Angiotensin-(1-7) potentiates the coronary vasodilatatory effect of bradykinin in the isolated rat heart

It has been shown that angiotensin-(1-7) (Ang-(1-7)) infusion potentiates the bradykinin (BK)-induced hypotensive response in conscious rats. The present study was conducted to identify Ang-(1-7)-BK interactions in the isolated rat heart perfused according to the Langendorff technique. Hearts were excised and perfused through the aortic stump under a constant flow with Krebs-Ringer solution and the changes in perfusion pressure and heart contractile force were recorded. Bolus injections of BK (2.5, 5, 10 and 20 ng) produced a dose-dependent hypotensive effect. Ang-(1-7) added to the perfusion solution (2 ng/ml) did not change the perfusion pressure or the contractile force but doubled the hypotensive effect of the lower doses of BK. The BK-potentiating Ang-(1-7) activity was blocked by pretreatment with indomethacin (5 mg/kg, ip) or L-NAME (30 mg/kg, ip). The Ang-(1-7) antagonist A-779 (50 ng/ml in Krebs-Ringer) completely blocked the effect of Ang-(1-7) on BK-induced vasodilation. These data suggest that the potentiation of the BK-induced vasodilation by Ang-(1-7) can be attributed to the release of nitric oxide and vasodilator prostaglandins through an Ang-(1-7) receptor-mediated mechanism.

Relative influence of age, resting heart rate and sedentary life style in short-term analysis of heart rate variability

In order to assess the relative influence of age, resting heart rate (HR) and sedentary life style, heart rate variability (HRV) was studied in two different groups. The young group (YG) consisted of 9 sedentary subjects aged 15 to 20 years (YG-S) and of 9 nonsedentary volunteers (YG-NS) also aged 15 to 20. The elderly sedentary group (ESG) consisted of 16 sedentary subjects aged 39 to 82 years. HRV was assessed using a short-term procedure (5 min). R-R variability was calculated in the time-domain by means of the root mean square successive differences. Frequency-domain HRV was evaluated by power spectrum analysis considering high frequency and low frequency bands. In the YG the effort tolerance was ranked in a bicycle stress test. HR was similar for both groups while ESG showed a reduced HRV compared with YG. Within each group, HRV displayed a negative correlation with HR. Although YG-NS had better effort tolerance than YG-S, their HR and HRV were not significantly different. We conclude that HRV is reduced with increasing HR or age, regardless of life style. The results obtained in our short-term study agree with others of longer duration by showing that age and HR are the main determinants of HRV. Our results do not support the idea that changes in HRV are related to regular physical activity.

Heart rate variability under resting conditions in postmenopausal and young women

The aim of the present study was to compare the modulation of heart rate in a group of postmenopausal women to that of a group of young women under resting conditions on the basis of R-R interval variability. Ten healthy postmenopausal women (mean ± SD, 58.3 ± 6.8 years) and 10 healthy young women (mean ± SD, 21.6 ± 0.82 years) were submitted to a control resting electrocardiogram (ECG) in the supine and sitting positions over a period of 6 min. The ECG was obtained from a one-channel heart monitor at the CM5 lead and processed and stored using an analog to digital converter connected to a microcomputer. R-R intervals were calculated on a beat-to-beat basis from the ECG recording in real time using a signal-processing software. Heart rate variability (HRV) was expressed as standard deviation (RMSM) and mean square root (RMSSD). In the supine position, the postmenopausal group showed significantly lower (P<0.05) median values of RMSM (34.9) and RMSSD (22.32) than the young group (RMSM: 62.11 and RMSSD: 49.1). The same occurred in the sitting position (RMSM: 33.0 and RMSSD: 18.9 compared to RMSM: 57.6 and RMSSD: 42.8 for the young group). These results indicate a decrease in parasympathetic modulation in postmenopausal women compared to young women which was possibly due both to the influence of age and hormonal factors. Thus, time domain HRV proved to be a noninvasive and sensitive method for the identification of changes in autonomic modulation of the sinus node in postmenopausal women.

