Dissociation of blood pressure reduction from end-organ damage in TGR(mREN2)27 transgenic hypertensive rats.
OBJECTIVE
Since the biochemical disturbance underlying hypertension may be an important determinant of patient outcome, we compared the effects of early treatment with different antihypertensive drugs on end-organ damage in the TGR(mREN2)27 transgenic rat (REN-2). In these REN-2 rats, hypertension is primarily caused by increased activity of the tissue renin-angiotensin system.


METHODS
Seven-week-old REN-2 rats were either untreated or treated orally with an optimal daily dose of carvedilol (30 mg/kg), hydralazine (30 mg/kg), losartan (10 mg/kg) or quinapril (15 mg/kg). Nontransgenic littermates served as normotensive controls. After 11 weeks of treatment, we determined plasma norepinephrine concentrations, left ventricular atrial natriuretic factor messenger RNA and cardiac and vascular function and hypertrophy.


RESULTS
Chronic treatment with carvedilol and hydralazine significantly decreased blood pressure to a similar level but failed to normalize it, whereas both losartan and quinapril completely normalized blood pressure. Despite a blood pressure reduction in all treatment groups, only losartan, quinapril and hydralazine preserved endothelial function, while carvedilol did not. Furthermore, losartan and quinapril prevented cardiac and medial hypertrophy. The expression of atrial natriuretic factor messenger RNA paralleled the hemodynamic changes. Plasma norepinephrine levels were normalized by losartan or quinapril but remained increased after carvedilol and hydralazine treatment.


CONCLUSIONS
In REN-2 hypertensive rats, end-organ damage can be prevented by both inhibition of the angiotensin converting enzyme and blockade of the angiotensin II type 1 receptor, but not by merely lowering blood pressure. When blood pressure is not fully normalized, the effects on end-organs are clearly dissociated from the antihypertensive effects.
Teisman
A C
AC
Department of Clinical Pharmacology, University of Groningen, The Netherlands. cliphar@med.rug.nl
Pinto
Y M
YM
Buikema
H
H
Flesch
M
M
Böhm
M
M
Paul
M
M
van Gilst
W H
WH
D000804:Angiotensin II / Q000494:pharmacology / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use; D000077261:Carvedilol; D006334:Heart Function Tests / Q000187:drug effects; D006830:Hydralazine / Q000494:pharmacology / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use; D009638:Norepinephrine / Q000097:blood; D011412:Propanolamines / Q000494:pharmacology / Q000627:therapeutic use; D000077583:Quinapril; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000494:pharmacology / Q000627:therapeutic use; D044005:Tetrahydroisoquinolines
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002227:Carbazoles; D007546:Isoquinolines; D011412:Propanolamines; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; D000077261:Carvedilol; D000804:Angiotensin II; D006830:Hydralazine; D009320:Atrial Natriuretic Factor; D012083:Renin; D019808:Losartan; D000077583:Quinapril; D009638:Norepinephrine