Embusartan

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.

In the pithed rat model, endogenously generated angiotensin (Ang) II can enhance sympathetic neurotransmission by acting on Ang II type 1 (AT1) receptors that are located on sympathetic nerve terminals.

To compare the inhibitory potency of candesartan, valsartan, eprosartan and embusartan in blocking presynaptically and postsynaptically located AT1 receptors.

To investigate blockade of presynaptic AT1 receptors, we studied the effect of AT1 receptor blockade on the sequelae of electrical stimulation of the thoracolumbar sympathetic outflow (0.25-8 Hz). To investigate the interaction between postsynaptic AT1 blockers and alpha-adrenoceptors, the effects of these compounds on pressor responses to exogenous noradrenaline were determined. To investigate blockade of postsynaptic AT1 receptors, we studied the effect of the AT1 antagonists on dose-response curves elicited by exogenous Ang II.

The stimulation-induced increase in diastolic blood pressure (DBP) and the Ang II-elicited DBP response were dose-dependently reduced by all AT1 receptor blockers. Interestingly, the greatest doses of the AT1 antagonists caused less than maximal reduction in the stimulation-induced increase in DBP, resulting in a U-shaped dose-response relationship. To compare sympathoinhibitory potencies, the doses that, at 2 Hz, reduced the change in DBP by 20 mmHg (ED20 values, expressed as -log mol/kg) were calculated; they were 5.50 +/- 0.12, 5.77 +/- 0.10, 6.32 +/- 0.12 and 5.62 +/- 0.13 for valsartan, candesartan, eprosartan and embusartan, respectively. The order of potency, therefore, was eprosartan> valsartan = candesartan = embusartan (where > signifies P < 0.05). To compare the order of potency for inhibition of the Ang II-induced increase in DBP, we calculated pA2 values (the X intercept in Schild regression). They were 7.20 +/- 0.17, 8.01 +/- 0.01, 7.20 +/- 0.03 and 7.25 +/- 0.16, for valsartan, candesartan, eprosartan and embusartan, respectively. Accordingly, the order of potency for inhibition of the direct pressor effects of Ang II was candesartan> valsartan = eprosartan = embusartan (where > signifies P < 0.05).

In the pithed rat, the effects on DBP of stimulation of the thoracolumbar spinal cord are partly dependent on endogenously formed Ang II. These effects can be counteracted by blockade of presynaptically located AT1 receptors. No interaction was found between postsynaptically located AT1 receptors and alpha-adrenoceptors. The order of potency of the agents tested for sympathoinhibition clearly differed from that for inhibition of the direct pressor effects of Ang II. These findings suggest considerable differences in affinity of the various AT1 blockers for pre- and postsynaptic AT1 receptors.