Rubens Fazan

Heart Rate Variability and Baroreceptor Function in Chronic Diabetic Rats

In conscious chronic (12 to 18 weeks) streptozotocin diabetic rats, we examined the changes in basal heart rate, with particular attention to heart rate variability assessed by evaluating the standard deviation (bpm) of the lengths of adjacent pulse pressure. We also investigated in anesthetized rats the ability of the aortic baroreceptors to acutely (30 minutes) reset to hypertensive levels. For this purpose, pressure-nerve activity curves for the baroreceptors were obtained, and gain (slope of the curve) and mean arterial pressure at 50% of maximal baroreceptor activity were calculated. The shift of the pressure-nerve activity curve was used as an index of resetting. Conscious diabetic rats (n=6) exhibited lower mean arterial pressure (93+/-6 versus 109+/-4 mm Hg), heart rate (272+/-25 versus 359+/-11 bpm), and heart rate variability (18+/-7 versus 36+/-6 bpm) than control rats (n=7). Under anesthesia, diabetic rats (n=7) and control rats (n=8) exhibited similar mean arterial pressure (113+/-6 versus 109+/-7 mm Hg in control rats ), mean arterial pressure at 50% of maximal baroreceptor activity (117+/-5 versus 107+/-6 bpm), gain (1.66+/-0.08 versus 1.81+/-0.05%/mm Hg), and extent of resetting (44+/-12 versus 49+/-9%) to hypertensive levels. The present study demonstrated that conscious chronic diabetic rats presented lower heart rate variability than control rats. On the other hand, chronic diabetes was not associated with alterations in baroreceptor function or its ability to rapidly reset to hypertensive levels.

Myocardial performance in conscious streptozotocin diabetic rats

BackgroundIn spite of a large amount of studies in anesthetized animals, isolated hearts, and in vitro cardiomyocytes, to our knowledge, myocardial function was never studied in conscious diabetic rats. Myocardial performance and the response to stress caused by dobutamine were examined in conscious rats, fifteen days after the onset of diabetes caused by streptozotocin (STZ). The protective effect of insulin was also investigated in STZ-diabetic rats.MethodsCardiac contractility and relaxation were evaluated by means of maximum positive (+dP/dtmax) and negative (-dP/dtmax) values of first derivative of left ventricular pressure over time. In addition, it was examined the myocardial response to stress caused by two dosages (1 and 15 μg/kg) of dobutamine. One-way analysis of variance (ANOVA) was used to compare differences among groups, and two-way ANOVA for repeated measure, followed by Tukey post hoc test, to compare the responses to dobutamine. Differences were considered significant if P < 0.05.ResultsBasal mean arterial pressure, heart rate, +dP/dtmax and -dP/dtmax were found decreased in STZ-diabetic rats, but unaltered in control rats treated with vehicle and STZ-diabetic rats treated with insulin. Therefore, insulin prevented the hemodynamic and myocardial function alterations observed in STZ-diabetic rats. Lower dosage of dobutamine increased heart rate, +dP/dtmax and -dP/dtmax only in STZ-diabetic rats, while the higher dosage promoted greater, but similar, responses in the three groups. In conclusion, the results indicate that myocardial function was remarkably attenuated in conscious STZ-diabetic rats. In addition, the lower dosage of dobutamine uncovered a greater responsiveness of the myocardium of STZ-diabetic rats. Insulin preserved myocardial function and the integrity of the response to dobutamine of STZ-diabetic rats.ConclusionThe present study provides new data from conscious rats showing that the cardiomyopathy of this pathophysiological condition was expressed by low indices of contractility and relaxation. In addition, it was also demonstrated that these pathophysiological features were prevented by the treatment with insulin.

Increase in parasympathetic tone by pyridostigmine prevents ventricular dysfunction during the onset of heart failure

