Atrial natriuretic peptide in multiple system atrophy.

Central nervous system feedback loops centered on hypothalamic neurons control atrial natriuretic peptide (ANP). We evaluated the ANP response to arterial hypotension, isotonic blood volume expansion, and increase in plasma osmolality in 14 patients with multiple system atrophy (MSA). Seven of the patients were characterized by a lack of vasopressin response to hypotension (MSA type B), suggesting chronic sinoaortic denervation, and seven by a preserved response (MSA type A). Orthostatic hypotension decreased ANP in controls and type A patients, whereas ANP in type B was not affected. Isotonic saline infusion increased ANP and diuresis in controls and type A patients, whereas it did not affect ANP in type B. Osmotic load increased plasma osmolality and vasopressin in controls and MSA patients and ANP in controls and type A but not in type B patients. In MSA patients with altered afferent control of vasopressin, ANP secretion is not stimulated by blood volume expansion, osmotic load, or blood pressure, suggesting that afferent excitatory control plays a role in the release of ANP.

Angiotensin converting enzyme binding sites in human heart and lung: comparison with rat tissues.

1. Angiotensin converting enzyme (ACE), a dipeptidyl carboxypeptidase which catalyzes the final activation step in the formation of angiotensin II, was identified by radioligand studies in rat heart and lung. In this work we identified ACE binding sites in human left ventricle and lung by radioligand binding using the ACE inhibitor [3H]-ramiprilat in all tissues tested was saturable, temperature and zinc-dependent, and inhibited by EDTA. In human left ventricle homogenate we found a density of binding sites of 121 +/- 15 fmol mg-1 protein (n = 4) with an affinity (Kd) of 850 +/- 55 pM, whereas in rat left ventricle the same values were 23 +/- 4 fmol mg-1 protein and 315 +/- 30 pM, (n = 4), respectively. 3. [3H]-ramiprilat binding to rat (n = 4) and human lung (n = 4) showed a binding site density of 2132 +/- 155 and 1085 +/- 51 fmol mg-1 protein respectively with an affinity of 639 +/- 54 and 325 +/- 22 pM. The lung:heart ratio of ACE binding site density was about 9:1 in man and 100:1 in rat. 4. The binding affinities of 13 ACE inhibitors were evaluated on human heart and lung: the drugs tested showed a wide range of affinities for the ACE binding sites in both tissues, and the affinity for lung was significantly greater than for heart for most of the drugs. 5. The greater potency of some ACE inhibitors in displacing [3H]-ramiprilat in human lung compared with the heart indicates differences between ACE binding sites in these tissues and suggests the possibility of a selective organ-targeted therapeutic approach.

Altered vasopressin response to metoclopramide in multiple system atrophy: evidence of a cholinergic defect in the hypothalamus.

Multiple system atrophy (MSA) is a heterogeneous group of central neurological degenerations often associated with diffuse deterioration of the hypothalamic cholinergic neurons. In the hypothesis of an altered cholinergic regulation of vasopressin release, we evaluated vasopressin response to metoclopramide (20 mg i.v.), a cholinomimetic agonist, in 12 MSA patients. In the same patients the hemodynamic and osmolal control of vasopressin was also evaluated. We found that MSA patients had significantly lower basal plasma vasopressin values and higher plasma osmolality than control subjects. However, they displayed a normal vasopressin response to osmotic stimulation. During head-up tilting, orthostatic hypotension occurred in all patients, and the vasopressin response to hypotension was severely blunted in 5 of 12 patients, thus demonstrating the presence of a lesion of the afferent noradrenergic pathways. Metoclopramide increased vasopressin in control subjects, whereas MSA patients did not display any increase in vasopressin. These results clearly indicate that cholinergic neurons that regulate vasopressin release are damaged in MSA. Such an alteration may be dissociated from the lesion of the afferent noradrenergic pathways. As a consequence of the altered vasopressin release, MSA patients show lower plasma vasopressin levels with consequent propensity to dehydration and hypovolemia, which may further aggravate their hypotension.

Cortisol resistance in acquired immunodeficiency syndrome.

