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Hypertension. 2002;39:e27-e28
doi: 10.1161/01.HYP.0000017852.34860.8F
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(Hypertension. 2002;39:e27.)
© 2002 American Heart Association, Inc.

Letters to the Editor

No Net Effect of Angiotensin II on Blood Pressure?

Martin P. Schuijt; Pramod R. Saxena; A.H. Jan Danser

Department of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands

To the Editor:

With great interest we read the recent study by Carey et al1 on angiotensin (Ang) II type 2 receptor (AT2) receptor–mediated hypotension in anesthetized and conscious rats. These data oppose our findings on the lack of AT2 receptor–mediated systemic hemodynamic effects in anesthetized rats.2 To explain this discrepancy, Carey et al propose that the doses of the Ang II type 1 (AT1) and AT2 receptor antagonists used in our study (irbesartan and PD123319, respectively) were insufficient to unmask AT2 receptor–mediated vasodilation. However, the same doses were high enough to observe AT2 receptor–mediated vasodilation in the rat coronary vascular bed.3 Furthermore, the dose of irbesartan that we used was high enough to fully block the Ang II–induced vasoconstrictor effects in our study, as well as in studies by others.4 Moreover, the PD123319 dose that we used is known to result in micromolar concentrations in blood plasma,5 ie, concentrations that are high enough to selectively block AT2 receptors. Higher doses lead to concentrations that also interfere with AT1 receptors.5

Carey et al mention that AT2 receptors in the adult rat are present in low copy compared with AT1 receptors. In agreement with this concept, exogenous Ang II induces vasoconstriction in the absence of AT receptor blockers, and AT1 receptor blockade with either losartan or valsartan results in vasodilation. Unfortunately, the authors did not study the effect of PD123319 alone. If, indeed, Ang II normally has a net vasoconstrictor effect, based on the much larger density of AT1 receptors compared with AT2 receptors, full blockade of both AT1 and AT2 receptors should result in a net decrease in blood pressure. Remarkably, however, the authors observe a normal blood pressure during combined AT1 and AT2 receptor blockade, as if normally Ang II has no net effect on blood pressure.

In this regard, it is important to realize that combined infusions of AT receptor antagonists have been reported to interfere with the effective plasma and tissue levels of the drugs6 and that PD123319 is transformed to a metabolite with AT1 receptor antagonist properties in vivo.7 Thus, pharmacokinetic interactions should be considered when interpreting the data by Carey et al, particularly because these studies lasted several days (thus allowing significant generation of interfering metabolites), and the AT2 receptor–mediated effects in conscious animals became maximal after only 8 days.

Finally, the systemic vasodilation observed by Carey et al with the partial AT2 receptor agonist CGP-42112 is in full agreement with the CGP-42112–induced renal vasodilator responses that were described earlier by Macari et al.5 In the latter study, however, this effect was ascribed to the AT1 receptor–blocking capacity of CGP-42112. The nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methylester (L-NAME), reversed the CGP-42112–induced vasodilation, leading Carey et al to suggest that the AT2 receptor–mediated effects depend on NO. However, physiological receptor antagonism, ie, 2 independent opposite effects, cannot be excluded as an explanation for this finding. Furthermore, it is difficult to understand why the authors, in contrast to many previous studies, did not observe a hypertensive effect of L-NAME.

References

  1. Carey RM, Howell NL, Jin XH, Siragy HM. Angiotensin type 2 receptor-mediated hypotension in angiotensin type-1 receptor-blocked rats. Hypertension. 2001; 38: 1272–1277.[Abstract/Free Full Text]
  2. Schuijt MP, de Vries R, Saxena PR, Danser AHJ. No vasoactive role of the angiotensin II type 2 receptor in normotensive Wistar rats. J Hypertens. 1999; 17: 1879–1884.[CrossRef][Medline] [Order article via Infotrieve]
  3. Schuijt MP, Basdew M, van Veghel R, de Vries R, Saxena PR, Schoemaker RG, Danser AHJ. AT2 receptor–mediated vasodilation in the heart: effect of myocardial infarction. Am J Physiol. 2001; 281: H2590–H2596.
  4. Christophe B, Libon R, Cazaubon C, Nisato D, Manning A, Chatelain P. Effects of irbesartan (SR47436/BMS-186295) on angiotensin II–induced pressor responses in the pithed rat: potential mechanisms of action. Eur J Pharmacol. 1995; 281: 161–171.[CrossRef][Medline] [Order article via Infotrieve]
  5. Macari D, Bottari S, Whitebread S, de Gasparo M, Levens N. Renal actions of the selective angiotensin AT2 receptor ligands CGP 42112B and PD 123319 in the sodium-depleted rat. Eur J Pharmacol. 1993; 249: 85–93.[CrossRef][Medline] [Order article via Infotrieve]
  6. Widdop RE, Gardiner SM, Kemp PA, Bennett T. Inhibition of the haemodynamic effects of angiotensin II in conscious rats by AT2-receptor antagonists given after the AT1-receptor antagonist, EXP 3174. Br J Pharmacol. 1992; 107: 873–880.[Medline] [Order article via Infotrieve]
  7. Widdop RE, Gardiner SM, Kemp PA, Bennett T. Central administration of PD123319 or EXP-3174 inhibits effects of angiotensin II. Am J Physiol. 1993; 264: H117–H125.[Medline] [Order article via Infotrieve]

