Contribution of nitric oxide to exercise-induced changes in healthy volunteers: effects of acute exercise and long-term physical training.

Endothelium plays a central role in the regulation of regional blood flow through the release of certain vasoactive substances. We conducted this study to test whether an increase in the production of nitric oxide (NO) metabolites, atrial natriuretic peptide (ANP) and plasma and intraplatelet cyclic guanosine 3':5' monophosphate (cGMP) is involved in the adaptation to chronic exercise in physically trained people and in the vasodilatation induced by acute physical exercise. We studied one group of 10 trained athletes and another group of 10 untrained people. We measured plasma levels of nitrites, nitrates and cGMP and intraplatelet levels of cGMP, as an indicator of intracellular guanylate cyclase activity, and ANP before and after a maximal treadmill test. Resting cardiac rate (CR) and systolic blood pressure (SBP) were lower in the athlete group than in the control group (73.8 +/- 3.6 vs. 92 +/- 5.9; P < 0.02 and 110 +/- 2.58 vs. 118 +/- 3.27; P < 0.02 respectively). SBP did not show differences between groups after the exercise test. Diastolic blood pressure (DBP) at rest was lower in the athlete group (71 +/- 1.79 vs. 80.5 +/- 3.53; P < 0.03) and the decrease after maximal exercise was more pronounced in this group (64 +/- 2.67 vs. 74.5 +/- 3.2; P < 0.02). Basal plasma nitrites were 4.9 +/- 0.8 in the athlete group and 1.9 +/- 0.3 in the control group (P < 0.05). After exercise, test differences between groups remained (P < 0.05). Nitrates were significantly higher in the group of athletes and did not show exercise-related changes. Plasma levels of cGMP and ANP increased in both groups after the treadmill test, with no differences between groups. Among the athletes, cGMP increased from 1.11 +/- 0.1 to 2.6 +/- 0.4 (P < 0.001), whereas in the untrained group plasma cGMP rose from 1.14 +/- 0.09 to 1.86 +/- 0.2 (P < 0.01). There was a significant correlation between the increases in plasma cGMP and the atrial natriuretic peptide in both groups (r = 0.91, P < 0.0002, for athletes; and r= 0.68, P < 0.04, for control group). The intraplatelet concentration of cGMP did not show differences between groups and did not change after exercise. In conclusion, we have found increased basal levels of plasma nitrite and nitrate in trained subjects. Exercise does not produce differences in the increments of these metabolites. Therefore, we speculate the release of nitric oxide is not augmented by exercise in trained athletes.

[The acute and chronic effects of 10-mg nitroglycerin patches in stable angina of effort]. / Estudio del efecto agudo y crónico de los parches de 10 mg de nitroglicerina en la angina de esfuerzo estable.

INTRODUCTION AND OBJECTIVES: To assess the anti-ischemic efficacy of nitroglycerin patches (10 mg/day), we studied, by means of serial exercise testing (Bruce protocol), 10 patients with stable effort angina in a randomized, placebo-controlled, cross-over, double-blind essay. METHODS: Patients were exercised 1, 4, 12 and 24 hours after a single patch, and 4 and 12 hours after a 48 hours therapy course. Chronic therapy was assessed after both continuous and intermittent (intermission of 12 hours) patch application. RESULTS: After single patch, time to angina and time to 1 mm ST depression were significantly increased with respect to placebo at 1-hour test (83 +/- 27 s and 119 +/- 39 s, respectively), 4-hour test (100 +/- 34 s and 87 +/- 29 s, respectively) and 12-hour test (46 +/- 15 s and 64 +/- 20 s, respectively). No effect was demonstrated at 24-hour test. After continuous treatment no differences with respect to placebo were found at any test. After intermittent treatment time to angina was prolonged (75 +/- 23 s) only at 4-hour test, and time to 1 mm ST depression at 4-hour test (61 +/- 19 s) and 12-hour test (41 +/- 14 s). CONCLUSIONS: Nitroglycerin patches improve parameters of exercise ischemia for a 12 hours period. Tolerance is developed very early and provokes absolute lack of efficacy. Tolerance can be avoided with intermittent patch application. No treatment schedule shows 24 hours efficacy.

[The acute and chronic effects of 50 mg of isosorbide 5-mononitrate with delayed action in patients with stable angina of effort]. / Estudio del efecto agudo y crónico de 50 mg de 5-mononitrato de isosorbida de liberación retardada en pacientes con angina de esfuerzo estable.

In 10 patients with stable effort angina and angiographically demonstrated coronary artery disease, serial exercise test were performed in order to assess the efficacy and duration of the anti-ischemic effects of a single dose (50 mg) of a sustained-release preparation of 5-isosorbide mononitrate (5-IMN). The possible presence of a tolerance phenomenon was also sought. The study was randomized, double-blind and placebo-controlled. Four hours after an acute dose of 5-IMN, time for -1 mm ST segment depression significatively increased as compared with basal test and placebo test (367 +/- 92 vs 199 +/- 87 and 250 +/- 78 sec respectively, p less than 0.0004). At the same test, total exercise time also increased from 282 +/- 92 sec (basal) and 323 +/- 91 sec (placebo) to 424 +/- 91 sec (p less than 0.008). At 12 hours test, total exercise time was also significantly increased as compared with basal test and placebo test (354 +/- 109 vs 282 +/- 92 and 291 +/- 90 sec respectively; p less than 0.01). These effects were not present when the patients were tested 24 hours after active drug administration. After daily administration of a single dose of 5-IMN during a 3 week period, 4 and 12 hours test demonstrated a persistent and significant anti-ischemic effect, similar to the acute figures. Thus, an acute dose of 50 mg of a sustained-release preparation of 5-IMN reveals significant anti-ischemic effects which remain 4 and 12 hours after drug administration. Chronic administration of the preparation for 3 weeks (single daily dose) is equally effective, without any evidence of tolerance phenomenon.