Visualizing oxidative stress-induced depression of cardiac vagal baroreflex by MRI/DTI in a mouse neurogenic hypertension model.

A clinical hallmark of hypertension is impairment of the cardiac vagal baroreflex, which maintains stable blood pressure and heart rate under physiological conditions. There is also evidence that oxidative stress in the brain is associated with neurogenic hypertension. We tested the hypothesis that an augmented superoxide level in the nucleus tractus solitarii (NTS), the terminal site of baroreceptor afferents, contributes to the depression of cardiac vagal baroreflex by disrupting the connectivity between the NTS and the nucleus ambiguus (NA), the origin of the vagus nerve, during neurogenic hypertension. An experimental model of neurogenic hypertension that employed intracerebroventricular infusion of angiotensin II in male adult C57BL/6 mice was used. Based on tractographic evaluations using magnetic resonance imaging/diffusion tensor imaging of the medulla oblongata in the brain stem, we found that the connectivity between the NTS and NA was disrupted in neurogenic hypertension, concurrent with impairment of the cardiac vagal baroreflex as detected by radiotelemetry. We further found that the disrupted NTS-NA connectivity was reversible, and was related to oxidative stress induced by augmented levels of NADPH oxidase-generated superoxide in the NTS. We conclude that depression of the cardiac vagal baroreflex induced by oxidative stress in the NTS in the context of neurogenic hypertension may be manifested in the form of dynamic alterations in the connectivity between the NTS and NA.

Angiotensin 1A receptors transfected into caudal ventrolateral medulla inhibit baroreflex gain and stress responses.

AIMS: The caudal ventrolateral medulla (CVLM) is important for autonomic regulation and is rich in angiotensin II type 1A receptors (AT(1A)R). To determine their function, we examined whether the expression of AT(1A)R in the CVLM of mice lacking AT(1A)R (AT(1A)(-/-)) alters baroreflex sensitivity and cardiovascular responses to stress. METHODS AND RESULTS: Bilateral microinjections into the CVLM of AT(1A)(-/-) mice of lentivirus with the phox-2 selective promoter (PRSx8) were made to express either AT(1A)R (Lv-PRSx8-AT(1A)) or green fluorescent protein (Lv-PRSx8-GFP) as a control. Radiotelemetry was used to record mean arterial pressure (MAP), heart rate (HR), and locomotor activity. Following injection of Lv-PRSx8-GFP, robust neuronal expression of GFP was observed with ∼60% of the GFP-positive cells also expressing the catecholamine-synthetic enzyme tyrosine hydroxylase. After 5 weeks, there were no differences in MAP or HR between groups, but the Lv-PRSx8-AT(1A)- injected mice showed reduced baroreflex sensitivity (-25%, P = 0.003) and attenuated pressor responses to cage-switch and restraint stress compared with the Lv-PRSx8-GFP-injected mice. Reduced MAP mid-frequency power during cage-switch stress reflected attenuated sympathetic activation (Pgroup × stress = 0.04). Fos-immunohistochemistry indicated greater activation of forebrain and hypothalamic neurons in the Lv-PRSx8-AT(1A) mice compared with the control. CONCLUSION: The expression of AT(1A)R in CVLM neurons, including A1 neurons, while having little influence on the basal blood pressure or HR, may play a tonic role in inhibiting cardiac vagal baroreflex sensitivity. However, they strongly facilitate the forebrain response to aversive stress, yet reduce the pressor response presumably through greater sympatho-inhibition. These findings outline novel and specific roles for angiotensin II in the CVLM in autonomic regulation.

Renin-angiotensin and sympathetic nervous system contribution to high blood pressure in Schlager mice.

