Alberto Del Bo

Sympathetic Activation and Loss of Reflex Sympathetic Control in Mild Congestive Heart Failure

BACKGROUND Baroreflex control of sympathetic activity is impaired in severe congestive heart failure (CHF), probably causing the marked sympathetic activation typical of this condition. Little information exists, however, as to whether baroreflex impairment and related sympathetic activation also occur in mild CHF. METHODS AND RESULTS We studied 19 patients (age, 57.5 +/- 2.2 years, mean +/- SEM) with CHF in New York Heart Association (NYHA) class III or IV and with a marked reduction in left ventricular ejection fraction (LVEF, 30.1 +/- 1.5% from echocardiography) and 17 age-matched patients with CHF in NYHA class I or II and with an only slightly reduced LVEF (44.9 +/- 3.3%) that never was < 40%. Seventeen age-matched healthy subjects served as control subjects. Primary measurements included beat-to-beat arterial blood pressure (with the Finapres technique), heart rate (from ECG), and postganglionic muscle sympathetic nerve activity (MSNA, from microneurography at the peroneal nerve). Measurements were performed at baseline and during baroreceptor stimulation (intravenous phenylephrine infusion), baroreceptor deactivation (intravenous nitroprusside infusion), and cold-pressor test. Baseline blood pressure was similar in the three groups, whereas heart rate was progressively greater from control subjects to patients with mild and severe CHF, MSNA (bursts per 100 heart beats) increased significantly and markedly from control subjects to patients with mild and severe CHF (47.1 +/- 2.9 versus 64.4 +/- 6.2 and 82.1 +/- 3.4, P < .05 and P < .01, respectively). Heart rate and MSNA were progressively reduced by phenylephrine infusion and progressively increased by nitroprusside infusion. Compared with control subjects, the responses were strikingly impaired in severe CHF patients, but a marked impairment also was seen in mild CHF patients. On average, baroreflex sensitivity in mild CHF patients was reduced by 59.1 +/- 5.5% (MSNA) and 64.8 +/- 4.8% (heart rate). In contrast, reflex responses to the cold-pressor test were similar in the three groups. CONCLUSIONS These results demonstrate that in mild CHF patients the baroreceptor inhibitor influence on heart rate and MSNA is already markedly impaired. This impairment may be responsible for the early sympathetic activation that occurs in the course of CHF.

Fluctuations of Radial Artery Distensibility Throughout the Menstrual Cycle

Estrogen administration has a number of favorable cardiovascular effects, and recent evidence suggests that these include an increase in arterial distensibility. Whether this is also the case for the physiological changes in estrogen production during the menstrual cycle has never been determined, however. In 21 premenopausal healthy women, we continuously measured radial artery diameter and blood pressure by an echo-tracking device and a beat-to-beat finger device, respectively. Arterial distensibility was calculated as distensibility/blood pressure curve. The measurements were made during the follicular, ovulatory, and luteal phases of the menstrual cycle. As expected, compared with the follicular phase, plasma estradiol, follicle-stimulating hormone, luteinizing hormone, and prolactin were increased in the ovulatory phase, whereas progesterone was increased in the luteal phase, together with antidiuretic hormone. Radial artery distensibility was increased in the ovulatory and reduced in the luteal phase, the changes being independent of the small, concomitant blood pressure changes. The arterial wall stiffening seen in the luteal phase was associated with a reduction in the flow-dependent endothelial dilatation of the radial artery as assessed by the hyperemia after short-term ischemia of the hand. Thus, the natural menstrual cycle is characterized by alterations in radial artery distensibility. The mechanisms responsible for this phenomenon remain to be clarified. It is possible, however, that the greater arterial distensibility of the ovulatory phase is due to an estrogen-dependent reduction in vascular smooth muscle tone, whereas the arterial stiffening of the luteal phase depends on vascular smooth muscle contraction due to more complex hormonal phenomena, ie, an endothelial impairment due to estrogen reduction but also to an increase in progesterone and antidiuretic hormone levels.

