AT2 Receptor-Mediated Relaxation Is Preserved After Long-Term AT1 Receptor Blockade (original) (raw)
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Journal of the renin-angiotensin-aldosterone system : JRAAS, 2002
Angiotensin II (Ang II) causes facilitation of sympathetic neurotransmission via prejunctionallylocated AT 1 -receptors. The pithed rat is a suitable model to study the interactions between endogenously produced Ang II and the sympathetic nervous system at the peripheral level. Previously, we demonstrated that inhibition of the facilitatory actions of Ang II is a class effect of all AT 1 -receptor blockers (ARB). However, all ARBs caused less than maximal inhibition after the highest dose, thus causing a U-shaped dose-response curve with respect to sympatho-inhibition. In the present study, we investigated whether the AT 2 -receptor is involved in this 'upturn' of the dose-response relationship. Accordingly, we studied the effect of the ARB, irbesartan (1-60 mg/kg), on the sequelae of electric stimulation of the thoraco-lumbar sympathetic outflow in the presence and absence of the AT 2blocker, PD 123319 (0.5 mg/kg +50 µg/kg/min). Additionally, the effect of the combined (nonselective) AT 1 /AT 2 -receptor antagonist saralasin (0.001, 0.003, 0.01 or 0.03 mg/kg/min), on stimulation-induced responses was studied. In addition, we measured PRA-levels after administration of irbesartan, in this model.
British Journal of Pharmacology, 2010
Background and purpose: Angiotensin type 2 receptor (AT2 receptor) stimulation evokes vasodilator effects in vitro and in vivo that oppose the vasoconstrictor effects of angiotensin type 1 receptors (AT1 receptors). Recently, a novel non-peptide AT2 receptor agonist, Compound 21, was described, which exhibited high AT2 receptor selectivity. Experimental approach: Functional cardiovascular effects of the drug candidate Compound 21 were assessed, using mouse isolated aorta and rat mesenteric arteries in vitro and in conscious spontaneously hypertensive rats (SHR). Key results: Compound 21 evoked dose-dependent vasorelaxations in aortic and mesenteric vessels, abolished by the AT2 receptor antagonist, PD123319. In vivo, Compound 21 administered alone, at doses ranging from 50 to 1000 ng•kg-1 •min-1 over 4 h did not decrease blood pressure in conscious normotensive Wistar-Kyoto rats or SHR. However, when given in combination with the AT1 receptor antagonist, candesartan, Compound 21 (300 ng•kg-1 •min-1) lowered blood pressure in SHR only. Further analysis in separate groups of conscious SHR revealed that, at a sixfold lower dose, Compound 21 (50 ng•kg-1 •min-1) still evoked a significant depressor response in adult SHR (~30 mmHg) when combined with different doses of candesartan (0.01 or 0.1 mg•kg-1). Moreover, the Compound 21-evoked depressor effect was abolished when co-infused (50 mg•kg-1 •min-1 for 2 h) with the AT2 receptor antagonist PD123319. Conclusion and implications: Collectively, our results indicate that acute administration of Compound 21 evoked blood pressure reductions via AT2 receptor stimulation. Thus Compound 21 can be considered an excellent drug candidate for further study of AT2 receptor function in cardiovascular disease.
Hypertension, 2001
Angiotensin II exerts a potent role in the control of hemodynamic and renal homeostasis. Angiotensin II is also a local and biologically active mediator involved in both endothelial and smooth muscle cell function acting on 2 receptor subtypes: type 1 (AT 1 R) and type 2 (AT 2 R). Whereas the key role of AT 2 R in the development of the embryo has been extensively studied, the role of AT 2 R in the adult remains more questionable, especially in humans. In vitro studies in cultured cells and in isolated segments of aorta have shown that AT 2 R stimulation could lead to the production of vasoactive substances, among which NO is certainly the most cited, suggesting that acute AT 2 R stimulation will produce vasodilation. However, in different organs or in small arteries isolated from different type of tissues, other vasoactive substances may also mediate AT 2 R-dependent dilation. Sometimes, such as in large renal arteries, AT 2 R stimulation may lead to vasoconstriction, although it is not always seen. In isolated arteries submitted to physiological conditions of pressure and flow, AT 2 R stimulation may also have a role in shear stress-induced dilation through a endothelial production of NO. Thus, when acutely stimulated, the most probable response expected from AT 2 R stimulation will be a vasodilation. Therefore, in the perspective of a chronic AT 1 R blockade in patients, overstimulation of AT 2 R might be beneficial, given their potential vasodilator effect.
