Resistance Exercise Restores Endothelial Function and Reduces Blood Pressure in Type 1 Diabetic Rats

Background: Resistance exercise effects on cardiovascular parameters are not consistent. Objectives: The effects of resistance exercise on changes in blood glucose, blood pressure and vascular reactivity were evaluated in diabetic rats. Methods: Wistar rats were divided into three groups: control group (n = 8); sedentary diabetic (n = 8); and trained diabetic (n = 8). Resistance exercise was carried out in a squat device for rats and consisted of three sets of ten repetitions with an intensity of 50%, three times per week, for eight weeks. Changes in vascular reactivity were evaluated in superior mesenteric artery rings. Results: A significant reduction in the maximum response of acetylcholine-induced relaxation was observed in the sedentary diabetic group (78.1 ± 2%) and an increase in the trained diabetic group (95 ± 3%) without changing potency. In the presence of NG-nitro-L-arginine methyl ester, the acetylcholine-induced relaxation was significantly reduced in the control and trained diabetic groups, but not in the sedentary diabetic group. Furthermore, a significant increase (p < 0.05) in mean arterial blood pressure was observed in the sedentary diabetic group (104.9 ± 5 to 126.7 ± 5 mmHg) as compared to that in the control group. However, the trained diabetic group showed a significant decrease (p < 0.05) in the mean arterial blood pressure levels (126.7 ± 5 to 105.1 ± 4 mmHg) as compared to the sedentary diabetic group. Conclusions: Resistance exercise could restore endothelial function and prevent an increase in arterial blood pressure in type 1 diabetic rats.

Resistance Training After Myocardial Infarction in Rats: Its Role on Cardiac and Autonomic Function

Background: Although resistance exercise training is part of cardiovascular rehabilitation programs, little is known about its role on the cardiac and autonomic function after myocardial infarction. Objective: To evaluate the effects of resistance exercise training, started early after myocardial infarction, on cardiac function, hemodynamic profile, and autonomic modulation in rats. Methods: Male Wistar rats were divided into four groups: sedentary control, trained control, sedentary infarcted and trained infarcted rats. Each group with n = 9 rats. The animals underwent maximum load test and echocardiography at the beginning and at the end of the resistance exercise training (in an adapted ladder, 40% to 60% of the maximum load test, 3 months, 5 days/week). At the end, hemodynamic, baroreflex sensitivity and autonomic modulation assessments were made. Results: The maximum load test increased in groups trained control (+32%) and trained infarcted (+46%) in relation to groups sedentary control and sedentary infarcted. Although no change occurred regarding the myocardial infarction size and systolic function, the E/A ratio (-23%), myocardial performance index (-39%) and systolic blood pressure (+6%) improved with resistance exercise training in group trained infarcted. Concomitantly, the training provided additional benefits in the high frequency bands of the pulse interval (+45%), as well as in the low frequency band of systolic blood pressure (-46%) in rats from group trained infarcted in relation to group sedentary infarcted. Conclusion: Resistance exercise training alone may be an important and safe tool in the management of patients after myocardial infarction, considering that it does not lead to significant changes in the ventricular function, reduces the global cardiac stress, and significantly improves the vascular and cardiac autonomic modulation in infarcted rats.

Chronic Stress Improves NO- and Ca2+ Flux-Dependent Vascular Function: A Pharmacological Study

Background: Stress is associated with cardiovascular diseases. Objective: This study aimed at assessing whether chronic stress induces vascular alterations, and whether these modulations are nitric oxide (NO) and Ca2+ dependent. Methods: Wistar rats, 30 days of age, were separated into 2 groups: control (C) and Stress (St). Chronic stress consisted of immobilization for 1 hour/day, 5 days/week, 15 weeks. Systolic blood pressure was assessed. Vascular studies on aortic rings were performed. Concentration-effect curves were built for noradrenaline, in the presence of L-NAME or prazosin, acetylcholine, sodium nitroprusside and KCl. In addition, Ca2+ flux was also evaluated. Results: Chronic stress induced hypertension, decreased the vascular response to KCl and to noradrenaline, and increased the vascular response to acetylcholine. L-NAME blunted the difference observed in noradrenaline curves. Furthermore, contractile response to Ca2+ was decreased in the aorta of stressed rats. Conclusion: Our data suggest that the vascular response to chronic stress is an adaptation to its deleterious effects, such as hypertension. In addition, this adaptation is NO- and Ca2+-dependent. These data help to clarify the contribution of stress to cardiovascular abnormalities. However, further studies are necessary to better elucidate the mechanisms involved in the cardiovascular dysfunction associated with stressors. (Arq Bras Cardiol. 2014; [online].ahead print, PP.0-0)