OBJECTIVE: Schlager hypertensive (BPH/2J) mice have been suggested to have high blood pressure (BP) due to an overactive sympathetic nervous system (SNS), but the contribution of the renin-angiotensin system (RAS) is unclear. In the present study, we examined the cardiovascular effects of chronically blocking the RAS in BPH/2J mice. METHODS: Schlager normotensive (BPN/3J, n = 6) and BPH/2J mice (n = 8) received the angiotensin AT 1A-receptor antagonist losartan (150 mg/kg per day) in drinking water for 2 weeks. Pre-implanted telemetry devices were used to record mean arterial pressure (MAP), heart rate (HR) and locomotor activity. RESULTS: MAP was reduced by losartan treatment in BPN/3J (-23 mmHg, P < 0.01) and in BPH/2J mice (-25 mmHg, P < 0.001), whereas HR was increased. Losartan had little effect on initial pressor responses to feeding or to stress, but did attenuate the sustained pressor response to cage-switch stress. During the active period, the hypotension to sympathetic blockade with pentolinium was greater in BPH/2J than BPN/3J (suggesting neurogenic hypertension), but was not affected by losartan. During the inactive period, a greater depressor response to pentolinium was observed in losartan-treated animals. CONCLUSION: The hypotensive actions of losartan suggest that although the RAS provides an important contribution to BP, it contributes little, if at all, to the hypertension-induced or the greater stress-induced pressor responses in Schlager mice. The effects of pentolinium suggest that the SNS is mainly responsible for hypertension in BPH/2J mice. However, the RAS inhibits sympathetic vasomotor tone during inactivity and prolongs sympathetic activation during periods of adverse stress, indicating an important sympatho-modulatory role.

Sleep related changes in blood pressure in hypocretin-deficient narcoleptic mice.

STUDY OBJECTIVES: Although blood pressure during sleep and the difference in blood pressure between sleep and wakefulness carry prognostic information, little is known on their central neural mechanisms. Hypothalamic neurons releasing hypocretin (orexin) peptides control wake-sleep behavior and autonomic functions and are lost in narcolepsy-cataplexy. We investigated whether chronic lack of hypocretin signaling alters blood pressure during sleep. DESIGN: Comparison of blood pressure as a function of the wake-sleep behavior between 2 different hypocretin-deficient mouse models and control mice with the same genetic background. SETTING: N/A. SUBJECTS: Hypocretin-ataxin3 transgenic mice with genetic ablation of hypocretin neurons (TG, n = 12); hypocretin gene knock-out mice (KO, n = 8); congenic wild-type controls (WT, n = 10). INTERVENTIONS: Instrumentation with electrodes for sleep recordings and a telemetric blood pressure transducer. MEASUREMENTS AND RESULTS: Blood pressure was significantly higher in either TG or KO than in WT during non-rapid eye movement sleep (NREMS; 4 ± 2 and 7 ± 2 mm Hg, respectively) and rapid eye movement sleep (REMS; 11 ± 2 and 12 ± 3 mm Hg, respectively), whereas it did not differ significantly between groups during wakefulness. Accordingly, the decrease in blood pressure between either NREMS or REMS and wakefulness was significantly blunted in TG and KO with respect to WT. CONCLUSIONS: Chronic lack of hypocretin signaling may entail consequences on blood pressure that are potentially adverse and that vary widely among wake-sleep states.

Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney-specific isoform of WNK1 and prevents hypertension.

Mutations in WNK1 and WNK4 lead to familial hyperkalemic hypertension (FHHt). Because FHHt associates net positive Na(+) balance together with K(+) and H(+) renal retention, the identification of WNK1 and WNK4 led to a new paradigm to explain how aldosterone can promote either Na(+) reabsorption or K(+) secretion in a hypovolemic or hyperkalemic state, respectively. WNK1 gives rise to L-WNK1, an ubiquitous kinase, and KS-WNK1, a kinase-defective isoform expressed in the distal convoluted tubule. By inactivating KS-WNK1 in mice, we show here that this isoform is an important regulator of sodium transport. KS-WNK1(-/-) mice display an increased activity of the Na-Cl cotransporter NCC, expressed specifically in the distal convoluted tubule, where it participates in the fine tuning of sodium reabsorption. Moreover, the expression of the ROMK and BKCa potassium channels was modified in KS-WNK1(-/-) mice, indicating that KS-WNK1 is also a regulator of potassium transport in the distal nephron. Finally, we provide an alternative model for FHHt. Previous studies suggested that the activation of NCC plays a central role in the development of hypertension and hyperkalemia. Even though the increase in NCC activity in KS-WNK1(-/-) mice was less pronounced than in mice overexpressing a mutant form of WNK4, our study suggests that the activation of Na-Cl cotransporter is not sufficient by itself to induce a hyperkalemic hypertension and that the deregulation of other channels, such as the Epithelial Na(+) channel (ENaC), is probably required.

