Titre du document / Document title

Sympatho-inhibitory properties of various AT¹ receptor antagonists

Auteur(s) / Author(s)

BAIT Jippe C. ; MATHY Marie-Jeanne ; PFAFFENDORF Martin ; VAN ZWIETEN Peter A. ;

Résumé / Abstract

It is well known that angiotensin II (Ang II) can facilitate the effects of sympathetic neurotransmission. In the present study, using various experimental models, we investigated the inhibitory effects of several Ang II subtype 1 receptor (AT¹) antagonists on this Angll-induced facilitation. We compared the sympatho-inhibitory potencies of the AT¹ blockers with their respective potencies regarding inhibition of the direct vasoconstrictor effects of Ang II. In the isolated mesenteric artery, we investigated the effects of Ang II in the presence and absence of losartan, irbesartan and telmisartan on stimulation-induced vasoconstrictor responses. In the pithed rat, we studied the effect of AT¹ blockade on the sequelae of electrical stimulation of the thoracolumbar sympathetic outflow (presynaptic AT¹ blockade) as well as on dose-response curves elicited by exogenous Ang II (postsynaptic AT¹ blockade). Additionally, we compared the sympatho-inhibitory of irbesartan in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. In the isolated mesenteric artery, Ang II (10 nM) significantly enhanced stimulation-induced vasoconstrictor responses. The enhancement could be antagonized in a concentration-dependent manner by losartan (1 nmol/l to 1 μmol/l), irbesartan (0.1 nmol/l to 0.1μmol/l) and telmisartan (0.01 nmol/l to 0.01 μmol/l). The sympatho-inhibitory potency was telmisartan > irbesartan > losartan. In the pithed normotensive rat, the stimulation-induced increase in diastolic blood pressure (DBP) as well as the Ang II-elicited DBP response were dose-dependently reduced by all the AT¹ receptor blockers investigated. The order of potency with respect to sympatho-inhibition was eprosartan > valsartan = candesartan = embusartan = telmisartan > losartan > irbesartan (comparison of doses which at 2 Hz reduced ADBP by 20 mmHg, differences significant at P < 0.05). The order of potency regarding inhibition of the Ang II-induced DBP increase was candesartan > embusartan = valsartan = eprosartan = telmisartan > irbesartan > losartan (comparison of the antagonist concentration, in the presence of which twice the agonist concentration is needed to cause the same effect [pA² values], differences significant at P < 0.05). In the pithed SHR and the normotensive WKY rat the sympatho-inhibitory potency of irbesartan did not differ significantly between both strains. It can be concluded that all AT¹ receptor antagonists appear to possess sympatho-inhibitory properties, which may be of potential interest in the treatment of hypertension and heart failure. Our findings suggest differences in pre- and postsynaptic inhibition between the various compounds, since for eprosartan and losartan the sympatholytic doses and postsynaptic inhibitory doses differed far less than for the other AT¹ receptor antagonists.

Revue / Journal Title

Journal of hypertension. Supplement   ISSN 0952-1178 

Source / Source

2002, vol. 20, n^o5, pp. S3-S11

Langue / Language

Anglais

Editeur / Publisher

Lippincott Williams & Wilkins, Hagerstown, MD, ETATS-UNIS  (1983) (Revue)

Localisation / Location

INIST-CNRS, Cote INIST : 20680 S, 35400010827328.0010