Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers synergistically increase coronary blood flow in canine ischemic myocardium: role of bradykinin.

Abstract

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 microg/kg/min) or ARB (RNH-6270, 10 microg/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 microm) also increased, with these changes being attenuated by either N(omega)-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.

• Authors: Masafumi Kitakaze, Hiroshi Asanuma, Hiroharu Funaya, Koichi Node, Seiji Takashima, Shoji Sanada, Masanori Asakura, Hisakazu Ogita, Jiyoong Kim, Masatsugu Hori
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 40 Issue 1 Pg. 162-6 (Jul 03 2002) ISSN: 0735-1097 [Print] United States
• PMID: 12103271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin Receptor Antagonists
• Angiotensin-Converting Enzyme Inhibitors
• Bradykinin Receptor Antagonists
• Imidazoles
• Receptors, Angiotensin
• Tetrazoles
• Thiazepines
• Angiotensin II
• temocaprilat
• Nitric Oxide
• icatibant
• olmesartan
• Bradykinin
• NG-Nitroarginine Methyl Ester

Topics

• Angiotensin II (metabolism)
• Angiotensin Receptor Antagonists
• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Bradykinin (analogs & derivatives, pharmacology, physiology)
• Bradykinin Receptor Antagonists
• Coronary Circulation (drug effects)
• Coronary Vessels (drug effects)
• Dogs
• Drug Synergism
• Imidazoles (pharmacology)
• Myocardial Ischemia (physiopathology)
• NG-Nitroarginine Methyl Ester (pharmacology)
• Nitric Oxide (metabolism)
• Receptors, Angiotensin (drug effects)
• Tetrazoles (pharmacology)
• Thiazepines (pharmacology)
• Vasodilation (drug effects)