Sex hormone modulation of serotonin-induced coronary vasodilation in isolated heart

The present study was designed to evaluate the differences in the coronary vasodilator actions of serotonin (5-HT) in isolated heart obtained from naive or castrated male and female rats that were treated with either estrogen or testosterone. Hearts from 12 groups of rats were used: male and female naive animals, castrated, castrated and treated with 17ß-estradiol (0.5 µg kg-1 day-1) for 7 or 30 days, and castrated and treated with testosterone (0.5 mg kg-1 day-1) for 7 or 30 days. After treatment, the vascular reactivity of the coronary bed was evaluated. Baseline coronary perfusion pressure (CPP) was determined and dose-response curves to 5-HT were generated. Baseline CPP differed between male (70 ± 6 mmHg, N = 10) and female (115 ± 6 mmHg, N = 12) naive rats. Maximal 5-HT-induced coronary vasodilation was higher (P<0.05) in naive female than in naive male rats. In both sexes, 5-HT produced endothelium-dependent coronary vasodilation. After castration, there was no significant difference in baseline CPP between hearts obtained from male and female rats (75 ± 7 mmHg, N = 8, and 83 ± 5 mmHg, N = 8, respectively). Castration reduced the 5-HT-induced maximal vasodilation in female and male rats (P<0.05). Estrogen treatment of castrated female rats restored (P<0.05) the vascular reactivity. In castrated male rats, 30 days of estrogen treatment increased (P<0.05) the responsiveness to 5-HT. The endothelium-dependent coronary vasodilator actions of 5-HT are greater in female rats and are modulated by estrogen. A knowledge of the mechanism of action of estrogen on coronary arteries could aid in the development of new therapeutic strategies and potentially decrease the incidence of cardiovascular disease in both sexes.

Heart rate and body weight alterations in juvenile specimens of the tropical land snail Megalobulimus sanctipauli during dormancy

The time course of heart rate and body weight alterations during the natural period of dormancy were determined in active feeding and dormant juvenile specimens of Megalobulimus sanctipauli. In both groups, heart rate markedly decreased during the first 40 days of dormancy, tending to stabilize thereafter. This time period coincided with the decrease in environmental temperature during autumn-winter. At the end of the dormancy period, surviving active feeding and dormant snails showed a significant decrease in heart rate which, however, was significantly greater in the latter group. Total body weight decreased concomitantly with heart rate in dormant snails but remained constant in active feeding snails. Body hydration induced significant increases in weight and heart rate in surviving dormant snails. Feeding following hydration promoted a new significant increase in heart rate but not in weight. These results indicate that the decrease in heart rate observed in juvenile specimens of M. sanctipauli during dormancy may be due to at least three factors: 1) decrease in environmental temperature during autumn-winter, 2) starvation which leads to the depletion of endogenous fuel reserves and to a probable decrease in hemolymph nutrient levels, and 3) dehydration which leads to a probable decrease in hemolymph volume and venous return and/or to an increase in hemolymph osmolarity.

Effects of aerobic exercise training on heart rate variability during wakefulness and sleep and cardiorespiratory responses of young and middle-aged healthy men

The purpose of the present study was to evaluate the effects of aerobic physical training (APT) on heart rate variability (HRV) and cardiorespiratory responses at peak condition and ventilatory anaerobic threshold. Ten young (Y: median = 21 years) and seven middle-aged (MA = 53 years) healthy sedentary men were studied. Dynamic exercise tests were performed on a cycloergometer using a continuous ramp protocol (12 to 20 W/min) until exhaustion. A dynamic 24-h electrocardiogram was analyzed by time (TD) (standard deviation of mean R-R intervals) and frequency domain (FD) methods. The power spectral components were expressed as absolute (a) and normalized units (nu) at low (LF) and high (HF) frequencies and as the LF/HF ratio. Control (C) condition: HRV in TD (Y: 108, MA: 96 ms; P<0.05) and FD - LFa, HFa - was significantly higher in young (1030; 2589 ms²/Hz) than in middle-aged men (357; 342 ms²/Hz) only during sleep (P<0.05); post-training effects: resting bradycardia (P<0.05) in the awake condition in both groups; VO2 increased for both groups at anaerobic threshold (P<0.05), and at peak condition only in young men; HRV in TD and FD (a and nu) was not significantly changed by training in either groups. The vagal predominance during sleep is reduced with aging. The resting bradycardia induced by short-term APT in both age groups suggests that this adaptation is much more related to intrinsic alterations in sinus node than in efferent vagal-sympathetic modulation. Furthermore, the greater alterations in VO2 than in HRV may be related to short-term APT.

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.

