Sympatho-inhibitory properties of various AT1 receptor antagonists.
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 Ang II-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 mumol/l), irbesartan (0.1 nmol/l to 0.1 mumol/l) and telmisartan (0.01 nmol/l to 0.01 mumol/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 delta DBP 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, 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.
Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. J.C.Balt@amc.uva.nl
Jippe C
JC
Balt
Marie-Jeanne
MJ
Mathy
Martin
M
Pfaffendorf
Peter A
PA
van Zwieten
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D013565:Sympatholytics / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D044140:Receptor, Angiotensin, Type 1; D013565:Sympatholytics