Cardiovascular Autonomic Dysfunction in Patients with Morbid Obesity

Abstract Background: Morbid obesity is directly related to deterioration in cardiorespiratory capacity, including changes in cardiovascular autonomic modulation. Objective: This study aimed to assess the cardiovascular autonomic function in morbidly obese individuals. Methods: Cross-sectional study, including two groups of participants: Group I, composed by 50 morbidly obese subjects, and Group II, composed by 30 nonobese subjects. The autonomic function was assessed by heart rate variability in the time domain (standard deviation of all normal RR intervals [SDNN]; standard deviation of the normal R-R intervals [SDNN]; square root of the mean squared differences of successive R-R intervals [RMSSD]; and the percentage of interval differences of successive R-R intervals greater than 50 milliseconds [pNN50] than the adjacent interval), and in the frequency domain (high frequency [HF]; low frequency [LF]: integration of power spectral density function in high frequency and low frequency ranges respectively). Between-group comparisons were performed by the Student’s t-test, with a level of significance of 5%. Results: Obese subjects had lower values of SDNN (40.0 ± 18.0 ms vs. 70.0 ± 27.8 ms; p = 0.0004), RMSSD (23.7 ± 13.0 ms vs. 40.3 ± 22.4 ms; p = 0.0030), pNN50 (14.8 ± 10.4 % vs. 25.9 ± 7.2%; p = 0.0061) and HF (30.0 ± 17.5 Hz vs. 51.7 ± 25.5 Hz; p = 0.0023) than controls. Mean LF/HF ratio was higher in Group I (5.0 ± 2.8 vs. 1.0 ± 0.9; p = 0.0189), indicating changes in the sympathovagal balance. No statistical difference in LF was observed between Group I and Group II (50.1 ± 30.2 Hz vs. 40.9 ± 23.9 Hz; p = 0.9013). Conclusion: morbidly obese individuals have increased sympathetic activity and reduced parasympathetic activity, featuring cardiovascular autonomic dysfunction.

Methodological Gaps in Left Atrial Function Assessment by 2D Speckle Tracking Echocardiography

Abstract The assessment of left atrial (LA) function is used in various cardiovascular diseases. LA plays a complementary role in cardiac performance by modulating left ventricular (LV) function. Transthoracic two-dimensional (2D) phasic volumes and Doppler echocardiography can measure LA function non‑invasively. However, evaluation of LA deformation derived from 2D speckle tracking echocardiography (STE) is a new feasible and promising approach for assessment of LA mechanics. These parameters are able to detect subclinical LA dysfunction in different pathological condition. Normal ranges for LA deformation and cut-off values to diagnose LA dysfunction with different diseases have been reported, but data are still conflicting, probably because of some methodological and technical issues. This review highlights the importance of an unique standardized technique to assess the LA phasic functions by STE, and discusses recent studies on the most important clinical applications of this technique.

The Effect of Sleep Deprivation on Cardiac Function and Tolerance to Ischemia-Reperfusion Injury in Male Rats

Abstract Background: Sleep deprivation (SD) is strongly associated with elevated risk for cardiovascular disease. Objective: To determine the effect of SD on basal hemodynamic functions and tolerance to myocardial ischemia-reperfusion (IR) injury in male rats. Method: SD was induced by using the flowerpot method for 4 days. Isolated hearts were perfused with Langendorff setup, and the following parameters were measured at baseline and after IR: left ventricular developed pressure (LVDP); heart rate (HR); and the maximum rate of increase and decrease of left ventricular pressure (±dp/dt). Heart NOx level, infarct size and coronary flow CK-MB and LDH were measured after IR. Systolic blood pressure (SBP) was measured at start and end of study. Results: In the SD group, the baseline levels of LVDP (19%), +dp/dt (18%), and -dp/dt (21%) were significantly (p < 0.05) lower, and HR (32%) was significantly higher compared to the controls. After ischemia, hearts from SD group displayed a significant increase in HR together with a low hemodynamic function recovery compared to the controls. In the SD group, NOx level in heart, coronary flow CK-MB and LDH and infarct size significantly increased after IR; also SD rats had higher SBP after 4 days. Conclusion: Hearts from SD rats had lower basal cardiac function and less tolerance to IR injury, which may be linked to an increase in NO production following IR.

