Yasuhiko Matsu-ura

Impact of Coronary Risk Factors on Contribution of Nitric Oxide and Adenosine to Metabolic Coronary Vasodilation in Humans

OBJECTIVES The contribution of nitric oxide (NO) and adenosine to the increase in coronary blood flow (CBF) induced by cardiac pacing was investigated in 28 subjects with angiographically normal coronary arteries with and without one or more risk factors for atherosclerosis. BACKGROUND NO and adenosine are important in the regulation of coronary circulation, and the inhibition of NO synthesis increases adenosine production during cardiac pacing in experimental models. METHODS Coronary artery diameters and CBF were assessed by quantitative coronary arteriography and Doppler flow velocity measurement. Plasma levels of nitrites and nitrates (NOx) (stable end products of NO), adenosine and lactate were measured, and blood gas analysis was performed. RESULTS The extent of CBF response to cardiac pacing did not differ between the 14 subjects with and the 8 subjects without risk factors for atherosclerosis. NOx (12.0+/-0.9 vs. 14.9+/-1.1 ,amol/liter [mean+/-SD], p < 0.05), but not adenosine (50.8+/-7.2 vs. 50.8+/-6.5 nmol/liter), levels in coronary sinus blood increased in the subjects without risk factors. In contrast, adenosine (58.9+/-7.5 vs. 77.4+/-9.8 nmol/liter, p < 0.05), but not NOx (11.1+/-1.1 vs. 12.2+/-1.1 micromol/liter), levels increased in subjects with risk factors. Aminophylline, an antagonist of adenosine receptors, blunted CBF response to cardiac pacing in six subjects with risk factors. The number of risk factors showed a negative correlation (p < 0.05) with NOx production and a positive correlation (p < 0.05) with adenosine production during cardiac pacing, respectively. CONCLUSIONS NO and adenosine are increased during metabolic coronary vasodilation induced by cardiac pacing. Adenosine production may be a compensatory mechanism when NO production is reduced.

Secretion of Lipocalin-Type Prostaglandin D Synthase (β-Trace) from Human Heart to Plasma During Coronary Circulation

Prostaglandin (PG) D2 is actively formed in a variety of tissues and cells,1 and is involved in many physiological events; e.g., it regulates sleep and ocular pressure, prevents platelet aggregation, and induces vasodilation and bronchoconstriction.2,3 Two distinct types of PGD synthase (PGDS), which catalyzes the isomerization of PGH2 to PGD2, have been isolated and characterized:4 one is glutathione-independent, the lipocalin-type PGDS (L-PGDS);5 and the other is glutathione-requiring, the hematopoietic PGDS.6 L-PGDS is responsible for biosynthesis of PGD2 in the central nervous system and male genital organs of various mammals, and is secreted into the cerebrospinal fluid and seminal plasma, respectively, as “β-trace”.7,8 In this study, we found that mRNA for human L-PGDS was most intensely expressed in the heart among various tissues examined and that the L-PGDS-like immunoreactivity is localized in myocardial cells, atrial endocardial cells, and the synthetic state of smooth muscle cells in the arteriosclerotic plaques. We also demonstrated that the enzyme, β-trace, is secreted into the plasma of the coronary circulation of angina patients.9

Effect of Theophylline on Adaptation of the Heart to Myocardial Ischemia During Percutaneous Transluminal Coronary Angioplasty in Patients With Stable Angina Pectoris

This study was designed to examine whether theophylline, an adenosine receptor antagonist, affects cardiac adaptation to ischemia during progression of repetitive balloon inflations of percutaneous transluminal coronary angioplasty (PTCA). Theophylline abolished this cardiac adaptation, suggesting that endogenous adenosine is a key mediator for cardiac adaptation during PTCA.

Roles of Systemic Nitric Oxide Metabolites for Human Coronary Circulation

Several previous studies have suggested decreased bioactivity of nitric oxide (NO) in coronary artery diseases using NO synthase inhibitors. Nitrite is delivered as bioactive NO in the forearm circulation. However, the role(s) of NO metabolites in the systemic and coronary circulation are still unknown. The aim of this study was to investigate the role(s) of systemic NO metabolites for human coronary circulation in patients with and without coronary spastic angina (CSA). Twenty-nine patients with chest symptoms were enrolled to perform the acetylcholine (Ach) provocative test. Blood was sampled from the aorta at baseline, and from the great cardiac vein at baseline and after Ach to measure plasma levels of nitrate and nitrite (NOx). The epicardial left anterior descending artery was examined by quantitative angiography. The patients were divided into the two groups according to the Ach provocative test. In the non-CSA group, the NOx uptake across the coronary circulation correlated with the endothelium-dependent vasoresponse to Ach (r = −0.61, p < 0.05) and NOx levels of the aorta also correlated (r = −0.72, p < 0.005), which suggested the compensatory increase of systemic NOx levels for impaired endothelial function. In the CSA group, the NOx uptake across the coronary circulation did not correlate with the vasoresponse to Ach (r = 0.29, p = 0.28). However, NOx levels of the aorta correlated with vasosensitivity to Ach (r = 0.61, p < 0.005). The higher systemic NOx levels correlated well with the vasodilator responsiveness to Ach. These results suggest that systemic NOx is delivered into the coronary circulation as bioactive NO to preserve endothelial function in the non-CSA patients, and to attenuate Ach-induced vasoconstriction in the CSA patients. There is a possibility that systemic NOx plays a complementary role on impaired coronary vasoregulation.

Pharmacological Modification of Ischemic Preconditioning During Percutaneous Transluminal Coronary Angioplasty

In the progression of repetitive balloon inflations during percutaneous transluminal coronary angioplasty (PTCA), the heart becomes more tolerant to ischemia. The study reported here analyzed the effects of theophylline and nicorandil on this intriguing phenomenon. Twenty-one patients with stable angina pectoris due to a significant stenosis at the left anterior descending; artery were subjected to PTCA. The balloon was inflated twice for two minutes each with a three-minute reperfusion period. Theophyylline, an adenosine receptor antagonist, was intravenously administered (0.6mg/kg/hr) to six patients during PTCA (theophylline group). Nicorandil, a hybrid between nitrate and an ATP-sensitive potassium channel opener, was intravenously administered (6 mg/hr) to nine patients during PTCA (nicorandil group). The rest of the patients served as controls (ischemic preconditioning group, n = 6). Cardiac adaptation to the second ischemia was observed in the ischemic preconditioning group, judging from lactate metabolism and electrocardiography. In both the theophylline and nicorandil groups, the difference between the two ischemic events was abolished. In the nicorandil group, the severity of the first ischemia was less than that of the ischemic preconditioning group. In conclusion, signal transduction through the adenosine receptor and opening of the ATP-sensitive potassium channels might play key roles, interactively or independently, in the cardioprotection observed in the process of PTCA.