Intrauterine L-NAME Exposure Weakens the Development of Sympathetic Innervation and Induces the Remodeling of Arterial Vessels in Two-Week-Old Rats.

Nitric oxide (NO) has been shown to stimulate differentiation and increase the survival of ganglionic sympathetic neurons. The proportion of neuronal NOS-immunoreactive sympathetic preganglionic neurons is particularly high in newborn rats and decreases with maturation. However, the role of NO in the development of vascular sympathetic innervation has never been studied before. We tested the hypothesis that intrauterine NO deficiency weakened the development of vascular sympathetic innervation and thereby changed the contractility of peripheral arteries and blood pressure level in two-week-old offspring. Pregnant rats consumed NOS inhibitor L-NAME (250 mg/L in drinking water) from gestational day 10 until delivery. Pups in the L-NAME group had a reduced body weight and blood level of NO metabolites at 1-2 postnatal days. Saphenous arteries from two-week-old L-NAME offspring demonstrated a lower density of sympathetic innervation, a smaller inner diameter, reduced maximal active force and decreased α-actin/ß-actin mRNA expression ratio compared to the controls. Importantly, pups in the L-NAME group exhibited decreased blood pressure levels before, but not after, ganglionic blockade with chlorisondamine. In conclusion, intrauterine L-NAME exposure is followed by the impaired development of the sympathetic nervous system in early postnatal life, which is accompanied by the structural and functional remodeling of arterial blood vessels.

TASK-1 channel blockade by AVE1231 increases vasocontractile responses and BP in 1- to 2-week-old but not adult rats.

BACKGROUND AND PURPOSE: The vasomotor role of K2P potassium channels during early postnatal development has never been investigated. We tested the hypothesis that TASK-1 channel (K2P family member) contribution to arterial vascular tone and BP is higher in the early postnatal period than in adulthood. EXPERIMENTAL APPROACH: We studied 10- to 15-day-old ("young") and 2- to 3-month-old ("adult") male rats performing digital PCR (dPCR) (using endothelium-intact saphenous arteries), isometric myography, sharp microelectrode technique, quantitative PCR (qPCR) and Western blotting (using endothelium-denuded saphenous arteries), and arterial pressure measurements under urethane anaesthesia. KEY RESULTS: We found mRNA of Kcnk1-Kcnk7, Kcnk12, and Kcnk13 genes to be expressed in rat saphenous artery, and Kcnk3 (TASK-1) and Kcnk6 (TWIK-2) were most abundant in both age groups. The TASK-1 channel blocker AVE1231 (1 µmol·L-1 ) prominently depolarized arterial smooth muscle and increased basal tone level and contractile responses to methoxamine of arteries from young rats but had almost no effect in adult rats. The level of TASK-1 mRNA and protein expression was higher in arteries from young compared with adult rats. Importantly, intravenous administration of AVE1231 (4 mg·kg-1 ) had no effect on mean arterial pressure in adult rats but prominently raised it in young rats. CONCLUSION AND IMPLICATIONS: We showed that TASK-1 channels are important for negative feedback regulation of vasocontraction in young but not adult rats. The influence of TASK-1 channels most likely contributes to low BP level at perinatal age.

Moderate morning rise in blood pressure has lowest risk of stroke but only in women.

BACKGROUND: The morning period which is recognized as the highest risk for cardiovascular events is associated with a surge in blood pressure (BP). However, it is unclear what aspect of this rise is important. AIM: To determine whether the rate of rise (RoR), the magnitude (day night difference) or the product [BP power (BPPower)] is associated with increased cardiovascular risk. METHODS: We developed a logistic equation method to fit individual 24-h patterns of BP to determine RoR, amplitude and BPPower using the ambulatory recordings from the Ohasama study including 564 men and 971 women (16.6 years follow-up). RESULTS: Men had a higher risk of cardiovascular events than women (24, 16%, P < 0.001). Age and night BP were strong linear risk predictors. In men sorting risk by quintiles of BPPower (adjusted for age, night BP, smoking status) revealed no clear linear or nonlinear pattern. However, in women BPPower had a U-shaped relationship with the lowest risk being the 2-3rd quintile for all cardiovascular events (Pquadratic = 0.01) including cardiovascular death (Pquadratic = 0.03) and nonfatal stroke (Pquadratic = 0.02). A similar but less clear trend was observed with the RoR but only stroke (infarct) reached significance (Pquadratic = 0.03) while sorting by range showed a U shaped pattern for combined cardiovascular events (Pquadratic = 0.04). CONCLUSION: These findings suggest that the morning BPPower is an important independent risk factor for predicting cardiovascular events and stroke but only in women with median levels having the lowest risk.