Standardization of a computerized method for calculating autonomic function test responses in healthy subjects and patients with diabetes mellitus

The objectives of the present study were 1) to compare results obtained by the traditional manual method of measuring heart rate (HR) and heart rate response (HRR) to the Valsalva maneuver, standing and deep breathing, with those obtained using a computerized data analysis system attached to a standard electrocardiograph machine; 2) to standardize the responses of healthy subjects to cardiovascular tests, and 3) to evaluate the response to these tests in a group of patients with diabetes mellitus (DM). In all subjects (97 healthy and 143 with DM) we evaluated HRR to deep breathing, HRR to standing, HRR to the Valsalva maneuver, and blood pressure response (BPR) to standing up and to a sustained handgrip. Since there was a strong positive correlation between the results obtained with the computerized method and the traditional method, we conclude that the new method can replace the traditional manual method for evaluating cardiovascular responses with the advantages of speed and objectivity. HRR and BPR of men and women did not differ. A correlation between age and HRR was observed for standing (r = -0.48, P<0.001) and deep breathing (r = -0.41, P<0.002). Abnormal BPR to standing was usually observed only in diabetic patients with definite and severe degrees of autonomic neuropathy.

Autonomic processing of the cardiovascular reflexes in the nucleus tractus solitarii

The nucleus tractus solitarii (NTS) receives afferent projections from the arterial baroreceptors, carotid chemoreceptors and cardiopulmonary receptors and as a function of this information produces autonomic adjustments in order to maintain arterial blood pressure within a narrow range of variation. The activation of each of these cardiovascular afferents produces a specific autonomic response by the excitation of neuronal projections from the NTS to the ventrolateral areas of the medulla (nucleus ambiguus, caudal and rostral ventrolateral medulla). The neurotransmitters at the NTS level as well as the excitatory amino acid (EAA) receptors involved in the processing of the autonomic responses in the NTS, although extensively studied, remain to be completely elucidated. In the present review we discuss the role of the EAA L-glutamate and its different receptor subtypes in the processing of the cardiovascular reflexes in the NTS. The data presented in this review related to the neurotransmission in the NTS are based on experimental evidence obtained in our laboratory in unanesthetized rats. The two major conclusions of the present review are that a) the excitation of the cardiovagal component by cardiovascular reflex activation (chemo- and Bezold-Jarisch reflexes) or by L-glutamate microinjection into the NTS is mediated by N-methyl-D-aspartate (NMDA) receptors, and b) the sympatho-excitatory component of the chemoreflex and the pressor response to L-glutamate microinjected into the NTS are not affected by an NMDA receptor antagonist, suggesting that the sympatho-excitatory component of these responses is mediated by non-NMDA receptors.

Molecular biology of the kallikrein-kinin system: from structure to function

The participation of the kallikrein-kinin system, comprising the serine proteases kallikreins, the protein substrates kininogens and the effective peptides kinins, in some pathological processes like hypertension and cardiovascular diseases is still a matter of controversy. The use of different experimental set-ups in concert with the development of potent and specific inhibitors and antagonists for the system has highlighted its importance but the results still lack conclusivity. Over the last few years, transgenic and gene-targeting technologies associated with molecular biology tools have provided specific information about the elusive role of the kallikrein-kinin system in the control of blood pressure and electrolyte homeostasis. cDNA and genomic sequences for kinin receptors B2 and B1 from different species were isolated and shown to encode G-protein-coupled receptors and the structure and pharmacology of the receptors were characterized. Transgenic animals expressing an overactive kallikrein-kinin system were established to study the cardiovascular effects of these alterations and the results of these investigations further corroborate the importance of this system in the maintenance of normal blood pressure. Knockout animals for B2 and B1 receptors are available and their analysis also points to the role of these receptors in cardiovascular regulation and inflammatory processes. In this paper the most recent and relevant genetic animal models developed for the study of the kallikrein-kinin system are reviewed, and the advances they brought to the understanding of the biological role of this system are discussed.

Pulmonary function, cholinergic bronchomotor tone, and cardiac autonomic abnormalities in type 2 diabetic patients