Cardiovascular rhythms and cardiac baroreflex sensitivity in AT(1A) receptor gain-of-function mutant mice.

A mutant mouse expressing a gain-of-function of the AT(1A) angiotensin II receptor was engineered to study the consequences of a constitutive activation of this receptor on blood pressure (BP). Cardiovascular rhythms and spontaneous cardiac baroreflex sensitivity (BRS) were evaluated using telemetric BP recordings of five transgenic (AT(1A)MUT) and five wild (AT(1A)WT) mice. The circadian rhythms were described with the Chronos-Fit program. The gain of the transfer function between systolic BP (SBP) and pulse intervals used to estimate the spontaneous BRS (ms/mmHg) was calculated in the low frequency (0.15-0.60 Hz) band. Transgenic AT(1A)MUT exhibited higher BP and heart rate (HR) levels compared to controls (SBP AT(1A)MUT 134.6 +/- 5.9 mmHg vs. AT(1A)WT 110.5 +/- 5.9; p < 0.05; HR AT(1A)MUT 531.0 +/- 14.9 vs. AT(1A)WT 454.8 +/- 5.4 beats/min; p = 0.001). Spontaneous BRS was diminished in transgenic mice (AT(1A)MUT 1.23 +/- 0.17 ms/mmHg vs. AT(1A)WT 1.91 +/- 0.18 ms/mmHg; p < 0.05). Motor activity did not differ between groups. These variables exhibited circadian changes, and the differences between the strains were maintained throughout the cycle. The highest values for BP, HR, and locomotor activity were observed at night. Spontaneous BRS varied in the opposite direction, with the lowest gain estimated when BP and HR were elevated (i.e., at night, when the animals were active). It is likely the BP elevation of the mutant mice results from the amplification of the effects of AngII at different sites. Future studies are necessary to explore whether AT(1A) receptor activation at the central nervous system level effectively contributed to the observed differences.

Tuning of the sequence technique.

The sequence method was first described by Di Rienzo in cats and applied in different species including humans. Until now, no systematic study of spontaneous baroreflex sensitivity (BRS) has been performed by the sequence method in mice. This study aimed to characterize the best estimates of BRS using the sequence method by tuning all the possible parameters, specifically, the number of beats involved in a sequence, the minimal changes in blood-pressure (BP) ramps, and the minimal changes in pulse-interval (PI) ramps. Also, the relevance to set a minimal correlation coefficient in the regression line between BP and PI was tested. An important point was the delay to be applied between BP and PI. This delay represents the physiological time for the baroreflex loop to efficiently correct the BP variations.

A role for succinate dehydrogenase genes in low chemoresponsiveness to hypoxia?

The detection of hypoxia by the carotid bodies elicits a ventilatory response of utmost importance for tolerance to high altitude. Germline mutations in three genes encoding subunit B, C and D of succinate dehydrogenase (SDHB, SDHC and SDHD) have been associated with paragangliomas of the carotid body. We hypothesized that SDH dysfunction within the carotid body could result in low chemoresponsiveness and intolerance to high altitude. The frequency of polymorphisms of SDHs, hypoxia-inducible factor type 1 (HIF1alpha) and angiotensin converting enzyme (ACE) genes was compared between 40 subjects with intolerance to high altitude and a low hypoxic ventilatory response at exercise (HVRe < or = 0.5 ml min(-1) kg(-1); HVR- group) and 41 subjects without intolerance to high altitude and a high HVRe (> or = 0.80 ml min(-1) kg(-1); HVR+). We found no significant association between low or high HVRe and (1) the allele frequencies for nine single nucleotide polymorphisms (SNPs) in the SDHD and SDHB genes, (2) the ACE insertion/deletion polymorphism and (3) four SNPs in the HIF1alpha gene. However, a marginal significant association was found between the synonymous polymorphism c.18A>C of the SDHB gene and chemoresponsiveness: 8/40 (20%) in the HVR- group and 3/41 (7%) in the HVR+ group (p = 0.12). A principal component analysis showed that no subject carrying the 18C allele had both high ventilatory and cardiac response to hypoxia. In conclusion, no clear association was found between gene variants involved in oxygen sensing and chemoresponsiveness, although some mutations in the SDHB and SDHD genes deserve further investigations in a larger population.

