Prevention of hypertension by irbesartan in Dahl S rats relates to central angiotensin II type 1 receptor blockade.
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 micromol Na(+)/g) or regular (101 micromol Na(+)/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 microg. kg(-1). d(-1), oral treatment with control versus irbesartan at 125 or 500 mg. kg(-1). d(-1) once daily by gavage, or subcutaneous treatment with control versus irbesartan at 50 or 150 mg. kg(-1). d(-1) 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 approximately 160 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.
Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. fleenen@ottawaheart.ca
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Leenen
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Yuan
D000284:Administration, Oral; D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000517:prevention & control*; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D000077405:Irbesartan; D008297:Male; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012084:Renin-Angiotensin System / Q000187:drug effects; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; D000804:Angiotensin II; D000077405:Irbesartan