Pharmacology of atriopeptin in the adult rat: power spectra of the fluctuations in heart rate]

The persistence of the cardiac beat-to-beat control is studied in the anesthetized and the pithed adult rat by means of spectral analysis. The data show that atriopeptin affects the amplitude of the heart rate low frequency fluctuations, significantly increasing the spectral patterns both in the anesthetized and the pithed rat. The atriopeptin enhancement of the low frequency range in heart rate fluctuations provides further insight into the hypothesis that beat to beat variability in hemodynamic parameters reflects a compensatory response in the short term cardiovascular control.     

Antiarrhythmic drugs and the modulation of autonomic control of heart rate in rabbits

A model of the components of autonomic control of heart rate was developed and used for the evaluation of quantitative contribution of sympathetic and vagal tone to cardiac function. In conscious rabbits, sequential inhibition of muscarinic and beta receptors was produced and the relative contributions of vagal and sympathetic tone were characterized. Based on the model, the magnitude of presynaptic interaction between the vagal and sympathetic nerve endings was evaluated. From data in the literature, similar analysis of the control of heart rate was performed for the rat, dog, and human subject and compared with that of the rabbit. The results show that the resting rabbit heart is under less vagal tone than sympathetic tone as compared with other species. The effects of acute administration of amiodarone on the sympathetic and parasympathetic control of heart rate as well as intrinsic heart rate were investigated. Amiodarone decreased the heart rate, which resulted from a direct effect on the sinoatrial (SA) node. In addition, it attenuated the vagal as well as the sympathetic effects on the SA node. The effect on vagal component was greater. Further, the effects of other antiarrhythmic drugs on the electrocardiographic PP and PR intervals were studied. The usefulness of this model for the analysis of the effects of antiarrhythmic drugs is presented.     

M-chlorophenylpiperazine increases blood pressure and heart rate in pithed and conscious rats

In pithed rats, m-chlorophenylpiperazine (m-CPP) produced marked, dose-dependent (ED50 = 0.18 mumol) increases in mean arterial blood pressure which peaked within 1 minute and were sustained over 15 minutes. Two serotonin antagonists, metergoline and ritanserin, completely blocked the pressor responses to 2.5 mg/kg m-CPP in pithed adrenal demedullated rats, while alpha-adrenergic blockade by prazosin plus yohimbine was without effect, suggesting that the doubling in blood pressure produced by m-CPP was mediated via serotonin receptors within blood vessels. Somewhat smaller increases in blood pressure over baseline values were observed after m-CPP administration to conscious, freely moving rats. A small but statistically significant increase in heart rate peaked 5 minutes after m-CPP and also was blocked by metergoline but was only minimally affected by ritanserin or the prazosin-yohimbine combination. These results with m-CPP support other evidence for two or more separable effects of serotonergic agonists on the peripheral cardiovascular system.     

Chronic intermittent hypoxia impairs baroreflex control of heart rate but enhances heart rate responses to vagal efferent stimulation in anesthetized mice

Chronic intermittent hypoxia (CIH) leads to increased sympathetic nerve activity and arterial hypertension. In this study, we tested the hypothesis that CIH impairs baroreflex (BR) control of heart rate (HR) in mice, and that decreased cardiac chronotropic responsiveness to vagal efferent activity contributes to such impairment. C57BL/6J mice were exposed to either room air (RA) or CIH (6-min alternations of 21% O(2) and 5.7% O(2), 12 h/day) for 90 days. After the treatment period, mice were anesthetized (Avertin) and arterial blood pressure (ABP) was measured from the femoral artery. Mean ABP (MABP) was significantly increased in mice exposed to CIH (98.7 +/- 2.5 vs. RA: 78.9 +/- 1.4 mmHg, P < 0.001). CIH increased HR significantly (584.7 +/- 8.9 beats/min; RA: 518.2 +/- 17.9 beats/min, P < 0.05). Sustained infusion of phenylephrine (PE) at different doses (0.1-0.4 microg/min) significantly increased MABP in both CIH and RA mice, but the ABP-mediated decreases in HR were significantly attenuated in mice exposed to CIH (P < 0.001). In contrast, decreases in HR in response to electrical stimulation of the left vagus nerve (30 microA, 2-ms pulses) were significantly enhanced in mice exposed to CIH compared with RA mice at low frequencies. We conclude that CIH elicits a sustained impairment of baroreflex control of HR in mice. The blunted BR-mediated bradycardia occurs despite enhanced cardiac chronotropic responsiveness to vagal efferent stimulation. This suggests that an afferent and/or a central defect is responsible for the baroreflex impairment following CIH.     