Phase synchronization of baroreflex oscillations of blood pressure and pulse interval in rats: the effects of cardiac autonomic blockade and gradual blood loss.

OBJECTIVE: Phase synchronization of arterial pressure (AP) and pulse interval (PI) oscillations in the low-frequency band (around 0.4 Hz in rats) is governed by baroreflex activity. In long-term stationary data recordings, such synchronization can be estimated by the coherence. The phase synchronization index (PSI) can be used as well. The aim of this study was to correlate PSI and the coherence of AP and PI under stationary conditions and to estimate the informativity of PSI as a measure of baroreflex activity during transient processes. APPROACH: AP and PI were recorded in conscious Wistar rats using femoral artery catheters. To study the hemodynamics during hemorrhage, blood was gradually withdrawn (20 ml × kg-1 over 30 min) through a catheter in the carotid artery. MAIN RESULTS: PSI and coherence spectra calculated from 30-minute AP and PI recordings demonstrated distinct peaks at the frequency of 0.4 Hz; these indicators correlate well with each other (Pearson r = 0.920, p  < 0.0001). Both PSI and coherence were markedly suppressed by vagal blockade (methylatropine) and tended to reduce after sympathetic blockade (atenolol). Importantly, PSI demonstrated dynamic alterations during gradual hemorrhage. During the initial approx. 10 min of hemorrhage, AP did not change but PI was noticeably shortened, and PSI increased, which indicates the activation of the baroreflex. With further blood loss, baroreflex influences were not enough to prevent blood pressure from falling, and under such conditions PSI decreased. SIGNIFICANCE: PSI, like coherence, is an informative measure of baroreflex activity under stationary conditions. In addition, PSI permits us to follow the coupling between the baroreflex oscillations of AP and PI during transient processes, which strengthens its informative value.

Protective Effects of Dinitrosyl Iron Complexes under Oxidative Stress in the Heart.

Background. Nitric oxide can successfully compete with oxygen for sites of electron-transport chain in conditions of myocardial hypoxia. These features may prevent excessive oxidative stress occurring in cardiomyocytes during sudden hypoxia-reoxygenation. Aim. To study the action of the potent stable NO donor dinitrosyl iron complex with glutathione (Oxacom®) on the recovery of myocardial contractile function and Ca2+ transients in cardiomyocytes during hypoxia-reoxygenation. Results. The isolated rat hearts were subjected to 30 min hypoxia followed by 30 min reoxygenation. The presence of 30 nM Oxacom in hypoxic perfusate reduced myocardial contracture and improved recovery of left ventricular developed pressure partly due to elimination of cardiac arrhythmias. The same Oxacom concentration limited reactive oxygen species generation in hypoxic cardiomyocytes and increased the viability of isolated cardiomyocytes during hypoxia from 12 to 52% and after reoxygenation from 0 to 40%. Oxacom prevented hypoxia-induced elevation of diastolic Ca2+ level and eliminated Ca2+ transport alterations manifested by slow Ca2+ removal from the sarcoplasm and delay in cardiomyocyte relaxation. Conclusion. The potent stable NO donor preserved cardiomyocyte integrity and improved functional recovery at hypoxia-reoxygenation both in the isolated heart and in cardiomyocytes mainly due to preservation of Ca2+ transport. Oxacom demonstrates potential for cardioprotection during hypoxia-reoxygenation.

Associations of blood pressure variability and retinal arteriolar diameter in participants with type 2 diabetes.

