and total peripheral conductance, calf vascular resistance and FMD were measured during baseline rest, and again commencing 45 min after treadmill exercise. Fourteen premenopausal women completed the identical protocol to obtain reference values for the after-effects of exercise in healthy females.In postmenopausal women, exercise was followed by falls in systolic BP (P0.01) and diastolic BP (P0.001). BP did not fall after exercise in premenopausal women. In both groups the cardiac output (P0.01) increased and the calf vascular resistance (P0.01) and total peripheral resistance (P0.05) decreased after exercise, but resistance fell more (P0.05) in postmenopausal women. Baseline FMD was greater in premenopausal women (12.1 +/- 1.5 versus 5.3 +/- 1.3%, P0.01), and similar before and after exercise, whereas prior exercise nearly doubled the FMD of postmenopausal women (to 9.9 +/- 1.4%, P0.01). These increases in FMD correlated with baseline values (r = -0.75, P0.01) and with relative changes in total peripheral conductance (r = 0.72, P0.02). The latter relationship was absent in premenopausal women (r = -0.29).In postmenopausal women, acute dynamic exercise elicits sustained increases in FMD that could facilitate post-exercise hypotension in this population. These observations reinforce the concept of exercise as an important non-pharmacological intervention to modify cardiovascular risk in postmenopausal women.

BACKGROUND Dihydropyridines have both sympathoexcitatory and sympathoinhibitory effects. To date, the latter have been characterized only in animals. During chronic treatment with long-acting dihydropyridines, sympathoexcitatory effects mediated via the arterial baroreflex are unlikely. However, increases in plasma angiotensin II in response to dihydropyridines could contribute to increases in sympathetic activity during chronic treatment. Such increases may be less in older than in young patients. METHODS We evaluated the effects of 4 weeks of treatment with low-dose nifedipine gastrointestinal therapeutic system (GITS; 20 mg/day) compared with placebo on muscle sympathetic nerve activity and plasma noradrenaline, in relation to changes in plasma renin activity and plasma angiotensin II and blood pressure in young and older patients with mild hypertension. RESULTS Nifedipine GITS decreased systolic and diastolic blood pressures significantly, by 10 +/- 3 mmHg and 7 +/- 2 mmHg respectively, in older patients (age 67 +/- 2 years), but not in younger patients (age 45 +/- 2 years) (decreases of 1 +/- 3 mmHg and 1 +/- 2 mmHg, respectively). Nifedipine GITS caused only minor changes in plasma renin activity and plasma angiotensin II in young and older patients. Compared with changes in response to placebo (-5.7 +/- 2.4 bursts/min), sympathetic activity was increased significantly by nifedipine GITS in the young patients (2.0 +/- 1.7 bursts/min; P < 0.05), but not in older patients (5.4 +/- 1.3 bursts/min by placebo compared with 4.1 +/- 3.5 bursts/min by nifedipine GITS). CONCLUSION We conclude that age-related differences in the response of muscle sympathetic nerve activity (and plasma noradrenaline) to low-dose nifedipine GITS in patients with mild hypertension are unlikely to be mediated by plasma angiotensin II. An increase in sympathetic activity may contribute to the absent blood pressure response in young patients with hypertension.

Activated coagulation Factor XII (FXIIa) infusion increases peripheral resistance (TPR) and mean arterial pressure (MAP) of Brown Norway but not plasma kininogen deficient Brown Norway Katholiek (BNK) rats. FXIIa concentrations are elevated in hypertensive end-stage renal disease patients receiving conventional haemodialysis (CHD). Conversion to nocturnal haemodialysis (NHD) lowers peripheral resistance and MAP.To determine whether the plasma coagulation FXIIa-kallikrein-kinin axis contributes to the hypertension of chronic kidney disease (CKD).Plasma FXIIa and haemodynamic data were acquired in 11 CHD patients before and after 2 months of NHD. Cardiac and systemic haemodynamics of Brown Norway and BNK rats rendered hypertensive and uremic by 5/6 nephrectomy (NX) were determined before and after acute FXIIa inhibition.FXIIa was increased three-fold in CHD patients relative to control plasma (P0.05). After conversion to NHD, both ΔMAP and ΔTPR correlated with ΔFXIIa. In rats, plasma FXIIa was three-fold higher in both NX groups than respective SHAM controls (all P0.05), but MAP (147 ± 4 vs. 133 ± 2 mmHg; P0.05) and TPR (2.8 ± 0.2 vs. 2.3 ± 0.2 units; P0.05) were greater in Brown Norway NX (n = 16) than in BNK (n = 15) NX rats. FXIIa correlated with MAP only in Brown Norway NX, and plasma catecholamines were increased relative to SHAM only in Brown Norway NX (P0.05). In Brown Norway NX rats, FXIIa inhibitor infusion decreased MAP (-12 mmHg) and TPR (-0.5 Units) (both P0.05), and halved catecholamines (P0.05). No such changes occurred in BNK NX rats.FXIIa-kininogen mediated vasoconstriction contributes significantly to CKD hypertension in Brown Norway rats; this novel mechanism may be active in humans with CKD.

