Strain-dependent differences of restraint stress-induced hypertension in WKY and SHR Alexander Grundt, Christina Grundt, Stefan Gorbey, Martin A. Thomas, Björn Lemmer ⁎ Institute of Experimental and Clinical Pharmacology and Toxicology, Ruprecht-Karls-Universität of Heidelberg, Mannheim, Germany abstract article info Article history: Received 22 January 2009 Received in revised form 18 February 2009 Accepted 26 February 2009 Keywords: Restrained stress Tail-cuff Radiotelemetry Hypertension Sympathetic nervous activity 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. © 2009 Elsevier Inc. All rights reserved. 1. Introduction The tail-cuff (TC) method is employed to monitor conscious blood pressure (BP) in transgenic and/or knock-out rodents in order to correlate it with molecular modifications and/or drug effects [1,2]. The American Heart Association recommended tail-cuff measurement for high-throughput experimental design [3] but pointed out that the agreement with radiotelemetric data is dependent on the tail-cuff method used [4]. The draw-back of the TC method is that the fixation of animals leads to a stress reaction [5–9] characterised by an increase in cardiovascular parameters such as blood pressure and heart rate. Stress reactions are usually mediated by the sympathetic nervous system, which activity is circadian time-dependent as well as strain- dependent and dominantly regulates blood pressure and heart rate. Therefore, analyzing and comparing antihypertensive drug effects by the TC device in different rat strains or under antihypertensive therapy require information about the activity and capacity of the sympathetic nervous system in the strains compared. An additional confounding factor using the TC method is that circadian rhythms in blood pressure and heart rate in normotensive, hypertensive and knock-out rodents [10–13] are not taken into account. Animal experiments that aim to identify antihypertensive effects of drugs were usually performed in normotensive Wistar Kyoto rats (WKY) as controls and the hypertensive backcross of WKY, the spontaneously hypertensive rats (SHR) [14]. SHR develop an essential hypertension between 12 and 20 weeks of age resulting in left heart hypertrophy and hypertension related end organ damages as seen as in human patients with essential hypertension [15]. As in most patients with essential/primary hypertension the fundamental cause of hypertension in SHR is still far from being solved. Nevertheless, SHR were frequently used to identify antihypertensive drug effects by TC blood pressure measurements and data were compared to normo- tensive WKY [14]. However, it was not yet tested, whether restraint stress by TC procedure modifies antihypertensive drug effects equally in SHR and WKY. We, therefore, compared antihypertensive drug effects in WKYand SHR in unrestraint freely moving rats by radiotelemetry and under restraint stress conditions during TC procedure. In addition, plasma norepenephrine (NE) and angiotensin II (ATII) levels were deter- mined. The aim of this study was to get more insight into strain- specific differences in response to antihypertensive treatment during Physiology & Behavior 97 (2009) 341–346 ⁎ Corresponding author. Institute of Experimental and Clinical Pharmacology and Toxicology, Ruprecht-Karls-Universität Heidelberg, Maybachstrasse 14, 68169 Mannheim, Germany. Tel.: +49 621 383 9704. E-mail address: bjoern.lemmer@pharmtox.uni-heidelberg.de (B. Lemmer). 0031-9384/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2009.02.029 Contents lists available at ScienceDirect Physiology & Behavior journal homepage: www.elsevier.com/locate/phb