The Angiotensin II AT2 Receptor Is an AT1Receptor Antagonist
Journal of Biological …
The vasopressor angiotensin II activates AT 1 and AT 2 receptors. Most of the knownin vivo effects of angiotensin II are mediated by AT 1 receptors while the biological functions of AT 2 receptors are less clear. We report here that the AT 2 receptor binds directly to the AT 1 receptor ...
Mechanistic Differences of Various AT1-Receptor Blockers in Isolated Vessels of Different Origin
Hypertension, 1999
The functional inhibitory characteristics of the angiotensin II type 1 receptor blockers (ARB) candesartan; irbesartan; and losartan and its active metabolite EXP 3174 (EXP) were studied in rabbit aortic strips and rat portal vein preparations in vitro. Moreover, plasma-protein binding was determined, and the binding was high (Ͼ98.5%) for all ARBs. These values were needed to relate the concentrations of the ARBs used in vitro to the nonprotein bound concentrations in clinical use. In both vascular preparations, candesartan caused a marked decrease in the maximal contractile response of the angiotensin II (Ang II) concentration-response curve. Losartan, EXP, and irbesartan caused a rightward parallel shift without any major effects on the maximal response to Ang II. The inhibitory effect of candesartan developed slowly (maximal effect after Ͼ30 minutes) and lasted Ͼ2 hours despite repeated washing of the vessels. The effect of losartan, irbesartan, and EXP had a faster onset, and most of the inhibitory effect disappeared after washing. The duration of the inhibitory effects of the ARBs were not related to lipophilicity of the compounds. Cooling of the rat portal vein preparations to 4°C before administration of candesartan prevented the persistent inhibition of Ang II response seen at 37°C. For the other ARBs studied, the magnitude of inhibition and the speed of recovery of the Ang II response were independent of the incubation temperature before washing. In addition, when candesartan was given to conscious rats, the inhibitory effect on Ang II-induced blood pressure responses persisted during the 24-hour period despite nondetectable plasma concentrations of candesartan at 24 hours. It is concluded that functional inhibitory characteristics of candesartan differ from those of the other ARBs tested. At clinically relevant concentrations, candesartan is an insurmountable and long-lasting antagonist of the vascular contractile responses to Ang II.
Pharmacological aspects of candesartan, an effective AT1-receptor blocker
European Heart Journal Supplements, 2004
Blockade of the angiotensin type-1 (AT 1) receptor represents a rational therapeutic strategy in cardiovascular disease since it inhibits AT 1-receptor-mediated vasoconstriction, cardiovascular remodelling, and vascular inflammation, while preserving AT 2-receptor-mediated vasodilatation and antiproliferative effects. The AT 1-receptor blockers currently available bind selectively to the AT 1 receptor, but there are marked differences in their affinity for the receptor and their duration of binding. Of the existing agents, candesartan has the highest affinity for the AT 1 receptor and has a long duration of binding. Furthermore, candesartan markedly decreases the maximal response to angiotensin II and thus acts as an insurmountable inhibitor; agents such as irbesartan and EXP-3174 (the active metabolite of losartan) can also reduce the maximal response to angiotensin II, although to a lesser extent. In contrast, agents such as losartan act as surmountable inhibitors. These pharmacological differences are reflected in clinically relevant differences regarding the duration of antihypertensive action between agents. In the decade since the introduction of the first AT 1-receptor blocker, the therapeutic role of these agents has expanded beyond hypertension to include conditions such as heart failure and diabetic nephropathy. This expanded role reflects the emerging evidence for additional benefits at target organ level that appear to be independent of blood pressure control.
