A possible mode of cardiovascular actions of dopamine in dogs.
(17/19128)
A possible mode of cardiovascular actions of dopamine was studied using ephedrine. In the dog pretreated with repeated administrations of ephedrine (total dose, 40 or 80 mg/kg, i.v.) or with combined administrations of ephedrine (total dose, 90 mg/kg, s.c. and i.v.) and reserpine (2 mg/kg, s.c., 24 hr previously), pressor responses to dopamine were eliminated and reversed to depressor responses whereas depressor responses to dopamine were potentiated. Positive chronotropic effects of dopamine were almost eliminated. Pressor and positive chronotropic effects of tyramine were almost abolished. Sympathomimetic effect of noradrenaline and adrenaline were potentiated while those of isoprenaline were inhibited. In the heart-lung preparation of ephedrine-treated dogs (total dose, 40 mg/kg, i.v.), cardiac stimulating effects of dopamine and tyramine were strongly depressed, and those of noradrenaline, adrenaline and isoprenaline were reduced to some extent. In the open-chest dogs, after pretreatment of cocaine (4 mg/kg, i.v.), pressor, positive inotropic and chronotropic effects of noradrenaline were potentiated, whilst those of tyramine were inhibited. Those of dopamine were not visibly altered, but depressor, negative chronotropic and inotropic effects of dopamine appeared at small doses. In the ephedrine-pretreated dogs, these sympathomimetic effects of dopamine and tyramine after cocaine were strongly depressed and those of noradrenaline were inhibited to a certain degree. The results obtained with ephedrine suggest that dopamine differs from other catecholamines and tyramine in the mode of cardiovascular actions. (+info)
Pharmacodynamic actions of (S)-2-[4,5-dihydro-5-propyl-2-(3H)-furylidene]-1,3-cyclopentanedione (oudenone).
(18/19128)
The pharmacodynamic actions of (S)-2-[4,5-dihydro-5-propyl-2(3H)-furylidene]-1,3-cyclopentanedione (oudenone) were studied in both anesthetized animals and isolated organs. Oudenone (10--40 mg/kg i.v.) induced an initial rise in blood pressure followed by a prolonged hypotension in the anesthetized rats. In unanesthetized spontaneously hypertensive rats (SHR), oudenone (5--200 mg/kg p.o.) caused a dose-related decrease in the systolic blood pressure. The initial pressor effect was diminished by pretreatments with phentolamine, guanethidine, hexamethonium and was abolished in the pithed rats. In addition, intracisternal administrations of oudenone (100--600 mug/kg) showed a marked increase in blood pressure in the anesthetized rats, suggesting that the pressor effect may be due to centrally mediated actions. Oudenone, given intra-arterially into the femoral artery (400--800 mug/kg), caused a long-lasting vasodilation in anesthetized dogs. At a relatively high dose (40 mg/kg i.v.), oudenone antagonized all pressor responses to autonomic agents and central vagus nerve stimulation in anesthetized rats and dogs, however, oudenone showed no anti-cholinergic,-histaminergic, beta-adrenergic and adrenergic neuron blocking properties. (+info)
2,3,7,8-Tetrachlorodibenzo-p-dioxin alters cardiovascular and craniofacial development and function in sac fry of rainbow trout (Oncorhynchus mykiss).
(19/19128)
Hallmark signs of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity in rainbow trout sac fry, are yolk sac edema, hemorrhage, craniofacial malformation, and growth retardation culminating in mortality. Our objective was to determine the role of cardiovascular dysfunction in the development of this toxicity. An embryotoxic TCDD dose (385 pg/g egg) caused a progressive reduction in blood flow in rainbow trout sac fry manifested first and most dramatically in the 1st and 2nd branchial arches and vessels perfusing the lower jaw. Blood flow was reduced later in the infraorbital artery and occipital vein of the head as well as segmental vessels and caudal vein of the trunk. Reduced perfusion occurred last in gill branchial arteries involved with oxygen uptake and the subintestinal vein and vitelline vein involved with nutrient uptake. Although heart rate throughout sac fry development was not affected, heart size at 50 days post-fertilization (dpf) was reduced far more than body weight or length, suggesting that the progressive circulatory failure caused by TCDD is associated with reduced cardiac output. Craniofacial development was arrested near hatch, giving rise to craniofacial malformations in which the jaws and anterior nasal structures were underdeveloped. Unlike the medaka embryo, in which TCDD causes apoptosis in the medial yolk vein, endothelial cell death was not observed in rainbow trout sac fry. These findings suggest a primary role for arrested heart development and reduced perfusion of tissues with blood in the early-life stage toxicity of TCDD in trout. (+info)
A method for determining baroreflex-mediated sympathetic and parasympathetic control of the heart in pregnant and non-pregnant sheep.
