Franco Franchi

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.

Acute Effects of Physiological Increments of Brain Natriuretic Peptide in Humans

To investigate the effects of physiological increases in plasma brain natriuretic peptide concentration in humans, we studied six healthy volunteers who received incremental infusions (0.25 pmol/kg per minute in the first hour and 0.50 pmol/kg per minute in the second) of synthetic human brain natriuretic peptide-32 in a placebo-controlled, crossover study. Peptide plasma levels were 1.69 +/- 0.39 pmol/L at baseline and rose 1.5- and 3-fold with the lower and higher doses, respectively. These values were within the normal range and also comparable to those reported in patients with mild essential hypertension. The urinary excretion rate of cGMP also increased during brain natriuretic peptide infusion, indicating stimulation of natriuretic peptide receptors. Peptide administration induced a significant 1.7-fold increase in urinary sodium excretion without affecting renal plasma flow (para-aminohippurate clearance), glomerular filtration rate (creatinine clearance), and urine flow rate. Fractional proximal sodium reabsorption (lithium clearance method) was unchanged, and fractional distal sodium reabsorption significantly decreased. Brain natriuretic peptide caused no changes in arterial pressure, heart rate, hematocrit, and serum proteins, but it exerted an inhibitory effect on the renin-aldosterone axis, as indicated by the significant 50% or more decrease of plasma renin activity and urinary excretion rate of aldosterone. These results suggest that brain natriuretic peptide may be involved in the overall regulation of body fluid and cardiovascular homeostasis in humans, mainly through its natriuretic and endocrine effects.

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.

Autonomic Regulation of Heart Rate and QT Interval in Nonalcoholic Cirrhosis with Ascites

BACKGROUND/AIMS Autonomic neuropathy, as indicated by alterations in standard cardiovascular tests, is frequently encountered in cirrhosis. We investigated the autonomic modulation of the heart in nonalcoholic cirrhosis with ascites by evaluating the 24-hour heart rate variability (HRV), a powerful noninvasive tool to assess the sympathovagal balance of the heart. METHODS Low (LF) and high frequency (HF) components and their ratio, and time domain indexes of HRV were evaluated in 24-hour, daytime and nighttime periods in 12 patients and 12 healthy subjects, together with the conventional and dynamic QT interval. RESULTS Cirrhotic patients had values of the mean RR interval and frequency domain indexes in the whole 24-hour period similar to those of healthy subjects, despite higher than normal plasma norepinephrine levels. Patients also showed lower LF and higher HF values than controls during the day, a reduction in time domain indexes, and no circadian rhythm of frequency domain indexes. QT parameters were similar in the 2 groups, but patients had a blunted QT rhythm and a reduced QT variability. CONCLUSIONS Patients with nonalcoholic cirrhosis and ascites have an impaired autonomic regulation of the heart, which involves both the sympathetic and the parasympathetic branches of the autonomic nervous system.

Plasma Levels of Natriuretic Peptides During Ventricular Pacing in Patients with a Dual Chamber Pacemaker

The mechanism(s) responsible for the release of brain natriuretic peptide (BNP), a cardiac hormone of ventricular origin, are still not completely understood. We measured plasma atrial natriuretic peptide (ANP) and BNP in 15 subjects (10 men, mean age 67 ± 3 years) with a dual chamber pacemaker and unimpaired heart function during ventricular pacing, which is known to induce an increase in atrial pressure and plasma ANP concentration. Under ECC monitoring, all subjects received sequential atrioventricular pacing for 30 minutes and ventricular pacing for 30 minutes, at the same rate of 80 beats/min. Arterial pressure and plasma BNP and ANP levels were measured every 10 minutes throughout the study. Ventricular pacing led to atrioventricular dissociation in eight subjects and to retrograde ventriculo‐atrial conduction in seven. Arterial pressure remained unchanged in all subjects. In the group with atrioventricular dissociation, plasma ANP increased from 10.14 ± 0.58 to 16.72 ± 0.92 fmol/mL at the 60th minute (P < 0.0001), whereas plasma BNP did not change at all (fiom 1.26 ± 0.07 to 1.16 ± 0.09 fmol/mL). In the group with retrograde conduction, plasma ANP concentration doubled (fiom 10.95 ± 1.66 to 21.40 ± 1.51 fmol/mL, P < 0.0001), BNP increased 1.5‐fold (from 1.16 ± 0.06 to 1.64 ± 0.14 fmol/mL, P < 0.001), and the ANP: BNP ratio augmented fiom 10:1 to 13.4:1. These results indicate that the release of ANP and BNP is regulated by different mechanisms, supporting the view that there is a dual natriuretic peptide system, comprising ANP fiom the atria and BNP fiom the ventricles.

