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CHANGES IN THE IN VITRO PHARMACODYNAMIC PROPERTIES OF METOPROLOL IN ATRIA ISOLATED FROM SPONTANEOUSLY HYPERTENSIVE RATS
Author(s) -
Di Verniero Carla,
Höcht Christian,
Opezzo Javier A W,
Taira Carlos A
Publication year - 2007
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2007.04566.x
Subject(s) - metoprolol , chronotropic , medicine , endocrinology , agonist , chemistry , propranolol , dissociation constant , heart rate , receptor , blood pressure
SUMMARY1 The present study addressed possible changes in the dissociation constant of metoprolol and its inverse agonist activity in spontaneously hypertensive rats (SHR). In addition, a possible correlation between cardiac hypertrophy and the inverse agonist activity of metoprolol was explored. 2 In order to determine the dissociation constant (expressed as the pK b ) of metoprolol, a cumulative concentration–response curve to noradrenaline was constructed in the absence or presence of metoprolol (0.1, 1 or 10 µmol/L). In a second experiment, a cumulative concentration–response curve to metoprolol was constructed to determine its inverse agonist activity. 3 The ventricular weight of SHR was significantly greater compared with Wistar‐Kyoto (WKY) rats. A rightward shift of the concentration–response curve to noradrenaline was observed in SHR compared with WKY rats. The pK b of metoprolol was smaller in SHR compared with WKY rats (6.35 ± 0.14 vs 6.99 ± 0.12, respectively; P < 0.05). No difference was observed in the maximal response (E max ) of the concentration–time effect of metoprolol in WKY rats and SHR (−29.1 ± 7.1 vs −28.2 ± 8.5%, respectively; n = 6 for both). However, the concentration of metoprolol eliciting a half‐maximal effect (expressed as the pEC 50 ) was significantly smaller in SHR compared with WKY rats (4.82 ± 0.07 vs 5.29 ± 0.13, respectively; n = 6; P < 0.05). Although a significant correlation ( r = –0.876) between the ventricular weight/bodyweight (VW/BW) ratio and the pEC 50 of the chronotropic effect of metoprolol was found, no relationship ( r = –0.257) was found between the VW/BW ratio and E max . 4 In summary, the present study provides the first evidence of a change in the in vitro pharmacodynamic properties of metoprolol in SHR. The sympathetic overactivity present in SHR not only reduces the positive chronotropic effect of noradrenaline, but also diminishes the constant dissociation of metoprolol from atrial β 1 ‐adrenoceptors and its inverse agonist activity. A significant correlation between the VW/BW ratio and the inverse agonist potency of metoprolol was found, suggesting a possible link between cardiac hypertrophy and the reduction of the inverse agonist activity of metoprolol.