(20/19128)
1. The cardiac baroreflex was measured in four non-pregnant and six pregnant ewes before and during beta-adrenoreceptor blockade with propranolol and before and during vagal blockade with atropine. Arterial pressure was raised by phenylephrine and lowered by sodium nitroprusside. The relationships between mean arterial pressure (MAP) and heart rate (HR), between MAP and heart rate variability (HRV) measured as the coefficient of variation (c.v.) of the mean pulse interval (PI), and between MAP and HRV measured by power spectral analysis were determined. 2. The MAP-HR relationship showed that in pregnant ewes the gain of the cardiac baroreflex was reduced when compared with non-pregnant ewes. Threshold and saturation pressures were higher, maximum achievable HR was lower and there was a decrease in the operating range. 3. V-shaped relationships were obtained between MAP and HRV (measured as the c.v. of PI) and between MAP and power spectral density in the frequency range 0.04-0. 08 Hz. Using selective autonomic blockade the negative, or downward, slope of the V shape was shown to be a measure of baroreceptor-induced, sympathetically mediated effects on HRV. The upward, or positive, slope of the V shape was a measure of baroreceptor-induced, vagally mediated effects. Similar results were also obtained from the cardiac power spectrum, but it was less sensitive. The MAP at which the two slopes intersected was the same as the resting MAP. 4. In pregnant ewes, the slope of the downward limb of the V-shaped relationship between HRV (when measured as the c.v. of PI) and MAP was less than in non-pregnant ewes. 5. The relationship between MAP and the coefficient of variation of the mean pulse interval can therefore be used to measure the degree to which baroreceptor-induced sympathetic and parasympathetic activity affects the heart. 6. The resting MAP is the pressure at which the net effect of these sympathetic and parasympathetic influences on the heart is at a minimum. Studies of both the MAP-HR and MAP-HRV relationships in pregnant and non-pregnant sheep show that in pregnant sheep, there is attenuation of baroreceptor-mediated sympathetic effects on the heart. (+info)
Arousal from sleep shortens sympathetic burst latency in humans.
(21/19128)
1. Bursts of sympathetic activity in muscle nerves are phase-locked to the cardiac cycle by the sinoaortic baroreflexes. Acoustic arousal from non-rapid eye movement (NREM) sleep reduces the normally invariant interval between the R-wave of the electrocardiogram (ECG) and the peak of the corresponding sympathetic burst; however, the effects of other forms of sleep disruption (i.e. spontaneous arousals and apnoea-induced arousals) on this temporal relationship are unknown. 2. We simultaneously recorded muscle sympathetic nerve activity in the peroneal nerve (intraneural electrodes) and the ECG (surface electrodes) in seven healthy humans and three patients with sleep apnoea syndrome during NREM sleep. 3. In seven subjects, burst latencies were shortened subsequent to spontaneous K complexes (1.297 +/- 0.024 s, mean +/- s. e.m.) and spontaneous arousals (1.268 +/- 0.044 s) compared with latencies during periods of stable NREM sleep (1.369 +/- 0.023 s). In six subjects who demonstrated spontaneous apnoeas during sleep, apnoea per se did not alter burst latency relative to sleep with stable electroencephalogram (EEG) and breathing (1.313 +/- 0.038 vs. 1.342 +/- 0.026 s); however, following apnoea-induced EEG perturbations, burst latencies were reduced (1.214 +/- 0.034 s). 4. Arousal-induced reduction in sympathetic burst latency may reflect a temporary diminution of baroreflex buffering of sympathetic outflow. If so, the magnitude of arterial pressure perturbations during sleep (e.g. those caused by sleep disordered breathing and periodic leg movements) may be augmented by arousal. (+info)
A comparison of an A1 adenosine receptor agonist (CVT-510) with diltiazem for slowing of AV nodal conduction in guinea-pig.
