Atrial natriuretic factor. What's in a name?
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Angiotensin II↗
Biomedical subjects
D de Wildt
Publications and source records attributed to D de Wildt.
Calcium interferes with the cardiodepressive effects of beta-blocker overdose in isolated rat hearts.
Propranolol, timolol and sotalol were compared with respect to their cardiotoxic properties in isolated, spontaneously beating rat hearts. Propranolol and timolol induced a dose-dependent decrease in myocardial contractility. A high dose of sotalol had only modest negative inotropic effects. Similar reductions in myocardial contractility were observed in isolated, ventricle-stimulated rat hearts. These observations were similar to those in a previous study in which spontaneously beating and ventricle-stimulated reserpinized rat hearts were investigated. Spontaneously beating rat hearts were perfused with a high-, a normal- and a low-Ca++ medium, each with and without propranolol, timolol and sotalol. Addition of each beta-blocker to a normal-Ca++ medium induced a decrease of myocardial contractility and of heart rate and an increase of AV-conduction time when compared with the drug-free medium. In a high-Ca++ medium containing the same concentration of each beta-blocker, a less pronounced decrease of myocardial contractility was observed. Heart rate decreased and AV-conduction time increased to the same extent as after perfusion with the drug containing normal-Ca++ medium. With respect to the corresponding drug-free medium perfusion with a low-Ca++ medium with each beta-blocker enhanced the decline in myocardial contractility, most pronounced in propranolol and timolol containing media. For propranolol and sotalol the decrease in heart rate and increase in AV-conduction time were similar to the results after administration of the same beta-blocker in a high- and a normal-Ca++ perfusion media. Timolol caused an electromechanical dissociation. It was concluded that in beta-blocker intoxication the negative-inotropic phenomena cannot be explained by an action of the drugs on the beta-receptor since the results in reserpinized and non-reserpinized rat hearts were similar. Other effects have to be responsible for the observed cardiotoxic phenomena. The present results indicate that these phenomena can be influenced by Ca++ and or can be attributed to differences in lipophilicity.
Adrenergic beta-Antagonists↗
Respiratory arrest as main determinant of toxicity due to overdose with different beta-blockers in rats.
Propranolol, timolol and sotalol were compared regarding their toxicological effects on the cardiovascular and respiratory system. Each drug was administered intravenously to anaesthetized spontaneously breathing and artificially ventilated rats. After the start of infusion in spontaneously breathing rats each drug induced an expected decrease in arterial blood pressure and heart rate. An increase in PQ, QRS and QT interval was observed. From 5/8 of the survival time onwards these changes were accentuated. PaO2, pH and respiratory rate decreased and PaCO2 increased. The rats died as a result of respiratory arrest. Artificial ventilation of rats infused with the same doses increased the survival time significantly. The total doses administered before the animals died as a result of cardiovascular failure were significantly higher for each drug. The initial decreases in arterial blood pressure and heart rate were similar to those in spontaneously breathing rats. Thereafter, significantly smaller decreases were observed. The increases in PQ, QRS and QT interval were significantly less than in spontaneously breathing rats. Blood gases remained unchanged except for a decrease in pH in case of timolol.
Adrenergic beta-Antagonists↗
Dopamine and isoproterenol in imipramine intoxication in the dog.
Artificially ventilated anesthetized dogs were given imipramine 7.5 mg/kg/hr i.v. In the first group (n = 6) mechanical cardiac activity was no longer detectable after a cumulative dose of 20.0 +/- 6.6 mg/kg (mean +/- sd). When aortic flow had decreased to 75% of its initial value, in a second group (n = 5) of experiments dopamine 10 micrograms/kg/min and in a third group (n = 5) isoproterenol 1 microgram/kg/min were administered i.v.. The doses of dopamine and isoproterenol were doubled when aortic flow had again decreased to 75% and 100%, respectively, of the original values. Cardiac mechanical activity was not detectable after a cumulative dose of 43.8 +/- 13.3 in the dopamine and 42.5 +/- 8.0 mg imipramine/kg in the isoproterenol group. These values differed significantly from that in the reference group (both 0.01 greater than p greater than 0.001). In the first group plasma imipramine concentrations at the end of the experiments were 3.06 +/- 0.66, in the second 3.36 +/- 0.66 and in the third 3.32 +/- 1.10 mg/1. Desipramine concentrations were 0.078 +/- 0.06, 0.162 +/- 0.076 and 0.383 +/- 0.09 mg/1 respectively. Dopamine induced a hemodynamic profile of low output and high pressure and isoproterenol one of low pressure and high output. It is concluded that dopamine combined with isoproterenol might be effective in counteracting the cardiodepressant action of imipramine.
