AT(1) receptor blockers prevent sympathetic hyperactivity and hypertension by chronic ouabain and hypertonic saline.
Sympathetic hyperactivity and hypertension caused by chronic treatment with ouabain or sodium-rich artificial cerebrospinal fluid (aCSF) can be prevented by central administration of an angiotensin type 1 (AT(1)) receptor blocker. In the present study, we assessed whether, in Wistar rats, chronic peripheral treatment with the AT(1) receptor blockers losartan and embusartan can exert sufficient central effects to prevent these central effects of ouabain and sodium. Losartan or embusartan (both at 100 mg x kg(-1) x day(-1)) were given subcutaneously once daily. Ouabain (50 microg/day) was infused subcutaneously, and sodium-rich aCSF (1.2 M Na(+), 5 microl/h) was infused intracerebroventricularly, both by osmotic minipump for 13-14 days. The mean arterial pressure (MAP) at rest and in response to air stress and intracerebroventricularly injection of guanabenz (75 microg/7.5 microl), ANG II (30 ng/3 microl), and ouabain (0.5 microg/2 microl) were then measured. In control rats, chronic treatment with ouabain subcutaneously and hypertonic saline intracerebroventricularly both increased baseline MAP by 20-25 mmHg and enhanced twofold the pressor responses to air stress and depressor responses to the alpha(2)-adrenoceptor agonist guanabenz. Simultaneous treatment with losartan or embusartan fully prevented hypertension, maintained normal responses to air stress and guanabenz, and attenuated pressor responses to acute intracerebroventricular injection of ANG II and ouabain. We concluded that peripheral administration of losartan as well as embusartan can cause sufficient central effects to prevent the sympathetic hyperactivity and hypertension induced by chronic peripheral ouabain and central sodium.
Zhang
J
J
Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7 Canada.
Leenen
F H
FH
D000392:Air Movements; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002908:Chronic Disease; D006143:Guanabenz / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D007276:Injections, Intraventricular; D019808:Losartan / Q000494:pharmacology; D008297:Male; D010042:Ouabain / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012462:Saline Solution, Hypertonic / Q000494:pharmacology; D013312:Stress, Physiological / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D002316:Cardiotonic Agents; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012462:Saline Solution, Hypertonic; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010042:Ouabain; D006143:Guanabenz; D019808:Losartan