Blood pressure variability is associated with macrovascular complications and stroke, but its association with the microcirculation in type II diabetes has not been assessed. This study aimed to determine the relationship between blood pressure variability indices and retinal arteriolar diameter in non-diabetic and type II diabetes participants. Digitized retinal images were analysed to quantify arteriolar diameters in 35 non-diabetic (aged 52 ± 11 years; 49% male) and 28 type II diabetes (aged 61 ± 9 years; 50% male) participants. Blood pressure variability was derived from 24-h ambulatory blood pressure. Arteriolar diameter was positively associated with daytime rate of systolic blood pressure variation (p = 0.04) among type II diabetes participants and negatively among non-diabetics (p = 0.008; interaction p = 0.001). This finding was maintained after adjusting for age, sex, body mass index and mean daytime systolic blood pressure. These findings suggest that the blood pressure variability-related mechanisms underlying retinal vascular disease may differ between people with and without type II diabetes.

Endothelial nitric oxide weakens arterial contractile responses and reduces blood pressure during early postnatal development in rats.

OBJECTIVE: During maturation the vascular system undergoes structural and functional remodeling. At the systemic level it results in a gradual increase of arterial blood pressure during postnatal ontogenesis. The mechanisms of maintaining the blood pressure at a comparatively low level during the early postnatal development are not completely understood. Recently we showed that the hindlimb arteries of young (1-2 wk-old) rats exhibited an enhanced endothelial NO-pathway activity, which weakened their contractile responsiveness compared to the arteries of adult rats. Here we tested the hypothesis that an increased tonic endothelial NO production can take place in the whole vascular system leading to a decreased level of systemic blood pressure in young rats. DESIGN AND METHODS: Segments of small mesenteric, saphenous, sural and intrarenal arteries were isolated from the young (2 wk-old), juvenile (4 wk-old) and adult (10-12 wk-old) male rats and tested in a wire isometric myograph. Anticontractile effect of NO was evaluated by the effects of NOS inhibitor L-NNA on both arterial spontaneous tone and constrictor responses to methoxamine (α1-adrenoceptor agonist). In addition, eNOS and arginase-2 mRNA expression in arterial preparations by qPCR and serum nitrite/nitrate levels by Griess reaction were estimated. Blood pressure with an intra-carotid artery catheter was measured in conscious rats. RESULTS: In all arteries of 2 wk rats except the renal ones, L-NNA exposure resulted in a considerable tonic contraction and a remarkable enhancement of contractile responses to methoxamine. The effect of L-NNA gradually decreased with age and by 10-12 weeks became very small in the mesenteric arteries and disappeared in the sural and saphenous arteries. Although no difference in eNOS mRNA expression was found, the content of arginase-2 mRNA was significantly lower in young rats compared to adults. Serum levels of NO metabolites were two-fold higher in 2 wk-old rats than in adult rats. Along with that, arterial blood pressure was by half lower but rose more prominently after administration of l-NAME in young rats than in adults. CONCLUSIONS: In young rats, tonic release of NO by the endothelium considerably weakens contractile responses of arteries supplying intestine, skin and skeletal muscles, which receive a high proportion of the cardiac output. Such anticontractile effect of NO can be an important mechanism responsible for the blood pressure reduction in immature circulatory system.

Characteristics of renal sympathetic nerve single units in rabbits with angiotensin-induced hypertension.

