E Moerman

Release of dopamine β-hydroxylase and chromogranin A upon stimulation of the splenic nerve

Two proteins present in noradrenergic vesicles of the splenic nerve (dopamine beta-hydroxylase and chromogranin A) are released into the perfusate from the spleen when the splenic nerve is stimulated. Experiments in which drugs were added to the perfusion fluid showed that the proteins were released from terminals of the splenic nerve. There was a correlation between the amounts of the proteins released and the quantity of noradrenaline released; and the release process was dependent upon calcium. It is suggested that the proteins are released from the large dense-cored vesicles present in the terminals of the splenic nerve, and that secretion from these vesicles occurs by exocytosis.

Influence of lansoprazole treatment on diazepam plasma concentrations

The possible influence of long‐term treatment with lansoprazole on the single‐dose pharmacokinetics of diazepam was investigated in 12 healthy male volunteers. In this double‐blind randomized crossover study, 60 mg lansoprazole or placebo was administered once daily for 10 days. One hour after administration on day 7, 0.1 mg/kg diazepam was administered intravenously, and blood was collected up to 96 hours after the injection for plasma diazepam and desmethyldiazepam measurement. During the placebo session, the plasma elimination half‐life, clearance, and volume of distribution of diazepam were 26.0 ± 1.6 hours, 22.5 ± 1.1 ml/hr/kg, and 0.82 ± 0.04 L/kg, respectively. These parameters were not significantly different during the lansoprazole session. The mean plasma concentrations of desmethyldiazepam were similar in both sessions. These findings illustrate that long‐term treatment with a therapeutic dose of lansoprazole does not interfere with the metabolism of diazepam.

Haemodynamic and humoral responses to chronic ketanserin treatment in essential hypertension.

Ketanserin (120 mg/day) or placebo was given orally to 14 patients with mild to moderate essential hypertension according to a double blind crossover protocol, each treatment period lasting six weeks. Resting intra-arterial pressure in the recumbent position was reduced from 150/84 to 141/77 mm Hg; the hypotensive effect persisted throughout an uninterrupted graded exercise test to the point of exhaustion. The haemodynamic effects were similar at rest and during exercise. Overall, systemic vascular resistance decreased by 14%, heart rate fell by 5%, but stroke volume and cardiac output increased. Mean pulmonary arterial pressure and capillary wedge pressure were not significantly affected, but pulmonary vascular resistance decreased by 15%. The pressor response to methoxamine was significantly reduced by ketanserin. Both plasma noradrenaline and adrenaline concentrations increased, plasma renin activity and angiotensin II concentration decreased, and plasma aldosterone concentration was unchanged. The data indicate that ketanserin induces arteriolar dilatation, possibly related to an alpha-1-antagonistic action and to a reduced circulating angiotensin II concentration. The haemodynamic response is complex, and an increase in cardiac output limits the hypotensive effect. There is no firm evidence of an effect on venous tone as cardiac filling pressures do not change.

The nature of opioid involvement in the hemodynamic respiratory and humoral responses to exercise.

After 30 min rest in the lying position, 12 healthy male volunteers (average age 22 years) received, in a randomized double-blind cross-over protocol, either saline or naloxone (10 mg iv followed by a continuous infusion of 10 mg/hr). Thereafter they rested for a further 30 min in the recumbent position and for 15 min sitting on a bicycle ergometer; they then exercised to exhaustion. At rest plasma levels of adrenocorticotropin (ACTH), cortisol, and aldosterone increased during infusion of naloxone, while body temperature decreased. During exercise the difference in plasma ACTH between naloxone and saline periods was abolished, while the differences in plasma cortisol and aldosterone lost statistical significance. Intra-arterial pressure, heart rate, ventilation, O2 uptake, and CO2 output were continuously monitored throughout the experiment and were not affected by naloxone. This was also the case for several hormonal and biochemical measurements, including those of plasma renin, angiotensin II, norepinephrine, 13,14-dihydro-15-keto-prostaglandin F2 alpha, glucose and lactate, and serum insulin and growth hormone. Exercise performance was not changed by naloxone. In conclusion (1) during exhaustive graded exercise of short duration opioidergic inhibition of the pituitary-adrenocortical axis is probably not sustained, (2) apart from the latter mechanism, the present study does not support the hypothesis that endogenous opioids are involved in various hemodynamic, respiratory, and hormonal responses to this type of exercise.

Acute haemodynamic and humoral responses to felodipine and metoprolol in mild hypertension

SummaryOral administration of felodipine to 10 patients with mild essential hypertension acutely reduced systemic vascular resistance (SVR) by 40% after 30 min. The change in SVR was significantly related to age (r=−0.74). The reduction in the intraarterially measured brachial artery pressure was limited to 15/13 mmHg, due to a rise in cardiac output (CO). The tachycardia was sustained for 90 min, as was an elevation of plasma noradrenaline. There was a transient increase in stroke volume, associated with a reduction in pulmonary capillary wedge pressure, which was at least partly due to a reduced intravascular volume. In contrast to SVR, pulmonary vascular resistance was not affected by felodipine. Addition of intravascular metoprolol after 90 min decreased HR and CO and augmented SVR. The felodipine-induced rise in plasma renin activity (PRA) of 100% was completely reversed by metoprolol. Plasma angiotensin II (PA II) rose by 15% during felodipine, whereas plasma aldosterone concentration (PAC) was not affected. Thus, actuely administered felodipine was a potent dilator of systemic but not of pulmonary arterioles, it stimulated the sympathetic nervous system, and reduced left ventricular filling pressure. The rise in plasma renin did not result in a higher plasma aldosterone level, due partly to reduced generation of angiotensin II.

