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Oral Presentations

Aliskiren increases tissue kallikrein expression andbradykinin levels in the heart

Duncan Campbell a,b,∗, Yuan Zhang b, Darren Kelly b,Richard Gilbert c

a St. Vincent’s Institute of Medical Research, Fitzroy, Victoria,Australiab Department of Medicine, University of Melbourne,St. Vincent’s Hospital, Fitzroy, Victoria, Australiac University of Toronto, St. Michael’s Hospital. Ontario, Canada

Aliskiren is an orally active highly specific renininhibitor with IC50 of 0.6 nmol/L for human reninand 4.5 nmol/L for mouse renin. To explore the poten-tial mechanisms of aliskiren’s actions, we comparedthe effects of aliskiren (10 mg/kg per day by sub-ceiafigatrsAinrnrerooband

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Urocortin 2 induces potent long-lasting inhibition ofcardiac sympathetic drive despite baroreflex activation inconscious sheep

Chris Charles ∗, David Jardine, Gary Nicholls,Miriam Rademaker, Mark Richards

Christchurch Cardioendocrine Research Group, University ofOtago, Christchurch, New Zealand

Emerging evidence suggests that the urocortin (Ucn)peptides are involved in pressure and volume regulationwith possible involvement in the pathophysiology of car-diovascular disease. We have recently reported that Ucn1exhibits potent inhibition of cardiac sympathetic nerveactivity (CSNA) in normal sheep. However, little is knownabout possible interactions between Ucn2 and the sym-

utaneous osmotic minipump), angiotensin convertingnzyme inhibitor perindopril (0.2 mg/kg per day in drink-ng water), and their combination, on angiotensin (Ang)nd bradykinin peptides in non-diabetic and diabeticemale heterozygous (mRen-2)27 rats. The (mRen-2)27 rats a Sprague-Dawley rat transgenic for the mouse Ren-2ene, and is a high Ang II model of hypertension. Plasmaliskiren levels (∼500 nmol/L) were at the upper part ofhe therapeutic range in humans. The three treatment

pathetic nervous system. Accordingly, we have examinedthe effects of Ucn2 on CSNA, hemodynamics and plasmacatecholamines in normal conscious sheep. Bolus intra-venous administration (25 and 100fYg) of Ucn2 resultedin the expected hemodynamic actions of transient fallsin arterial pressure (p = 0.016) with more sustained risesin heart rate (p < 0.001) and cardiac output (p < 0.001) andfalls in peripheral resistance (p < 0.001). CSNA burst fre-quency showed a biphasic response (p < 0.001) with an

egimens produced equivalent reductions in blood pres-ure, cardiac hypertrophy, and plasma aldosterone levels.liskiren reduced Ang I levels in blood and Ang II levels

acute rise followed by a more prolonged fall. All otherindices of CSNA showed prolonged, dose-dependent fallsin response to Ucn2 administration (all p < 0.001). Ucn2iltieaitm

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n lung, but did not affect Ang II levels in blood, kid-ey, or heart. Contrary to what might be expected of aenin inhibitor, aliskiren increased Ang I levels in kid-ey and Ang II levels in brain, reduced Ang II/Ang Iatio in kidney and lung, and increased bradykinin lev-ls and tissue kallikrein expression in heart. Aliskiren alsoeduced cardiac fibrosis. We conclude that whereas somef aliskiren’s actions were consistent with renin inhibition,thers suggested mechanisms additional to renin inhi-ition. By increasing cardiac tissue kallikrein expressionnd bradykinin levels, aliskiren offers the potential for aew strategy for prevention and treatment of myocardialysfunction and heart failure.

oi:10.1016/j.hlc.2007.11.002

nduced a short-lived activation of plasma norepinephrineevels (p = 0.006). In conclusion, this is the first studyo report actions of Ucn2 on SNA and indicates potentnhibition of sympathetic traffic to the heart despite a gen-ralised baroreceptor-induced activation of sympatheticctivity. These findings suggest an important role for Ucn2n cardiovascular homeostasis and warrant further inves-igation for potential therapeutic applications in acute

yocardial injury and heart disease.

oi:10.1016/j.hlc.2007.11.003

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