We examined the effect of chronic angiotensin (Ang II)-induced hypertension on activity of postganglionic renal sympathetic units to determine whether altered whole renal nerve activity is due to recruitment or changes in firing frequency. Rabbits were treated with a low (20 ng kg(-1) min(-1), 8 weeks) or high dose (50 ng kg(-1) min(-1), 4 weeks) of Ang II before the experiment under chloralose-urethane anaesthesia. Spontaneously active units were detected from multiunit recordings using an algorithm that separated units by action potential shape using templates that matched spikes within a prescribed standard deviation. Multiunit sympathetic nerve activity was 40% higher in rabbits treated with low-dose Ang II than in sham (P = 0.012) but not different in high-dose Ang II. Resting firing frequency was similar in sham rabbits (1.00 ± 0.09 spikes s(-1), n = 144) and in those treated with high-dose Ang II (1.10 ± 0.08 spikes s(-1), n = 112) but was lower with low-dose Ang II (0.65 ± 0.08 spikes s(-1), n = 149, P < 0.05). Unit firing rhythmicity was linked to the cardiac cycle and was similar in sham and low-dose Ang II groups but 29-32% lower in rabbits treated with high-dose Ang II (P < 0.001). Cardiac linkage followed a similar pattern during hypoxia. All units showed baroreceptor dependency. Baroreflex gain and range were reduced and curves shifted to the right in Ang II groups. Firing frequency during hypoxia increased by +39% in low-dose Ang II and +82% in shams, but the greatest increase was in the high-dose Ang II group (+103%, P(dose) = 0.001). Responses to hypercapnia were similar in all groups. Increases in sympathetic outflow in hypertension caused by low-dose chronic Ang II administration are due to recruitment of neurons, but high-dose Ang II increases firing frequency in response to chemoreceptor stimuli independently of the arterial baroreceptors.

Effects of vitamin E, vitamin C and polyphenols on the rate of blood pressure variation: results of two randomised controlled trials.

High blood pressure (BP) variability, which may be an important determinant of hypertensive end-organ damage, is emerging as an important predictor of cardiovascular health. Dietary antioxidants can influence BP, but their effects on variability are yet to be investigated. The aim of the present study was to assess the effects of vitamin E, vitamin C and polyphenols on the rate of daytime and night-time ambulatory BP variation. To assess these effects, two randomised, double-blind, placebo-controlled trials were performed. In the first trial (vitamin E), fifty-eight individuals with type 2 diabetes were given 500 mg/d of RRR-α-tocopherol, 500 mg/d of mixed tocopherols or placebo for 6 weeks. In the second trial (vitamin C-polyphenols), sixty-nine treated hypertensive individuals were given 500 mg/d of vitamin C, 1000 mg/d of grape-seed polyphenols, both vitamin C and polyphenols, or neither (placebo) for 6 weeks. At baseline and at the end of the 6-week intervention, 24 h ambulatory BP and rate of measurement-to-measurement BP variation were assessed. Compared with placebo, treatment with α-tocopherol, mixed tocopherols, vitamin C and polyphenols did not significantly alter the rate of daytime or night-time systolic BP, diastolic BP or pulse pressure variation (P>0·05). Treatment with the vitamin C and polyphenol combination resulted in higher BP variation: the rate of night-time systolic BP variation (P= 0·022) and pulse pressure variation (P= 0·0036) were higher and the rate of daytime systolic BP variation was higher (P= 0·056). Vitamin E, vitamin C or grape-seed polyphenols did not significantly alter the rate of BP variation. However, the increase in the rate of BP variation suggests that the combination of high doses of vitamin C and polyphenols could be detrimental to treated hypertensive individuals.

Predictors of mean arterial pressure morning rate of rise and power function in subjects undergoing ambulatory blood pressure recording.

BACKGROUND: We determined clinical predictors of the rate of rise (RoR) in blood pressure in the morning as well as a novel measure of the power of the BP surge (BP(power)) derived from ambulatory blood pressure recordings. METHODS: BP(power) and RoR were calculated from 409 ambulatory blood pressure (ABP) recordings from subjects attending a cardiovascular risk clinic. Anthropometric data, blood biochemistry, and history were recorded. The 409 subjects were 20-82 years old (average 57, SD = 13), 46% male, 9% with hypertension but not on medication and 34% on antihypertensive medication. RESULTS: Average RoR was 11.1 mmHg/hour (SD = 8) and BP(power) was 273 mmHg(2)/hour (SD = 235). Only cholesterol, low density lipoprotein and body mass index (BMI) were associated with higher BP(power) and RoR (P<0.05) from 25 variables assessed. BP(power) was lower in those taking beta-blockers or diuretics. Multivariate analysis identified that only BMI was associated with RoR (4.2% increase/unit BMI, P = 0.020) while cholesterol was the only remaining associated variable with BP(power) (17.5% increase/mmol/L cholesterol, P = 0.047). A follow up of 213 subjects with repeated ABP after an average 1.8 years identified that baseline cholesterol was the only predictor for an increasing RoR and BP(power) (P<0.05). 37 patients who commenced statin subsequently had lower BP(power) whereas 90 age and weight matched controls had similar BP(power) on follow-up. CONCLUSIONS: Cholesterol is an independent predictor of a greater and more rapid rise in morning BP as well as of further increases over several years. Reduction of cholesterol with statin therapy is very effective in reducing the morning blood pressure surge.

