Effects of an HMG-CoA Reductase Inhibitor in Combination with an ACE Inhibitor or Angiotensin II Type 1 Receptor Antagonist on Myocardial Metabolism in Ischemic Rabbit Hearts

Abstract

We investigated the effects of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, pravastatin, an angiotensin converting enzyme (ACE) inhibitor, temocaprilat, and an angiotensin II type 1 (AT1) receptor antagonist, CV-11974, on myocardial metabolism during ischemia in isolated rabbit hearts using phosphorus 31-nuclear magnetic resonance ( 31 P-NMR) imaging. Forty-five minutes of continuous normothermic global ischemia was carried out. Pravastatin, temocaprilat, CV-11974 or a nitric oxide synthase inhibitor, L-NAME was administered from 60 min prior to the global ischemia. Japanese white rabbits were divided into the following experimental groups, a control group (n 7), a group treated with pravastatin (P group; n 7), a group treated with pravastatin and temocaprilat (P T group; n 7), a group treated with pravastatin and CV-11974 (P CV group; n 7), and a group treated with pravastatin and L-NAME (P L-NAME group; n 7). During ischemia, P group, as well as either P T group or P CV group, showed a significant inhibition of the decreases in adenosine triphosphate (ATP) and intracellular pH (pHi) (p 0.01, respectively, at the end of ischemia compared to the control group as well as P L-NAME group), and a significant inhibition of the increase in inorganic phosphate (Pi) (p 0.01, respectively, compared with the control group as well as P L-NAME group). These results suggest that pravastatin significantly improved myocardial energy metabolism during myocardial ischemia. This beneficial effect was dependent on NO synthase.However, this beneficial effect was not enhanced by either temocaprilat or CV-11974.

Cardioprotection by Metformin Is Abolished by a Nitric Oxide Synthase Inhibitor in Ischemic Rabbit Hearts.

“…The action of the KATP channels has been shown to reduce the infarct size in several animal models (21,22). Furthermore, we have found that NO synthase has a cardioprotective effect on myocardial metabolism against ischemic injury due to the opening of KATP channels (10,11).…”

“…Other studies have suggested that metformin increases nitric oxide (NO) production (7)(8)(9). Furthermore, we have reported that NO directly protected the myocardium from ischemic injury (10,11). Therefore, both metformin and the activation of NO may play roles in the reduction of myocardial ischemic damage.…”

Cardioprotection with pioglitazone is abolished by nitric oxide synthase inhibitor in ischemic rabbit hearts–comparison of the effects of pioglitazone and metformin

“…The action of the K ATP channels has been shown to reduce the infarct size in several animal models [39,40]. Furthermore, we have found that NO synthase has a cardioprotective effect on myocardial metabolism against ischemic injury due to the opening of the K ATP channel [41,42]. In regard to the relationship between the opening of mitoK ATP channels and cardioprotection against ischemic damage, it is reasonable to suggest that mitoK ATP channel openers release Ca 2+ from Ca 2+ -loaded mitochondria [43].…”