This study concerns 9 iv drug abusers with acquired immunodeficiency syndrome (AIDS) who developed hypercortisolism without the clinical signs or metabolic consequences of hypercortisolism. All patients were characterized by an Addisonian picture (weakness, weight loss, hypotension, hyponatremia, and intense mucocutaneous melanosis). An acquired form of peripheral resistance to glucocorticoids was suspected. We, therefore, examined glucocorticoid receptor characteristics on mononuclear leukocytes by measuring [3H]dexamethasone binding and the effect of dexamethasone on [3H]thymidine incorporation, which is one of the effects of glucocorticoid receptor activation. Glucocorticoid receptor density was increased in AIDS patients with an Addisonian picture (group 1; 16.2 +/- 9.4 fmol/million cells) compared to values in 12 AIDS patients without an Addisonian picture (group 2; 6.05 +/- 2.6 fmol/million cells; P less than 0.01) and sex- and age-matched controls (3.15 +/- 2.3 fmol/million cells; P less than 0.01). The affinity of glucocorticoid receptors (Kd) was strikingly decreased (9.36 +/- 3.44 nM in group 1; 3.2 +/- 1.5 nM in group 2; 2.0 +/- 0.8 nM in controls; P less than 0.01). [3H]Thymidine incorporation was decreased dose-dependently by dexamethasone in controls and patients; the effect was significantly blunted (P less than 0.05) in group 1 patients, which suggests that activation of glucocorticoid receptor is impaired as a result of the glucocorticoid receptor abnormality. In conclusion, AIDS patients with hypercortisolism and clinical features of peripheral resistance to glucocorticoids are characterized by abnormal glucocorticoid receptors on lymphocytes. Resistance to glucocorticoids implies a complex change in immune-endocrine function, which may be important in the course of immunodeficiency syndrome.

Beta-adrenergic receptors and reflex tachycardia after single and repeated felodipine administration in essential hypertension.

To verify the possible contribution of beta-adrenergic receptor down-regulation to the reversal of reflex tachycardia during chronic treatment with a dihydropyridine calcium antagonist, 11 hypertensive patients were studied with noninvasive blood pressure (BP) and heart rate (HR) monitoring after a placebo period, and on the first and seventh day of felodipine administration, 5 mg twice daily. Plasma catecholamines and neutrophil beta-adrenergic receptors were measured on the first and seventh day of treatment, immediately before and 2 h after drug administration. The first administration of felodipine was followed by a significant drop in BP (peak reduction in mean BP 24 +/- 7 mm Hg), lasting 6 h and mirrored by reflex tachycardia (peak increase in HR 14 +/- 9 beats/min). On the morning of the seventh day, 12 h after the previous felodipine administration, mean BP (MBP) was 16 mm Hg lower than on the last placebo day, while HR was unchanged. The next administration of felodipine was followed by a smaller drop in BP (MBP - 15 +/- 7 mm Hg; NS vs. placebo), while reflex tachycardia was the same as after acute felodipine (HR 13 +/- 8 beats/min; p less than 0.05 vs. placebo, NS vs. acute administration). Plasma noradrenaline concentration increased after both acute and chronic administration (p less than 0.0001), and preadministration values were highest on day 7 (p less than 0.05). Neutrophil beta-adrenergic receptor density and affinity did not change either acutely or chronically. This study gives both indirect and direct evidence that beta-adrenoceptor down-regulation does not occur during repeated felodipine administration in hypertension. Reflex tachycardia is not abolished, but is reset to lower BP levels.

Effects of a cable car trip on blood pressure and cardiovascular hormones in lowlander and highlander normotensives.

