Low anxiety males display higher degree of salt sensitivity, increased autonomic reactivity, and higher defensiveness.

BACKGROUND: Psychological parameters such as heightened anxiety and defensiveness are associated with increased cardiovascular morbidity and mortality. Autonomic dysfunction is considered to be an important pathogenetic pathway. Little research has been done regarding potential links between emotional factors and salt sensitivity. The aim of the present study was to determine whether subjects with different levels of trait anxiety differ in the degree of salt sensitivity and autonomic reactivity to a mental stress task. METHODS: Seventy-two young normotensive men were phenotyped for salt sensitivity and underwent a standardized mental stress test and psychological assessment. According to their trait anxiety test scores, they were classified as low-, moderate- or high-anxiety subjects. A measure of defensiveness was used to assess self-deceptive tendencies. RESULTS: Low-anxiety subjects displayed a higher degree of salt sensitivity compared to moderate- and high-anxiety subjects (P < 0.001), increased heart rate (HR) and electrodermal responses to the stressor compared to moderate-anxiety subjects (P < 0.01 and P < 0.05 respectively) and elevated levels of self-deception compared to moderate- and high-anxiety subjects (P < 0.001). CONCLUSION: Low-anxiety subjects were characterized by a higher degree of salt sensitivity and increased autonomic responsiveness. Defensiveness was also shown to be elevated in this group and might be the underlying psychological trait explaining these findings. Future research on the associations of anxiety and cardiovascular risk should implement measurement of defensiveness in order to identify these subjects at potential risk for cardiovascular disease despite self-reports of low anxiety.

Salt-sensitive men show reduced heart rate variability, lower norepinephrine and enhanced cortisol during mental stress.

Salt sensitivity (SS) represents a risk factor for essential hypertension, which has been related to enhanced cardiovascular stress reactivity possibly mediated by increased noradrenergic susceptibility. We investigated biophysiological responses to mental stress in salt-sensitive (ss) and salt-resistant (sr) subjects, hypothesizing lower heart rate variability (HRV) and higher cortisol in the ss. A total of 48 healthy normotensive Caucasian men (age 25.6+/-2.6, body mass index 22.9+/-2.3) were phenotyped for SS (defined as significant drop in mean arterial pressure>3 mm Hg under the low-salt diet) by a 2-week high- versus low-salt diet. Subjects underwent a standardized mental stress task with continuous cardiovascular monitoring before, during and after the test (Finapres; Ohmeda, Louisville, CO, USA). Blood samples were drawn to examine cortisol and catecholamines before, after and 20 min after stress. The task elicited significant increases of systolic blood pressure (SBP), diastolic BP (DBP) and heart rate (HR) and a significant decrease of HRV (all time effects P<0.0001). The ss subjects showed lower norepinephrine (NE) and higher cortisol, indicated by significant group effects (P=0.009 and 0.025, respectively). HR increased and HRV decreased more in the ss under the stress, shown by significant time by group interactions (P=0.045 and 0.003, respectively). The observation of a more pronounced HR rise coupled with a greater decrease of HRV in healthy ss men under the influence of brief mental stress confirms their enhanced physiological stress reactivity. The lower peripheral NE may represent an effort to compensate for increased noradrenergic receptor sensitivity. The enhanced cortisol levels are backed by recent genetic findings on HSD11B2 polymorphisms and may promote hypertension.

Patients with haematological malignancies show a restricted body image focusing on function and emotion.

The diagnosis of cancer threatens the psychological and bodily integrity. Based on this assumption, we aimed to explore how newly diagnosed patients cope with special regard to the body image (BI). In total, 40 patients (32 haematological malignancies) were assessed by questionnaires on mood, complaints, self-regulation and quality of life (QOL). The BI was assessed by the 'Body Grid' which reveals the constructs patients choose to characterize the body. The constructs were categorized using a model of six predefined categories comprising: emotion, control, activity, strength, function and appearance. Tinnitus sufferers and medical students served as comparison groups. Cancer patients showed significantly more anxious depression and a significantly lower QOL than controls. Their BI was restricted, focusing the functional status of body organs (e.g. opposing healthy vs. ill organs) as well as emotional aspects (e.g. trust vs. fear). The data convey fundamental psychological distress in newly diagnosed cancer patients. Restriction of BI and use of functional constructs may help to buffer the threat to body integrity. The emotional constructs reflect the existential impact. The data give a clear indication for the need for early psychosocial support which should aim at stabilizing the psychological and bodily integrity of the patient.

Inhibition of C1q-beta-amyloid binding protects hippocampal cells against complement mediated toxicity.

Activation of complement by beta-amyloid (A beta) contributes to the pathology of Alzheimer's disease (AD). Here, we show that C1-Inhibitor (C1-Inh) protects cultured rat hippocampal cells against beta-amyloid induced complement lysis indicating a classical pathway-mediated activation mechanism. We report on screening of compound libraries to identify compounds that inhibit C1q binding to beta-amyloid. Characterization of these compounds revealed that C1q possessed distinct binding sites for beta-amyloid and antibodies. One selected compound protected cultured hippocampal cells against complement-dependent beta-amyloid toxicity. These results provide evidence that complement has the potential to damage hippocampal cells, and C1q is a relevant target to suspend this deleterious mechanism in Alzheimer's disease.

Is myosin phosphatase regulated in vivo by inhibitor-1? Evidence from inhibitor-1 knockout mice.