Response

Robert M. Carey; Nancy L. Howell; Xiao-Hong Jin; Helmy M. Siragy

University of Virginia School of Medicine, Charlottesville, Virginia

We appreciate the interest of Schuijt et al in our paper, "Angiotensin II type 2 receptor–mediated hypotension in angiotensin type-1 receptor–blocked rats."1 As we stated in our report, several studies have failed to demonstrate AT2 receptor–mediated reduction in blood pressure (BP) in the intact rat. Our explanation for this discrepancy was that these previous studies most likely used much smaller doses of the AT2 receptor blocker, PD 123319, than our study and never demonstrated that PD 123319 fully blocked the AT2 receptor. In our study we used PD 123319 at 50 µg/kg per minute, an infusion rate that blocked specifically the AT2 receptor as demonstrated by its ability to decrease renal production of nitric oxide and cGMP without influencing AT1 receptor activity.2,3 The affinity of PD 123319 for the AT2 receptor is about 17 nmol/L.4–7 Previously, we demonstrated that the AT1 receptor is responsible for prostaglandin E2 (PGE2) release in the kidney1 and that PD 123319 50 µg/kg per minute did not reduce renal PGE2.

Schuijt et al correctly observed that we did not study the effect of PD 123319 alone on BP. However, it had already been demonstrated that PD 123319 enhances the pressor effect of Ang II.8 Previous studies also demonstrated that animals lacking the AT2 receptor exhibit higher BP than their wild-type controls.9–12 Schuijt et al state that PD 123319 is transformed to a metabolite with AT1 receptor antagonist properties. This could happen only if PD 123319 were used in heroic doses that approach the Ki for the AT1 receptor at about 100 µmol.13 In our study, the PD 123319 infusion rate was <1 µmol/kg per minute, a concentration far below the Ki for the AT1 receptor.

The concept that full blockade of both AT1 and AT2 receptors should result in a net decrease in BP is flawed, because several other compensatory mechanisms would be expected to maintain normal BP.

Concerning the effects of the AT2 receptor agonist CGP-42112 (CGP), it is known that CGP at large doses (>1000 µg/kg per minute) can cross over to influence the AT1 receptor. Previous studies reported that both CGP and PD 123319 have a similar Ki for the AT2 receptor.14 Macari et al reported that large doses of CGP block14 and stimulate15 the AT1 receptor. Thus, it is very important to limit the CGP dose to less than 1 µmol/L. In our studies the CGP dose was confined within this limitation. Recent studies by Bautista et al16 confirm this conclusion and clearly show that CGP at 1 µmol/L has renal vasodilator effects through stimulation of the AT2 receptor.

The AT2 receptor has a very high affinity for CGP with IC50 of 4+2.2 nmol, whereas AT1 receptor has a low affinity for CGP with an IC50 of 11.4+1.9 µmol.17 An approximately 3000-fold difference in affinity exists between the AT2 and AT1 receptors for the AT2-selective agonist CGP. High micromolar concentrations of CGP that completely displace Ang II from AT1 receptor in response to CGP is not an AT1-receptor attribute, but rather should be considered an AT2-receptor –specific phenomenon.17 All these data confirm the specificity and effects of the AT2 receptor agonist CGP at the infusion rates employed in our study.

Schuijt et al question why NG-nitro-L-arginine methylester (L-NAME) did not produce a hypertensive effect. We did not administer L-NAME alone in our study. However, L-NAME did increase BP during CGP administration.