Relationships of vascular function with measures of ambulatory blood pressure variation.

BACKGROUND: Characteristics of short-term blood pressure (BP) variation may influence cardiovascular disease risk via effects on vascular function. OBJECTIVE: In a cross-sectional study of a group of treated hypertensive and untreated largely normotensive subjects we investigated the relationships of measures of short-term BP variation with brachial artery vasodilator function. METHODS: A total of 163 treated hypertensive (n = 91) and untreated largely normotensive (n = 72) men and women were recruited from the general population. Measures of systolic and diastolic BP variation were calculated from 24 h ambulatory BP assessments and included: (i) rate of measurement-to-measurement BP variation (SBP-var and DBP-var); and (ii) day-to-night BP dip (SBP-dip and DBP dip). Endothelium-dependent vasodilation was assessed as flow-mediated dilation (FMD) and endothelium-independent vasodilation was assessed in response to glyceryl trinitrate (GTN). Relationships were explored using univariate and multivariate linear regression. RESULTS: The relationships of brachial artery vasodilator function with BP variation were not significantly different between treated hypertensive and untreated subjects, therefore these groups were combined for analysis. In univariate analysis, higher SBP-var (P < 0.001) and lower DBP-dip (P = 0.004) were associated with lower FMD; and higher SBP-var (P = 0.002) and lower SBP-dip (P = 0.003) and DBP-dip (P = 0.001) were associated with lower GTN-mediated dilation. In multivariate analysis, lower SBP-dip (P = 0.007) and DBP-dip (P = 0.03) were independently associated with lower GTN response. CONCLUSIONS: Our results indicate that a lower day-to-night BP dip is independently associated with impaired smooth muscle cell function. Although rate of BP variation was associated with measures of endothelial and smooth muscle cell function, relationships were attenuated after accounting for age and BP.

Stimulation of angiotensin type 1A receptors on catecholaminergic cells contributes to angiotensin-dependent hypertension.

Hypertension contributes to multiple forms of cardiovascular disease and thus morbidity and mortality. The mechanisms inducing hypertension remain unclear although the involvement of homeostatic systems, such as the renin-angiotensin and sympathetic nervous systems, is established. A pivotal role of the angiotensin type 1 receptor in the proximal tubule of the kidney for the development of experimental hypertension is established. Yet, other systems are involved. This study tests whether the expression of angiotensin type 1A receptors in catecholaminergic cells contributes to hypertension development. Using a Cre-lox approach, we deleted the angiotensin type 1A receptor from all catecholaminergic cells. This deletion did not alter basal metabolism or blood pressure but delayed the onset of angiotensin-dependent hypertension and reduced the maximal response. Cardiac hypertrophy was also reduced. The knockout mice showed attenuated activation of the sympathetic nervous system during angiotensin II infusion as measured by spectral analysis of the blood pressure. Increased reactive oxygen species production was observed in forebrain regions, including the subfornical organ, of the knockout mouse but was markedly reduced in the rostral ventrolateral medulla. These studies demonstrate that stimulation of the angiotensin type 1A receptor on catecholaminergic cells is required for the full development of angiotensin-dependent hypertension and support an important role for the sympathetic nervous system in this model.

Reduced preprandial dipping accounts for rapid elevation of blood pressure and renal sympathetic nerve activity in rabbits fed a high-fat diet.