Animals↗
Different toxicological profiles for various beta-blocking agents on cardiac function in isolated rat hearts.
Propranolol, timolol and sotalol were compared regarding their cardiotoxic properties in isolated, perfused and catecholamine depleted rat hearts. Catecholamine depletion was performed in order to exclude interference of the drugs with beta-adrenergic receptors. The results demonstrate that both in spontaneously beating and atrial- stimulated hearts propranolol (3 - 30 micrograms/ml) and timolol (30 - 300 micrograms/ml) induced a dose dependent decrease in myocardial contractility, stimulus formation and stimulus conduction. Lacking local anesthetic properties as evidenced by effects on coronary flow and threshold voltage in the heart it can be deduced that the negative inotropic effect and an impaired stimulus conduction due to timolol can neither attributed to beta-adrenoceptor antagonism nor membrane stabilising activity. In addition, both propranolol (5 micrograms/ml) and timolol (200 micrograms/ml) reduced myocardial contractility to the same extent in ventricular-paced hearts. Therefore, a direct myocardial depressive effect rather than an indirect effect due to a reduced heart rate must be responsible for the negative inotropy. The hydrophilic beta-blocker sotalol demonstrated a slight cardiodepressant activity either in the spontaneously beating and atrial-stimulated hearts (30 - 300 micrograms/ml) or ventricular-paced hearts (300 micrograms/ml). It is concluded that the toxicological profile of various beta-blocking drugs might be determined by an yet unknown pharmacological property apart from beta-adrenoceptor blockade or membrane stabilising activity. Furthermore, the degree of lipophilicity of the drug might be an important determinant for the cardiotoxic profile of this class of drugs.
Animals↗
A case of acebutolol intoxication.
A case of a nonfatal acebutolol intoxication in a 15 year old female is described. Ingestion of 7600 mg acebutolol resulted in a plasma acebutolol concentration of 15 mg/1 one hour after ingestion. The patient remained conscious, had a severe hypotension and the electrocardiogram showed a 1st degree AV-block and severe intraventricular conduction disturbances at a rate of 70 bpm. After the administration of calcium gluconate and plasma the blood pressure gradually increased to normal values in 2 hours time. Plasma halflife of acebutolol was 8 hours. Pathophysiology of acebutolol intoxication is discussed.
Acebutolol↗
H-Pro-[3H]Leu-Gly-NH2: uptake and metabolism in rat brain.
The uptake and metabolism of H-Pro-[3H]Leu-Gly-NH2 ([3H]PLG) in rat brain was investigated by reverse-phase paired-ion high pressure liquid chromatography. Following in vitro incubation of [3H]PLG with rat brain subcellular preparations, the microsomal-cytosol fraction was about twice as active in degrading PLG as the crude mitochondrial-synaptosomal fraction. For both enzyme preparations the pH optimum was found at pH 7-7.5. The major labeled metabolite was [3H]leucine, whereas 3H]labeled Leu-Gly-NH2 as the only labeled peptide intermediate was found in trace amounts. After intravenous injection of [3H]PLG the uptake of unmetabolized peptide in the brain appeared to be very low: 0.008% and 0.001% of the administered dose/g tissue at 2 and 5 min after injection respectively, while at longer survival times intact peptide was below the detection limit. Compared with the intravenous route of administration, intracerebroventricular injection of [3H]PLG yielded much higher brain concentrations of unmetabolized PLG. Following both routes of administration, the metabolite profile was in agreement with that obtained after in vitro incubation. However, the in vivo experiments also showed considerable incorporation of [3H]leucine liberated from [3H]PLG into proteins. Both the in vitro and in vivo results indicate that the initial cleavage of PLG in rat brain occurs at the NH2-terminus and that the dipeptide intermediate H-Leu-Gly-NH2 is subsequently hydrolyzed to its constituent amino acids very rapidly.
Animals↗