(22/19128)
1. The purpose of this study was to compare the pharmacological properties (i.e. the AV nodal depressant, vasodilator, and inotropic effects) of two AV nodal blocking agents belonging to different drug classes; a novel A1 adenosine receptor (A1 receptor) agonist, N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside (CVT-510), and the prototypical calcium channel blocker diltiazem. 2. In the atrial-paced isolated heart, CVT-510 was approximately 5 fold more potent to prolong the stimulus-to-His bundle (S-H interval), a measure of slowing AV nodal conduction (EC50 = 41 nM) than to increase coronary conductance (EC50 = 200 nM). At concentrations of CVT-510 (40 nM) and diltiazem (1 microM) that caused equal prolongation of S-H interval (approximately 10 ms), diltiazem, but not CVT-510, significantly reduced left ventricular developed pressure (LVP) and markedly increased coronary conductance. CVT-510 shortened atrial (EC50 = 73 nM) but not the ventricular monophasic action potentials (MAP). 3. In atrial-paced anaesthetized guinea-pigs, intravenous infusions of CVT-510 and diltiazem caused nearly equal prolongations of P-R interval. However, diltiazem, but not CVT-510, significantly reduced mean arterial blood pressure. 4. Both CVT-510 and diltiazem prolonged S-H interval, i.e., slowed AV nodal conduction. However, the A1 receptor-selective agonist CVT-510 did so without causing the negative inotropic, vasodilator, and hypotensive effects associated with diltiazem. Because CVT-510 did not affect the ventricular action potential, it is unlikely that this agonist will have a proarrythmic action in ventricular myocardium. (+info)
Effects of tumour necrosis factor-alpha on left ventricular function in the rat isolated perfused heart: possible mechanisms for a decline in cardiac function.
(23/19128)
1. The cardiac depressant actions of TNF were investigated in the isolated perfused rat heart under constant flow (10 ml min(-1)) and constant pressure (70 mmHg) conditions, using a recirculating (50 ml) mode of perfusion. 2. Under constant flow conditions TNF (20 ng ml(-1)) caused an early (< 25 min) decrease in left ventricular developed pressure (LVDP), which was maintained for 90 min (LVDP after 90 min: control vs TNF; 110 +/- 4 vs 82 +/- 10 mmHg, P < 0.01). 3. The depression in cardiac function seen with TNF under constant flow conditions, was blocked by the ceramidase inhibitor N-oleoylethanolamine (NOE), 1 microM, (LVDP after 90 min: TNF vs TNF with NOE; 82 +/- 10 vs 11 +/- 5 mmHg, P < 0.05). 4. In hearts perfused at constant pressure, TNF caused a decrease in coronary flow rate (change in flow 20 min after TNF: control vs TNF; -3.0 +/- 0.9 vs -8.7 +/- 1.2 ml min(-1), P < 0.01). This was paralleled by a negative inotropic effect (change in LVDP 20 min after TNF: control vs TNF; -17 +/- 7 vs -46 +/- 6 mmHg, P < 0.01). The decline in function was more rapid and more severe than that seen under conditions of constant flow. 5. These data indicate that cardiac function can be disrupted by TNF on two levels, firstly via a direct, ceramidase dependant negative inotropic effect, and secondly via an indirect coronary vasoconstriction. (+info)
Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of Ito1 in cardiac electrogenesis.
(24/19128)
1. In the present study, two new peptides, phrixotoxins PaTx1 and PaTx2 (29-31 amino acids), which potently block A-type potassium currents, have been purified from the venom of the tarantula Phrixotrichus auratus. 2. Phrixotoxins specifically block Kv4.3 and Kv4.2 currents that underlie I(to1), with an 5 < IC50 < 70 nM, by altering the gating properties of these channels. 3. Neither are the Shaker (Kv1), Shab (Kv2) and Shaw (Kv3) subfamilies of currents, nor HERG, KvLQT1/IsK, inhibited by phrixotoxins which appear specific of the Shal (Kv4) subfamily of currents and also block I(to1) in isolated murine cardiomyocytes. 4. In order to evaluate the physiological consequences of the Ito1 inhibition, mice were injected intravenously with PaTx1, which resulted in numerous transient cardiac adverse reactions including the occurrence of premature ventricular beats, ventricular tachycardia and different degrees of atrioventricular block. 5. The analysis of the mouse electrocardiogram showed a dose-dependent prolongation of the QT interval, chosen as a surrogate marker for their ventricular repolarization, from 249 +/- 11 to 265 +/- 8 ms (P < 0.05). 6. It was concluded that phrixotoxins, are new and specific blockers of Kv4.3 and Kv4.2 potassium currents, and hence of I(to1) that will enable further studies of Kv4.2 and Kv4.3 channel and/or I(to1) expression. (+info)