The effects of a cable car trip from 1370 m (4500 ft) to 3460 m (11350 ft) were studied in 6 lowlanders (3 men and 3 women, mean age 31 +/- 4 years, living at an altitude of less than 500 m) and in 10 highlanders (all males, mean age 37 +/- 12 years, ski teachers and cable car workers working for greater than or equal to 6 months/year at a greater than 3000 m). Cuff blood pressure (BP), heart rate, plasma catecholamines, serum renin, aldosterone, ACTH and cortisol were measured immediately before and 20 min after the trip, at rest and at the same air temperature. A handgrip test was also performed under the same conditions. At baseline, lowlanders and highlanders showed significant differences in diastolic BP (86 +/- 5 mmHg in lowlanders and 91 +/- 4 mmHg in highlanders, p = 0.05), plasma noradrenaline (323 +/- 114 pg/ml in lowlanders and 585 +/- 255 in highlanders, p less than 0.05), serum renin (10 +/- 6 pg/ml in lowlanders and 17 +/- 8 in highlanders, p less than 0.05), and serum cortisol (163 +/- 54 ng/ml in lowlanders and 120 +/- 25 in highlanders, p less than 0.01). The acute exposure to high altitude did not modify BP, heart rate or any of the measured cardiovascular hormones in either group. The handgrip test provoked a significant increase in systolic and diastolic BP in both lowlanders and highlanders (p less than 0.01), and this response was not modified by the change in altitude; however, highlanders showed significantly smaller increases in systolic BP than lowlanders at both altitudes (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in alpha-1 and beta-2 adrenoceptor density in human hepatocellular carcinoma.

Catecholamines are involved critically in the mechanisms of liver cell proliferation by acting on hepatic alpha-1 and beta-2 adrenoceptors. To identify the role of these receptors in human hepatocellular carcinoma (HCC), the density was examined of alpha-1 and beta-2 adrenoceptors with their affinity and coupling of beta-2 adrenoceptors to adenylate cyclase in HCC tissue and in nonadjacent/nontumor tissue from the same livers. Studies were also done on healthy livers from age-matched and sex-matched patients undergoing abdominal surgery for nonhepatic diseases. Twenty-two HCC had a decrease of about 72% in alpha-1 adrenoceptor density compared with their nonadjacent/nontumor tissue and a decrease of about 40% compared with healthy controls. Nonadjacent/nontumor tissue from HCC patients had a 125% increase in alpha-1 adrenoceptor density compared with healthy livers. Twenty-three of 24 HCC had an increase of about 180% in beta adrenoceptor density compared with their nonadjacent/nontumor tissue and healthy controls. Beta adrenoceptors were coupled to adenylate cyclase, as evidenced by a guanosine triphosphate-mediated right shift in (-)-isoproterenol competition isotherms and by cyclic adenosine monophosphate (cAMP) production after stimulation with (-)-isoproterenol. The HCC tissue yielded a larger increase in cAMP than nonadjacent/nontumor tissue and healthy controls. The authors conclude that a higher density of alpha-1 adrenoceptors in nonadjacent/nontumor tissue from HCC characterizes the "healthy" part of the liver in HCC patients and that an increase in beta-2 and a decrease in alpha-1 adrenoceptor densities characterize the tumor part of the liver in human HCC.

[Hemodynamic response to somatostatin at rest and during sympathetic activation in idiopathic orthostatic hypotension]. / Risposta emodinamica alla somatostatina a riposo e durante attivazione simpatica nella ipotensione ortostatica idiopatica.

Idiopathic orthostatic hypotension (IOH) represents a degenerative disorder of the peripheral nervous system characterized by low values of arterial blood pressure during orthostatism, with reduction in serum catecholamines. Since treatment of symptomatic IOH has been unsatisfactory till now, we studied the hemodynamic response to somatostatin (S) (Octreotide, 100 micrograms sc) at rest (R) and during sympathetic activation (tilting, T) by means of 2D and/or color Doppler echocardiography, in 5 ambulatory IOH patients (4M, 1F; aged 65 +/- 5 years), with simultaneous recording of blood pressure and heart rate. Post-S, an increased blood pressure was evident during T without heart rate modifications (pre- vs post-S, SAP: 92 +/- 9 vs 148 +/- 12; DAP: 61 +/- 4 vs 90 +/- 9 mmHg; p less than 0.05), while systolic echo parameters did not change significantly. Doppler aortic velocity curve showed during T a reduction of Vmax (pre- vs post-S: 0.98 +/- 0.09 vs 0.73 +/- 0.03 m/s; p less than 0.05) and of cardiac output, due to unchanged preload. Pre-S, at rest, Doppler mitral velocity curve presented a normal E/A ratio as in normal subjects, with a reduced E peak and an increased A peak post-S, indirect signs of increased afterload. Pre-S, E and A peak velocities underwent progressive decrease during T, markedly more evident post-S. Total peripheral resistance, at rest and during T, increased post-S too (pre- vs post-S, rest: 2406 +/- 267 vs 3162 +/- 599; T: 1634 +/- 201 vs 2784 +/- 425 dyne*s/cm-5; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory-burst stimulants desensitize beta-2 adrenoceptors on human polymorphonuclear leukocytes.

