Restoration of the blood pressure circadian rhythm by direct renin inhibition and blockade of angiotensin II receptors in mRen2.Lewis hypertensive rats.
BACKGROUND
Alterations in the circadian arterial pressure rhythm predict cardiovascular mortality. We examined the circadian arterial pressure rhythm and the effect of renin-angiotensin system blockade in congenic mRen2.Lewis hypertensive rats, a renin-dependent model of hypertension derived from the backcross of transgenic hypertensive [mRen-2]27 rats with Lewis normotensive ones.


METHODS
Twenty-nine mRen2.Lewis hypertensive rats were randomly assigned to drink tap water (vehicle; n = 9), valsartan (30 mg/kg/day; n = 10), or valsartan (30 mg/kg/day) combined with aliskiren given subcutaneously (50 mg/kg/day; n = 10) for 2 weeks. Arterial pressure, heart rate, and locomotive activity were recorded with chronically implanted radiotelemetry probes. The awake/asleep ratio was calculated as [awake mean arterial pressure (MAP) mean - asleep MAP mean)] / (awake MAP mean) x 100. Plasma renin activity (PRA) and concentration (PRC), and plasma and kidney angiotensin II (Ang II) were measured by radioimmunoassay (RIAs).


RESULTS
Untreated hypertensive rats showed an inverse arterial pressure rhythm, higher at day and lower at night, accompanied by normal rhythms of heart rate and locomotive activity. Treatment with valsartan or aliskiren and valsartan normalized the elevated arterial pressure and the arterial pressure rhythm, with the combination therapy being more effective in reducing MAP and in restoring the awake/asleep ratio. While PRA and PRC increased with the treatments, the addition of aliskiren to valsartan partially reversed the increases in plasma Ang II levels. Valsartan and the aliskiren and valsartan combination markedly reduced the renal cortical content of Ang II.


CONCLUSIONS
The altered circadian arterial pressure rhythm in this renin-dependent hypertension model uncovers a significant role of Ang II in the desynchronization of the circadian rhythm of arterial pressure, heart rate, and locomotive activity.
Division of Surgical Sciences, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA. nmoniwa@wakehealth.edu
Norihito
N
Moniwa
Jasmina
J
Varagic
Sarfaraz
S
Ahmad
Jessica L
JL
VonCannon
Carlos M
CM
Ferrario
D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005650:Fumarates / Q000008:administration & dosage / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D055647:Rats, Transgenic; D011945:Receptors, Angiotensin / Q000187:drug effects* / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D000092502:Renin Inhibitors
D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D005650:Fumarates; D011945:Receptors, Angiotensin; D012083:Renin; D013777:Tetrazoles; D014633:Valine; D000068756:Valsartan; D000092502:Renin Inhibitors; C446481:aliskiren