1. The Ca(2+) sensitivity of smooth muscle contractility is modulated via regulation of phosphatase activity. Protein phosphatase inhibitor-1 (I-1) is the classic type-1 phosphatase inhibitor, but its presence and role in cAMP-dependent protein kinase (PKA) modulation of smooth muscle is unclear. To address the relevance of I-1 in vivo, we investigated smooth muscle function in a mouse model lacking the I-1 protein (I-1((-/-)) mice). 2. Significant amounts of I-1 protein were detected in the wild-type (WT) mouse aorta and could be phosphorylated by PKA, as indicated by (32)P-labelled aortic extracts from WT mice. 3. Despite the significant presence of I-1 in WT aorta, phenylephrine and KCl concentration- isometric force relations in the presence or absence of the PKA pathway activator isoproterenol (isoprenaline) were unchanged compared to I-1((-/-)) aorta. cGMP-dependent protein kinase (PKG) relaxation pathways were also not different. Consistent with these findings, dephosphorylation rates of the 20 kDa myosin light chains (MLC(20)), measured in aortic extracts, were nearly identical between WT and I-1((-/-)) mice. 4. In the portal vein, I-1 protein ablation was associated with a significant (P < 0.05) rightward shift in the EC(50) of isoproterenol relaxation (EC(50) = 10.4 +/- 1.4 nM) compared to the WT value (EC(50) = 3.5 +/- 0.2 nM). Contraction in response to acetylcholine as well as Ca(2+) sensitivity were similar between WT and I-1((-/-)) aorta. 5. Despite the prevalence of I-1 and its activation by PKA in the aorta, I-1 does not appear to play a significant role in contractile or relaxant responses to any pharmacomechanical or electromechanical agonists used. I-1 may play a role as a fine-tuning mechanism involved in regulating portal vein responsiveness to beta-adrenergic agonists.

Smooth muscle-targeted overexpression of insulin-like growth factor I results in enhanced vascular contractility.

Insulin-like growth factor I (IGF-I) has been postulated to function as a vasodilator. We explored the vasoactive effects of chronic elevations of arterial IGF-I levels in SMP8-IGF-I mice, in which IGF-I is overexpressed in smooth muscle (SM) by means of a SM alpha-actin promoter. Denuded aortas from SMP8-IGF-I mice generated increased force in response to KCl or phenylephrine and had greater sensitivity to KCl depolarization. This is not due to desensitization of a SM NO pathway, as pretreatment with n-omega-nitro-L-arginine affected both wild-type and SMP8-IGF-I aortas to a similar degree. The increased contractility ex vivo is not associated with changes in heart rate or blood pressure. Total smooth muscle myosin heavy chain (SMHC) messenger RNA (mRNA) was greater in SMP8-IGF-I aortas, with preferential expression of SMHC-A. Reciprocal effects on contractility and SMHC mRNA were observed in SMP8-IGFBP-4 animals, in which IGF-binding protein-4 was overexpressed through the same promoter. Also, SM alpha-actin mRNA was increased in the aortas from SMP8-IGF-I mice. In summary, chronic arterial overexpression of IGF-I is associated with increased contractility. These effects differ from those seen after acute exposure to the growth factor and may relate to IGF-mediated changes in expression and relative isoform abundance of critical contractile proteins.

Identification of the elements regulating the expression of the cell adhesion molecule MCAM/MUC18. Loss of AP-2 is not required for MCAM expression in melanoma cell lines.

The cell adhesion molecule melonoma cell adhesion molecule (MCAM)/MUC18/CD146 is specifically up-regulated on tumors of neuroectodermal origin and in animal models confers metastatic capacity to human melanoma cells. To identify critical regions regulating MCAM expression in melanomas, 1 kilobase of the MCAM 5' region was analyzed for promoter activity and transcription factor binding in 1 glioma, 1 carcinoma, and 4 melanoma cell lines. The minimal MCAM promoter (-106/+22 base pair (bp)) consists of 4 Sp-1 sites, two AP-2 elements, one cAMP responsive element, and the initiator surrounding the transcriptional start site. Analysis of mutated constructs indicated that the cAMP-responsive element is a major transcriptional activator in the majority of cell lines. Site-directed mutagenesis revealed that, in AP-2 expressing cells, the AP-2 site within the core promoter (-23 bp) has an inhibitory influence on MCAM expression while the AP-2 sites at -131 and -302 bp are activating. Functional AP-2 was observed in both MCAM positive and MCAM negative melanoma cell lines indicating that expression of MCAM does not require loss of this transcription factor. Furthermore, all MCAM constructs were strongly expressed in MCAM negative as well as MCAM positive cells, indicating that the expression of this gene is not controlled solely by the presence of transactivating factors binding to the investigated region.

Vasorelaxant properties of parathyroid hormone-related protein in the mouse: evidence for endothelium involvement independent of nitric oxide formation.

PTH-related peptide is produced in vascular smooth muscle and is believed to participate in the local control of vascular tone. The recent identification of mid-region PTHrP peptides, as well as the discovery of multiple receptors in blood vessels, raises new questions concerning the mechanisms by which PTHrP relaxes the vasculature. In this study, we examined these mechanisms in two vascular beds of the mouse. PTHrP-(1-34) and PTH-(1-34), but not PTHrP-(38-64) or PTHrP-(38-94), caused concentration-dependent relaxation of pre-contracted aortas and reduced the spontaneous phasic activity of the portal vein. PTHrP and PTH-induced aortic relaxations were largely endothelium dependent, whereas an intact endothelium was not necessary for maximal portal vein relaxation. The endothelium-dependent component of PTHrP and PTH-induced aortic relaxations were unaffected by pretreatment with either L-NNA or indomethacin but were abolished by pretreatment with tetrabutyl ammonium. These results demonstrate that the N-terminal portions of PTHrP and PTH are required for their vasorelaxant activity in the mouse. In addition, maximal relaxant activity of PTHrP and PTH in murine aorta is dependent on the endothelium, which appears to involve the generation of an endothelium-derived hyperpolarizing factor.