Yasushi Okazaki

Attenuation of increased regional myocardial oxygen consumption during exercise as a major cause of warm-up phenomenon

OBJECTIVESnThe aim of this study was to test the hypothesis that the warm-up phenomenon is attributable to a reduction of increased myocardial oxygen consumption rather than to increased coronary blood flow during exercise.nnnBACKGROUNDnThe underlying mechanism of the warm-up phenomenon is not elucidated.nnnMETHODSnThirteen patients with effort angina were subjected to two consecutive supine ergometer exercise tests performed 15 min apart. All patients had severe proximal stenosis (> 90%) in the left anterior descending coronary artery. Great cardiac vein flow was measured before and during exercise. Both regional myocardial oxygen consumption and adenosine release were determined.nnnRESULTSnExercise was continued for significantly longer before angina onset in the second than in the first exercise test (507 +/- 44 vs. 410 +/- 42 s, p < 0.01). The extent of ST segment depression in lead V5 of the electrocardiogram (ECG) was larger at the time of angina onset in the first (1.7 +/- 0.2 mm) than in the second (1.1 +/- 0.2 mm, p < 0.01) exercise test. Neither systemic hemodynamic variables nor great cardiac vein flow differed between the first and second exercise tests. In contrast, regional myocardial oxygen consumption assessed at 3 min of exercise was significantly (p < 0.01) less in the second than in the first test (8.0 +/- 0.8 vs. 8.7 +/- 0.9 ml/min). Adenosine release during the second test was higher (p < 0.05) than in the first test (2.5 +/- 0.5 vs. 3.9 +/- 0.5 nmol/min at 3 min of the first and second tests, p < 0.01).nnnCONCLUSIONSnThese results indicate that the warm-up phenomenon is not attributable to increased coronary flow but to attenuation of increased regional myocardial oxygen consumption, which may be mediated by adenosine A1 receptor activation.

α1-Adrenoceptor Activation Increases Ecto-5′-Nucleotidase Activity and Adenosine Release in Rat Cardiomyocytes by Activating Protein Kinase C

Background Adenosine is an important regulator of many cardiac functions and is synthesized primarily by ecto- and cytosolic 5′-nucleotidase. We have previously reported that α 1 -adrenoceptor blockade attenuates adenosine release from ischemic myocardium, raising the possibility that α 1 -adrenoceptor activation activates 5′-nucleotidase. This study tested whether activation of protein kinase C by α 1 -adrenoceptor activation increases 5′-nucleotidase activity and augments adenosine release. Methods and Results Cardiomyocytes were isolated from adult male Wistar rats and suspended in modified HEPES-Tyrode’s buffer solution. After stabilization, the cardiomyocytes were incubated with and without an exposure to norepinephrine (10 −9 to 10 −5 mol/L) while being treated with propranolol and yohimbine or with and without an exposure to methoxamine (10 −9 to 10 −5 mol/L). Ecto-5′-nucleotidase activity was increased by norepinephrine and methoxamine during 30 minutes in a dose-dependent manner, whereas cytosolic 5′-nucleotidase was not activated. These increases in ecto-5′-nucleotidase activity were inhibited by GF109203X, an inhibitor of protein kinase C, and mimicked by phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C. The increase in ecto-5′-nucleotidase was not prevented by cycloheximide. When ecto-5′-nucleotidase activity increased, adenosine release was augmented in methoxamine- and PMA-treated cardiomyocytes (1299±252% and 1372±149%, respectively) compared with the untreated group (578±26%). The increase in adenosine release was blunted by GF109203X and α,β-methyleneadenosine 5′-diphosphate, an inhibitor of ecto-5′-nucleotidase. Conclusions Thus, we conclude that α 1 -adrenoceptor–mediated increases in ecto-5′-nucleotidase activity are attributed to activation of protein kinase C in rat cardiomyocytes.

Possible Mechanisms of the Beneficial Effects of Nitroglycerin in Patients with Effort Angina: Potential Roles of Collateral Circulation

Although nitrates are very effective for the treatment of effort angina, the precise mechanisms of the beneficial effects are still unclear. In order to clarify what the mechanisms of the beneficial effects of one of these nitrates, nitroglycerin, we performed exercise stress tests on patients with effort angina and examined the effects of nitroglycerin on coronary and systemic hemodynamics using the following two exercise protocols. In the first, a noninvasive study, 105 patients with stable effort angina were evaluated, and in the second, an invasive study, 50 patients with stable effort angina were employed. In the noninvasive study, the rough correlation between the severity of coronary stenosis and the exercise tolerance time was shown, and those patients with collaterals showed a greater increase in exercise time after sublingual nitroglycerin administration compared to those without collaterals. In the invasive study, the reduction in pulmonary arterial end-diastolic pressure during 3 min of exercise correlated well with the increase in exercise time after pretreatment with sublingual nitroglycerin. Furthermore, the coronary angiogram during exercise-induced angina showed the more enhanced collateral opacification after pretreatment with nitroglycerin. Thus, the effects of nitroglycerin on the exercise tolerance time are considered to be due to: (1) relaxation of the stenotic coronary artery and the improvements of coronary circulation, (2) reduction of preload due to decreae in the systemic peripheral vascular resistance, (3) improvement of myocardial energy efficiency possibly due to reduction of ventricular volume, and (4) increase in coronary blood flow to the ischemic area through collaterals.