Gustavo J. J. Silva

Exercise Training Increases Baroreceptor Gain Sensitivity in Normal and Hypertensive Rats

Exercise training attenuates arterial hypertension and increases baroreflex sensitivity in spontaneous hypertension. However, no information exists regarding the portion of the baroreflex arch in which this attenuation takes place. We tested the hypothesis that exercise training increases the afferent pathway sensitivity of baroreflex control in both normotensive and spontaneously hypertensive rats (SHR). Arterial pressure and whole-nerve activity of the aortic baroreceptor (multifiber preparation) were evaluated in 30 male rats assigned to 4 groups: sedentary and exercise-trained normotensive rats and sedentary and exercise-trained SHR. Exercise training was performed on a motor treadmill, 5 d/wk for 60 minutes, gradually progressing toward a speed of 26.8 m/min. Exercise training reduced mean arterial pressure in conscious exercise-trained SHR (183±4 versus 165±7 mm Hg). The relation between changes in aortic baroreceptor discharge and changes in systolic arterial pressure increased significantly in exercise-trained normotensive rats (2.09±0.1 versus 1.44±0.1%/mm Hg) and exercise-trained SHR (0.92±0.1 versus 0.71±0.1%/mm Hg) compared with their respective sedentary rats. Likewise, the average aortic baroreceptor gain sensitivity (calculated by logistic equation) was significantly higher in exercise-trained normotensive rats (2.25±0.19 versus 1.77±0.03%/mm Hg) and exercise-trained SHR (1.07±0.04 versus 0.82±0.05%/mm Hg) compared with their respective sedentary control rats. In conclusion, exercise training increases aortic baroreceptor gain sensitivity in normotensive and SHR, thus improving baroreceptor sensitivity, which may result in a more efficient arterial pressure regulation by the baroreflexes.

Acute and Chronic Effects of Exercise on Baroreflexes in Spontaneously Hypertensive Rats

We studied the effects of acute and chronic exercise on the arterial baroreflex and chemosensitive cardiopulmonary baroreflex (CCB) in spontaneously hypertensive rats (SHR). Arterial baroreflex and CCB were evaluated in normotensive rats (NR, n=11) and SHR (n=5) at rest and after 30 minutes of an acute bout of exercise (45 minutes at 50% of VO2max). In addition, these baroreflexes were evaluated in sedentary (n=5) and exercise-trained (n=9) SHR. Exercise training was performed on a motor treadmill, 5 days/week, during 60 minutes, at 50% of VO2max. Baroreflex bradycardia and tachycardia, analyzed by baroreflex sensitivity index (delta heart rate/delta mean arterial pressure), were significantly lower in SHR than in NR (0.7+/-0.1 versus 2.0+/-0.1 and 1.8+/-0.2 versus 3.4+/-0.1 beats per minute [bpm]/mm Hg, respectively). During the recovery period from acute exercise, baroreflex bradycardia was significantly higher than at rest only in SHR (1.7+/-0.1 versus 0.7+/-0.1 bpm/mm Hg). Hypotension and bradycardia induced by CCB stimulation (5-hydroxytryptamine, I.V.) were similar between SHR and NR, and an acute exercise bout did not change these responses. Exercise training markedly improved baroreflex bradycardia and tachycardia in SHR (1.9+/-0.1 versus 0.7+/-0.1 and 2.9+/-0.1 versus 1.8+/-0.2 bpm/mm Hg, respectively). Exercise-trained rats had greater bradycardiac (118+/-26 versus 14+/-2 and 209+/-30 versus 19+/-5 bpm to 1 and 2 microg/kg 5-HT, respectively) and hypotensive (30+/-6 versus 15+/-3 and 45+/-7 versus 17+/-2 mm Hg to 1 and 2 microg/kg 5-hydroxytryptamine, respectively) responses to CCB stimulation. In conclusion, an acute bout of exercise increases baroreflex bradycardia in SHR, and exercise training attenuates hypertension concomitant with improved arterial baroreflex and CCB sensitivity in SHR.

Effects of Exercise Training on Baroreflex Control of the Cardiovascular System

Abstract: Dynamic exercise training has been recommended as an antihypertensive therapy and as a way to modify the effects of many cardiovascular risk factors (Arakawa, 1993; Arroll and Beaglehole, 1992; Kelly and McClellan, 1994: see references 1–3 in the paper). However, the mechanisms underlying the blood‐pressure lowering effect of chronic exercise are still poorly understood. It has been suggested that a decrease in sympathetic tone is one of the major effects elicited by chronic exercise on the cardiovascular system. The importance of the sympathetic component is confirmed in this review, since it was found that in spontaneously hypertensive rats (SHR) a marked decrease in sympathetic activity occurred after exercise training. Moreover, our findings suggest that this effect is mediated by improving the depressed baroreceptor function, which is, in part, responsible for the attenuation of the baroreflex sensitivity observed in the sedentary SHR (Krieger et al., 1998, 1999; see references 4 and 5 in the paper).

