Strain-dependent differences of restraint stress-induced hypertension in WKY and SHR.

The aim of our study was to investigate differences in restraint stress-response between normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) and the consequences for tail-cuff (TC) blood pressure measurements. We therefore radiotelemetrically collected cardiovascular data from WKY and SHR that underwent TC procedures and measured plasma norepinephrine (NE) and angiotensin II (ATII) levels as well as gene expression of the adrenal and hypothalamic tyrosine-hydroxylase, the rate-limiting enzyme in NE synthesis. Furthermore, we determined the effects of antihypertensive therapy using the beta(1)-receptor antagonist metoprolol, the alpha(1)-receptor antagonist doxazosin and the AT(1)-receptor antagonist telmisartan as mono- or combination therapies during the TC procedure. Results show that the TC procedure induced a stress reaction characterised by greatly increasing heart rate (HR) and blood pressure (BP) and elevating plasma norepinephrine and angiotensin II concentrations. Strain-dependent differences were found concerning stress reactions during rest (more pronounced effects) and activity of the two rat strains. In both strains, metoprolol inhibited the TC-induced increase in HR and doxazosin the TC-induced increase in BP. Telmisartan, in addition, reduced hypertension in SHR, slightly reduced the TC-induced increase of BP in SHR but had no effect in WKY. The cardiovascular data as well as those on NE, ATII and TH expression clearly show that SHR are less able to cope with stress-related mechanisms than the normotensive WKY. Since TC activates both the sympathetic as well as renin-angiotensin system this method is not appropriate to evaluate neither physiological nor drug-induced effects on BP and HR.

Correlation of soluble gp130 serum concentrations with arterial blood pressure.

OBJECTIVES: An increased blood pressure can elicit remodeling of the cardiovascular system. Experimental data have implicated gp130, a subunit of the receptor for interleukin-6 (IL-6)-related cytokines, in the regulation of proliferation and apoptosis of cardiomyocytes and vascular smooth muscle cells (VSMC). Here, we investigate whether serum soluble gp130 concentrations correlate with blood pressure in humans, whether gp130 expression in the aorta differs between hypertensive and control rats, and whether angiotensin II or endothelin regulate gp130 expression in human VSMC. METHODS: We measured serum concentrations of soluble gp130, IL-6, the soluble IL-6 receptor, and the intima-media thickness of the common carotid artery in stroke patients (n = 48) and in elderly controls (n = 48). Furthermore, soluble gp130 levels were measured in young controls (n = 200). Expression of gp130 in Wistar-Kyoto (n = 12), spontaneously hypertensive rats (n = 12), and human VSMC was detected by real-time reverse transcription-PCR and immunohistochemistry. RESULTS: Soluble gp130 serum concentrations correlated with blood pressure in stroke patients and in elderly and young controls and with the intima-media thickness of the common carotid artery in stroke patients. The hypothesis that elevated soluble gp130 derives from the vascular system was supported by the enhanced expression of gp130 in the aortic wall of spontaneously hypertensive rats. Furthermore, treatment of human VSMC with angiotensin II stimulated gp130 expression. CONCLUSION: Our data suggest that soluble gp130 serum concentrations are correlated with blood pressure and may reflect vascular remodeling in response to arterial hypertension.

