Lucia Ianni

In Vivo Evidence That Endogenous Dopamine Modulates Sympathetic Activity in Man

Dopamine receptors type 2 (D2)-like receptor blockers cause an increase in the norepinephrine response to intense physical exercise. However, during intense physical exercise, D2-like antagonists also cause an increase in the epinephrine response, which itself might cause an increase in plasma norepinephrine through the activation of beta2 presynaptic receptors. Therefore, we evaluated the effect of domperidone, a D2-like antagonist, on the norepinephrine response to physical exercise in 6 Addison patients (3 were adrenalectomized and 3 had adrenal tuberculosis). In these patients, the norepinephrine increase observed during exercise was significantly higher after the administration of domperidone than a placebo (F=4,328; P<0.001). Because peripheral plasma norepinephrine does not reflect the sympathetic tone to the heart accurately, we evaluated the effect of domperidone administration (20 mg orally) on the sympathovagal balance, which was measured by the ratio between the high- and low-frequency components of heart rate variability, in 9 normal volunteers in the supine and sitting positions. When compared with placebo, domperidone caused a significant increase in the low/high frequency ratio (P<0.05) in the sitting position without modifying basal and stimulated norepinephrine plasma levels or blood pressure. These data support a role for endogenous dopamine in modulating norepinephrine release by human sympathetic nerves in vivo.

Dopamine and Sympathoadrenal Activity in Man

The sympathetic adrenal (SA) activity can be modulated by dopamine (DA) through D2 receptors. In man, using D2 antagonists, it has been demonstrated that endogenous DA plays an inhibitory modulation of the SA system during high degree of SA activation. D2 agonists are able to induce a decrease in norepinephrine (NE) release either in vitro or in vivo. This effect leads, in vivo, to a decrease in blood pressure (BP) and to an activation of arterial baroreceptors. Therefore, in vivo, the D2 mediated inhibition of epinephrine (E) release, which is clearly demonstrated in vitro, is overwhelmed by the baroreceptor-mediated activation of the splachnic nerve. As a consequence, the in vivo administration of D2 agonists can induce a different effect on the net peripheral sympathetic tone of an organ, depending on the balance between the degree of the baroreceptor-mediated sympathetic activation and the inhibitory D2-mediated inhibition of NE release at the tissue level. In the present paper we investigated the in vivo effect of placebo (PL) or acute oral bromocriptine (BC) administration on plasma CA and on the cardiac sympatho-vagal balance of 7 normal volunteers, as assessed by power spectral analysis of heart rate (HR) variability (autoregressive method), either in resting or sitting position. Low frequency (LF) and high frequency (HF) components, both expressed in normalized units (nU), and LF/HF ratio were calculated. BC caused a decrease in BP, plasma NE and no change in HR in resting and sitting position. Plasma E increased in sitting position. At the heart level, after BC, we observed, during rest, an increase in LF and LF/HF ratio and a decrease in HF while in sitting position LF did not increase further. These data show that BC, while reducing BP through a decrease of plasma NE, increases LF/HF ratio (sympathetic tone) without any change in heart rate. These data seem to confirm that BC causes an inhibitory modulation of the SA system acting predominantly at the periphery through D2 presynaptic receptors.

Centrally mediated effects of bromocriptine on cardiac sympathovagal balance.

Bromocriptine, a dopamine agonist, is known to lower cardiovascular mortality in l-dopa-treated patients with Parkinson’s disease, probably by reducing the cardiac sympathetic activity. We aimed at unmasking the central effects of bromocriptine on the heart by power spectrum analysis. Ten healthy subjects (aged 31±2 years) in supine and sitting positions were evaluated after the administration of bromocriptine (2.5 mg) alone and after pharmacological peripheral D2-like blockade by domperidone (20 mg). We calculated (autoregressive method) the following: the low-frequency (LF) component (an index of cardiac sympathetic tone), the high-frequency (HF) component (an index of cardiac vagal tone), and the LF/HF ratio (an index of cardiac sympathovagal balance). With subjects in the supine position, bromocriptine alone induced a significant increase in the LF component and the LF/HF ratio, together with a reduction in norepinephrine plasma levels and blood pressure values. These conflicting effects can be explained as the combined result of direct and indirect (reflex-mediated) actions of bromocriptine in vivo. No changes in cardiac autonomic drive were observed with subjects in the sitting position. After domperidone pretreatment, bromocriptine induced a reduction in the LF component and in the LF/HF ratio. The sitting position caused an increase in heart rate and in the LF/HF ratio. We demonstrated both peripheral and central effects of bromocriptine. In particular, pretreatment with a peripheral antagonist (domperidone) allowed us to unmask the central effect of bromocriptine on cardiac sympathetic drive.