OBJECTIVES To determine the acute effects of continuous positive airway pressure (CPAP) on baroreceptor reflex sensitivity (BRS) for heart rate during sleep in congestive heart failure (CHF) patients with obstructive sleep apnea (OSA). DESIGN AND METHODS In eight CHF patients with OSA not previously treated with CPAP, spontaneous BRS was assessed during overnight polysomnography prior to the onset of sleep, and during stage 2 non-rapid eye movement sleep (NREM) before, during and after application of CPAP. RESULTS CPAP alleviated OSA and acutely increased the slope of BRS (median, 25%,75%) [from 3.9 (3.5, 4.8) to 6.2 (4.6, 26.2) ms/mmHg, P

BACKGROUND In patients with end-stage renal disease receiving conventional hemodialysis, both the frequency with which brief rises or falls in systolic blood pressure initiate concordant changes in pulse interval (arterial baroreflex effectiveness index), and the gain of reflex heart rate responses to these stimuli (arterial baroreflex sensitivity) are diminished. In chronic renal failure, low baroreflex effectiveness index and baroreflex sensitivity are associated with increased rates of all-cause mortality and sudden death, respectively. Conversion to home nocturnal hemodialysis augments baroreflex sensitivity but its effects on baroreflex effectiveness index have not been reported. METHODS In 20 consecutive hypertensive conventional hemodialysis patients training to transition to nocturnal hemodialysis (age 41 +/- 2 years; mean +/- standard error), baroreflex effectiveness index, baroreflex sensitivity (sequence method) and total arterial compliance (stroke volume/pulse pressure) were determined during quiet rest before and 2 months after conversion. RESULTS With nocturnal hemodialysis, dialysis frequency doubled, the dose per session increased by 70% and antihypertensive medications were withdrawn (from 2.5 +/- 0.3 to 0.2 +/- 0.1 drugs/patient, P < 0.01) because systolic blood pressure fell (from 139 +/- 5 to 119 +/- 4 mmHg, P < 0.05). Baroreflex effectiveness index increased from (0.33 +/- 0.03 to 0.42 +/- 0.03, P = 0.01). Baroreflex sensitivity increased from 5.60 +/- 0.88 to 8.48 +/- 1.60 ms/mmHg (P < 0.05). Changes in total arterial compliance correlated with changes in baroreflex sensitivity (r = 0.63, P = 0.004) but not baroreflex effectiveness index (r = 0.05, P = 0.95), suggesting independent mechanisms for their attenuation and recovery in end-stage renal disease. CONCLUSION Nocturnal hemodialysis increases baroreflex effectiveness index in addition to baroreflex sensitivity. The hypothesis that such changes might reduce cardiovascular event rates in this high-risk population merits prospective evaluation. More frequent engagement of the arterial baroreflex after conversion to nocturnal hemodialysis may improve short-term cardiovascular regulation.

Patients with either heart failure or obstructive sleep apnea have a reduced baroreflex sensitivity for heart rate, a sign of poor prognosis. We previously demonstrated that nocturnal application of continuous positive airway pressure to heart failure patients with obstructive sleep apnea increased baroreflex sensitivity acutely, but it is not known whether these effects persist into wakefulness.To determine whether treating obstructive sleep apnea in heart failure patients with continuous positive airway pressure improves baroreflex sensitivity during wakefulness.Spontaneous baroreflex sensitivity was assessed during wakefulness in 33 heart failure patients (left ventricular ejection fractionor = 45%) with obstructive sleep apnea (apnea-hypopnea indexor = 20). Subsequently, baroreflex sensitivity was reassessed 1 month after patients were randomly allocated to nocturnal continuous positive airway pressure treatment or no treatment (control).Compared with the 14 control patients, the 19 continuous positive airway pressure-treated patients experienced a greater increase in baroreflex sensitivity [median, (25%, 75%)] [from 5.4 (2.2, 8.3) to 7.9 (4.4, 9.4) ms/mmHg; P = 0.01] and left ventricular ejection fraction (P0.001). In addition, daytime systolic blood pressure and heart rate decreased more in the continuous positive airway pressure group (from 122 +/- 15 to 113 +/- 12 mmHg; P = 0.02, and from 66 +/- 8 to 62 +/- 8 bpm; P0.001, respectively) than in the control group.Treatment of coexisting obstructive sleep apnea by continuous positive airway pressure in heart failure patients improves baroreflex sensitivity during wakefulness in addition to improving left ventricular ejection fraction and lowering blood pressure and heart rate. These data indicate that the improved autonomic regulation of heart rate in heart failure patients treated for obstructive sleep apnea during sleep persists into wakefulness.