Heart failure (HF) is characterized by elevated sympathetic activity and reduced parasympathetic control of the heart. Experimental evidence suggests that the increase in parasympathetic function can be a therapeutic alternative to slow HF evolution. The parasympathetic neurotransmission can be improved by acetylcholinesterase inhibition. We investigated the long-term (4 wk) effects of the acetylcholinesterase inhibitor pyridostigmine on sympathovagal balance, cardiac remodeling, and cardiac function in the onset of HF following myocardial infarction. Myocardial infarction was elicited in adult male Wistar rats. After 4 wk of pyridostigmine administration, per os, methylatropine and propranolol were used to evaluate the cardiac sympathovagal balance. The tachycardic response caused by methylatropine was considered to be the vagal tone, whereas the bradycardic response caused by propranolol was considered to be the sympathetic tone. In conscious HF rats, pyridostigmine reduced the basal heart rate, increased vagal, and reduced sympathetic control of heart rate. Pyridostigmine reduced the myocyte diameter and collagen density of the surviving left ventricle. Pyridostigmine also increased vascular endothelial growth factor protein in the left ventricle, suggesting myocardial angiogenesis. Cardiac function was assessed by means of the pressure-volume conductance catheter system. HF rats treated with pyridostigmine exhibited a higher stroke volume, ejection fraction, cardiac output, and contractility of the left ventricle. It was demonstrated that the long-term administration of pyridostigmine started right after coronary artery ligation augmented cardiac vagal and reduced sympathetic tone, attenuating cardiac remodeling and left ventricular dysfunction during the progression of HF in rats.

Reflex control of arterial pressure and heart rate in short-term streptozotocin diabetic rats

Impaired baroreflex sensitivity in diabetes is well described and has been attributed to autonomic diabetic neuropathy. In the present study conducted on acute (10-20 days) streptozotocin (STZ)-induced diabetic rats we examined: 1) cardiac baroreflex sensitivity, assessed by the slope of the linear regression between phenylephrine- or sodium nitroprusside-induced changes in arterial pressure and reflex changes in heart rate (HR) in conscious rats; 2) aortic baroreceptor function by means of the relationship between systolic arterial pressure and aortic depressor nerve (ADN) activity, in anesthetized rats, and 3) bradycardia produced by electrical stimulation of the vagus nerve or by the iv injection of methacholine in anesthetized animals. Reflex bradycardia (-1.4 +/- 0.1 vs -1.7 +/- 0.1 bpm/mmHg) and tachycardia (-2.1 +/- 0.3 vs -3.0 +/- 0.2 bpm/mmHg) were reduced in the diabetic group. The gain of the ADN activity relationship was similar in control (1.7 +/- 0.1% max/mmHg) and diabetic (1.5 +/- 0.1% max/mmHg) animals. The HR response to vagal nerve stimulation with 16, 32 and 64 Hz was 13, 16 and 14% higher, respectively, than the response of STZ-treated rats. The HR response to increasing doses of methacholine was also higher in the diabetic group compared to control animals. Our results confirm the baroreflex dysfunction detected in previous studies on short-term diabetic rats. Moreover, the normal baroreceptor function and the altered HR responses to vagal stimulation or methacholine injection suggest that the efferent limb of the baroreflex is mainly responsible for baroreflex dysfunction in this model of diabetes.

The treatment with pyridostigmine improves the cardiocirculatory function in rats with chronic heart failure

Sympathetic hyperactivity and its outcome in heart failure have been thoroughly investigated to determine the focus of pharmacologic approaches targeting the sympathetic nervous system in the treatment of this pathophysiological condition. On the other hand, therapeutic approaches aiming to protect the reduced cardiac parasympathetic function have not received much attention. The present study evaluated rats with chronic heart failure (six to seven weeks after coronary artery ligation) and the effects of an increased parasympathetic function by pyridostigmine (an acetylcholinesterase inhibitor) on the following aspects: arterial pressure (AP), heart rate (HR), baroreceptor and Bezold-Jarisch reflex, pulse interval (PI) and AP variability, cardiac sympathetic and parasympathetic tonus, intrinsic heart rate (i-HR) and cardiac function. Conscious rats with heart failure exhibited no change in HR, Bezold-Jarisch reflex, PI variability and cardiac sympathetic tonus. On the other hand, these animals presented hypotension and reduced baroreflex sensitivity, power in the low frequency (LF) band of the systolic AP spectrum, cardiac parasympathetic tonus and i-HR, while anesthetized rats exhibited reduced cardiac performance. Pyridostigmine prevented the attenuation of all the parameters examined, except basal AP and cardiac performance. In conclusion, the blockade of acetylcholinesterase with pyridostigmine was revealed to be an important pharmacological approach, which could be used to increase parasympathetic function and to improve a number of cardiocirculatory parameters in rats with heart failure.