Tissue kallikrein deficiency and renovascular hypertension in the mouse.

The kallikrein kinin system (KKS) is involved in arterial and renal functions. It may have an antihypertensive effect in both essential and secondary forms of hypertension. The role of the KKS in the development of two-kidneys, one-clip (2K1C) hypertension, a high-renin model, was investigated in mice rendered deficient in tissue kallikrein (TK) and kinins by TK gene inactivation (TK-/-) and in their wild-type littermates (TK+/+). Four weeks after clipping the renal artery, blood flow was reduced in the clipped kidney (2K1C-TK+/+: -90%, 2K1C-TK-/-: -93% vs. sham-operated mice), and the kidney mass had also decreased (2K1C-TK+/+: -65%, 2K1C-TK-/-: -66%), whereas in the unclipped kidney, blood flow (2K1C-TK+/+: +19%, 2K1C-TK-/-: +17%) and kidney mass (2K1C-TK+/+: +32%, 2K1C-TK-/-: +30%) had both increased. The plasma renin concentration (2K1C-TK+/+: +78%, 2K1C-TK-/-: +65%) and renal renin content of the clipped kidney (2K1C-TK+/+: +58%, 2K1C-TK-/-: +65%) had increased significantly. There was no difference for these parameters between 2K1C-TK+/+ and 2K1C-TK-/- mice. Blood pressure monitored by telemetry and by plethysmography, rose immediately after clipping in both genotypes, and reached similar levels (2K1C-TK+/+: +24%, 2K1C-TK-/-: +21%). 2K1C-TK+/+ and 2K1C-TK-/- mice developed similar concentric left ventricular hypertrophy (+24% and +17%, respectively) with normal cardiac function. These findings suggest that in the context of chronic unilateral reduction in renal blood flow, TK and kinins do not influence the trophicity of kidneys, the synthesis and secretion of renin, blood pressure increase, and cardiac remodeling due to renin angiotensin system activation.

Acute effects of sildenafil on flow mediated dilatation and cardiovascular autonomic nerve function in type 2 diabetic patients.

BACKGROUND: Sildenafil, frequently used as on demand medication for the treatment of erectile dysfunction (ED), has been suggested to improve endothelial function but also to alter blood pressure (BP) and induce sympathetic activation. In people with type 2 diabetes mellitus (T2DM), a high-risk population, the safety profile and the effects on endothelial function of a maximal sildenafil dose (100 mg) have not been investigated and therefore constituted the aim of our study. METHODS: A double-blind, placebo-controlled, cross-over trial using a single dose of 100 mg sildenafil or placebo has been conducted in 40 subjects with T2DM without known CVD. Haemodynamic parameters, flow mediated dilatation (FMD) in brachial artery, cardiovascular autonomic function tests and spontaneous baroreflex sensitivity (BRS) were measured. RESULTS: Sixty minutes after administration of sildenafil but not placebo, a fall of supine systolic blood pressure (SBP) (-5.41 +/- 1.87 vs. + 0.54 +/- 1.71 mmHg) and diastolic blood pressure (DBP) (-4.46 +/- 1.13 vs. + 0.89 +/- 0.94 mmHg), as well as orthostatic SBP (-7.41 +/- 2.35 vs. + 0.94 +/- 2.06 mmHg) and DBP (-5.65 +/- 1.45 vs. + 1.76 +/- 1.00 mmHg) during standing occurred, accompanied by an increase in heart rate (+1.98 +/- 0.69 vs. - 2.42 +/- 0.59 beats/min) (all p < 0.01 vs. placebo). Changes in BP to standing up, FMD, time domain and frequency domain indices of heart rate variability (HRV) and BRS were comparable between sildenafil and placebo. CONCLUSIONS: Sildenafil administered at a maximum single dose to T2DM men results in a mild increase in heart rate and decrease in BP, but it induces neither an acute improvement of FMD nor any adverse effects on orthostatic BP regulation, HRV and BRS.