Heart rate recovery after exercise: relations to heart rate variability and complexity

Physical exercise is associated with parasympathetic withdrawal and increased sympathetic activity resulting in heart rate increase. The rate of post-exercise cardiodeceleration is used as an index of cardiac vagal reactivation. Analysis of heart rate variability (HRV) and complexity can provide useful information about autonomic control of the cardiovascular system. The aim of the present study was to ascertain the association between heart rate decrease after exercise and HRV parameters. Heart rate was monitored in 17 healthy male subjects (mean age: 20 years) during the pre-exercise phase (25 min supine, 5 min standing), during exercise (8 min of the step test with an ascending frequency corresponding to 70% of individual maximal power output) and during the recovery phase (30 min supine). HRV analysis in the time and frequency domains and evaluation of a newly developed complexity measure - sample entropy - were performed on selected segments of heart rate time series. During recovery, heart rate decreased gradually but did not attain pre-exercise values within 30 min after exercise. On the other hand, HRV gradually increased, but did not regain rest values during the study period. Heart rate complexity was slightly reduced after exercise and attained rest values after 30-min recovery. The rate of cardiodeceleration did not correlate with pre-exercise HRV parameters, but positively correlated with HRV measures and sample entropy obtained from the early phases of recovery. In conclusion, the cardiodeceleration rate is independent of HRV measures during the rest period but it is related to early post-exercise recovery HRV measures, confirming a parasympathetic contribution to this phase.

Gender-related differences in the effects of nitric oxide donors on neuroleptic-induced catalepsy in mice

It has been suggested that nigrostriatal dopaminergic transmission is modulated by nitric oxide (NO). Since there is evidence that gonadal hormones can affect extrapyramidal motor behavior in mammals, we investigated the effects of isosorbide dinitrate (ISD), linsidomine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP), three pharmacologically different NO donors, on neuroleptic-induced catalepsy in 60- to 80-day-old male and female albino mice. Catalepsy was induced with haloperidol (1 mg/kg, ip) and measured at 30-min intervals by means of a bar test. Drugs (or appropriate vehicle) were injected ip 30 min before haloperidol, with each animal being used only once. ISD (5, 20 and 50 mg/kg) caused a dose-dependent inhibition of catalepsy in male mice (maximal effect 120 min after haloperidol: 64% inhibition). In the females only at the highest dose of ISD was an attenuation of catalepsy observed, which was mild and short lasting. SIN-1 (10 and 50 mg/kg) did not significantly affect catalepsy in female mice, while a significant attenuation was observed in males at the dose of 50 mg/kg (maximal inhibition: 60%). SNAP (20 mg/kg) significantly attenuated catalepsy in males 120 min after haloperidol (44% inhibition), but had no significant effect on females. These results basically agree with literature data showing that NO facilitates central dopaminergic transmission, although the mechanisms are not fully understood. They also reveal the existence of gender-related differences in this nitrergic modulation in mice, with females being less affected than males.

The availability of full match sibling donors and feasibility of allogeneic bone marrow transplantation in Brazil

The feasibility of allogeneic bone marrow transplantation (alloBMT) in a developing country has not yet been demonstrated. Many adverse factors including social and economic limitations may reduce the overall results of this complex and expensive procedure. Our objective was to characterize the most important clinical, social and economic features of candidates for transplantation and their potential donors as well as the influence of these factors on overall survival in a retrospective and exploratory analysis at a university hospital. From July 1993 to July 2001, candidates for BMT were referred to the Bone Marrow Transplantation Unit by Hematology and Oncology Centers from several regions of Brazil. A total of 1138 patients were referred to us as candidates for alloBMT. Median age was 25 years (range: 2 months-60 years), 684 (60.1%) were males and 454 (39.9%) were females. The clinical indications were severe aplastic anemia and hematological malignancies. From the total of 1138 patients, 923 had HLA-typing; 497/923 (53.8%) candidates had full match donors; 352/1138 (30.8%) were eligible for alloBMT. Only 235 of 352 (66.7%) were transplanted. Schooling was 1st to 8th grade for 123/235 (52.3%); monthly family income ranged from US$60 (7%) to more than US$400 (36%). Overall survival for patients with chronic myeloid leukemia, severe aplastic anemia and acute myeloid leukemia was 58, 60 and 30%, respectively. Thus, overall survival rates for the most frequent hematological diseases were similar to those reported in the International Registry, except for acute myeloid leukemia. This descriptive and exploratory analysis suggests the feasibility of alloBMT in a developing country like Brazil.

