[Clinical trial of a new antihypertensive preparation: guanfacine].
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Biomedical subjects
Publications and source records attributed to B Trimarco.
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Previous studies have shown that phentolamine is able to reverse the reflex vasodilatation produced by transitory baroreceptor stimulation by blocking sympathetic, histaminergic, and cholinergic components. A direct anticholinergic action of phentolamine has never been described; however, since it is known that this drug is capable of inhibiting histamine release during the reflex vasodilatation, it is possible that its ability to block the cholinergic component of the reflex is related to the latter property. Therefore, this study was undertaken in an attempt to identify possible relationships between cholinergic and histaminergic components of the reflex vasodilatation. Accordingly, in mongrel dogs the gracilis muscle was isolated and perfused and then loaded with 14C-labeled histamine. A transitory systemic hypertension was induced by intravenous injection of norepinephrine; this produced a reflex vasodilatation, shown by the fall in perfusion pressure, which was accompanied by an increase of histamine release from the muscle. Vagal block induced by atropine pretreatment reduced the fall in perfusion pressure induced by the systemic hypertension and produced a reduction of histamine release during the vasodilatation. In another group of animals a vasodilatation in the perfused muscle was induced by injection of acetylcholine. This response was accompanied by an increase in histamine release from the gracilis muscle. Alpha-receptor blockade, which has been shown to inhibit histamine release, reduced this acetyl-choline-induced vasodilatation. These results, while confirming the participation of the cholinergic system in the reflex vasodilatation elicited by transitory stimulation of the arterial baroreceptors, seem to demonstrate that this component is mediated almost exclusively by histamine release.
This study was designed to investigate whether the cholinergic system is involved in the genesis of the reflex vasodilatation which follows the systemic hypertension induced by fast intravenous injection of norepinephrine in the dog. Accordingly, in 7 dogs the gracilis muscle was isolated and perfused and the reflex evoked. The analysis of the integrated areas of vasodilatation after atropine pretreatment showed a significant decrease of the reflex response in the perfused circulation. In fact, the mean value of the integrated areas of vasodilatation which was 66 +/- 8 mm Hg/min in the control condition, was reduced to 45 +/- 4 mm Hg/min after administration of atropine in the gracilis artery; meanwhile the integrated areas of systemic hypertension did not show any change. Phentolamine intra-arterial administration completely abolished the reflex. These results suggest the existence of a cholinergic component in the reflex vasodilatation induced by transitory baroreceptorial stimulation.
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This study was designed to evaluate the usefulness of non-invasive parameters in the follow-up of cardiopathic patients without valvular cardiac diseases. In 49 patients suffering from heart disease we have studied the changes of radiologic cardiac measurements and systolic time intervals (STI) in the 4 functional classes of the NYHA classification, investigating also the existence of any relationship between these different parameters. Only the patients in the 3rd and the 4th functional classes showed significant changes in STI and radiologic measurements, as compared with the control group. Moreover, significant negative correlations have been observed between relative heart volume and LVET (r = 0.69, P less than 0.001) and LVETc (r = 0.82, P less than 0.001) and positive correlations between relative heart volume and PEP (r = 0.59, P less than 0.01) and PEP/LVET ratio (r = 0.75, P less than 0.001). These results, while confirming the close correlation between STI and cardiac performance, seem to demonstrate that relative heart volumetry is a fairly accurate index of the cardiac conditions in non-valvular heart diseases.
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The antihypertensive effect of atenolol, a new beta 1 receptor blocking agent, was studied in a double blind non cross-over trial in 40 patients (pts) affected by mild to moderately severe essential hypertension with normal plasma renin activity. After a run-in period (15 days) of placebo treatment pts were assigned to two groups. The first (group A) continued placebo treatment for 30 days, the second (Group B) were given atenolol (ICI 66082) 100 mg daily for 30 days also. Atenolol significantly reduced systolic and diastolic blood pressure in recumbent and standing position and heart rate at rest. No significantly changes of the same parameters were observed in group A. Body weight and plasma renin activity was unchanged in both groups. Atenolol treatment never was discharged in order to side effects. These results seem to suggest that atenolol can be an useful drug in the treatment of systemic blood hypertension.