Association between glutathione S-transferase polymorphisms and triglycerides and HDL-cholesterol

OBJECTIVE Null genotypes of glutathione S-transferase (GSTs) exhibit absence of enzymatic activity and are hypothesized to modulate an increased risk of developing cardiovascular disease. The aim of this study was to identify the potential association between GSTM1 and GSTT1 deleted polymorphisms with cardiovascular risk factors and coronary atherosclerosis in two independent urban populations. METHODS AND RESULTS Genotype distribution of GSTM1 and GSTT1 deleted polymorphism were examined in a sample of 1577 individuals from the general population and a replication sample of 871 individuals submitted to coronary angiography. Triglycerides, HDL-cholesterol and the triglycerides/HDL ratio were significantly associated with a double-deleted genotype in individuals from the general population. These findings were replicated in a second, independent, population of individuals submitted to coronary angiography. In addition, coronary artery disease severity was also associated with GSTs genotypes and the risk conferred from GSTs genotype was mainly due to triglycerides/HDL ratio information. CONCLUSIONS The data suggest that the presence of a double deletion genotypes of the GSTM1 and GSTT1 genes is associated with hypertriglyceridemia and low HDL-cholesterol levels in humans. These novel findings may provide a new unexplored link between lipid metabolism and GST homeostasis.

Congenic strains provide evidence that four mapped loci in chromosomes 2, 4, and 16 influence hypertension in the SHR

To dissect the genetic architecture controlling blood pressure (BP) regulation in the spontaneously hypertensive rat (SHR) we derived congenic rat strains for four previously mapped BP quantitative trait loci (QTLs) in chromosomes 2, 4, and 16. Target chromosomal regions from the Brown Norway rat (BN) averaging 13-29 cM were introgressed by marker-assisted breeding onto the SHR genome in 12 or 13 generations. Under normal salt intake, QTLs on chromosomes 2a, 2c, and 4 were associated with significant changes in systolic BP (13, 20, and 15 mmHg, respectively), whereas the QTL on chromosome 16 had no measurable effect. On high salt intake (1% NaCl in drinking water for 2 wk), the chromosome 16 QTL had a marked impact on SBP, as did the QTLs on chromosome 2a and 2c (18, 17, and 19 mmHg, respectively), but not the QTL on chromosome 4. Thus these four QTLs affected BP phenotypes differently: 1) in the presence of high salt intake (chromosome 16), 2) only associated with normal salt intake (chromosome 4), and 3) regardless of salt intake (chromosome 2c and 2a). Moreover, salt sensitivity was abrogated in congenics SHR.BN2a and SHR.BN16. Finally, we provide evidence for the influence of genetic background on the expression of the mapped QTLs individually or as a group. Collectively, these data reveal previously unsuspected nuances of the physiological roles of each of the four mapped BP QTLs in the SHR under basal and/or salt loading conditions unforeseen by the analysis of the F2 cross.

Critical analysis of autoregressive and fast Fourier transform markers of cardiovascular variability in rats and humans

The autonomic nervous system plays an important role in physiological and pathological conditions, and has been extensively evaluated by parametric and non-parametric spectral analysis. To compare the results obtained with fast Fourier transform (FFT) and the autoregressive (AR) method, we performed a comprehensive comparative study using data from humans and rats during pharmacological blockade (in rats), a postural test (in humans), and in the hypertensive state (in both humans and rats). Although postural hypotension in humans induced an increase in normalized low-frequency (LFnu) of systolic blood pressure, the increase in the ratio was detected only by AR. In rats, AR and FFT analysis did not agree for LFnu and high frequency (HFnu) under basal conditions and after vagal blockade. The increase in the LF/HF ratio of the pulse interval, induced by methylatropine, was detected only by FFT. In hypertensive patients, changes in LF and HF for systolic blood pressure were observed only by AR; FFT was able to detect the reduction in both blood pressure variance and total power. In hypertensive rats, AR presented different values of variance and total power for systolic blood pressure. Moreover, AR and FFT presented discordant results for LF, LFnu, HF, LF/HF ratio, and total power for pulse interval. We provide evidence for disagreement in 23% of the indices of blood pressure and heart rate variability in humans and 67% discordance in rats when these variables are evaluated by AR and FFT under physiological and pathological conditions. The overall disagreement between AR and FFT in this study was 43%.