Consumption of a high-fat diet (HFD) by rabbits results in increased blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) within 1 wk. Here, we determined how early this activation occurred and whether it was related to changes in cardiovascular and neural 24-h rhythms. Rabbits were meal-fed a HFD for 3 wks, then a normal-fat diet (NFD) for 1 wk. BP, HR, and RSNA were measured daily in the home cage via implanted telemeters. Baseline BP, HR, and RSNA over 24 h were 71 ± 1 mm Hg, 205 ± 4 beats/min and 7 ± 1 normalized units (nu). The 24-h pattern was entrained to the feeding cycle and values increased from preprandial minimum to postprandial maximum by 4 ± 1 mm Hg, 51 ± 6 beats/min, and 1.6 ± .6 nu each day. Feeding of a HFD markedly diminished the preprandial dip after 2 d (79-125% of control; p < 0.05) and this reduction lasted for 3 wks of HFD. Twenty-four-hour BP, HR, and RSNA concurrently increased by 2%, 18%, and 22%, respectively. Loss of preprandial dipping accounted for all of the BP increase and 50% of the RSNA increase over 3 wks and the 24-h rhythm became entrained to the light-dark cycle. Resumption of a NFD did not alter the BP preprandial dip. Thus, elevated BP induced by a HFD and mediated by increased sympathetic nerve activity results from a reduction in preprandial dipping, from the first day. Increased calories, glucose, insulin, and leptin may account for early changes, whereas long-term loss of dipping may be related to increased sensitivity of sympathetic pathways.

Black tea lowers the rate of blood pressure variation: a randomized controlled trial.

BACKGROUND: Measures of blood pressure variation have been associated with cardiovascular disease and related outcomes. The regular consumption of black tea can lower blood pressure, but its effects on blood pressure variation have yet to be investigated. OBJECTIVE: We aimed to assess the effects of black tea consumption on the rate of ambulatory blood pressure variation. DESIGN: Men and women (n = 111) with systolic blood pressure between 115 and 150 mm Hg at screening were recruited in a randomized, controlled, double-blind, 6-mo parallel-designed trial designed primarily to assess effects on blood pressure. Participants consumed 3 cups/d of either powdered black tea solids (tea) or a flavonoid-free caffeine-matched beverage (control). The 24-h ambulatory blood pressure level and rate of measurement-to-measurement blood pressure variation were assessed at baseline, day 1, and 3 and 6 mo. RESULTS: Across the 3 time points, tea, compared with the control, resulted in lower rates of systolic (P = 0.0045) and diastolic (P = 0.016) blood pressure variation by ~10% during nighttime (2200-0600). These effects, which were immediate at day 1 and sustained over 6 mo, were independent of the level of blood pressure and heart rate. The rate of blood pressure variation was not significantly altered during daytime (0800-2000). CONCLUSIONS: These findings indicate that a component of black tea solids, other than caffeine, can influence the rate of blood pressure variation during nighttime. Thus, small dietary changes have the potential to significantly influence the rate of blood pressure variation. This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTR12607000543482.

Metyrapone and fluoxetine suppress enduring behavioral but not cardiac effects of subchronic stress in rats.