In 49 patients suffering of heart diseases we have studied the changes of radiologic cardiac measurements and systolic time intervals (STI) in the four functional classes of the New York Heart Association (NYHA) classification, investigating also the existence of any relationship between these different parameters. Only the patients in functional classes 3rd and 4th showed significant changes in STI and radiologic measurements as compared to the control group. Moreover, a significant negative correlation has been observed between relative heart volume and left ventricular ejection time (LVET) (r = 0.69, P less than 0.001) and LVETc (r = 0.82, P less than 0.001) and a positive correlation between relative heart volume and pre-ejection period (PEP) (r = 0.59, P less than 0.01) and PEP/LVET ratio (r = 0.75, P less than 0.001). These results seem to demonstrate that relative heart volumetry is a fairly accurate index of the cardiac conditions in non valvular heart diseases.
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1 The effects of guanethidine pretreatment on the release of [14C]-histamine during the reflex vasodilatation induced in the atropinized gracilis muscle by rapid intravenous administration of noradrenaline, were studied in dogs. 2 After guanethidine treatment the haemodynamic reflex response was completely abolished and no appreciable modification of [14C]-histamine release from the gracilis muscle following intravenous noradrenaline was observed. 3 These results suggest the hypothesis that the withdrawal of the sympathetic discharge represents the mechanism of histamine release during the reflex vasodilatation. Therefore, guanethidine would suppress both the passive and the histaminergic component of the baroreceptor reflex through the abolition of the sympathetic tone.
These experiments have been designed to study the influence of alanine infusion of glucose dynamics in the dog and to further elucidate the role of pancreatic hormones in the interaction of alanine with glucose homeostasis. The primed constant infusion of glucose-2-t was used in order to quantitate the rates of glucose production by the liver (Ra) and glucose utilization (Rd). In a first group of experiments, the intravenous infusion of alanine at the rate of 2 mg./kg./min. produced a moderate enhancement of plasma insulin (IRI), while pancreatic glucagon (IRG) increased more consistently. This different pattern of IRI and IRG response caused the insulin/glucagon molar ratio to decline progressibely throughout the experiment. Both rates of glucose turnover increased significantly during alanine infusion. Since Ra rose more rapidly thanRd did initially, hyperglycemia developed. Later, glucose production slowly decreased and, in spite of the sustained hyperglucagonemia, reached levels very close to the baseline in the second part of the experiment. A significant direct correlation between Ra and IRG was found, while the changes in Ra correlated inversely with those in I/G molar ratio. In a second group of experiments, alanine was infused at the same dose together with 0.4 microng./kg./min. of cyclic somatostatin. In the first part of the infusion, IRG fell more than IRI did, so that I/G ratio increased. Later, IRI levels maintained at low values while IRG returned slowly to the baseline and consequently I/G ratio significantly decreased. Glucose production fell rapidly soon after the beginning of the infusion, and therefore hypoglycemia developed. Later, Ra increased progressively to levels above baseline and plasma glucose returned to the preinfusion levels. As in the the first group of experiments, a significant direct correlation between Ra and IRG and an inverse correlation between the changes in Ra and I/G ratio were observed. These experiments demonstrate that alanine infusion produces an acceleration of glucose turnover and that a clear interrelationship between the release of glucose by the liver and the mobilization of pancreatic hormones exists. Finally, the experiments with somatostatin indicate that hyperglucagonemia is one of the mechanisms underlying the stimulatory effect of alanine on glucose production.
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This study was designed to investigate the possibility of a histamine mediation in muscular vasodilation induced by beta adrenoceptor stimulation. Accordingly, in seven dogs the effects of isoproterenol administration on the release of 14C-histamine from the perfused gracilis muscle were studied. Beta adrenoceptors stimulation induced a vasodilatation, as shown by a decrease in perfusion pressure(-43 +/- 12 mm Hg); simultaneously, a significant increase of the radioactivity measured in the venous blood effluent from the gracilis muscle was observed. Both these events were blocked by propranolol. In the other five dogs, chlorpheniramine was able to reduce the vasodilatation induced by the injection in the gracilis muscle of isoproterenol. Under control conditions, isoproterenol induced a fall in perfusion pressure of 44 +/- 5 mm Hg while, after chlorpheniramine, perfusion pressure decreased by only 24 +/- 4 mm Hg. The results of this study seem to confirm the possibility of a histamine mediation in isoproterenol-induced vasodilatation. However, further investigation is needed in order to identify the exact role of histamine in the geneis of this phenomenon.
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