Autonomic control of heart rate in the adult, aquatic Notophthalmus viridescens viridescens

1. We investigated the role of the autonomic nervous system in the control of the heart rate using an isolated heart preparation. 2. Addition of the parasympathetic blocker, atropine, to the organ bath resulted in an increase in heart rate as expected. 3. Addition of the sympathetic blocker, ergotamine, to the organ bath showed no change in the heart rate. 4. Addition of the sympathetic blocker, propranolol, to the organ bath resulted in the expected decrease in heart rate. 5. Both the sympathetic and parasympathetic nervous systems appear to play a role in the control of the heart rate.     

Power spectra of the inter-cycle heart fluctuations in Xenopus laevis (L.), conscious or pithed, exposed to temperature changes and pharmacological treatments]

Spectral analysis of spontaneous heart rate fluctuations, a powerful noninvasive tool for quantifying autonomic nervous system activity, was assessed in Xenopus Laevis, intact or spinalized, at different temperatures and by use of pharmacological tools. As expected, increasing the body temperature resulted in a positive chronotropic effect, both in the conscious and the spinalized preparations. Characteristic modifications of the spontaneous heart rate fluctuations were detected in both the experimental conditions. Different receptor drugs, which selectively interfere with the variously superimposed vegetative sections of the nervous control, had been proved to be effective in the new assay.     

L-thyroxine and L-triiodothyronine in the cerebral tissues of the adult rat. Effect of hypothyroidism]

The L-thyroxine and L-triiodothyronine concentrations in several brain areas (cerebral cortex, brain stem, hypothalamus, total brain and hypophysis) in normal and hypothyroid rats have been studied. Results show that L-thyroxine values at tissue level are inferior in the hypothyroid group, although non-significant with respect to the control group, whereas L-triiodothyronine presents values similar to the hypothyroid group and its control in all the brain regions studied with the exception of hypophysis. These results show that in hypothyroid situations exist a compensatory mechanism for maintaining the adequate L-triiodothyronine levels in several brain areas, although the serum levels are strongly decreased in hypothyroid animals.     

Effect of neuromuscular blocking drugs on arterial pressure and heart rate in rats

The effects of neuromuscular blocking drugs on mean arterial pressure (MAP) and heart rate (HR) were studied in rats which were anaesthetised, tracheotomized and ventilated artificially. The arterial pressure was recorded from the carotid artery. Seven neuromuscular blocking drugs were injected intravenously at doses of 1, 5, and 25 mumol/kg. d-Tubocurarine, alcuronium and vecuronium lowered MAP in a dose dependent manner (maximum 40%). Succinylcholine, 1 mumol/kg, reduced MAP and HR, whereas the two larger doses increased them. Gallamine, 25 mumol/kg, or metocurine and pancuronium, 1 or 5 mumol/kg, each, induced short-lasting rises in MAP. Pancuronium, 25 mumol/kg, decreased MAP by 25%, while the largest dose of metocurine appeared to be toxic. The cardiovascular responses to neuromuscular blocking drugs were antagonized or abolished by pretreatment with the ganglionic blocking agent pentolinium. Pentolinium itself markedly reduced MAP and HR. After ganglionic blockade and restoration of MAP by noradrenaline infusion, all the neuromuscular blocking drugs induced short-lasting increases in MAP (10-30%), except d-tubocurarine which still reduced MAP by 30%, a fall which, in contrast to the effect in the absence of the pretreatments, was transient. This response to d-tubocurarine could not be abolished by a combined pretreatment with H1 and H2 antagonists showing that the hypotensive effect of this drug was not due to the liberation of histamine. These results suggest that the cardiovascular responses to neuromuscular blocking drugs in rats might be partly due to ganglionic effects. Other mechanisms are also involved since after the restoration of blood pressure by noradrenaline during the ganglionic blockade some cardiovascular responses to these drugs still occurred.     