This prospective study analyzed the involvement of the autonomic nervous system in pulmonary and cardiac function by evaluating cardiovascular reflex and its correlation with pulmonary function abnormalities of type 2 diabetic patients. Diabetic patients (N = 17) and healthy subjects (N = 17) were evaluated by 1) pulmonary function tests including spirometry, He-dilution method, N2 washout test, and specific airway conductance (SGaw) determined by plethysmography before and after aerosol administration of atropine sulfate, and 2) autonomic cardiovascular activity by the passive tilting test and the magnitude of respiratory sinus arrhythmia (RSA). Basal heart rate was higher in the diabetic group (87.8 ± 11.2 bpm; mean ± SD) than in the control group (72.9 ± 7.8 bpm, P<0.05). The increase of heart rate at 5 s of tilting was 11.8 ± 6.5 bpm in diabetic patients and 17.6 ± 6.2 bpm in the control group (P<0.05). Systemic arterial pressure and RSA analysis did not reveal significant differences between groups. Diabetes intragroup analysis revealed two behaviors: 10 patients with close to normal findings and 7 with significant abnormalities in terms of RSA, with the latter subgroup presenting one or more abnormalities in other tests and clear evidence of cardiovascular autonomic dysfunction. End-expiratory flows were significantly lower in diabetic patients than in the control group (P<0.05). Pulmonary function tests before and after atropine administration demonstrated comparable responses by both groups. Type 2 diabetic patients have cardiac autonomic dysfunction that is not associated with bronchomotor tone alterations, probably reflecting a less severe impairment than that of type 1 diabetes mellitus. Yet, a reduction of end-expiratory flow was detected.

Reactive oxygen species and angiotensin II signaling in vascular cells: implications in cardiovascular disease

Diseases such as hypertension, atherosclerosis, hyperlipidemia, and diabetes are associated with vascular functional and structural changes including endothelial dysfunction, altered contractility and vascular remodeling. Cellular events underlying these processes involve changes in vascular smooth muscle cell (VSMC) growth, apoptosis/anoikis, cell migration, inflammation, and fibrosis. Many factors influence cellular changes, of which angiotensin II (Ang II) appears to be amongst the most important. The physiological and pathophysiological actions of Ang II are mediated primarily via the Ang II type 1 receptor. Growing evidence indicates that Ang II induces its pleiotropic vascular effects through NADPH-driven generation of reactive oxygen species (ROS). ROS function as important intracellular and intercellular second messengers to modulate many downstream signaling molecules, such as protein tyrosine phosphatases, protein tyrosine kinases, transcription factors, mitogen-activated protein kinases, and ion channels. Induction of these signaling cascades leads to VSMC growth and migration, regulation of endothelial function, expression of pro-inflammatory mediators, and modification of extracellular matrix. In addition, ROS increase intracellular free Ca2+ concentration ([Ca2+]i), a major determinant of vascular reactivity. ROS influence signaling molecules by altering the intracellular redox state and by oxidative modification of proteins. In physiological conditions, these events play an important role in maintaining vascular function and integrity. Under pathological conditions ROS contribute to vascular dysfunction and remodeling through oxidative damage. The present review focuses on the biology of ROS in Ang II signaling in vascular cells and discusses how oxidative stress contributes to vascular damage in cardiovascular disease.

Cardiovascular responses to locomotor activity and feeding in unrestrained three-toed sloths, Bradypus variegatus

Heart rate (HR) and systolic (SBP), diastolic (DBP) and mean (MBP) blood pressure were recorded by biotelemetry in nine conscious unrestrained sloths for 1 min every 15 min over a 24-h period. The animals were allowed to freely move in an acoustically isolated and temperature-controlled (24 ± 1ºC) experimental room with light-dark cycle (12/12 h). Behavior was closely monitored through a unidirectional visor and classified as resting (sitting or suspended), feeding (chewing and swallowing embauba leaves, Cecropia adenops), or locomotor activity around the tree trunk or on the room floor. Locomotor activity caused statistically significant increases in SBP (+8%, from 121 ± 22 to 131 ± 18 mmHg), DBP (+7%, from 86 ± 17 to 92 ± 10 mmHg), MBP (+8%, from 97 ± 19 to 105 ± 12 mmHg), and HR (+14%, from 84 ± 15 to 96 ± 15 bpm) compared to resting values, indicating a possible major influence of the autonomic nervous system on the modulation of cardiac function during this behavior. During feeding, the increase in blood pressure was even higher (SBP +27%, from 119 ± 21 to 151 ± 21 mmHg; DBP +21%, from 85 ± 16 to 103 ± 15 mmHg; MBP +24%, from 96 ± 17 to 119 ± 17 mmHg), while HR remained at 14% (from 84 ± 15 to 96 ± 10 bpm) above resting values. The proportionally greater increase in blood pressure than in HR during feeding suggests an increase in peripheral vascular resistance as part of the overall response to this behavior.