Sildenafil acts on the central nervous system increasing sympathetic activity

Sildenafil induces vasodilation and is used for treating erectile dysfunction. Although its influence on resting heart function appears to be minimal, recent studies suggest that sildenafil can increase sympathetic activity. We therefore tested whether sildenafil injected into the central nervous system alters the autonomic control of the cardiovascular system in conscious rats. The effect of sildenafil citrate injected into the lateral cerebral ventricle was evaluated in conscious rats by means of the recording of lumbar sympathetic nerve activity (LSNA), spectral analysis of systolic arterial pressure and heart rate variability, spontaneous baroreflex sensitivity, and baroreflex control of LSNA. Intracerebroventricular (ICV, 100 microg /5 microl) administration of sildenafil caused remarkable tachycardia without significant change in basal arterial pressure and was associated with a conspicuous increase (47 +/- 14%) in LSNA. Spectral analysis demonstrated that systolic arterial pressure oscillations in the low frequency (LF) range were increased (from 6.3 +/- 1.5 to 12.8 +/- 3.8 mmHg(2)), whereas the high frequency (HF) range was not affected by ICV administration of sildenafil. Sildenafil increased pulse interval oscillations at LF and decreased them at HF. The LF-HF ratio increased from 0.04 +/- 0.01 to 0.17 +/- 0.06. Spontaneous baroreflex sensitivity measured by the sequence method and the baroreflex relationship between mean arterial pressure and LSNA were not affected by ICV administration of sildenafil. In conclusion, sildenafil elicited an increase in sympathetic nerve activity that is not baroreflex mediated, suggesting that this drug is able to elicit an autonomic imbalance of central origin. This finding may have implications for understanding the cardiovascular outcomes associated with the clinical use of this drug.

Intravenous amiodarone modifies autonomic balance and increases baroreflex sensitivity in conscious rats

Amiodarone is an antiarrhythmic agent commonly used to treat cardiac arrhythmias. This study was designed to investigate the effects of intravenous amiodarone on the neural control of heart rate and arterial pressure and spontaneous baroreflex sensitivity (BRS). Experiments were carried out on conscious freely moving normotensive Wistar (WR) and spontaneously hypertensive rats (SHR). Arterial pressure was continuously monitored before and after amiodarone (50 mg/kg i.v.) or vehicle for 30 min. Heart rate (expressed as the pulse interval, PI) and systolic arterial pressure (SAP) variabilities were assessed using autoregressive spectral analysis. BRS was calculated as the alpha-index (the square root of the ratio between the PI and SAP powers). Amiodarone induced bradycardia and hypotension in both strains, with these effects being more intense in SHR. The variability profile of PI was characterized by a significant reduction of normalized low frequency (LF) and LF/HF ratio, while the high frequency (HF) component both in absolute and normalized units (nu) was increased in both WR and SHR strains. A significant decrease in SAP variance and its LF oscillation was observed. In addition, BRS was also increased in both groups, being more intense in SHR. In both WR and SHR, intravenous amiodarone had a considerable effect on heart rate variabilities (HRV), shifting cardiac sympathovagal balance toward a sympathetic inhibition and/or vagal activation, which were associated with an increase in spontaneous BRS. Decreases of SAP variance and LF(SAP) suggest sympatholytic effects on peripheral vessels. Besides the direct ion channel effects, these changes in the autonomic balance could contribute to the antiarrhythmic action of the intravenous amiodarone.

Effect of baroreceptor denervation on the autonomic control of arterial pressure in conscious mice

This study evaluated the role of arterial baroreceptors in arterial pressure (AP) and pulse interval (PI) regulation in conscious C57BL mice. Male animals, implanted with catheters in a femoral artery and a jugular vein, were submitted to sino‐aortic (SAD), aortic (Ao‐X) or carotid sinus denervation (Ca‐X), 5 days prior to the experiments. After basal recording of AP, the lack of reflex bradycardia elicited by administration of phenylephrine was used to confirm the efficacy of SAD, and cardiac autonomic blockade with methylatropine and propranolol was performed. The AP and PI variability were calculated in the time and frequency domains (spectral analysis/fast Fourier transform) with the spectra quantified in low‐ (LF; 0.25–1 Hz) and high‐frequency bands (HF; 1–5 Hz). Basal AP and AP variability were higher after SAD, Ao‐X or Ca‐X than in intact mice. Pulse interval was similar among the groups, whereas PI variability was lower after SAD. Atropine elicited a slight tachycardia in control mice but did not change PI after total or partial denervation. The bradycardia caused by propranolol was higher after SAD, Ao‐X or Ca‐X compared with intact mice. The increase in the variability of AP was accompanied by a marked increase in the LF and HF power of the AP spectra after baroreceptor denervation. The LF and HF power of the PI were reduced by SAD and by Ao‐X or Ca‐X. Therefore, both sino‐aortic and partial baroreceptor denervation in mice elicits hypertension and a remarkable increase in AP variability and cardiac sympathetic tonus. Spectral analysis showed an important contribution of the baroreflex in the power of LF oscillations of the PI spectra. Both sets of baroreceptors seem to be equally important in the autonomic regulation of the cardiovascular system in mice.

