Comparative analysis of telmisartan and olmesartan on cardiac function in the transgenic (mRen2)27 rat.
Telmisartan, an angiotensin receptor blocker, may have unique benefits as it possesses partial peroxisome proliferator-activated receptor (PPAR)-γ agonist activity in addition to antihypertensive effects. In this study, we test whether treatment with telmisartan ameliorates cardiovascular abnormalities to a greater extent than olmesartan, which has little PPAR-γ activity. The hypertensive rodent model of tissue renin-angiotensin system activation, transgenic (mRen2)27 (Ren2) rats and their littermate Sprague-Dawley controls were used. Rats were treated with telmisartan (2 mg · kg(-1) · day(-1)), olmesartan (2.5 mg · kg(-1) · day(-1)), or vehicle via drinking water for 3 wk; these doses achieved similar blood pressure control, as measured by telemetry. Ren2 rats displayed impaired diastolic and systolic function using left ventricular (LV) pressure-volume (P-V) analysis. Load-independent diastolic indexes, including the time constant of isovolumic relaxation and the slope of the end-diastolic P-V relationship, as well as systolic indexes, including preload recruitable stroke work, the dP/dt(max)-end-diastolic volume (EDV) relationship, and the P-V area-EDV relationship, were elevated in Ren2 rats compared with Sprague-Dawley controls (P < 0.05). The Ren2 myocardium exhibited parallel increases in the oxidant markers NADPH oxidase and 3-nitrotyrosine. The increase in the prohypertrophic protein Jak2 in Ren2 rats was associated with cardiac structural abnormalities using light microscopic and ultrastructural analysis, which included interstitial fibrosis, cardiomyocyte and LV hypertrophy, and mitochondrial derangements. Both angiotensin receptor blockers attenuate these abnormalities to a similar extent. Our data suggest that the beneficial effect of telmisartan and olmesartan on cardiac structure and function may be predominantly pressor-related or angiotensin type 1 receptor dependent in this model of renin-angiotensin system activation.
Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA.
Vincent G
VG
DeMarco
Megan S
MS
Johnson
Javad
J
Habibi
Lakshmi
L
Pulakat
Rukhsana
R
Gul
Melvin R
MR
Hayden
Roger D
RD
Tilmon
Kevin C
KC
Dellsperger
Nathaniel
N
Winer
Adam T
AT
Whaley-Connell
James R
JR
Sowers
D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006334:Heart Function Tests; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013686:Telemetry; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan; D053614:Janus Kinase 2; D000077333:Telmisartan