Reversible pulmonary trunk banding. VI: Glucose-6-phosphate dehydrogenase activity in rapid ventricular hypertrophy in young goats

OBJECTIVE Increased myocardial glucose-6-phosphate dehydrogenase (G6PD) activity occurs in heart failure. This study compared G6PD activity in 2 protocols of right ventricle (RV) systolic overload in young goats. METHODS Twenty-seven goats were separated into 3 groups: sham (no overload), continuous (continuous systolic overload), and intermittent (four 12-hour periods of systolic overload paired with a 12-hour resting period). During a 96-hour protocol, systolic overload was adjusted to achieve a 0.7 RV/aortic pressure ratio. Echocardiographic and hemodynamic evaluations were performed before and after systolic overload every day postoperatively. After the study period, the animals were humanely killed for morphologic and G6PD tissue activity assessment. RESULTS A 92.1% and 46.5% increase occurred in RV and septal mass, respectively, in the intermittent group compared with the sham group; continuous systolic overload resulted in a 37.2% increase in septal mass. A worsening RV myocardial performance index occurred in the continuous group at 72 hours and 96 hours, compared with the sham (P < .039) and intermittent groups at the end of the protocol (P < .001). Compared with the sham group, RV G6PD activity was elevated 130.1% in the continuous group (P = .012) and 39.8% in the intermittent group (P = .764). CONCLUSIONS Continuous systolic overload for ventricle retraining causes RV dysfunction and upregulation of myocardial G6PD activity, which can elevate levels of free radicals by NADPH oxidase, an important mechanism in the pathophysiology of heart failure. Intermittent systolic overload promotes a more efficient RV hypertrophy, with better preservation of myocardial performance and and less exposure to hypertrophic triggers.

Preservation of cardiac function in left ventricle cardiac hypertrophy using an AAV vector which provides VEGF-A expression in response to p53

Here we present the application of our adeno-associated virus (AAV2) vector where transgene expression is driven by a synthetic, p53-responsive promoter, termed PG, used to supply human vascular endothelial growth factor-A165 (VEGF-A). Thus, p53 is harnessed to promote the beneficial expression of VEGF-A encoded by the AAVPG vector, bypassing the negative effect of p53 on HIF-1α which occurs during cardiac hypertrophy. Wistar rats were submitted to pressure overload induced by thoracic aorta coarctation (TAC) with or without concomitant gene therapy (intramuscular delivery in the left ventricle). After 12 weeks, rats receiving AAVPG-VEGF gene therapy were compared to those that did not, revealing significantly improved cardiac function under hemodynamic stress, lack of fibrosis and reversal of capillary rarefaction. With these functional assays, we have demonstrated that application of the AAVPG-VEGF vector under physiologic conditions known to stimulate p53 resulted in the preservation of cardiac performance.

Bandagem reversível do tronco pulmonar IV: análise da hipertrofia aguda do ventrículo direito em modelo experimental de sobrecarga intermitente

AbstractObjectives: Adjustable pulmonary trunk (PT) bandingdevice may induce a more physiologic ventricle retrainingfor the two-stage Jatene operation. This experimental studyevaluates the acute hypertrophy (96 hours) of the rightventricle (RV) submitted to an intermittent pressureoverload. Methods: Five groups of seven young goats were distributedaccording to RV intermittent systolic overload duration (0,24, 48, 72 and 96 hours). The zero-hour group served as acontrol group. Echocardiographic and hemodynamicevaluations were performed daily. After completing thetraining program for each group, the animals were sacrificedfor water content and cardiac masses evaluation. Results: There was a significant increase in RV free wallthickness starting with the 48-hour group (p<0.05). However,a decreased RV ejection fraction, associated with animportant RV dilation and a significant increase in the RVvolume to mass ratio was observed at 24-hour training period,when compared to 96-hour period (p=0.003), with subsequentrecovery throughout the protocol. A 104.7% increase in RVmass was observed in the 96-hour group, as compared to thecontrol group, with no differences in water content betweenthese two groups. The daily mean increase in RV mass duringthe study period was 21.6% ± 26.8%. The rate of RV massacquisition for the overall study period of intermittentsystolic overload was 0.084 g/h ± 0.035 g/h. Conclusion: Intermittent PT banding has allowed asignificant RV mass acquisition in the 96-hour trained group.No myocardial water content changes were observed in thisgroup, suggesting an increased myocardial protein synthesis.Descriptors: Heart ventricles/physiopathology. Hypertrophy/physiopathology. Right ventricular hypertrophy. Transpositionof great vessels/surgery. Cardiac surgical procedures/methods.Goats.

Ace gene dosage influences the development of renovascular hypertension

1. Clinical and experimental evidence highlights the importance of the renin–angiotensin system in renovascular hypertension. Furthermore, genetic factors affecting angiotensin‐converting enzyme (ACE) could influence the development of renovascular hypertension.