Effects of hypertonic sodium chloride solution on the electrophysiologic alterations caused by bupivacaine in the dog heart

The effects of various hypertonic solutions on the intraventricular conduction, ventricular repolarization and the arrhythmias caused by the intravenous (iv) injection of bupivacaine (6.5 mg/kg) were studied in sodium pentobarbital-anesthetized mongrel dogs. Hypertonic solutions, given iv 5 min before bupivacaine, were 7.5% (w/v) NaCl, 5.4% (w/v) LiCl, 50% (w/v) glucose (2,400 mOsm/l, 5 ml/kg), or 20% (w/v) mannitol (1,200 mOsm/l, 10 ml/kg). Bupivacaine induced severe arrhythmias and ventricular conduction and repolarization disturbances, as reflected by significant increases in QRS complex duration, HV interval, IV interval and monophasic action potential duration, as well as severe hemodynamic impairment. Significant prevention against ventricular electrophysiologic and hemodynamic disturbances and ventricular arrhythmias was observed with 7.5% NaCl (percent increase in QRS complex duration: 164.4 ± 21.8% in the non-pretreated group vs 74.7 ± 14.1% in the pretreated group, P<0.05; percent increase in HV interval: 131.4 ± 16.1% in the non-pretreated group vs 58.2 ± 7.5% in the pretreated group, P<0.05; percent increase in monophasic action potential duration: 22.7 ± 6.8% in the non-pretreated group vs 9.8 ± 6.3% in the pretreated group, P<0.05; percent decrease in cardiac index: -46 ± 6% in the non-pretreated group vs -28 ± 5% in the pretreated group, P<0.05). The other three hypertonic solutions were ineffective. These findings suggest an involvement of sodium ions in the mechanism of hypertonic protection.

Impaired beta-adrenergic response and decreased L-type calcium current of hypertrophied left ventricular myocytes in postinfarction heart failure

Infarct-induced heart failure is usually associated with cardiac hypertrophy and decreased ß-adrenergic responsiveness. However, conflicting results have been reported concerning the density of L-type calcium current (I Ca(L)), and the mechanisms underlying the decreased ß-adrenergic inotropic response. We determined I Ca(L) density, cytoplasmic calcium ([Ca2+]i) transients, and the effects of ß-adrenergic stimulation (isoproterenol) in a model of postinfarction heart failure in rats. Left ventricular myocytes were obtained by enzymatic digestion 8-10 weeks after infarction. Electrophysiological recordings were obtained using the patch-clamp technique. [Ca2+]i transients were investigated via fura-2 fluorescence. ß-Adrenergic receptor density was determined by [³H]-dihydroalprenolol binding to left ventricle homogenates. Postinfarction myocytes showed a significant 25% reduction in mean I Ca(L) density (5.7 ± 0.28 vs 7.6 ± 0.32 pA/pF) and a 19% reduction in mean peak [Ca2+]i transients (0.13 ± 0.007 vs 0.16 ± 0.009) compared to sham myocytes. The isoproterenol-stimulated increase in I Ca(L) was significantly smaller in postinfarction myocytes (Emax: 63.6 ± 4.3 vs 123.3 ± 0.9% in sham myocytes), but EC50 was not altered. The isoproterenol-stimulated peak amplitude of [Ca2+]i transients was also blunted in postinfarction myocytes. Adenylate cyclase activation through forskolin produced similar I Ca(L) increases in both groups. ß-Adrenergic receptor density was significantly reduced in homogenates from infarcted hearts (Bmax: 93.89 ± 20.22 vs 271.5 ± 31.43 fmol/mg protein in sham myocytes), while Kd values were similar. We conclude that postinfarction myocytes from large infarcts display reduced I Ca(L) density and peak [Ca2+]i transients. The response to ß-adrenergic stimulation was also reduced and was probably related to ß-adrenergic receptor down-regulation and not to changes in adenylate cyclase activity.