Decreased contractility due to energy deprivation in a transgenic rat model of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is associated with cardiac hypertrophy, diastolic dysfunction, and sudden death. Recently, it has been suggested that inefficient energy utilization could be a common molecular pathway of HCM-related mutations. We have previously generated transgenic Sprague-Dawley rats overexpressing a truncated cardiac troponin T (DEL-TNT) molecule, displaying typical features of HCM such as diastolic dysfunction and an increased susceptibility to ventricular arrhythmias. We now studied these rats using 31P magnetic resonance spectroscopy (MRS). MRS demonstrated that cardiac energy metabolism was markedly impaired, as indicated by a decreased phosphocreatine to ATP ratio (-31%, p < 0.05). In addition, we assessed contractility of isolated cardiomyocytes. While DEL-TNT and control cardiomyocytes showed no difference under baseline conditions, DEL-TNT cardiomyocytes selectively exhibited a decrease in fractional shortening by 28% after 1 h in glucose-deprived medium (p < 0.05). Moreover, significant decreases in contraction velocity and relaxation velocity were observed. To identify the underlying molecular pathways, we performed transcriptional profiling using real-time PCR. DEL-TNT hearts exhibited induction of several genes critical for cardiac energy supply, including CD36, CPT-1/-2, and PGC-1alpha. Finally, DEL-TNT rats and controls were studied by radiotelemetry after being stressed by isoproterenol, revealing a significantly increased frequency of arrhythmias in transgenic animals. In summary, we demonstrate profound energetic alterations in DEL-TNT hearts, supporting the notion that inefficient cellular ATP utilization contributes to the pathogenesis of HCM.

Evidence for an estradiol-agonistic action of nebivolol in spontaneously hypertensive rats.

OBJECTIVES: Unlike classical beta1-selective blockers, nebivolol (NEB) has vasodilatory properties due to the release of nitric oxide (NO) by a mechanism that is, so far, unknown. We hypothesized that NEB stimulates NO release by binding to estrogen receptors (ER) and subsequent activation of endothelial NO synthase (eNOS). The aim of this study was to elucidate the underlying mechanism of NEB action by investigating estradiol-dependent effects of NEB on the NO system in spontaneously hypertensive rats (SHR). METHODS: The effects of NEB on the NO system were determined by measuring urinary nitrate/nitrite (NOx) as well as eNOS and caveolin-1 protein expression in aortae. RESULTS: NEB did not influence NOx excretion in sham-operated (SO) female rats during proestrus. In male and ovariectomized female (OVX) rats, NEB increased NOx excretion significantly, whereas N(G)-nitro-L-arginine methyl ester (L-NAME) inhibited the NEB-induced increase in NOx. ER blockade with ICI182,780 prevented NEB-induced NOx excretion in OVX rats. In the aortae of SO females, NEB treatment did not alter eNOS expression. In OVX rats eNOS expression was increased two-fold after NEB application and this could be prevented by pretreatment with ICI182,780. In contrast to eNOS, NEB did not influence caveolin-1 expression in either group. CONCLUSION: The ability of NEB to up-regulate NOx excretion in male and OVX SHR and the inhibitory effect of ICI182,780 on NEB-induced NOx excretion suggests that NEB has an estradiol-agonistic action in vivo. NEB provokes NO generation by up-regulation of eNOS protein expression, whereas the expression of the negative eNOS regulator caveolin-1 remains unaffected.

Gender dependency of circadian blood pressure and heart rate profiles in spontaneously hypertensive rats: effects of beta-blockers.

This study investigated (i) blood pressure (BP), heart rate (HR), and their relation to urinary NOx and eNOS protein expression in male and female spontaneously hypertensive rats (SHR), as well as (ii) gender-dependent cardiovascular effects of nebivolol (NEB) in comparison to metoprolol (MET) in SHR. BP and HR were measured telemetrically after a single intraperitoneal application of NEB or MET at 07.00 and 19.00 h in male rats and at 19.00 h in proestrus female rats. The two beta-blockers varied in time of decreasing BP and HR and also in duration. In males, MET decreased BP and HR for few hours exclusively when applied at the onset of the activity phase (i.e., at 19.00 h), while after its application at 07.00 h, BP and HR were unchanged. In females, MET also caused a short-lasting BP and HR reduction, with the effect being more pronounced than in males. In males, NEB at either dosing time decreased HR and BP to a greater extent than did MET. This effect was evident both during the activity and rest periods and persisted for at least five days. In females, NEB provoked a similar, but more pronounced, effect on BP and HR in comparison to males. These findings demonstrate that significant gender-dependent differences in the circadian profile of BP and HR exist. BP and urinary NOx as well as eNOS expression are inversely correlated, and the cardiovascular effects of NEB and MET vary, depending on the time of application as well as gender.