Hypothalamic kinin B1 receptor mediates orexin system hyperactivity in neurogenic hypertension.

Brain orexin system hyperactivity contributes to neurogenic hypertension. We previously reported upregulated neuronal kinin B1 receptor (B1R) expression in hypertension. However, the role of central B1R activation on the orexin system in neurogenic hypertension has not been examined. We hypothesized that kinin B1R contributes to hypertension via upregulation of brain orexin-arginine vasopressin signaling. We utilized deoxycorticosterone acetate (DOCA)-salt hypertension model in wild-type (WT) and B1R knockout (B1RKO) mice. In WT mice, DOCA-salt-treatment increased gene and protein expression of orexin A, orexin receptor 1, and orexin receptor 2 in the hypothalamic paraventricular nucleus and these effects were attenuated in B1RKO mice. Furthermore, DOCA-salt- treatment increased plasma arginine vasopressin levels in WT mice, but not in B1RKO mice. Cultured primary hypothalamic neurons expressed orexin A and orexin receptor 1. B1R specific agonist (LDABK) stimulation of primary neurons increased B1R protein expression, which was abrogated by B1R selective antagonist R715 but not by the dual orexin receptor antagonist, ACT 462206, suggesting that B1R is upstream of the orexin system. These data provide novel evidence that B1R blockade blunts orexin hyperactivity and constitutes a potential therapeutic target for the treatment of salt-sensitive hypertension.

Estrogen-dependent hypersensitivity to diabetes-evoked cardiac autonomic dysregulation: Role of hypothalamic neuroinflammation.

AIMS: To investigate if autonomic dysregulation is exacerbated in female rats, subjected to diabetes mellitus (DM), via a paradoxical estrogen (E2)-evoked provocation of neuroinflammation/injury of the hypothalamic paraventricular nucleus (PVN). MAIN METHODS: We measured cardiac autonomic function and conducted subsequent PVN neurochemical studies, in DM rats, and their respective controls, divided as follows: male, sham operated (SO), ovariectomized (OVX), and OVX with E2 supplementation (OVX/E2). KEY FINDINGS: Autonomic dysregulation, expressed as sympathetic dominance (higher low frequency, LF, band), only occurred in DM E2-replete (SO and OVX/E2) rats, and was associated with higher neuronal activity (c-Fos) and higher levels of TNFα and phosphorylated death associated protein kinase-3 (p-DAPK3) in the PVN. These proinflammatory molecules likely contributed to the heightened PVN oxidative stress, injury and apoptosis. The PVN of these E2-replete DM rats also exhibited upregulations of estrogen receptors, ERα and ERß, and proinflammatory adenosine A1 and A2a receptors. SIGNIFICANCE: The E2-dependent autonomic dysregulation likely predisposes DM female rats and women to hypersensitivity to cardiac dysfunction. Further, upregulations of proinflammatory mediators including adenosine A1 and A2 receptors, TNFα and DAPK3, conceivably explain the paradoxical hypersensitivity of DM females to PVN inflammation/injury and the subsequent autonomic dysregulation in the presence of E2.

Estrogen dependence of the renal vasodilatory effect of nicotine in rats: role of α7 nicotinic cholinergic receptor/eNOS signaling.

AIMS: We recently reported that acute exposure to nicotine vasodilates the renal vasculature of male rats via facilitation of endothelial nitric oxide synthase (eNOS). In this study, we investigated whether this effect of nicotine is sexually dimorphic and the role of estrogen in modulating the nicotine effect. MAIN METHODS: Nicotine-evoked vasodilation was evaluated in phenylephrine-preconstricted perfused kidneys obtained from male, proestrus female, ovariectomized (OVX) and estrogen-replaced OVX (OVXE(2)) rats. KEY FINDINGS: Nicotine infusion (5×10(-5), 1×10(-4), and 5×10(-4) M) produced greater concentration-dependent reductions in the renal perfusion pressure (RPP) in an isolated kidney from proestrus females than from males. Inhibition of NOS by N(G)-nitro-L-arginine abolished the nicotine-evoked reduction in RPP and abolished the gender difference in the nicotine effect. Nicotine vasodilation was also attenuated in kidneys isolated from OVX and diestrus rats, models characterized by reduced estrogen levels. Further, estrogen or L-arginine supplementation in OVX rats largely restored the renal vasodilatory response to nicotine. Estrogen receptor blockade by tamoxifen abrogated the enhanced nicotine-evoked vasodilation elicited by E(2) in OVX rats. The nitrite/nitrate levels and protein expressions of eNOS and α(7) nicotinic cholinergic receptor (α(7) nAChRs) were significantly higher in renal tissues of OVXE(2) compared with OVX rats, suggesting a facilitatory effect for E(2) on α(7) nAChRs/eNOS signaling. SIGNIFICANCE: Estrogen-dependent facilitation of NOS signaling mediates the enhanced vasodilator capacity of nicotine in the renal vasculature of female rats. Preliminary evidence also suggests a potential role for α(7) nAChRs in this estrogen-dependent phenomenon.