Ovariectomy does not affect the cardiac sympathovagal balance of female SHR but estradiol does

The low incidence of cardiovascular diseases, including hypertension, in premenopausal women has led to the conclusion that ovarian hormones may have a protective effect on the cardiovascular system. We evaluated the effects of ovariectomy and/or estradiol on sympathovagal balance and heart rate variability (HRV) in female spontaneously hypertensive rats (SHR) with tachycardia and compared them to Wistar rats (12 weeks old; N = 8-12). Ovariectomy (OVX) and/or estradiol (10 µg/kg) did not affect basal arterial pressure in either rat strain, but estradiol increased basal heart rate (HR) in OVX SHR (454 ± 18 vs 377 ± 9 bpm). HR changes elicited by methylatropine and propranolol were used to evaluate the sympathovagal balance. Ovariectomy did not affect the cardiac sympathovagal balance of any group, while estradiol increased sympathetic tone in OVX SHR (120 ± 8 vs 56 ± 10 bpm) and sham-operated Wistar rats (57 ± 7 vs 28 ± 4 bpm), and decreased the parasympathetic tone only in OVX SHR (26 ± 7 vs 37 ± 5 bpm). HRV was studied in the frequency domain (Fast Fourier Transformation). Spectra of HR series were examined at low frequency (LF: 0.2-0.75 Hz) and high frequency (HF: 0.75-3 Hz) bands. The power of LF, as well as the LF/HF ratio, was not affected by ovariectomy, but estradiol increased both LF (29 ± 4 vs 18 ± 3 nu in Wistar sham-operated, 26 ± 5 vs 15 ± 3 nu in Wistar OVX, 50 ± 3 vs 38 ± 4 nu in SHR sham-operated, and 51 ± 3 vs 42 ± 3 nu in SHR OVX) and LF/HF (0.48 ± 0.08 vs 0.23 ± 0.03 nu in Wistar sham-operated, 0.41 ± 0.14 vs 0.19 ± 0.05 nu in Wistar OVX, 0.98 ± 0.11 vs 0.63 ± 0.11 nu in SHR sham-operated, and 1.10 ± 0.11 vs 0.78 ± 0.1 nu in SHR OVX). Thus, we suggest that ovariectomy did not affect the cardiac sympathovagal balance of SHR or Wistar rats, while estradiol increased the sympathetic modulation of HR.

Autonomic modulation of arterial pressure and heart rate variability in hypertensive diabetic rats

OBJECTIVE The aim of the present study was to evaluate the autonomic modulation of the cardiovascular system in streptozotocin (STZ)-induced diabetic spontaneously hypertensive rats (SHR), evaluating baroreflex sensitivity and arterial pressure and heart rate variability. METHODS Male SHR were divided in control (SHR) and diabetic (SHR+DM, 5 days after STZ) groups. Arterial pressure (AP) and baroreflex sensitivity (evaluated by tachycardic and bradycardic responses to changes in AP) were monitored. Autoregressive spectral estimation was performed for systolic AP (SAP) and pulse interval (PI) with oscillatory components quantified as low (LF:0.2-0.6Hz) and high (HF:0.6-3.0Hz) frequency ranges. RESULTS Mean AP and heart rate in SHR+DM (131+/-3 mmHg and 276+/-6 bpm) were lower than in SHR (160+/-7 mmHg and 330+/-8 bpm). Baroreflex bradycardia was lower in SHR+DM as compared to SHR (0.55+/-0.1 vs. 0.97+/-0.1 bpm/mmHg). Overall SAP variability in the time domain (standard deviation of beat-by-beat time series of SAP) was lower in SHR+DM (3.1+/-0.2 mmHg) than in SHR (5.7+/-0.6 mmHg). The standard deviation of the PI was similar between groups. Diabetes reduced the LF of SAP (3.3+/-0.8 vs. 28.7+/-7.6 mmHg2 in SHR), while HF of SAP were unchanged. The power of oscillatory components of PI did not differ between groups. CONCLUSIONS These results show that the association of hypertension and diabetes causes an impairment of the peripheral cardiovascular sympathetic modulation that could be, at least in part, responsible for the reduction in AP levels. Moreover, this study demonstrates that diabetes might actually impair the reduced buffer function of the baroreceptors while reducing blood pressure.