Baroreflex control of heart rate in young and adult salt hypertensive inbred Dahl rats

Baroreflex control of heart rate was studied in inbred salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) Dahl rats that were subjected to chronic dietary sodium chloride loading (for 4 weeks) either in youth or only in adulthood, i.e. from the age of 4 or 12 weeks. Using phenylephrine administration to pentobarbital-anesthetized male rats we have demonstrated the decreased baroreflex sensitivity (lower slope for reflex bradycardia) in young prehypertensive SS/Jr rats fed a low-salt diet as compared to age-matched SR/Jr animals. High salt intake further suppressed baroreflex sensitivity in young SS/Jr but not in SR/Jr rats. Baroreflex sensitivity decreased with age in SR/Jr rats, whereas it increased in SS/Jr rats fed a low-salt diet. Thus at the age of 16 weeks baroreflex sensitivity was much higher in SS/Jr than in SR/Jr animals. High salt intake lowered baroreflex sensitivity even in adult SS/Jr rats without affecting it in adult SR/Jr rats. Nevertheless, baroreflex sensitivity was significantly lower in young SS/Jr rats with a severe salt hypertension than in adult ones with a moderate blood pressure elevation. It is concluded that the alterations of baroreflex sensitivity in young inbred SS/Jr rats (including the response to high salt intake) are similar to those described earlier for outbred salt-sensitive Dahl rats. We have, however, disclosed contrasting age-dependent changes of baroreflex sensitivity in both inbred substrains of Dahl rats.     

Complexity of heart rate fluctuations in near-term sheep and human fetuses during sleep.

We investigated how the complexity of fetal heart rate fluctuations (fHRF) is related to the sleep states in sheep and human fetuses. The complexity as a function of time scale for fetal heart rate data for 7 sheep and 27 human fetuses was estimated in rapid eye movement (REM) and non-REM sleep by means of permutation entropy and the associated Kullback-Leibler entropy. We found that in humans, fHRF complexity is higher in non-REM than REM sleep, whereas in sheep this relationship is reversed. To show this relation, choice of the appropriate time scale is crucial. In sheep fetuses, we found differences in the complexity of fHRF between REM and non-REM sleep only for larger time scales (above 2.5 s), whereas in human fetuses the complexity was clearly different between REM and non-REM sleep over the whole range of time scales. This may be due to inherent time scales of complexity, which reflect species-specific functions of the autonomic nervous system. Such differences have to be considered when animal data are translated to the human situation.     

Blood pressure and heart rate and withdrawal of antihypertensive drugs.

The immediate effects on heart rate and blood pressure of withdrawing antihypertensive drugs were studied over three-day periods in 26 patients. Four groups of drugs were studied. After withdrawal all patients taking clonidine showed a considerable increase in heart rate and blood pressure with intense ectopic activity. Patients taking postganglionic neurone-blocking drugs showed a similar but less pronounced reaction with increased ventricular ectopic activity. No alarming reactions were seen after withdrawal of methyldopa or beta-blocking drugs. Methyldopa and, especially, beta-blocking drugs are less likely to produce withdrawal reactions than clonidine or the postganglionic neurone-blocking drugs, and patients taking these drugs are therefore less likely to suffer violent reactions if they forget to take their tablets.     