In humans, chronic stressors have long been recognized as potential causes for cardiac dysregulation. Despite this, the underlying mechanistic links responsible for this association are still poorly understood. The purpose of this study was to determine whether exposure to a paradigm of subchronic stress can provoke enduring changes on the heart rate of experimental rats and, if so, to reveal the autonomic and neural mechanisms that mediate these effects. The study was conducted on adult male Sprague-Dawley rats instrumented for telemetric recording of heart rate and locomotor activity. Animals were submitted to a subchronic stress protocol, consisting of a 1-h foot shock session on five consecutive days. Heart rate and locomotor activity were recorded continuously for 3 days before and for 6 days after the subchronic stress period. Subchronic foot shock produced significant and enduring reduction in heart rate both during the dark/active [Δ= -23 ± 3 beats per minute (bpm)] and light/inactive (Δ= -20 ± 3 bpm) phases of the circadian cycle, and a reduction in locomotor activity during the dark/active phase [Δ= -54 ± 6 counts per hour (cph)]. The bradycardic effect of subchronic stress was not related to a reduced locomotion. Selective sympathetic (atenolol) and vagal (methyl-scopolamine) blockades were performed to reveal which autonomic component was responsible for this effect. We found that the fall in heart rate persisted after subchronic stress in animals treated with atenolol (active phase Δ= -16 ± 3 bpm, inactive phase Δ= -19 ± 2 bpm), whereas vagal blockade with scopolamine transiently prevented this effect, suggesting that the bradycardia following subchronic stress was predominantly vagally mediated. Fluoxetine (selective serotonin reuptake inhibitor) and metyrapone (inhibitor of corticosterone synthesis) treatments did not affect heart rate changes but prevented the reduction in locomotion. We conclude that subchronic stress exposure in rats reduces heart rate via a rebound in vagal activation and that this effect is serotonin- and corticosterone-independent.

A novel measure of the power of the morning blood pressure surge from ambulatory blood pressure recordings.

BACKGROUND: We defined a new measure of the morning blood pressure (BP) surge (MBPS) that is derived by the product of the rate of morning rise (RoR) and the amplitude (day-night difference) giving an effective "Power" of the BP rise (BP(Power)). We applied this method to determine whether morning BP(Power) is different in hypertensives compared to normotensives, males compared to females or altered by antihypertensive treatment. METHODS: BP(Power), RoR, and day-night amplitude were calculated using a double logistic fit of 691 ambulatory recordings. RESULTS: Ambulatory recordings from untreated male and female subjects showed that upper quartile (distributed by day BP, n = 100) had a 92% greater BP(Power) (P < 0.001) than the lower quartile subjects (n = 100) due to both a faster RoR and greater amplitude. Males had a 29% greater BP(Power) than females (P = 0.003). Untreated hypertensives and white coat hypertensives showed a greater morning BP(Power) (+158% and +86%, respectively) compared to matched normotensives. Subjects taking calcium channel blockers and diuretics alone or in combination with angiotensin receptor blockers had lower morning BP(Power) than those on angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor antagonists alone. CONCLUSIONS: A new measure of the MBPS, BP(Power) which is based on a mathematical estimate of the rate and amplitude of the rise, is higher in hypertensives, white coat hypertensives, and is modifiable by some specific antihypertensive therapies suggests that it may be theoretically useful to highlight those subjects at greatest risk of cardiovascular events and for determining the most benefit of antihypertensive therapy.

Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments. A limited understanding of the molecular mechanisms responsible for the development of AF has hindered treatment strategies. The purpose of this study was to assess whether reduced activation of phosphoinositide 3-kinase (PI3K, p110alpha) makes the compromised heart susceptible to AF. Risk factors for AF, including aging, obesity, and diabetes, have been associated with insulin resistance that leads to depressed/defective PI3K signaling. However, to date, there has been no link between PI3K(p110alpha) and AF. To address this question, we crossed a cardiac-specific transgenic mouse model of dilated cardiomyopathy (DCM) with a cardiac-specific transgenic mouse expressing a dominant negative mutant of PI3K (dnPI3K; reduces PI3K activity). Adult ( approximately 4.5 months) double-transgenic (dnPI3K-DCM), single-transgenic (DCM-Tg, dnPI3K-Tg), and nontransgenic mice were subjected to morphological, functional/ECG, microarray, and biochemical analyses. dnPI3K-DCM mice developed AF and had depressed cardiac function as well as greater atrial enlargement and fibrosis than DCM-Tg mice. AF was not detected in other groups. Aged DCM-Tg mice ( approximately 15 months) with a similar phenotype to dnPI3K-DCM mice (4.5 months) did not develop AF, suggesting loss of PI3K activity directly contributed to the AF phenotype. Furthermore, increasing PI3K activity reduced atrial fibrosis and improved cardiac conduction in DCM-Tg mice. Finally, in atrial appendages from patients with AF, PI3K activation was lower compared with tissue from patients in sinus rhythm. These results suggest a link between PI3K(p110alpha) and AF.

