The dynamics of the respiratory and cardiovascular systems were studied by continuously slowing respiration from 0.46 to 0.05 Hz. The time-frequency distribution and global spectral analysis were used to assess the R-R interval (R-R) and the systolic and diastolic blood pressure fluctuations in 16 healthy subjects. During rest, the nonrespiratory-to-respiratory frequency ratios were not affected by occasional slow breathing, whereas the low- (0.01-0.15 Hz) to high- (0.15-0.3 Hz) frequency indexes for blood pressure were increased (P < 0.05). The respiratory fluctuations in R-R and the systolic and diastolic pressures were paced over the 0.46- to 0.05-Hz range. As respiration slowed to 0.07-0.09 Hz, the frequency content of the respiration and cardiovascular variables increased sharply and nonlinearly to a maximum that exceeded values at higher frequencies (P < 0.001). The nonrespiratory frequency content remained stable in the 0.01- to 0.05-Hz range and did not significantly differ from that at rest. In contrast, the nonstable 0.05- to 0.1-Hz component was suppressed. A slow 0.012- to 0.017-Hz rhythm modulated respiration and hemodynamic fluctuations at both respiratory and nonrespiratory frequencies. The study indicated that respiration input should be considered in the interpretation of global spectra. Furthermore the time-frequency distributions demonstrated that a close nonlinear coupling exists between the respiratory and cardiovascular systems.

Neurohumoral activation at the time of hospital discharge in postinfarction patients is an independent sign of poor prognosis. This is particularly true for plasma renin activity and atrial natriuretic peptide. Except for 1-year cardiovascular mortality, captopril does not significantly modify these relations.

An enhanced .O2- formation resulting from an increased NADH oxidase activity was found in aorta from SHR and DOCA-HT rats. Cultured arterial SMCs from SHR also generated excessive .O2- formation under basal and stimulated conditions. The age-related increase in vascular .O2- formation in association with the rise in blood pressure in SHR suggests that the oxidative stress might contribute to the development of hypertension. NADH oxidase activity was greater in aorta of both hypertension models, but a decrease of Cu/Zn SOD activity could also contribute to the high level of aortic .O2- in DOCA-HT rats.

Several experimental and clinical evidences have linked an enhanced production of reactive oxygen species (ROS) to certain diseases of the cardiovascular system including hypertension and diabetes. However, it has never been clearly established whether the enhanced oxidative stress observed in those conditions is primary or secondary to the pathological process. Our experimental studies have permitted to demonstrate that ROS, mainly through the production of superoxide anion, can cause important alterations in the cellular signal transduction systems characterized by an enhanced production of inositol triphosphate and a reduced production of cyclic GMP in cultured vascular smooth muscle cells (SMC), thus favouring the vasoconstriction. Since those effects were found to be increased in SMC from spontaneously hypertensive rats (SHR), this suggested a greater sensitivity of the vascular tissue of SHR to the oxidative stress. Moreover, we also have observed an increased production of superoxide anion in the aorta of rats made hypertensive according to the SHR, glucose or angiotensin-induced and DOCA-salt models during the development of hypertension. Since the superoxide anion production could be correlated with the level of blood pressure and since the development of hypertension could be either totally prevented or markedly attenuated by chronic treatment with potent antioxidative therapies such as alpha lipoic acid or aspirin, this suggested a major contribution of vascular superoxide anion production in the development of hypertension in those models. Moreover, the development of insulin resistance, which is associated to the model of glucose-induced hypertension, was also found to be prevented by chronic antioxidant therapies, thus suggesting that oxidative stress plays an important role as well in the development of insulin resistance and type 2 diabetes. In conclusion, it appears that oxidative stress may constitute a major pathogenic factor in the development of hypertension and type 2 diabetes. Moreover, our studies suggest that the chronic treatment with appropriate antioxidative therapies could prevent the development of hypertension and diabetes as well as their complications in various experimental models of hypertension.

Abstract-The aim of the present study was to investigate whether a dietary supplementation of ␣-lipoic acid could prevent blood pressure elevation, insulin resistance, and the increase in aorta superoxide anion production in a new experimental model of hypertension associated with insulin resistance. Sprague-Dawley rats were given 10% D-glucose in their drinking water combined either with a normal chow diet or with an ␣-lipoic acid-supplemented diet and were compared with control rats during 3 weeks. Oxidative stress was evaluated by measuring the aortic superoxide anion production using the lucigenin chemiluminescence method. Increases in blood pressure, insulin resistance, and aorta superoxide production observed in glucose-fed rats were prevented by the supplementation of the diet with lipoic acid. Positive correlations were found between aortic superoxide production and blood pressure, between insulin resistance and blood pressure, or between superoxide production and insulin resistance. Moreover, a decrease in the activity of plasma glutathione peroxidase observed in the glucose-fed rats was prevented by lipoic acid treatment. These findings demonstrate that high-glucose feeding rapidly induced hypertension and insulin resistance in association with the induction of a vascular oxidative stress. The antihypertensive action and the prevention of insulin resistance by lipoic acid appears to be associated to its antioxidative properties because it prevented the increase in oxidative stress, as reflected by the normalization of superoxide anion production in aorta and the prevention of the fall in the activity of glutathione peroxidase in the glucose-fed rats. (Hypertension. 2002;39:303-307.)