Kidney International, 2005
AT-1 receptor antagonism modifies the mediation of endothelin-1, thromboxane A 2, and catecholamines in the renal constrictor response to angiotensin II. Objective. The present study investigated the consequences of partial AT 1 receptor blockade on the participation of catecholamines, thromboxane A 2 (TXA 2), and endothelin-1 (ET-1) in the renal vasoconstriction induced by angiotensin II (Ang II). Methods. For this purpose, the increase in renal perfusion pressure (RPP) produced by Ang II was studied in isolated kidneys from untreated or irbesartan-treated Wistar Kyoto and spontaneously hypertensive rats (SHR), in absence or presence of the alfa-1 receptor antagonist, prazosin, the TXA 2 receptor antagonist, ifetroban, or the ET A /ET B receptor antagonist, PD145065. Results. Systolic arterial pressure (SAP) was higher (P < 0.05) in SHR than in WKY. Increases in RPP produced by Ang II were comparable in kidneys from both untreated groups. Treatment with irbesartan reduced SAP and RPP in both strains in a comparable extent. Presence of prazosin, ifetroban, or PD145065 in perfusion media reduced (P < 0.05) Ang II maximal response in all groups. Maximal inhibition of Ang II-induced vasoconstriction produced by the 3 antagonists was comparable in untreated WKY, but that of ifetroban and PD145065 was lower (P < 0.05) than that of prazosin in untreated SHR. Maximal inhibition of Ang II-induced vasoconstriction produced by the 3 antagonists was comparable in WKY treated with irbesartan, and not different to that observed in untreated WKY. Maximal inhibitory effect of the 3 antagonists was higher (P < 0.05) in treated than in untreated SHR. Conclusion. The study further supports the importance of catecholamines, TXA 2 , and ET-1 as mediators of the renal vasoconstriction induced by Ang II in both normotensive and hypertensive rats. Hypertensive conditions appeared to reduce the participation of TXA 2 and ET-1 in Ang II-induced vasoconstriction when compared with normotensive conditions. Chronic partial blockade of AT 1 receptors did not affect the participation of catecholamines, TXA 2 , and ET-1 in normotensive rats, but increased the participation of the 3 mediators in SHR.
British Journal of Pharmacology, 1999
Human isolated subcutaneous arteries were studied under isometric conditions in a myograph. 2 Addition of angiotensin II (AII) induced a concentration-dependent increase in tone in isolated arteries. The active metabolite of candesartan (CV 11974), losartan and the active metabolite of losartan, E-3174 antagonized AII-induced tone in a non-competitive manner, but the AT 2 selective antagonist, PD123319, was without eect on responses to AII. The eects of candesartan, losartan and E-3174 were analysed using a classical model of non-competitive antagonism and a two-state receptor model. 3 Mechanical removal of the endothelium; pre-incubation with N o-nitro-L-arginine methyl ester hydrochloride (L-NAME); pre-incubation with indomethacin, a cyclo-oxygenase inhibitor; or preincubation with BQ 485, an endothelin antagonist; had no signi®cant eect on contractions induced by AII. 4 Our results suggest AII contracts human isolated resistance arteries by an action on AT 1 receptors and does not involve release of endothelial factors. Use of a two-state receptor model successfully described the action of the AT 1 antagonists without sacri®cing assumptions regarding the competitive nature of binding of these antagonists.
Hypertension, 2012
Angiotensin II type 2 (AT 2 ) receptor stimulation has been linked to vasodilation. Yet, AT 2 receptor-independent hypertension and hypotension (or no effect on blood pressure) have been observed in vivo after application of the AT 2 receptor agonist compound 21 (C21). We, therefore, studied its effects in vitro, using preparations known to display AT 2 receptor-mediated responses. Hearts of Wistar rats, spontaneously hypertensive rats (SHRs), C57Bl/6 mice, and AT 2 receptor knockout mice were perfused according to Langendorff. Mesenteric and iliac arteries of these animals, as well as coronary microarteries from human donor hearts, were mounted in Mulvany myographs. In the coronary vascular bed of Wistar rats, C57Bl/6 mice, and AT 2 receptor knockout mice, C21 induced constriction followed by dilation. SHR hearts displayed enhanced constriction and no dilation. Irbesartan (angiotensin II type 1 receptor blocker) abolished the constriction and enhanced or (in SHRs) reintroduced dilation, and PD123319 (AT 2 receptor blocker) did not block the latter. C21 relaxed preconstricted vessels of all species, and this did not depend on angiotensin II receptors, the endothelium, or the NO-guanylyl cyclase-cGMP pathway. C21 constricted SHR iliac arteries but none of the other vessels, and irbesartan prevented this. C21 shifted the concentration-response curves to U46619 (thromboxane A 2 analog) and phenylephrine (␣-adrenoceptor agonist) but not ionomycine (calcium ionophore) to the right. In conclusion, C21 did not cause AT 2 receptor-mediated vasodilation. Yet, it did induce vasodilation by blocking calcium transport into the cell and constriction via angiotensin II type 1 receptor stimulation. The latter effect is enhanced in SHRs. These data may explain the varying effects of C21 on blood pressure in vivo. (Hypertension. 2012;60:722-729.)