Anatomical basis for the fastigial pressor response

Electrical stimulation of rostromedial portion of cerebellar fastigial nucleus elicits integrated cardiovascular effects, which are neurally and humorally mediated. In this study, we sought to demonstrate the anatomical substrates of the fastigial pressor response (FPR) in the rat. The response was electrophysiologically localized in anesthetized, paralyzed-ventilated rats. Anterograde transport techniques were used to study the efferent projections of the fastigial pressor area; the distribution of efferent projection cells were then mapped by injecting retrograde tracers into anterogradely labeled sites. Electrolytic lesions were then placed bilaterally in selected brainstem areas in the attempt to block the pressor response. Sites of cerebellar stimulation and of brainstem lesions were subsequently histologically identified. The following lesions abolished the FPR: in nine animals lesions involved portions of the nucleus gigantocellularis dorsalis (NGCd), paramedian reticular formation (PMN) and the nucleus tractus solitarii (NTS) (in two animals fairly selectively the caudal NTS); in two other animals lesions destroyed the rostral ventrolateral medulla (C1 area) and in one animal the area encompassing the dorsal convexity of the superior cerebellar peduncle bordering the locus coeruleus-lateral parabrachial complex; partially effective were unilateral lesions of NGCd and NTS (three), bilateral lesions confined to NGCd and PMN (two), to vestibular complex and uncinate fasciculus (UF) (three), to UF and locus coeruleus (three) and to nucleus reticularis ventralis (two). Ineffective lesions involved A1 area, the nucleus gigantocellularis ventralis (NGCv), the spinal trigeminal nucleus and nucleus reticularis parvocellularis, the A5 area of the ventrolateral pons, the central gray and lateral mesencephalic tegmentum. It seems therefore that the pressor response elicited by stimulation of the cerebellar fastigial nucleus utilizes central specific pathways, as lesions involving other brainstem regions also known to participate in cardiovascular control do not affect the response. Furthermore, the FPR persisted after midbrain decerebration, thus demonstrating that it is organized beneath the midbrain.

Regulation of vasopressin release in moderately severe essential hypertension

Vasopressin plasma concentrations have been measured in two groups of subjects, 13 moderate essential hypertensive patients without target organ damage and eight control normotensive subjects, before and after the assumption of the upright position, and intravenous infusions of hypotonic saline (0.45% NaCl, 0.25 ml kg−1 min−1 for 1 h) and hypertonic saline (100 mmol NaCl in 50 ml). Plasma vasopressin in recumbent baseline conditions was not significantly different in the two groups. Upright posture and hypertonic challenge augmented, while hypotonic saline reduced plasma vasopressin levels, which were not significantly different between the two groups. Plasma renin activity increased in the upright position, was reduced by administration of hypotonic saline and unaffected by hypertonic saline, with no differences between the hypertensives and normotensives. After hypertonic saline, urinary flow rate and urinary sodium excretion in the hypertensive group increased to values significantly (p < 0.05) higher than in normotensive subjects. In conclusion our study excludes significant alteration of vasopressin regulation in moderate uncomplicated hypertension. In hypertensives although the response of vasopressin to an osmotic load is preserved, the data suggest that the renal handling of the osmotic load may be altered.

Hypercortisolism and Arterial Hypertension

AbstractBackground: A possible role of vasopressin in the development of arterial hypertension in patients with hypercortisolism was investigated. Methods: Four groups of subjects of both sexes were included. In all of them plasma vasopressin was determined. Twenty-four patients with Cushing’s disease (13 hypertensive and 11 still normotensive) were studied during the active period of the disease and after correction of hypercortisolism. A second group included 14 patients with Addison’s disease receiving specific hormone replacement. Thirty-two subjects with uncomplicated, untreated essential hypertension and a group of eight control healthy normotensive volunteers were also enrolled. Results: Baseline vasopressin (pg/mL) was higher (p < 0.05) in hypertensive patients with Cushing’s disease (3.2 ± 0.63) compared with all groups: normotensive patients with Cushing’s disease (1.6 ± 0.75), patients with Addison’s disease (1.9 ± 0.29), essential hypertensive patients (1.4 ± 0.21) and control normotensive volunteers (1.4 ± 0.20). Treatment reduced plasma cortisol, mean arterial pressure (MAP) and vasopressin in patients with Cushing’s disease. On examining those patients in detail, only 13 had no relapse of the disease after surgical treatment, and vasopressin and MAP were significantly reduced only in the seven who were previously hypertensive. Conclusions: Our data show that in normotensive patients with Cushing’s disease, plasma vasopressin is lower than in patients with hypertension. Moreover, after an effective surgical treatment, plasma vasopressin is lowered concurrently with lowering of MAP only in patients who were hypertensive. Patients with Addison’s disease receiving specific hormone replacement have low/normal plasma cortisol and normal vasopressin levels. Our observations suggest that vasopressin may have a role in the genesis or in development of hypertension associated with high levels of plasma cortisol.

