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EXPERIMENTAL STUDY

Angiotensin-converting enzymeinhibitors and angiotensin iireceptor blockers synergistically increasecoronary blood flow in canine ischemic myocardium

Role of bradykinin

Masafumi Kitakaze, MD, FACC^*,*, Hiroshi Asanuma, MD, Hiroharu Funaya, MD, Koichi Node, MD, Seiji Takashima, MD, Shoji Sanada, MD, Masanori Asakura, MD, Hisakazu Ogita, MD, Jiyoong Kim, MD^* and Masatsugu Hori, MD, FACC

^* Cardiovascular Division of Internal Medicine, National Cardiovascular Center, Osaka University Graduate School of Medicine, Suita, Japan
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan

Manuscript received November 26, 2001; revised manuscript received April 5, 2002, accepted April 8, 2002.

^* Reprint requests and correspondence: Dr. Masafumi Kitakaze, Cardiovascular Division of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita 565-8565, Japan.
kitakaze{at}zf6.so-net.ne.jp

OBJECTIVES: We examined whether the combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) synergistically mediates coronary vasodilation and improves myocardial metabolic and contractile dysfunction in ischemic hearts.

BACKGROUND: Either an ACE inhibitor or ARB mediates coronary vasodilation in ischemic hearts.

METHODS: In dogs with myocardial ischemia, we infused an ACE inhibitor (temocaprilat, 10 µg/kg/min) or ARB (RNH-6270, 10 µg/kg/min) into the coronary artery.

RESULTS: Perfusion pressure of the left anterior descending coronary artery was reduced from 104 ± 8 to 42 ± 2 mm Hg, so that coronary blood flow (CBF) decreased to one-third of the baseline value. Ten minutes after starting the infusion of temocaprilat, the cardiac bradykinin level increased (from 32 ± 6 to 98 ± 5 pg/ml). Coronary blood flow (29 ± 2 to 44 ± 3 ml/100 g/min) and the cardiac level of nitric oxide (NO) (7.8 ± 1.9 to 17.5 ± 3.2 µm) also increased, with these changes being attenuated by either N-nitro-L-arginine methyl ester or HOE140. RNH-6270 alone caused a modest increase in CBF (34 ± 3 ml/100 g/min), with no increase in the cardiac NO or bradykinin levels. Both temocaprilat and RNH-6270 caused a further increase in both CBF (51 ± 4 ml/100 g/min) and cardiac NO levels, without increasing the bradykinin level, and these changes were inhibited by HOE140. In the nonischemic heart, RNH-6270 augmented bradykinin-induced increases in CBF.

CONCLUSIONS: The combination of an ACE inhibitor and ARB mediates greater increases in CBF and more potent cardioprotective effects through bradykinin-dependent mechanisms than either drug alone.

Abbreviations and Acronyms   ACE   angiotensin-converting enzyme   ARB   angiotension II receptor blocker   CBF   coronary blood flow   CPP   coronary perfusion pressure   L-NAME   N-nitro-L-arginine methyl ester   LAD   left anterior descending coronary artery   LER   lactate extraction ratio   NO   nitric oxide

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