Persistent cardiovascular effects of chronic renin-angiotensin system inhibition following withdrawal in adult spontaneously hypertensive rats.
OBJECTIVE
It is generally accepted that short-term (4 weeks) inhibition of the renin-angiotensin system (RAS) of young spontaneously hypertensive rats (SHR) in their prehypertensive phase confers long-lasting protection from fully hypertensive levels in adulthood. However, there is very little data pertaining to the effects of such treatment in adult SHR with established hypertension. Therefore, we determined the relative effects of angiotensin converting enzyme (ACE) inhibition (perindopril), AT1 receptor blockade (candesartan cilexetil) and RAS-independent vasodilatation (hydralazine) and their withdrawal in adult SHR, on blood pressure measured by radiotelemetry, as well as on cardiac and vascular structure.


METHODS
Adult male SHR were instrumented with radiotelemetry probes to measure blood pressure and heart rate continuously. SHR were given either vehicle, perindopril (1 mg/kg per day), candesartan cilexetil (2 mg/ kg per day) or hydralazine (30 mg/kg per day) at equieffective depressor doses for 4 weeks (treatment study). Separate groups of animals were also given identical treatments but were then monitored for a further 8 weeks after drug withdrawal (withdrawal study). An indirect in-vivo assessment of whole body vascular hypertrophy (mean arterial pressure during maximum vasoconstriction) was made during and after drug withdrawal, as was the pressor activity evoked by angiotensin I and angiotensin II. The effect of antihypertensive treatment on microalbuminuria was also assessed during and after drug withdrawal. Finally, left ventricular: body weight (Iv: bw) and mesenteric media: lumen ratios were determined either immediately after 4-week treatment (treatment study) or 8 weeks later (withdrawal study).


RESULTS
Perindopril persistently lowered blood pressure in adult SHR whereas blood pressure returned to vehicle levels within approximately 4 and 15 days after withdrawal of hydralazine and candesartan cilexetil, respectively. Cardiac hypertrophy was reduced by all three treatments, but to a lesser extent by hydralazine (treatment study), and this regression of cardiac hypertrophy persisted only with both types of RAS inhibition (withdrawal study). Vascular hypertrophy, measured indirectly and directly, was also reduced by all three treatments, with perindopril and candesartan cilexetil causing hypotrophic and eutrophic remodelling, respectively (treatment study), although these changes were generally not maintained after drug withdrawal (withdrawal study). Angiotensin I-induced pressor responses were equally inhibited during treatment with either candesaran cilexetil or perindopril (and were unaffected by hydralazine) but normalized rapidly in both groups (within approximately 2-4 days) after withdrawal of RAS inhibition. In addition, there was a small age-related increase in microalbuminuria over the study period, which was not significantly affected by any treatment.


CONCLUSIONS
Following 4-week treatment, candesartan cilexetil, perindopril and hydralazine caused similar antihypertensive effects; however, only perindopril persistently reduced blood pressure following drug withdrawal. Both types of RAS inhibition and hydralazine caused marked cardiac and vascular remodelling during treatment, whereas only the RAS inhibitors persistently regressed cardiac hypertrophy 8 weeks later. Collectively, these results indicate the importance of the RAS for the maintenance of hypertension and cardiovascular hypertrophy in adult SHR, as well as identifying differential effects of ACE inhibition and AT1 receptor blockade on persistent blood pressure reduction.
Paull
J R
JR
Department of Pharmacology, Monash University, Melbourne, Victoria, Australia.
Widdop
R E
RE
D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D006332:Cardiomegaly / Q000473:pathology; D002319:Cardiovascular System / Q000187:drug effects*; D004334:Drug Administration Schedule; D006339:Heart Rate / Q000187:drug effects; D006830:Hydralazine / Q000008:administration & dosage / Q000494:pharmacology; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology*; D007668:Kidney / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D020913:Perindopril / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013777:Tetrazoles; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014665:Vasodilator Agents; D000804:Angiotensin II; D006830:Hydralazine; D000803:Angiotensin I; C077793:candesartan cilexetil; D020913:Perindopril