Hormonal factors in the control of heart rate in normoxaemic and hypoxaemic fetal, neonatal and adult sheep

The relationship of plasma levels of adrenaline, noradrenaline, arginine vasopressin (AVP) and plasma renin activity (PRA) to heart rate were studied in normoxaemic and hypoxaemic fetal, neonatal and adult sheep. The mean heart rate response of fetuses at the end of a 30 minute period of 10% oxygen delivery to the maternal ewe was tachycardia. However bradycardia, usually of a transient nature, was observed in 9 of the 12 fetuses (P less than 0.05). Multiple regression analysis was used to determine the contribution of blood gas, blood pressure and plasma hormone levels to the variance in heart rate in the perinatal sheep. 22% of the variance in fetal heart rate was provided by PRA and age from conception (P less than 0.001). Tachycardia was the invariable heart rate response of the neonates and adults to hypoxaemia. 61% of the variance in neonatal heart rate was contributed by PaO2, PaCO2, AVP, PRA and systolic blood pressure (SBP, P less than 0.001). PaO2 and plasma levels of adrenaline were significantly related to adult heart rate (P less than 0.001). Those fetuses which developed bradycardia had lower PaO2 but higher AVP and PRA during hypoxaemia than those which did not develop bradycardia. The major determinant of the area of the fetal bradycardia response was found, by multiple regression analysis, to be plasma adrenaline concentration (P less than 0.05). Thus different hormonal factors may play a role in the regulation of heart rate in normoxaemic and hypoxaemic fetal, neonatal and adult sheep.     

Inotropic responses of the left ventricle to changes in heart rate in anesthetized rabbits

Factors known to influence left ventricular contractility include preload, afterload, circulating catecholamine concentration, efferent sympathetic discharge, and heart rate. Heart rate influences have been primarily determined in the dog, whereas the influence of heart rate in smaller mammals has not been determined. Eight pentobarbital-anesthetized rabbits were instrumented to measure electrocardiogram, heart rate, left ventricular pressure, end-diastolic pressure, dP/dt, and mean and pulsatile aortic pressures. Systematic bradycardia was induced by stimulating the peripheral end of the sectioned right vagus nerve. Between 293 and 235 beats/min, there was no change in (dP/dt)max as heart rate was decreased. Below this range there was a direct relationship between (dP/dt)max and heart rate. Preload remained unchanged down to 132 beats/min. There was a small but significant decrease in afterload (0.09 mmHg X beat-1 X min-1; 1 mmHg = 133.32 Pa) throughout the decrease in heart rate. Infusion of propranolol (2.0 mg/kg) produced no marked change in the heart rate - (dP/dt)max relationship, although both resting heart rate and (dP/dt)max were reduced. This study demonstrates that (dP/dt)max is not influenced by changes in heart rate above 235 beats/min in the pentobarbital-anesthetized rabbit. These results differ from findings in other animals, and demonstrate that species and heart rate ranges must be considered when drawing conclusions regarding (dP/dt)max as a reliable index of contractility.     

Periodic fluctuations of the blood pressure and heart contraction rate in premature newborn infants

To study the postnatal development of circadian rhythm of the blood pressure and the heart rate these parameters were monitored automatically during 24-72 hours at 5h intervals. Fifty infants were investigated at the age 1, 2, 3, and 4 weeks. The results were compared with the cosine curves of different periods (1-48 h) by the IBM PC XT. The fluctuations with all mentioned periods including circadian could be determined in each infant, dominating period being of any duration. In traditional approach the expressiveness of periodical fluctuations is evaluated by the amplitude of cosine curve. Application of the criterion has shown that only amplitude values exceeding 8 mm Hg should be taken into account. Hence, the analysis of BP and HR time series has demonstrated that about 45-50% of the infants have noncircadian rhythms, 20-20% have no significant periodical fluctuations and only 25-30% have circadian rhythm.     

Effect of some acute and prophylactic antimigraine drugs on the vasodepressor sensory CGRPergic outflow in pithed rats