References

  1. Carey RM, Howell NL, Jin X-H, Siragy HM. Angiotensin type 2 receptor–mediated hypotension in angiotensin type-1 receptor–blocked rats. Hypertension. 2001; 38: 1272–1277.[Abstract/Free Full Text]
  2. Siragy HM, Carey RM. The subtype-2 (AT2) angiotensin receptor regulates renal cyclic guanosine 3',5'-monophosphate and AT1 receptor–mediated prostaglandin E2 production in conscious rats. J Clin Invest. 1996; 97: 1978–1982.[Medline] [Order article via Infotrieve]
  3. Siragy HM, Carey RM. The subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats. J Clin Invest. 1997; 100: 264–269.[Medline] [Order article via Infotrieve]
  4. Whitebread SE, Taylor V, Bottari SP, Kamber B, DeGasparo M. Radioiodinated CGP 42112A: a novel high affinity and highly selective ligand for the characterization of angiotensin AT2 receptors. Biochem Biophys Res Commun. 1991; 181: 1365–1371.[CrossRef][Medline] [Order article via Infotrieve]
  5. Chiu AT, Herblin WF, McCall De, Ardecky RJ, Carini DJ, Duncia JV, Pease LJ, Wong PC, Wexler RR, Johnson AT. Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun. 1989; 165: 196–203.[CrossRef][Medline] [Order article via Infotrieve]
  6. Dudley DT, Hubbell SE, Summerfelt RM. Characterization of angiotensin II (AT2) binding sites in R3T3 cells. Mol Pharmacol. 1991; 40: 360–367.[Abstract]
  7. Brechler V, Jones PW, Levens NR, DeGasparo M, Bottari SP. Agonistic and antagonistic properties of angiotensin analogs at the AT2 receptor in PC12W cells. Regul Pept. 1993; 44: 207–213.[CrossRef][Medline] [Order article via Infotrieve]
  8. Munzenmaier DH, Greene AS. Opposing actions of angiotensin II on microvascular growth and arterial blood pressure. Hypertension. 1996; 27: 760–765.[Abstract/Free Full Text]
  9. Gross V, Milia AF, Plehm R, Inagami T, Luft FC. Long-term blood pressure telemetry in AT2 receptor–disrupted mice. Hypertension. 2000; 18: 955–961.
  10. Akishita M. Yamada H, Dzau VJ, Horiuchi M. Increased vasoconstrictor response of the mouse lacking the angiotensin II type 2 receptor. Biochem Biophys Res Commun. 1999; 261: 345–349.[CrossRef][Medline] [Order article via Infotrieve]
  11. Tanaka M, Tsuchida S, Imai T, Fujii N, Miyazaki H, Ichiki T, Naruse M, Inagami T. Vascular response to angiotensin II is exaggerated through an upregulation of AT1 receptor in AT2 knockout mice. Biochem Biophys Res Commun. 1999; 258: 194–198.[CrossRef][Medline] [Order article via Infotrieve]
  12. Ichiki T, Labosky PA, Shiota C, Okuyama S, Imagawa Y, Fogo A, Niimura F, Ichikawa I, Hogan BL, Inagami T. Effects on blood pressure and exploratory behavior of mice lacking the angiotensin II type-2 receptors. Nature. 1995; 377: 748–750.[CrossRef][Medline] [Order article via Infotrieve]
  13. Bumpus FM, Catt KJ, Chiu AT, DeGasparo M, Goodfriend T, Husain A, Peach MJ, Taylor DG, Timmermans PB. Nomenclature for angiotensin receptors. A report of the nomenclature committee of the Council for High Blood Pressure Research. Hypertension. 1991; 17: 720–721.[Free Full Text]
  14. Macari D, Bottari S, Whitebread S, DeGasparo M, Levens N. Renal actions of the selective angiotensin AT2 receptor ligands CGP42112B and PD123319 in the sodium-depleted rat. Eur J Pharmacol. 1993; 249: 85–93.[CrossRef][Medline] [Order article via Infotrieve]
  15. Macari D, Whitebread S, Cumin F, DeGasparo M, Levens N. Renal actions of the angiotensin AT2 receptor ligands CGP42112 and PD123319 after blockade of the renin-angiotensin system. Eur J Pharmacol. 1994; 259: 27–36.[CrossRef][Medline] [Order article via Infotrieve]
  16. Bautista R, Sanchez A, Hernandez J, Oyekan A, Escalante B. Angiotensin II type AI (2) receptor mRNA expression and renal vasodilatation are increased in renal failure. Hypertension. 2001; 38: 669–673.[Abstract/Free Full Text]
  17. Hines J, Heerding JN, Fluharty SJ, Yee DK. Identification of angiotensin II type 2 (AT2) receptor domains mediating high-affinity CGP42112A binding and receptor activation. J Pharmacol Exp Ther. 2001; 298: 665–673.[Abstract/Free Full Text]




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