There is increasing evidence that blood coagulation factors can influence blood pressure. In the present study, we tested the hypothesis that the beta fragment of human coagulation factor XIIa (beta-FXIIa) induces adrenal catecholamine-mediated pressor and chronotropic responses via bradykinin generated from the plasma kallikrein-kinin system.In anaesthetized bioassay rats with blocked autonomic reflexes, in the Brown Norway strain a bolus injection of beta-FXIIa (1 microg/kg, administered intravenously) elicited a 170-fold rise in plasma epinephrine (from 0.12 +/- 0.02 to 20.58 +/- 2.42 nmol/l; P0.001) and a fivefold increase in plasma norepinephrine (from 0.11 +/- 0.02 to 0.57 +/- 0.09 nmol/l; P0.01), concurrent increases in systolic blood pressure (from 70 +/- 5 to 101 +/- 4 mmHg; P0.01) and heart rate (from 315 +/- 11 to 408 +/- 15 bpm; P0.01), and a doubling of bradykinin concentrations (P0.05). Bilateral adrenal medullectomy abolished both the catecholamine and the haemodynamic responses to beta-FXIIa. Catecholamine, bradykinin and haemodynamic responses to beta-FXIIa were absent in plasma kininogen-deficient Brown Norway Katholiek (BNK) rats. Exogenous bradykinin dose-dependently reproduced these catecholamine and haemodynamic responses in Brown Norway and BNK rats, but not in Brown Norway adrenal medullectomized rats.The pressor and chronotropic responses to beta-FXIIa in this bioassay preparation are mediated exclusively through adrenal catecholamine release, and require plasma kininogens for their full expression. These observations suggest that interaction between the coagulation, kallikrein-kinin and sympatho-adrenal systems can exert important pressor effects in the absence of counterregulatory autonomic reflexes.

Objectives Activation of the sympathetic nervous system, decreased heart rate variability (HRV), and loss of modulation of muscle sympathetic nerve activity (MSNA) within the low frequency (LF, 0.05-0.15 Hz) range are three adverse features of advanced congestive heart failure (CHF). In healthy men, atrial natriuretic peptide (ANP) infusion attenuates reflex increases in MSNA and reduces LF components of HRV spectral power. Sympathoinhibitory actions have also been documented in CHF, but effects on the variability of MSNA and HRV have not been described. Design and methods Heart rate and MSNA were recorded in 10 men (aged 39 ± 3 years, mean ± SE) with dilated cardiomyopathy (mean EF 20 ± 4%) treated with angiotensin converting enzyme (ACE) inhibitors. Subjects received i.v. ANP (50 μg bolus then 50 ng/kg/min) and nitroglycerin (NTG, 8 mg/min) as a hemodynamic control. Signals at baseline, and 13-20 min into each infusion were submitted to spectral analysis. Results ANP had no effect on HRV, but increased MSNA LF (from 7.9 ± 1.5 to 12.1 ± 2.6 U 2 ; P< 0.02) and total spectral power (from 47.9 ± 5.4 to 61.9 ± 6.8 U 2 ; P< 0.05). NTG had no effect on the variability of MSNA or HRV. Conclusions In CHF patients receiving ACE inhibitors, ANP (i) does not suppress HRV and (ii) enhances the modulation of MSNA, particularly within the LF range. This latter action is not observed with NTG. These findings suggest beneficial actions of exogenous ANP on neurogenic circulatory control.