We investigated the effect of respiratory-burst stimulants on beta-2 adrenoceptors in human polymorphonuclear leukocytes (PMNL). Pre-incubation of PMNL with these substances did not affect the number or affinity of the receptors but desensitized them, as shown by the "right-shift" in (-)-isoproterenol competition isotherms. H-7, an established protein kinase C inhibitor, and nimesulide, a new putative inhibitor of this enzyme, blunted both superoxide anion production and beta-2 adrenoceptor desensitization. A positive correlation was found between superoxide anion generation and the "right-shift" in isoproterenol competition isotherm (r = 0.92; p less than 0.01). Desensitization of beta-2 adrenoceptors was not due to superoxide anions per se since incubation of PMNL with superoxide anion scavengers (superoxide dismutase and catalase) did not modify the results.

Role of the Frank-Starling mechanism in maintaining cardiac output during increasing levels of treadmill exercise in beta-blocked normal men.

To determine the effects of beta blockade on hemodynamics during increasing levels of treadmill exercise, 10 healthy volunteers were studied after 1 week of placebo, and then after 1 week of treatment with oral propranolol, 80 mg twice daily, or dilevalol, 400 mg once daily. The study was randomized and double-blind, with a crossover sequence. Hemodynamics were measured by CO2 rebreathing at rest and at 25, 50, 75 and 100% of VO2 max. After placebo, cardiac output increased from 5.8 +/- 2.1 (rest), to 19.4 +/- 6.4 liters/min (100% VO2 max), mainly due to an increase in heart rate from 84 +/- 6 to 169 +/- 15 beats/min. Stroke volume increased from 70 +/- 27 (rest), to 137 +/- 65 ml (25% VO2 max), and then leveled off to 116 +/- 41 at 100% VO2 max. After both beta blockers, exercise cardiac output was maintained at 100% VO2 max: 20.1 +/- 9.3 liters/min with propranolol and 19.1 +/- 8.6 with dilevalol. However, a significant reduction versus placebo values was observed for cardiac output at 25% VO2 max, from 13.7 +/- 5.9 during placebo, to 9.4 +/- 2.5 during propranolol, and to 9.6 +/- 2.3 during dilevalol (both p less than 0.01 vs placebo). Maintenance of cardiac output with both beta blockers at higher levels of exercise came from an increased stroke volume (p less than 0.05 vs placebo), while heart rate (in beats/min) was greatly reduced (propranolol 61.6 +/- 9.4 rest, 90.1 +/- 10.7 at 100% VO2 max; dilevalol 70.8 +/- 6.4 rest, 99.2 +/- 11.8 at 100% VO2 max, p less than 0.01 vs placebo for each).(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of alpha 1-adrenergic receptors on sarcolemma from normal subjects and patients with idiopathic dilated cardiomyopathy: characteristics and linkage to GTP-binding protein.