Relationship between cardiovascular dysfunction and hyperglycemia in streptozotocin-induced diabetes in rats

Streptozotocin (STZ)-induced diabetes in rats is characterized by cardiovascular dysfunction beginning 5 days after STZ injection, which may reflect functional or structural autonomic nervous system damage. We investigated cardiovascular and autonomic function, in rats weighing 166 ± 4 g, 5-7, 14, 30, 45, and 90 days after STZ injection (N = 24, 33, 27, 14, and 13, respectively). Arterial pressure (AP), mean AP (MAP) variability (standard deviation of the mean of MAP, SDMMAP), heart rate (HR), HR variability (standard deviation of the normal pulse intervals, SDNN), and root mean square of successive difference of pulse intervals (RMSSD) were measured. STZ induced increased glycemia in diabetic rats vs control rats. Diabetes reduced resting HR from 363 ± 12 to 332 ± 5 bpm (P < 0.05) 5 to 7 days after STZ and reduced MAP from 121 ± 2 to 104 ± 5 mmHg (P = 0.007) 14 days after STZ. HR and MAP variability were lower in diabetic vs control rats 30-45 days after STZ injection (RMSSD decreased from 5.6 ± 0.9 to 3.4 ± 0.4 ms, P = 0.04 and SDMMAP from 6.6 ± 0.6 to 4.2 ± 0.6 mmHg, P = 0.005). Glycemia was negatively correlated with resting AP and HR (r = -0.41 and -0.40, P < 0.001) and with SDNN and SDMMAP indices (r = -0.34 and -0.49, P < 0.01). Even though STZ-diabetic rats presented bradycardia and hypotension early in the course of diabetes, their autonomic function was reduced only 30-45 days after STZ injection and these changes were negatively correlated with plasma glucose, suggesting a metabolic origin.

Baroreflex function in conscious rats submitted to iron overload

Our hypothesis is that iron accumulated in tissue, rather than in serum, may compromise cardiovascular control. Male Fischer 344 rats weighing 180 to 220 g were divided into 2 groups. In the serum iron overload group (SIO, N = 12), 20 mg elemental iron was injected ip daily for 7 days. In the tissue iron overload group (TIO, N = 19), a smaller amount of elemental iron was injected (10 mg, daily) for 5 days followed by a resting period of 7 days. Reflex heart rate responses were elicited by iv injections of either phenylephrine (0.5 to 5.0 µg/kg) or sodium nitroprusside (1.0 to 10.0 µg/kg). Baroreflex curves were determined and fitted to sigmoidal equations and the baroreflex gain coefficient was evaluated. To evaluate the role of other than a direct effect of iron on tissue, acute treatment with the iron chelator deferoxamine (20 mg/kg, iv) was performed on the TIO group and the baroreflex was re-evaluated. At the end of the experiments, evaluation of iron levels in serum confirmed a pronounced overload for the SIO group (30-fold), in contrast to the TIO group (2-fold). Tissue levels of iron, however, were higher in the TIO group. The SIO protocol did not produce significant alterations in the baroreflex curve response, while the TIO protocol produced a nearly 2-fold increase in baroreflex gain (-4.34 ± 0.74 and -7.93 ± 1.08 bpm/mmHg, respectively). The TIO protocol animals treated with deferoxamine returned to sham levels of baroreflex gain (-3.7 ± 0.3 sham vs -3.6 ± 0.2 bpm/mmHg) 30 min after the injection. Our results indicate an effect of tissue iron overload on the enhancement of baroreflex sensitivity.

Cardiovascular actions of angiotensin-(1-7)

Angiotensin-(1-7) (Ang-(1-7)) is now considered to be a biologically active member of the renin-angiotensin system. The functions of Ang-(1-7) are often opposite to those attributed to the main effector component of the renin-angiotensin system, Ang II. Chronic administration of angiotensin-converting enzyme inhibitors (ACEI) increases 10- to 25-fold the plasma levels of this peptide, suggesting that part of the beneficial effects of ACEI could be mediated by Ang-(1-7). Ang-(1-7) can be formed from Ang II or directly from Ang I. Other enzymatic pathways for Ang-(1-7) generation have been recently described involving the novel ACE homologue ACE2. This enzyme can form Ang-(1-7) from Ang II or less efficiently by the hydrolysis of Ang I to Ang-(1-9) with subsequent Ang-(1-7) formation. The biological relevance of Ang-(1-7) has been recently reinforced by the identification of its receptor, the G-protein-coupled receptor Mas. Heart and blood vessels are important targets for the formation and actions of Ang-(1-7). In this review we will discuss recent findings concerning the biological role of Ang-(1-7) in the heart and blood vessels, taking into account aspects related to its formation and effects on these tissues. In addition, we will discuss the potential of Ang-(1-7) and its receptor as a target for the development of new cardiovascular drugs.