Quantitation of catecholamines in urine and in plasma

Quantitation of urinary and plasma catecholamines (CA), dopamine (DA), noradrenaline (NA) and adrenaline (A) is important for the diagnosis of pheochromocytoma and neural crest tumors. In 1978 we described [l j a semi-automated method for the fluorimetric determination of DA, NA and A in urine combined with manual methods for the determination of the metabolites of these amines. This sensitive and reproducible analytical technique was subject to interferences by antihypertensive and sympathomimetic drugs. In order (1) to eliminate falsely positive results, through qualitative identification of the interfering compound and, at the same time, (2) to quantitate the catecholamines in urine of patients treated with either methyldopa, or isoprenaline or Idbetalol we introduced high-performance liquid chromatography with electrochemical detection (LCEC) in our laboratory procedure. This paper deals with practical aspects of the determination of urinary and plasma CA by fluorimetry and LCEC in practice. In this procedure LCEC is used as an alternative and complementary assay for CA determinations in samples presenting with ‘interfering substances’ and as an external quality control method for the routine semi-automated trihydroxyindole (THI) fluorimetric determination.

Estimation of plasma catecholamines in man.

Abstract The influence of body posture and muscular exercise on plasma noradrenaline and adrenaline concentrations was studied in man. The radiometric method of Passon and Peuler (Passon, Ph. and Peuler, J. (1973) Anal. Biochem. 51, 618) was used with slight modifications. With rigorous standardisation of sampling and storage procedures, reproducible results were obtained. Basal values of plasma catecholamines in man can be obtained from subjects after 30 min of rest in the supine position.

Differentiation of exercise-induced metabolic responses during selective beta 1- and beta 2-antagonism.

The effect of beta 1- or beta 2-antagonism on the plasma levels of glucose, lactate, triglycerides, and free fatty acids was studied in seventeen normal male volunteers. All subjects performed three graded and uninterrupted exercise tests until exhaustion. Prior to each exercise test they received in a randomized order during three consecutive days either placebo or a predominant beta 1-blocker (atenolol, 50 mg once per day) or a predominant beta 2-blocker (ICI 118,551, 20 mg t.i.d.), according to a double-blind cross-over study design. Atenolol increased the plasma level of glucose at rest but did not influence the rise in plasma glucose during exercise. ICI 118,551 did not change the resting plasma glucose level, but it prevented the exercise-induced rise in plasma glucose, observed during placebo. During beta 1-antagonism the plasma lactate concentration at rest and during or after exercise was not different from placebo. During beta 2-blockade the exercise-induced rise in plasma lactate tended to be suppressed, and during recovery the plasma lactate levels were significantly lower than during placebo. The serum triglycerides concentration at rest and exercise was not altered, either by beta 1- or by beta 2-antagonism. Atenolol and ICI 118,551 did not affect the serum level of free fatty acids at rest, but at moderate exercise the serum free fatty acids concentration was lower during beta 1-blockade than during placebo. Our results provide further evidence that beta 2-adrenergic receptors are involved in the regulation of the plasma levels of glucose and lactate during exercise.

Simultaneous quantitation of catecholamines and metabolites in urine

A semi-automated fluorimetric method for the quantitation of urinary catecholamines (dopamine, noradrenaline and adrenaline) combined with manual methods for the quantitation of their metabolites (homovanillic acid, normetanephrine, metanephrine and vanillylmandelic acid) is described. It provides a sensitive and reproducible analytical technique for routine use. Values obtained in healthy adults are given.

Influence of physical training on blood pressure, plasma renin, angiotensin and catecholamines in patients with ischaemic heart disease

SummaryEighteen patients with ischaemic heart disease were trained for 3 months, three times a week. The effectiveness of the training programme was demonstrated by increases of 27% in peak oxygen uptake and 29% in exercise duration, and by a decrease in resting and submaximal heart rates. Blood pressure, however, was not significantly affected during the training period. At rest and at submaximal exercise plasma renin activity (PRA) was lower after training. Plasma angiotensin I concentration (PA I) and angiotensin II concentration (PA II) were not significantly affected. Plasma aldosterone concentration (PAC), only measured at rest, was not significantly changed after the training period, while plasma norepinephrine (PNE) and epinephrine (PE) concentrations were significantly decreased, but only at high levels of exercise.A reduced sympathetic tone after training, suggested by the lower heart rates and the tendency to a decrease in PNE, is a likely explanation for the decrease in PRA. However, despite this decrease, PA I, PA II, and PAC were not significantly changed after training; the reason for this disrepancy is unknown.