A nonsecreting pheochromocytoma presenting as an incidental adrenal mass. Report on a case

A 25 year old women presented an incidental adrenal mass which was diagnosed to be a pheochromocytoma before surgery by means of a positive 131-l-MIBG scintigraphy. Urinary vanilmandelic acid resulted repeatedly normal as well as basal plasma norepinephrine (NE), epinephrine (E) and dopamine (DA). Urinary homovannilic acid resulted in the normal range. Stimulation tests with iv glucagone, tyramine and metoclopramide evoked normal NE and E responses while a slight increase in plasma DA was observed after metoclopramide. Oral Clonidine suppressed plasma catecholamines (CA) normally. Histologic and immunohistochemical studies confirmed that the tumor was a pheochromocytoma showing positivity for tyrosine hydroxylase but not for dopamine-ß-hydroxylase activity. This case is the first report on a completely asymptomatic pheochromocytoma presenting as an incidental adrenal mass which was investigated with repeated biochemical tests before surgery and demonstrates that, among the extremely variable functional attitudes of pheochromocytomas, a defect in CA synthesis and secretion is also to be included.

Hypoglycemia unawareness in a patient with dumping syndrome: Report of a case

We report the case of a 49-yr-old man affected by coma and hypoglycemia unawareness following repetitive hypoglycemic episodes due to dumping syndrome. The dumping syndrome, which was due to partial gastrectomy and vagotomy performed for recurrent peptic ulcer, was responsible for reactive hyperinsulinemia as demonstrated by an oral glucose tolerance test. While the glucose counterregulatory hormones were all normally sensitive to specific stimulation tests, insulin-induced hypoglycemia failed to induce an adequate counterregulatory response, causing no response in plasma norepinephrine, a slight and short increase in plasma Cortisol, ACTH and glucagon and an insufficient increase in plasma epinephrine and GH. This case demonstrates that hypoglycemia unawareness has to be taken into account not only in patients affected by IDDM or insulinoma but also in any case of reactive hypoglycemia.

Catecholamines and Blood Pressure Regulation

Catecholamines (CAs) play a central role in the regulation of blood pressure. Sympathetic adrenal effects are ultimately elicited by the neurotransmitter norepinephrine and the hormone epinephrine. Their release is under the control of higher centers and is finely modulated by several factors such as presynaptic receptors. Recent evidences suggest that also the peripheral dopaminergic system can participate in blood pressure regulation intervening in the blood flow regulation of some regions, and in sodium-water balance. The measurement of CAs in biological fluids has greatly enhanced our knowledge on the mechanisms regulating blood pressure and is widely applied in cardiovascular research. Clinical applications of CA measurement are still limited to the diagnosis of pheochromocytoma and to the differential diagnosis of hypotensive syndromes.

Glucocorticoid-Phenylethanolamine-N-methyltransferase Interactions in Humans

Publisher Summary Phenylethanolamine-N-methyltransferase (PNMT) is highly concentrated in the adrenal medulla but has also been demonstrated, although to a much limited extent, in other human tissues, such as lung, heart, kidney, liver, spleen, and pancreas. From in vitro and in vivo studies performed in several animal species, it is well known that in adrenal medulla PNMT activity is dependent on the high levels of glucocorticoids received from the cortex. In vivo data from studies performed in humans are scanty. In children with hypocortisolism because of adrenocotricotropic hormone (ACTH) deficiency, plasma Epi levels are lower. Stimulation of Epi secretion was achieved by intravenous glucagon. Patients with HP were studied while receiving thyroid, glucocorticoid, and sexual steroid replacement therapy. Obtained data confirm that in humans, adrenal PNMT activity seems to depend on the normal cortisol supply to the medulla from the cortex. In fact, in adults affected by HP because of ACTH deficiency, the adrenal medulla secretion is impaired in basal as well as in stimulated conditions. The deficiency of Epi secretion is very probably one of the most important factors causing an impaired response to hypoglycemia in these patients. In fact, the similar Epi/NE ratio found in the adrenal vein of patients with and without chronic hypercortisolism suggests that in humans, a normal cortisol secretion is sufficient to activate PNMT maximally. These results confirm the finding that in the adrenal medullas obtained at surgery from patients with cushings syndrome (CS), the PNMT activity resulted similar to that found in control human adrenal glands obtained at autopsy.