Longitudinal assessment of the effects of oestrogen on blood pressure and cardiovascular autonomic activity in female rats.

1. Published data concerning the effects of ovarian hormones on haemodynamic variability are contradictory. For the first time, the present study used radiotelemetric haemodynamic monitoring to investigate the long-term effects of chronic oestrogen depletion and repletion on cardiovascular autonomic control and arterial baroreflex sensitivity (BRS) in female rats. 2. Blood pressure (BP), heart rate (HR) and +dP/dt(max) of arterial pressure (an estimate of myocardial contractility) were monitored in sham-operated (SO), ovariectomized (OVX) and oestrogen-replaced OVX rats (OVXE2) for 16 weeks. Cardiovascular autonomic control and baroreflexes were assessed by frequency domain analysis of interbeat intervals (IBI) and systolic BP (SBP). 3. Compared with SO rats, OVX rats exhibited no changes in BP, short-lived decreases in HR and sustained reductions in +dP/dt(max) of arterial pressure. The high- (HF; 0.75-3 Hz) and low-frequency (LF; 0.25-0.75 Hz) components of spectral power of IBI were significantly decreased and increased, respectively, by ovariectomy. An increase in the IBI(LF/HF) ratio in OVX rats suggests a shift in the cardiac sympathovagal balance towards sympathetic dominance. Index alpha, the spectral index of spontaneous BRS, was reduced by OVX. 4. Oestrogen replacement caused significant reductions in BP and HR and reversed OVX-induced changes in +dP/dt(max) of arterial pressure and cardiac autonomic activity. The LF oscillations of SBP were reduced in OVXE2 rats, suggesting a reduction in vascular sympathetic tone by oestrogen. 5. These findings highlight the importance of long-term oestrogen therapy in rectifying the detrimental effects of depletion of ovarian hormones on the cardiovascular system and baroreflex.

Novel strategies and targets for the management of hypertension.

Hypertension, as the sole or comorbid component of a constellation of disorders of the cardiovascular (CV) system, is present in over 90% of all patients with CV disease and affects nearly 74 million individuals in the United States. The number of medications available to treat hypertension has dramatically increased during the past 3 decades to some 50 medications as new targets involved in the normal regulation of blood pressure have been identified, resulting in the development of new agents in those classes with improved therapeutic profiles (e.g., renin-angiotensin-aldosterone system; RAAS). Despite these new agents, hypertension is not adequately managed in approximately 30% of patients, who are compliant with prescriptive therapeutics, suggesting that new agents and/or strategies to manage hypertension are still needed. Some of the newest classes of agents have targeted other components of the RAS, for example, the selective renin inhibitors, but recent advances in vascular biology have provided novel potential targets that may provide avenues for new agent development. These newer targets include downstream signaling participants in pathways involved in contraction, growth, hypertrophy, and relaxation. However, perhaps the most unique approach to the management of hypertension is a shift in strategy of using existing agents with respect to the time of day at which the agent is taken. This new strategy, termed "chronotherapy," has shown considerable promise in effectively managing hypertensive patients. Therefore, there remains great potential for future development of safe and effective agents and strategies to manage a disorder of the CV system of epidemic proportion.

Chronic ethanol-clonidine hemodynamic interaction in telemetered spontaneously hypertensive rats.

Our previous studies have established that ethanol, administered acutely or chronically, attenuates the hypotensive action of the centrally acting drug clonidine. In this study, we employed the radiotelemetry technique to evaluate the long-term hemodynamic interaction between the two drugs administered simultaneously to spontaneously hypertensive rats (SHRs). Changes in blood pressure (BP), heart rate (HR), and their variability was determined in pair-fed rats receiving ethanol (5%, w/v), clonidine pellets (10 mg/pellet, s.c.), or their combination for 28 days. Ethanol feeding caused significant decreases and increases in BP and HR, respectively. The time-domain variability indices of BP and HR were also reduced by ethanol. Clonidine produced significant reductions in BP and HR that were evident for only 1-2 days and disappeared thereafter. In rats receiving the combined ethanol and clonidine treatment, hemodynamic changes were identical to those produced by ethanol alone. These findings suggest (i) long-term exposure of SHRs to moderate amounts of ethanol reduces HR variability, possibly due to diminished cardiac vagal modulation, and (ii) the lack of a maintained hypotensive response to clonidine, administered via timed-release pellets, made the evaluation of its chronic interaction with ethanol unfeasible.