Hypercortisolism and Arterial Hypertension: A Possible Role for Vasopressin

AbstractBackground: A possible role of vasopressin in the development of arterial hypertension in patients with hypercortisolism was investigated. Methods: Four groups of subjects of both sexes were included. In all of them plasma vasopressin was determined. Twenty-four patients with Cushing’s disease (13 hypertensive and 11 still normotensive) were studied during the active period of the disease and after correction of hypercortisolism. A second group included 14 patients with Addison’s disease receiving specific hormone replacement. Thirty-two subjects with uncomplicated, untreated essential hypertension and a group of eight control healthy normotensive volunteers were also enrolled. Results: Baseline vasopressin (pg/mL) was higher (p < 0.05) in hypertensive patients with Cushing’s disease (3.2 ± 0.63) compared with all groups: normotensive patients with Cushing’s disease (1.6 ± 0.75), patients with Addison’s disease (1.9 ± 0.29), essential hypertensive patients (1.4 ± 0.21) and control normotensive volunteers (1.4 ± 0.20). Treatment reduced plasma cortisol, mean arterial pressure (MAP) and vasopressin in patients with Cushing’s disease. On examining those patients in detail, only 13 had no relapse of the disease after surgical treatment, and vasopressin and MAP were significantly reduced only in the seven who were previously hypertensive. Conclusions: Our data show that in normotensive patients with Cushing’s disease, plasma vasopressin is lower than in patients with hypertension. Moreover, after an effective surgical treatment, plasma vasopressin is lowered concurrently with lowering of MAP only in patients who were hypertensive. Patients with Addison’s disease receiving specific hormone replacement have low/normal plasma cortisol and normal vasopressin levels. Our observations suggest that vasopressin may have a role in the genesis or in development of hypertension associated with high levels of plasma cortisol.

Vasopresin and Human Hypertension

Abstract1. Two clinical studies are reported which investigate: (1) the regulation of vasopressin release in moderate hypertensive subjects not under treatment compared to normotensives and, (2) the effects of antihypertensive treatment on vasopressin and on its osmoregulation in moderate hypertensives.2. In the first study two stimuli facilitating vasopressin release (active upright position and hypertonic saline infusion) and a stimulus inhibiting vasopressin release (hypotonic saline infusion) have been applied to 13 moderate essential hypertensives and 8 control normotensives. In the second study, limited to hypertensives, the effects on plasma vasopressin and other plasma and urine variables, of either acute (by clonidine, n = 6 or by sodium nitroprusside, n = 6) or chronic (antihypertensive treatment for 1 month, n = 8) blood pressure lowering, before and after the i.v. administration of a hypertonic NaCl solution, were investigated.3. Baseline plasma vasopressin was not different in hypertensive and in normotensive subjects. Upright posture and hypertonic challenge augmented, while hypotonic saline reduced plasma vasopressin levels with no difference between the two groups. Acute, but not chronic, lowering of blood pressure increased plasma vasopressin from 1.6 ± 0.63 to 3.4 ± 0.7 pg/mL (p < 0.05); administration of hypertonic saline further increased vasopressin to 10.8 ± 2.22 (p < 0.01) in the acute and to 6.0 ± 1.03 pg/mL (p < 0.01) in the chronic study.4. No significant alterations of the regulation of vasopressin have been found in moderate, uncomplicated hypertension. Moreover, acute lowering of blood pressure facilitated the release of vasopressin and its osmoregulation while a chronic antihypertensive treatment did not interfere with a normal control of vasopressin secretion.

Osmoregulation of vasopressin during acute lowering of arterial pressure by clonidine in moderate hypertension

Hypertonic saline (100 mmol in 50 ml) was injected intravenously over 5 min in two groups of moderate essential hypertensive patients (group 1, n = 13; group 2, n = 6). In group 2, arterial pressure had been lowered by infusion of clonidine (0.3 mg in 100 ml saline), from 186 +/- 8/116 +/- 3 to 146 +/- 9/98 +/- 5 mmHg (mean +/- s.e.m.). The hypertonic stimulus increased the plasma osmolality of all subjects from 288 +/- 1 to 296 +/- 1 mosmol/kg (P less than 0.01). Plasma vasopressin increased from baseline values that were not significantly different (P less than 0.01) in each of the two groups. The increase in plasma vasopressin was significantly greater (P less than 0.05) in the group 2 hypertensives with a reduced arterial pressure (+7.81 +/- 1.79 pg/ml) than in the group 1 untreated hypertensives (+3.15 +/- 1.2 pg/ml). In our study, acute lowering of arterial pressure by clonidine did not significantly change baseline vasopressin, but facilitated osmotically induced vasopressin secretion.