Tuba players reproduce a Valsalva maneuver while playing high notes.

Playing wind instruments requires expiratory efforts. Blowing low notes on a tuba means a low resistance to expiration while playing high notes requires a strenuous expiratory strain. The resulting high intrathoracic pressure may reproduce a Valsalva maneuver. Ten tuba players were asked to blow medium loud long (15 seconds) notes at three different pitches (low, middle, and high) and to perform Valsalva maneuvers at 10, 40, and 60 mmHg. Blood pressure (BP) was measured continuously with a Finapres monitor. The four classic phases of the Valsalva maneuver were reproduced with the notes. The expiratory effort produced systolic BP and pulse pressure falls reaching about 24 mmHg with the high note or the Valsalva 60. BP and pulse pressure falls were linearly related to stroke volume reductions. Reflex heart rate (HR) changes were inversely related to BP falls, with maximal increases for the high notes (24 beats/minute) and Valsalva 60 (33 beats/minute). High baroreflex sensitivity was associated with a high HR response. Total peripheral resistance was reflexly elevated to counteract cardiac output reductions. During rebreathing, BP overshoots reached 30 mmHg for the high note and 53 mmHg for the Valsalva 60. Altogether, these findings indicate that blowing notes on a tuba reproduces the cardiovascular changes seen with a Valsalva maneuver with the effects of blowing high notes being close to a classic (40 mmHg) Valsalva maneuver. In addition, the baroreflex sensitivity might be a predictor of the ability to surmount the BP intolerance that could occur during wind instrument playing.

Effects of atropine on the time and frequency domain estimates of blood pressure and heart rate variability in mice.

1. Indices quantifying blood pressure (BP) and heart rate (HR) variability have been recently developed and may be used to assess the contribution of the autonomic nervous system to cardiovascular fluctuations. 2. Cardiovascular variables were measured in eight conscious mice equipped with a BP telemetric device. Each recording session was conducted when the mice were at rest and included a control period, an injection of atropine methylnitrate (2 mg/kg) and a post-treatment recording. 3. Time domain indices were the mean pulse interval (PI) and NN (the normal-to-normal intervals), mean HR, standard deviation of PI (SDNN), the square root of the mean of the sum of the squares of differences between adjacent PI (RMSSD) and the pNN8 (NN8 count divided by the number of NN intervals). Frequency domain indices of HR variability were the low frequency (LF) zone (0.15-0.60 Hz) and the high frequency (HF, respiratory sinus arrhythmia) zone (2.5-5.0 Hz) of the PI power spectrum. The time domain index of spontaneous baroreflex sensitivity (BRS) was the slope of the linear PI and systolic BP relationship obtained using the sequence technique. The frequency domain indices of BRS were the gain of the transfer function between systolic BP and PI in the LF and HF bands. 4. Atropine markedly affected these variables, illustrating vagal predominance under resting conditions in mice. The preferable time and frequency domain indices for quantifying the vagal contribution to HR variability were the pNN8 and the LF gain.

Applicability of recent methods used to estimate spontaneous baroreflex sensitivity to resting mice.

Short-term blood pressure (BP) variability is limited by the arterial baroreflex. Methods for measuring the spontaneous baroreflex sensitivity (BRS) aim to quantify the gain of the transfer function between BP and pulse interval (PI) or the slope of the linear relationship between parallel BP and PI changes. These frequency-domain (spectral) and time-domain (sequence) techniques were tested in conscious mice equipped with telemetric devices. The autonomic relevance of these indexes was evaluated using pharmacological blockades. The significant changes of the spectral bandwidths resulting from the autonomic blockades were used to identify the low-frequency (LF) and high-frequency (HF) zones of interest. The LF gain was 1.45 +/- 0.14 ms/mmHg, with a PI delay of 0.5 s. For the HF gain, the average values were 2.0 +/- 0.19 ms/mmHg, with a null phase. LF and HF bands were markedly affected by atropine. On the same 51.2-s segments used for cross-spectral analysis, an average number of 26.4 +/- 2.2 slopes were detected, and the average slope in resting mice was 4.4 +/- 0.5 ms/mmHg. Atropine significantly reduced the slopes of the sequence method. BRS measurements obtained using the sequence technique were highly correlated to the spectral estimates. This study demonstrates the applicability of the recent methods used to estimate spontaneous BRS in mice. There was a vagal predominance in the baroreflex control of heart rate in conscious mice in the present conditions.