Objectives: Whether muscle sympathetic nerve activity (MSNA) is increased in young subjects with mild essential hypertension has not been firmly established, and the potential haemodynamic correlates of any such increase have not been specifically investigated. The objectives of this study were to quantitate MSNA from the peroneal nerve of young subjects with mild hypertension, to determine the haemodynamic and neurohumoral correlates of sympathetic vasoconstrictor nerve traffic in such subjects, and to document the stability of these observations. Design: Twelve young untrained subjects with mild essential hypertension (mean age 31 years, average clinic blood pressure 151/95 mmHg) and 11 age- and weight-matched normotensive subjects were studied on two sessions, at least 1 month apart, at the same time of day and under identical laboratory conditions. Methods: Blood pressure (non-invasive), microneurography (MSNA; peroneal nerve), cardiac output and calculated total peripheral resistance (echocardiography and continuous-wave Doppler) and calf blood flow and resistance (plethysmography) were recorded during supine rest and assessed for condition and study order effects by two-way analysis of variance. Reproducibility of MSNA was quantified by the standard deviation of the mean difference (SDD) between the values obtained on the two study days. Results: Muscle sympathetic nerve burst frequency and incidence, calf vascular resistance and cardiac output and index were significantly higher in hypertensive subjects, whereas heart rate, total peripheral resistance, plasma noradrenaline and plasma atrial natriuretic factor concentrations were similar in the two groups. There was no study order effect, in either group, on mean values for MSNA or these haemodynamic variables, but the SDD (day 1-day 2 variation) in muscle sympathetic burst frequency was significantly greater in hypertensive subjects. Conclusions: Mild essential hypertension in young subjects can be characterized by augmented MSNA as measured from the peroneal nerve, greater between-session variation in sympathetic burst frequency (but no study order effect), and increased calf vascular resistance and cardiac output. These sympathoneural and haemodynamic alterations are potential mechanisms of primary hypertension.

Adrenaline facilitates the neural release of endogenous noradrenaline by stimulating prejunctional beta-receptors on adrenergic nerve endings. Recently, we demonstrated the functional significance of this action in the control of vascular resistance in young subjects with normal blood pressure. In the present study, we tested the hypothesis that the effects of adrenaline on neurogenic vasoconstriction are exaggerated in humans with borderline hypertension. Forearm blood flow was measured simultaneously in the experimental and contralateral arms of seven young men with borderline hypertension. We compared forearm vasoconstrictor responses to a reflex stimulus to noradrenaline release (lower-body negative pressure, LBNP) and to intra-arterial infusion of noradrenaline before and 30 min after brachial artery infusion of adrenaline (50 ng/min). These doses had no systemic effects. In the experimental arm, the vasoconstrictor response to LBNP was 65% greater 30 min after the adrenaline infusion (P = 0.075), whereas the response to intra-arterial noradrenaline decreased by 36% (P greater than 0.1). Forearm vascular responses to LBNP in the contralateral control arm that did not receive adrenaline were similar before and after the adrenaline infusion. The ratio of forearm vasoconstrictor responses (i.e. the increase in forearm vascular resistance) with LBNP to the forearm vasoconstrictor response to noradrenaline in the experimental arm was used as an index of neural release of the neurotransmitter noradrenaline. This ratio increased from 0.8 to 2.1 (P less than 0.05) after the adrenaline infusion. These facilitatory neural after-effects of adrenaline were similar in magnitude to our previous observation in young normotensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE To determine the effects of prior exercise and naloxone on haemodynamics, muscle sympathetic nerve activity, pituitary hormones and ambulatory blood pressure. METHODS We studied 14 mild hypertensive and 14 normotensive subjects on two days. After baseline measurements, subjects were randomly allocated to vehicle or naloxone (0.4 mg/kg) 30 min before 45 min treadmill exercise. RESULTS In both groups blood pressure, stroke volume, and calf and total peripheral resistances were lower 1 h after exercise, whereas sympathetic activity was unchanged. In normotensive subjects naloxone abolished this calf vasodilation without altering muscle sympathetic nerve activity, and attenuated these haemodynamic aftereffects of exercise, implying a peripheral opioidergic mechanism. Naloxone had no haemodynamic effect in hypertensive subjects. In normotensives there was an inverse relationship between changes in blood pressure and sympathetic activity after vehicle and exercise. This was transformed by naloxone into a positive relationship (r = 0.69, P < 0.02) similar to that observed in hypertensives after vehicle and exercise. Naloxone did not alter the latter positive relationship. Naloxone altered exercise-induced changes in prolactin and luteinizing hormone, but only in normotensive males. In both groups ambulatory blood pressures and heart rates over 2 h after subjects left the laboratory were higher than the values recorded at baseline or 1 h after exercise, and were unaffected by naloxone. CONCLUSIONS The depressor effect of exercise is due to peripheral vasodilation, occurs in the absence of sympathetic withdrawal and is short-lived. Endogenous opioids, activated by running, participate in the haemodynamic, sympathoneural and pituitary hormone aftereffects of exercise in normotensive subjects, whereas in hypertensives these aftereffects of exercise are achieved through non-opioidergic mechanisms. These observations are consistent with the concept that activation of endogenous opioid systems by exercise is impaired in mild hypertension.