A Review of the New Angiotensin II‐Receptor Antagonist Irbesartan

Powell, J.R.; Reeves, Richard; Marino, Maria; Cazaubon, Catherine; Nisato, Dino

doi:10.1111/j.1527-3466.1998.tb00354.x

Cited by 20 publications

(13 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5,10,11 It is possible in these latter studies that sufficient amounts of the blockers reached the brain, causing blockade of the brain RAS and thereby blunting/prevention of the hypertension. To test this concept, we used chronic treatment with the lipophilic AT 1 receptor blocker irbesartan, 12 by either ICV infusion, once-daily gavage, or once-daily subcutaneous (SC) injection, and related the degree of central versus peripheral blockade (with ICV versus IV Ang II) to the antihypertensive effect in Dahl S rats on high-salt intake.…”

mentioning

confidence: 99%

Prevention of Hypertension by Irbesartan in Dahl S Rats Relates to Central Angiotensin II Type 1 Receptor Blockade

Leenen

Yuan

2001

Hypertension

View full text Add to dashboard Cite

Abstract-Hypertension in Dahl S rats on high-salt intake is in general considered a model of "low-renin hypertension," unresponsive to treatment with blockers of the renin-angiotensin system. However, direct central administration of an angiotensin II type 1 (AT 1 ) receptor blocker prevents both the sympathoexcitation and hypertension caused by high-salt intake in Dahl S rats. In the present study, we tested the hypothesis that chronic peripheral administration of an AT 1 receptor blocker inhibits the salt-induced hypertension relative to the extent of central AT 1 receptor blockade that is induced. Dahl S rats received a high-salt (1370 mol Na ϩ /g) or regular (101 mol Na ϩ /g) diet from 4 to 8 weeks of age. In 3 different sets of experiments, Dahl S on high salt were randomized to intracerebroventricular (ICV) treatment with control infusion versus irbesartan at 50 or 250 g ⅐ kg Ϫ1 ⅐ d Ϫ1 , oral treatment with control versus irbesartan at 125 or 500 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 once daily by gavage, or subcutaneous treatment with control versus irbesartan at 50 or 150 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 by once daily injection. At 8 weeks of age, MAP was measured in conscious rats at rest and in response to angiotensin II ICV or IV. On high-salt intake, Dahl S developed the anticipated marked increase in MAP to Ϸ160 mm Hg. Irbesartan ICV did not affect pressor responses to angiotensin II IV, but irbesartan administered subcutaneously or by gavage markedly inhibited these responses. Irbesartan ICV or by gavage partially inhibited pressor responses to angiotensin II ICV and the development of hypertension. Irbesartan subcutaneously at the higher dose more completely inhibited pressor responses to angiotensin II ICV and fully prevented the salt-induced hypertension. The degree of central but not peripheral AT 1 receptor blockade parallels the antihypertensive effect of irbesartan, indicating that inhibition of the brain renin-angiotensin system can contribute to a significant extent to the therapeutic effectiveness of AT 1 receptor blockers such as irbesartan when administered in sufficiently high doses to cause central AT 1 receptor blockade. Key Words: Rats, Dahl Ⅲ hypertension, sodium-dependent Ⅲ brain Ⅲ renin-angiotensin system Ⅲ receptors, angiotensin II Ⅲ irbesartan R ecent studies have demonstrated that the brain renin-angiotensin system (RAS) plays a pivotal role in the sympathoexcitation and hypertension caused by high-salt intake in animal models of salt-sensitive hypertension. Although it is not yet known whether (and where) angiotensin (Ang) II or III increases, Ang II type 1 (AT 1 ) receptor stimulation appears to be essential, because chronic intracerebroventricular (ICV) infusion of AT 1 receptor blockers prevents the sympathoexcitation and hypertension by highsalt intake in both spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (Dahl S) rats. [1][2][3] In contrast, the circulatory RAS is suppressed during the development of hypertension in Dahl S on high-salt intake, 4 -6 and this model of "low-renin hypertension...

show abstract

mentioning

confidence: 99%

Prevention of Hypertension by Irbesartan in Dahl S Rats Relates to Central Angiotensin II Type 1 Receptor Blockade

Leenen

Yuan

2001

Hypertension

View full text Add to dashboard Cite

show abstract

“…Irbesartan is approximately 1.5 times more lipophilic than losartan, and 100 times more so than EXP3174 [46]. The slower onset of action of irbesartan would not appear to be due to lower rate of absorption from the gut or first-pass metabolism, but may reflect more specifically the rate of tissue accessibility.…”

Section: Plasma Drug Concentrations Following Oral Administration Of mentioning

confidence: 92%

Comparative in vivo effects of irbesartan and losartan on angiotensin II receptor binding in the rat kidney following oral administration

et al. 2000

View full text Add to dashboard Cite

We examined the ability of the new non-peptide angiotensin II receptor antagonist irbesartan to inhibit AT(1) receptors in vivo in the rat kidney following oral administration, compared with the prototype drug losartan. Male Sprague-Dawley rats (250-300 g) were gavaged with either irbesartan or losartan at doses of 1, 3, 10, 30 or 100 mg/kg, or with corresponding vehicle. Rats were killed at 0, 1, 2, 8, or 24 h after drug administration, trunk blood was collected and the kidneys were removed. The effects of irbesartan and losartan on angiotensin II receptor binding were determined by quantitative in vitro autoradiography using the specific radioligand (125)I-[Sar(1),Ile(8)]angiotensin II. High levels of angiotensin II receptor binding in the rat kidney were demonstrated in the glomeruli and inner stripe of the outer medulla, which was attributed to AT(1) receptors. At 1 h after dosing, irbesartan (1-100 mg/kg) and losartan (1-30 mg/kg) significantly inhibited AT(1) receptor binding in all anatomical areas of the kidney, in a dose-dependent manner, with a maximal effect at 100 mg/kg and 30 mg/kg respectively. For a 10 mg/kg dose, inhibition of AT(1) receptor binding was maximal around 1-2 h after oral administration of losartan, whereas maximal binding occurred between 2 and 8 h for irbesartan; both drugs produced persistent tissue blockade at 24h. In radioligand binding studies, irbesartan, losartan and EXP3174 (1x10(-10) to 1x10(-5) M) displaced (125)I-[Sar(1),Ile(8)]angiotensin II binding from renal AT(1) receptors in a concentration-dependent manner, with a rank order of potency of irbesartan>EXP3174>losartan. The concentration required to displace 50% of radioligand binding (IC(50)) by irbesartan, EXP3174 and losartan was 1.00+/-0.2 nM, 3.5+/-0.4 nM and 8.9+/-1.1 nM respectively. In conclusion, the findings of the present study suggest that irbesartan and losartan produce effective and sustained inhibition of AT(1) receptors in vivo in the kidney following oral administration. However, irbesartan appears less potent, with respect to dosage, than losartan in vivo, despite having a higher affinity for AT(1) receptors in vitro. The reason for this apparent discrepancy is unclear, but it may reflect the slower onset of action of irbesartan and its rate of tissue accessibility. Inhibition of angiotensin II receptors in target tissues such as the kidney may represent an important action of AT(1) receptor antagonists, which may contribute to the beneficial effects of these agents in the clinical setting.

show abstract

“…It is effective in the elderly and nonelderly, men and women, and has attractive pharmacokinetic and clinical features [119][120][121][122][123][124][125][126][127][128][129][130][131][132].…”

Section: Scheme 2210 Synthesis Of Irbesartanmentioning

confidence: 99%