Standardization of an isolated pig heart preparation with parabiotic circulation: methodological considerations

In the present study we standardized an experimental model of parabiotic circulation of isolated pig heart. The isolated heart was perfused with arterial blood from a second animal as support and submitted to regional ischemia for 30 min, followed by total ischemia for 90 min and reperfusion for 90 min. Parameters for measurement of ventricular performance using different indices measured directly or indirectly from intraventricular pressure were defined as: maximum peak pressure, final diastolic pressure, pressure developed, first derivative of maximum pressure (dP/dt max), first derivative of minimum pressure (dP/dt min), systolic stress of the left ventricle (sigmas), and maximum elastance of the left ventricle. Isolated hearts subjected to regional and global ischemia presented significant worsening of all measured parameters. Less discriminative parameters were dP/dt max and dP/dt min. Elastance was the most sensitive parameter during the reperfusion period, demonstrating an early loss of ventricular function during reperfusion. The model proved to be stable and reproducible and permitted the study of several variables in the isolated heart, such as ischemia and reperfusion phenomena, the effects of different drugs, surgical interventions, etc. The model introduces an advantage over the classical models which use crystalloid solutions as perfusate, because parabiotic circulation mimics heart surgery with extracorporeal circulation.

Antagonism of the acute hemodynamic effects of captopril in decompensated congestive heart failure by aspirin administration

The concomitant use of angiotensin-converting enzyme inhibitors and aspirin may cause pharmacological antagonism. Hence we examined the effect of aspirin on the neurohormonal function and hemodynamic response to captopril in heart failure patients. Between April 1999 and August 2000, 40 patients were randomized into four equal groups: 1) captopril, 2) aspirin, 3) captopril-aspirin: captopril was given alone on the first day, followed by aspirin on the remaining days, and 4) aspirin-captopril: aspirin was given alone on the first day, followed by captopril on the remaining days. Hemodynamic, norepinephrine and prostaglandin measurements were performed pre- and post-medication for 4 days. Captopril (50 mg) was given orally every 8 h and 300 mg aspirin was given on the first day, and 100 mg/day thereafter. In the captopril group and only on the first day of captopril-aspirin, captopril produced increases in cardiac index (2.1 ± 0.6 to 2.5 ± 0.5 l min-1 m-2, P<0.0001), and reduced peripheral vascular resistance (1980 ± 580 to 1545 ± 506 dyn s-1 cm-5/m², P<0.0001) and pulmonary wedge pressure (20 ± 4 to 15 ± 4 mmHg, P<0.0001). In contrast, aspirin alone or associated with captopril showed no significant hemodynamic changes. Norepinephrine decreased (P<0.02) only in the captopril group. Prostaglandin levels did not differ significantly among groups. Thus, aspirin compromises the short-term hemodynamic and neurohormonal effects of captopril in patients with acute decompensated heart failure.

Role of nitric oxide of the median preoptic nucleus (MnPO) in the alterations of salivary flow, arterial pressure and heart rate induced by injection of pilocarpine into the MnPO and intraperitoneally

We investigated the effect of L-NAME, a nitric oxide (NO) inhibitor and sodium nitroprusside (SNP), an NO-donating agent, on pilocarpine-induced alterations in salivary flow, mean arterial blood pressure (MAP) and heart rate (HR) in rats. Male Holtzman rats (250-300 g) were implanted with a stainless steel cannula directly into the median preoptic nucleus (MnPO). Pilocarpine (10, 20, 40, 80, 160 µg) injected into the MnPO induced an increase in salivary secretion (P<0.01). Pilocarpine (1, 2, 4, 8, 16 mg/kg) ip also increased salivary secretion (P<0.01). Injection of L-NAME (40 µg) into the MnPO prior to pilocarpine (10, 20, 40, 80, 160 µg) injected into the MnPO or ip (1, 2, 4, 8, 16 mg/kg) increased salivary secretion (P<0.01). SNP (30 µg) injected into the MnPO or ip prior to pilocarpine attenuated salivary secretion (P<0.01). Pilocarpine (40 µg) injection into the MnPO increased MAP and decreased HR (P<0.01). Pilocarpine (4 mg/kg body weight) ip produced a decrease in MAP and an increase in HR (P<0.01). Injection of L-NAME (40 µg) into the MnPO prior to pilocarpine potentiated the increase in MAP and reduced HR (P<0.01). SNP (30 µg) injected into the MnPO prior to pilocarpine attenuated (100%) the effect of pilocarpine on MAP, with no effect on HR. Administration of L-NAME (40 µg) into the MnPO potentiated the effect of pilocarpine injected ip. SNP (30 µg) injected into the MnPO attenuated the effect of ip pilocarpine on MAP and HR. The present study suggests that in the rat MnPO 1) NO is important for the effects of pilocarpine on salivary flow, and 2) pilocarpine interferes with blood pressure and HR (side effects of pilocarpine), that is attenuated by NO.