Differential effects of metaboreceptor and chemoreceptor activation on sympathetic and cardiac baroreflex control following exercise in hypoxia in human.

Muscle metaboreceptors and peripheral chemoreceptors exert differential effects on the cardiorespiratory and autonomic responses following hypoxic exercise. Whether these effects are accompanied by specific changes in sympathetic and cardiac baroreflex control is not known. Sympathetic and cardiac baroreflex functions were assessed by intravenous nitroprusside and phenylephrine boluses in 15 young male subjects. Recordings were performed in random order, under locally circulatory arrested conditions, during: (1) rest and normoxia (no metaboreflex and no chemoreflex activation); (2) normoxic post-handgrip exercise at 30% of maximum voluntary contraction (metaboreflex activation without chemoreflex activation); (3) hypoxia without handgrip (10% O2 in N2, chemoreflex activation without metaboreflex activation); and (4) post-handgrip exercise in hypoxia (chemoreflex and metaboreflex activation). When compared with normoxic rest (-42 +/- 7% muscle sympathetic nerve activity (MSNA) mmHg(-1)), sympathetic baroreflex sensitivity did not change during normoxic post-exercise ischaemia (PEI; -53 +/- 9% MSNA mmHg(-1), P = 0.5) and increased during resting hypoxia (-68 +/- 5% MSNA mmHg(-1), P < 0.01). Sympathetic baroreflex sensitivity decreased during PEI in hypoxia (-35 +/- 6% MSNA mmHg(-1), P < 0.001 versus hypoxia without exercise; P = 0.16 versus normoxic PEI). Conversely, when compared with normoxic rest (11.1 +/- 1.7 ms mmHg(-1)), cardiac baroreflex sensitivity did not change during normoxic PEI (8.3 +/- 1.3 ms mmHg(-1), P = 0.09), but decreased during resting hypoxia (7.3 +/- 0.8 ms mmHg(-1), P < 0.05). Cardiac baroreflex sensitivity was lowest during PEI in hypoxia (4.3 +/- 1 ms mmHg(-1), P < 0.01 versus hypoxia without exercise; P < 0.001 versus normoxic exercise). The metaboreceptors and chemoreceptors exert differential effects on sympathetic and cardiac baroreflex function. Metaboreceptor activation is the major determinant of sympathetic baroreflex sensitivity, when these receptors are stimulated in the presence of hypoxia.

Sympathetic control of short-term heart rate variability and its pharmacological modulation.

The static relationship between heart rate (HR) and the activity of either vagal or sympathetic nerves is roughly linear within the physiological range of HR variations. The dynamic control of HR by autonomic nerves is characterized by a fixed time delay between the onset of changes in nerve activity and the onset of changes in HR. This delay is much longer for sympathetically than for vagally mediated changes in HR. In addition, the kinetics of the HR responses shows the properties of a low-pass filter with short (vagal) and long (sympathetic) time constants. These differences might be secondary to differences in nervous conduction times, width of synaptic cleft, kinetics of receptor activation and post-receptor events. Because of the accentuated low-pass filter characteristics of the HR response to sympathetic modulation, sympathetic influences are almost restricted to the very-low-frequency component of HR variability, but the chronotropic effects of vagal stimulation usually predominate over those of sympathetic stimulation in this frequency band. Oscillations in cardiac sympathetic nerve activity are not involved in respiratory sinus arrhythmia (high-frequency component) and make a minor contribution to HR oscillations of approximately 10-s period (low-frequency component of approximately 0.1 Hz), at least in the supine position. In the latter case, HR oscillations are derived mainly from a baroreflex, vagally mediated response to blood pressure Mayer waves. Beta-blockers and centrally acting sympathoinhibitory drugs share the ability to improve the baroreflex control of HR, possibly through vagal facilitation, which might be beneficial in several cardiovascular diseases.