AimsThis study analyzed in pithed rats the effect of several acute and prophylactic antimigraine drugs on the CGRPergic vasodepressor sensory outflow, in an attempt to investigate systemic cardiovascular effects in a model unrelated to migraine.Main methodsMale Wistar pithed rats were pretreated with continuous i.v. infusions of hexamethonium (2 μg/kg.min; to block autonomic outflow) and methoxamine (15–20 μg/kg.min; to maintain diastolic blood pressure at around 130 mmHg). Under these conditions, the effect of both electrical stimulation (0.56–5.6 Hz; 50 V and 2 ms) of the spinal cord (T₉–T₁₂) or i.v. bolus injections of exogenous α-CGRP (0.1–1 µg/kg) were studied in animals pretreated with continuous i.v. infusions of sumatriptan (1–100 μg/kg.min), ergotamine (0.18–0.56 μg/kg.min), dihydroergotamine (1–10 μg/kg.min), magnesium valproate (1000–1800 μg/kg.min), propranolol (100–300 μg/kg.min) or their respective vehicles.Key findingsElectrical stimulation of the spinal cord and i.v. bolus injections of exogenous α-CGRP resulted in, respectively, frequency- and dose-dependent decreases in diastolic blood pressure without affecting heart rate. Moreover, the infusions of sumatriptan, ergotamine and dihydroergotamine, but not of magnesium valproate, propranolol or their respective vehicles, dose-dependently inhibited the vasodepressor responses to electrical stimulation. In contrast, sumatriptan (10 μg/kg.min), ergotamine (0.31 μg/kg.min) and dihydroergotamine (3 μg/kg.min) failed to inhibit the vasodepressor responses to exogenous α-CGRP.SignificanceThe above findings suggest that the acute (rather than the prophylactic) antimigraine drugs attenuate the vasodepressor sensory outflow mainly by prejunctional mechanisms. This may be of particular relevance when considering potential cardiovascular adverse effects by acute antimigraine drugs.     

Autonomic control of heart rate during exercise studied by heart rate variability spectral analysis.

Spectral analysis of heart rate variability (HRV) might provide an index of relative sympathetic (SNS) and parasympathetic nervous system (PNS) activity during exercise. Eight subjects completed six 17-min submaximal exercise tests and one resting measurement in the upright sitting position. During submaximal tests, work rate (WR) was increased for the initial 3 min in a ramp fashion until it reached constant WRs of 20 W, or 30, 60, 90, 100, and 110% of the predetermined ventilatory threshold (Tvent). Ventilatory profile and alveolar gas exchange were monitored breath by breath, and beat-to-beat HRV was measured as R-R intervals of an electrocardiogram. Spectral analysis was applied to the HRV from 7 to 17 min. Low-frequency (0-0.15 Hz) and high-frequency (0.15-1.0 Hz) areas under power spectra (LO and HI, respectively) were calculated. The indicator of PNS activity (HI) decreased dramatically (P less than 0.05) when the subjects exercised compared with rest and continued to decrease until the intensity reached 60% Tvent. The indicator of SNS activity (LO/HI) remained unchanged up to 100% Tvent, whereas it increased abruptly (P less than 0.05) at 110% Tvent. The results suggested that (cardiac) PNS activity decreased progressively from rest to a WR equivalent to 60% Tvent, and SNS activity increased only when exercise intensity exceeded Tvent.     

Effect of prenatal hypoxia on heat stress-mediated cardioprotection in adult rat heart

Fetal programming has profound effects on cardiovascular function in later adult life. We tested the hypothesis that chronic hypoxic exposure during fetal development downregulates endogenous cardioprotective mechanisms in adult rats. Time-dated pregnant rats were divided between normoxic and hypoxic (10.5% O2 from days 15 to 21 of gestation) groups. The male progeny were studied at 2 mo of age. Rats were subjected to heat stress (42 degrees C for 15 min). After 24 h, hearts were excised and subjected to 30 min of global ischemia and 1 h of reperfusion. Prenatal hypoxia did not change adult rat body weight and heart weight, but significantly increased the cross-sectional area of a left ventricular (LV) myocyte. Heat stress significantly improved postischemic recovery of LV function in normoxic control rats, but not in prenatally hypoxic rats. The infarct size in the LV resulting from ischemia-reperfusion was reduced by the heat stress pretreatment in control rats, but not in prenatally hypoxic rats. In accordance, heat stress significantly increased LV myocardial content of heat shock protein 70 only in normoxic control rats. In addition, there was a significant decrease in the LV myocardial content of the PKC-epsilon isoform in prenatally hypoxic rats compared with control rats. We conclude that prenatal hypoxia causes in utero programming of hsp70 gene in the LV, leading to an inhibition of its response to heat stress and a loss of cardioprotection in later adult life.