Cardiovascular function in pregnancy: effects of posture

Objective To evaluate the cardiovascular response to active postural changes in pregnancy.

Cardiovascular Effects of Brain Natriuretic Peptide in Essential Hypertension

We evaluated the cardiovascular effects of pathophysiological plasma levels of brain natriuretic peptide in seven patients with mild to moderate essential hypertension by performing equilibrium radionuclide angiocardiography at baseline and during brain natriuretic peptide infusion at increasing doses (4, 8, 10, and 12 pmol/kg per minute for 20 minutes each). Brain natriuretic peptide induced a progressive reduction of left ventricular end-diastolic volume (from 107.5 +/- 10.3 to 89.0 +/- 11.0 mL at the end of all infusion periods) and end-systolic volume, whereas stroke volume did not show any significant change (from 64.9 +/- 5.9 to 62.7 +/- 7.8 mL). Cardiac output, arterial pressure, and peripheral vascular resistance did not change significantly. The lack of effects on systemic hemodynamics was probably due to compensatory activation of the sympathetic nervous system, as indicated by the significant increase in plasma norepinephrine levels (from 1.75 +/- 0.18 to 2.19 +/- 0.21 nmol/L), heart rate (from 68 +/- 6 to 81 +/- 6 beats per minute), peak ejection rate, and peak filling rate. These results indicate that brain natriuretic peptide, at the pathophysiological plasma concentrations reached in this study, influences cardiovascular homeostasis mainly by reducing cardiac preload.

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.

Effects of clonidine on power spectral analysis of heart rate variability in mild essential hypertension

Patients with essential hypertension often show alterations of the autonomic nervous system. We evaluated the sympathetic and parasympathetic drive to the heart in 12 mildly hypertensive patients and 9 healthy subjects by power spectral analysis of heart rate variability. All subjects underwent measurements of RR interval, low (LF) and high frequency (HF) components of heart rate variability, LF/HF ratio and blood pressure in the resting and sitting positions, both before and after oral clonidine (300 microg), a central sympatholytic agent. In the supine position before clonidine, hypertensive patients had higher blood pressure and lower HF values than healthy subjects. Clonidine induced increases in RR interval and HF in both groups, while LF and LF/HF ratio decreased in healthy subjects, but not in hypertensive patients. On assuming the sitting position, both groups showed reductions in RR and HF and increments in LF and LF/HF. In healthy subjects, the response to the postural challenge was unaffected by clonidine. In contrast, hypertensive patients showed no changes in LF and LF/HF ratio, and a significantly lower decrease in HF. These differences were probably due to the existence of two subsets of patients, one exhibiting similar responses to clonidine as healthy subjects, and the other showing no appreciable response to the drug. These results suggest that hypertensive patients have an altered sympatho-vagal balance to the heart, which can be unmasked by clonidine. This phenomenon should be taken into account to achieve a better control of the overall cardiovascular risk of hypertensive patients.

Systemic hemodynamics and renal function during brain natriuretic peptide infusion in patients with essential hypertension

We assessed the cardiovascular and renal effects of human brain natriuretic peptide (BNP) infused at a dose inducing an increase in plasma BNP to pathophysiologic levels, in eight hypertensive patients in a randomized, placebo-controlled, cross-over study. Left ventricular performance, cardiac output (echocardiography), heart rate, arterial pressure, glomerular filtration rate (GFR; creatinine clearance), sodium excretion, intrarenal sodium handling (lithium clearance method), and urine flow rate were measured in the infusion and postinfusion periods (1 h each), together with plasma BNP and the urinary excretion rate of cGMP. Plasma BNP levels increased from 2.90 +/- 0.74 to 36.43 +/- 5.51 pmol/L (P < .01) at the end of the infusion and were still elevated at the end of the postinfusion period (7.03 +/- 1.41 pmol/L, P < .05). The urinary excretion of cGMP was also significantly higher during BNP infusion. Left ventricular performance, cardiac output, arterial pressure, and peripheral vascular resistance were not affected by BNP. Peptide infusion induced a significant increase in GFR (placebo, 115 +/- 24; BNP, 147 +/- 19 mL/min), sodium excretion (placebo, 129 +/- 40; BNP, 243 +/- 60 mumol/min), and urine flow rate. All these effects were observed also in the postinfusion period. The natriuretic effect of BNP was attributable to both an increase in filtered sodium load and a reduction of distal sodium reabsorption. These results suggest that BNP may contribute to maintain renal function and sodium excretion in patients with essential hypertension.