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Acute Haemodynamic Effects of Tezosentan in rats with
monocrotaline –induced pulmonary hypertension
D. Pinto 1 , D. Silva 1 , D. Fontoura 1 , F. Vasques-Nóvoa 1 , A. P. Lourenço 1 and A. F. Leite-
Moreira 1
1 Department of Physiology, Faculty of Medicine, University of Porto, Portugal.
Introduction: Tezosentan, a short-acting intravenous (iv) dual endothelin-1 (ET-1) receptor
blocker [1], may be useful for acute haemodynamic control in patients with chronic pulmonary
hypertension (PH). Our goal was to evaluate the haemodynamic effects of tezosentan in
monocrotaline (MCT)-induced chronic PH.
Methods: Wistar rats (180-200g) were randomly injected with either 60mg.Kg -1 MCT or
vehicle, subcutaneously. Thereafter a subgroup of MCT-injected rats was gavaged daily with
300mg.Kg -1 bosentan (M+B, n=13) while another subgroup (M, n=20) and control rats (C,
n=7) received vehicle. At the 28 th day after injection, and 24 hours after interrupting bosentan,
right (RV) and left ventricular (LV) pressures were continuously recorded after thoracotomy
under anaesthesia with fentanil and sevoflurane, mechanical ventilation, and 0.6 mL.Kg -1 .h -1
saline as fluid replacement. Tezosentan was administered in cumulative iv doses of 0.5, 1, 2, 5,
10, and 20mg.Kg -1 , after stable effect of the previous dose. Statistical analysis was performed
by two-way repeated measures ANOVA. Quantitative variables are presented as mean ± SEM.
Results: During follow-up, 63% and 46% of M and M+B rats died, respectively, and 1 rat
from group M died during haemodynamic evaluation. Compared with C, RV systolic pressure
(SP) and relaxation constant τ were increased in M and M+B, while LVSP was decreased in M.
RVSP was dose-dependently reduced by tezosentan in M (from 58.8±1.0, at baseline, to
48.6±1.0 mmHg, with 20mg.Kg -1 ) and M+B (51.1±1.1 to 40.0±1.3 mmHg), with no change in
LVSP or heart rate, while no changes were observed in C (32.7±1.0 to 31.2±1.0 mmHg) (Fig.
1).
Fig. 1 – Haemodynamic effects of tezosentan.
Discussion: Tezosentan acutely reduces RVSP in chronic experimental PH. This effect is
preserved despite previous chronic ET-1 receptor blocker therapy. Tezosentan may prove to be
useful for haemodynamic handling of PH patients during cardiac surgery or in critical care.
References:
[1]. Clozel M, Ramuz H, Clozel JP, et al (1999), Pharmacology of tezosentan, new endothelin receptor
antagonist designed for parenteral use, J. Pharmacol. Exp. Ther. 290: 840-6.
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