Understanding the morning rise in blood pressure.

1. The morning period has been recognized as the highest risk period of the day for cardiovascular events, particularly stroke and is also associated with a rapid surge in blood pressure. 2. Evidence now exists to show that the morning surge in blood pressure is an independent risk factor in some elderly hypertensive subjects. 3. However, methods to assess the contribution of the morning blood pressure surge from ambulatory recordings or home recordings, using clock times or times of waking, do not take into consideration the individual patterns of blood pressure change which can range from a rapid rise prior to or following waking to a slow increase over several hours. 4. In the present review we describe a novel method for determining the individual changes using a double logistic equation fitted to the individual pattern of blood pressure change. 5. Methods are presented to determine the rate of rise function over the morning period as well as predicting the change over a fixed time window which may be useful in refining the contribution of the blood pressure surge to cardiovascular risk. 6. Hypertensive people have an exaggerated rise in morning blood pressure as well as a greater rate of rise. 7. Antihypertensive drugs and dosing regimes are being developed which may be useful adjuncts to standard therapy for preventing morning hypertension and hopefully also reducing cardiovascular damage or events.

Rate of morning increase in blood pressure is elevated in hypertensives.

BACKGROUND: We applied a new logistic curve fitting procedure to ambulatory blood pressure (ABP) recordings to determine whether the rate of increase in systolic (SBP), mean (MBP) and diastolic blood pressure (DBP) and heart rate (HR) in the morning is related to the level of BP in subjects. METHODS: The rate of transition in the morning and evening period was determined using a six-parameter double-logistic equation applied to 528 ABP recordings from a cardiovascular risk assessment clinic. Based on daytime BP (MBP, SBP, or DBP), the upper quartile (UQ, n = 132) and lower quartile (LQ) were compared. RESULTS: Subjects in the UQ of daytime MBP were hypertensive and showed greater day-night differences compared to normotensive subjects in the LQ (29 +/- 1 mm Hg for MBP compared to 20 +/- 1 mm Hg). The rate of morning increase in SBP and DBP was 42% and 30% greater in UQ subjects compared to the LQ subjects (P < .05). The rates of evening decrease in all BPs were 69% to 84% greater in the subjects in the UQ. Similar results were obtained if subjects were divided according to daytime SBP or DBP. The rate of morning increase in MBP was correlated with daytime BP, but not night-time or 24 h MBP. CONCLUSIONS: The rate of morning increase in BP is greater in those subjects with the highest daytime BP. The exaggerated rate of morning increase in BP in this group, which were all hypertensive, may also be important for greater cardiovascular risk.

Nonsymmetrical double logistic analysis of ambulatory blood pressure recordings.

We developed an asymmetric double logistic curve-fitting procedure for circadian analysis that can determine the rate of change in variables during the day-to-night separately from the night-to-day transition for use in animal studies. We now have applied this procedure to 24-h systolic (SAP) and diastolic arterial pressure (DAP) and heart rate ambulatory recordings from 302 patients. In 292 cases, all parameters showed a pattern of higher day and lower night values. In men there was a similar rate of transition between day and night or from night to day for both SAP and DAP that lasted 3-4 h, indicating a symmetrical diurnal pattern. By contrast, women showed a faster rate of decrease in mean arterial pressure in the evening compared with men (P < 0.05) and therefore showed an asymmetric diurnal SAP pattern. For both men and women, there was a markedly greater rate of morning increase in heart rate compared with the rate of evening decrease (2.2- and 1.9-fold, respectively, P < 0.001). The logistic method provided a better fit than the square-wave or the cosinor method (P < 0.001) and more appropriately detected nondippers. We conclude that analysis of ambulatory recordings by a new logistic curve-fitting method reveals more rapid reductions in evening SAP in women than men but both have two- to threefold more rapid morning rates of tachycardia. The ability of the double logistic method to determine the diurnal blood pressure rates of change independently is key to determining new markers for cardiovascular risk.