Gain-of-function mutant of angiotensin II receptor, type 1A, causes hypertension and cardiovascular fibrosis in mice.

The role of the renin-angiotensin system has been investigated by overexpression or inactivation of its different genes in animals. However, there is no data concerning the effect of the constitutive activation of any component of the system. A knockin mouse model has been constructed with a gain-of-function mutant of the Ang II receptor, type 1A (AT(1A)), associating a constitutively activating mutation (N111S) with a C-terminal deletion, which impairs receptor internalization and desensitization. In vivo consequences of this mutant receptor expression in homozygous mice recapitulate its in vitro characteristics: the pressor response is more sensitive to Ang II and longer lasting. These mice present with a moderate (~20 mmHg) and stable increase in BP. They also develop early and progressive renal fibrosis and cardiac fibrosis and diastolic dysfunction. However, there was no overt cardiac hypertrophy. The hormonal parameters (low-renin and inappropriately normal aldosterone productions) mimic those of low-renin human hypertension. This new model reveals that a constitutive activation of AT(1A) leads to cardiac and renal fibrosis in spite of a modest effect on BP and will be useful for investigating the role of Ang II in target organs in a model similar to some forms of human hypertension.

Specific serotonin reuptake inhibition in major depressive disorder adversely affects novel markers of cardiac risk.

There exists a growing body of evidence linking depression with cardiovascular events, although the mechanisms responsible remain unknown. We investigated the role of the autonomic nervous system and inflammation in the link between coronary heart disease and major depressive disorder (MDD), and examined the cardiac risk modification following pharmacological treatment of depression. We measured cardiac baroreflex function, heart rate variability, pulse pressure and high sensitivity C-reactive protein (hsCRP), all of which have an impact on cardiac risk, pre- and post-treatment in 25 patients with MDD, with no history of coronary heart disease, and in 15 healthy subjects. Treatment consisted of selective serotonin reuptake inhibitors for approximately 12 weeks. No significant differences were observed between untreated MDD patients and healthy subjects in blood pressure, heart rate, baroreflex sensitivity or heart rate variability. Pulse pressure and hsCRP, however, were significantly elevated in patients with MDD prior to treatment (p=0.023 and p=0.025, respectively). Moreover, while pharmacotherapy was effective in alleviating depression, surprisingly, each of cardiac baroreflex function, heart rate variability, pulse pressure and hsCRP was modified (p<0.05) in a manner likely to increase cardiac risk. In conclusion, this study demonstrated higher pulse pressure and hsCRP plasma levels in patients with MDD, which might contribute to increased cardiac risk. Following treatment vagal activity was reduced, as indicated by reductions in baroreflex sensitivity and heart rate variability, accompanied by increases in pulse pressure and plasma hsCRP levels. Mechanisms potentially responsible for generating cardiac risk in patients treated with selective serotonin reuptake inhibitors may need to be therapeutically targeted to reduce the incidence of coronary heart disease in this population.

The sympathetic nervous system and the metabolic syndrome.

Studies performed in the past two decades have unequivocally shown that several of the components of the metabolic syndrome are associated with indirect and direct markers of adrenergic overdrive. This is the case for hypertension and obesity, in which resting tachycardia, elevated plasma norepinephrine values, increased sympathetic nerve traffic, as well as augmented levels of total and regional norepinephrine spillover have been reported. This is also the case for insulin resistance, i.e. a metabolic condition frequently complicating the various components of the pathological condition identified as the 'metabolic syndrome'. After briefly describing the epidemiological and the cardiovascular risk profile of the disease, this paper will examine the behaviour of the sympathetic nervous system in the metabolic syndrome as well as the mechanisms potentially responsible for this neurogenic abnormality. This will be followed by an analysis of the role played by neuroadrenergic factors in disease progression as well as in the pathogenesis of its complications. Finally, the therapeutic implications of these findings will be highlighted.