Discontinuous density sucrose gradient centrifugation was used to isolate membrane vesicles from the left ventricle of three normal subjects (one prospective organ donor and two traffic victims whose hearts were obtained 1 hour after death) and nine patients undergoing cardiac transplantation as a consequence of idiopathic dilated cardiomyopathy. Sarcolemma-enriched subcellular fractions, detected in the interface between 8.55% and 25% sucrose, were identified by the increased activity of Na+,K+-ATPase and by enrichment in beta-adrenergic receptor density. The density of beta-adrenergic receptors was lower in vesicles from diseased hearts (610 +/- 71 fmol/mg protein) than in vesicles from normal hearts (1,410 +/- 226 fmol/mg protein; p less than 0.01). alpha 1-Adrenergic receptors were identified in these membrane vesicles by [3H]prazosin binding. Specific binding of [3H]prazosin was about 50% of the total binding at 1 nM, and alpha 1-adrenergic binding sites were saturable at approximately 3 nM. Scatchard analysis revealed 58 +/- 5 fmol/mg protein (KD = 0.90 +/- 0.08 nM) in pathological hearts and 30 +/- 5 fmol/mg protein (KD = 0.90 +/- 0.03 nM) in normal hearts (p less than 0.01). The displacement curve of (-)-norepinephrine in membrane vesicles from normal hearts delineated one subpopulation of alpha 1-adrenergic receptors; the addition of 0.1 mM GTP did not cause right shift. In membrane vesicles from diseased heart, the displacement curve of (-)-norepinephrine disclosed two subpopulations of alpha 1-adrenergic receptors. A right shift that occurred after addition of GTP showed that in this case alpha 1-adrenergic receptors were functionally coupled with GTP-binding protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in vasopressin regulation in Alzheimer's disease.

A decreased concentration of vasopressin (AVP) in the plasma of patients with Alzheimer's disease has been shown recently and suggests damage to hypothalamic neurosecretory cells. To verify this, osmolar and hypotension (sodium nitroprusside) stimulations on AVP release were applied. The effect of metoclopramide, a powerful stimulator of AVP, was also assessed. Patients with Alzheimer's disease released AVP normally after hypotension. However, AVP response to osmotic stimulation was altered in eight out of 10 patients, owing to low osmoreceptor sensitivity and/or high threshold. Metoclopramide increased AVP in controls but not in patients. Normal AVP response to hypotension in patients with Alzheimer's disease makes it unlikely that there is a significant anatomical loss or damage of hypothalamic neurosecretory cells. Alterations in osmoreceptor function and AVP unresponsiveness to metoclopramide point to damage in the control of AVP release in Alzheimer's disease.

Osmotic and nonosmotic control of vasopressin release in the elderly: effect of metoclopramide.

The study was undertaken to define the relationships between the arginine vasopressin (AVP) response to a pressure-volume stimulus (upright posture test), an osmolar challenge, and metoclopramide injection (20 mg, iv) in normal young and elderly subjects. Besides confirming previous findings of increased AVP responsiveness to osmolar challenge and reduced AVP responsiveness to upright posture in the elderly, we found that metoclopramide stimulated AVP release in both young [from 1.09 +/- 0.05 (mean +/- SD) to 1.77 +/- 0.05 pmol/L; P less than 0.05] and elderly subjects (from 1.54 +/- 0.18 to 4.73 +/- 1.82 pmol/L; P less than 0.01). The response was much greater in the elderly (P less than 0.01). The AVP responses to upright posture and metoclopramide were inversely correlated (r = -0.77; P less than 0.01), suggesting that the elderly have increased sensitivity to stimuli, such as metoclopramide, to counteract their reduced sensitivity to baroreceptor stimulation of AVP release.

Identification and characterization of alpha 1- and beta 2-adrenergic receptors in human liver.

Adrenergic receptors were identified in healthy human hepatic tissue from thirty-nine subjects undergoing elective abdominal surgery by using the specific alpha 1-antagonist [3H]-prazosin and the beta adrenergic antagonist [3H]-dihydroalprenolol ([3H]-DHA). [3H]-prazosin binding to plasma membranes was rapid, of high affinity, saturable and stereospecific with a maximal binding capacity (Bmax) of 74.1 +/- 5.5 fmol mg-1 of protein. The displacement curve for (-)-norepinephrine was better explained by a one-site binding and after addition of GTP 0.1 mM the curve was not right-shifted, suggesting the majority of alpha receptors in healthy human liver are of the alpha 1 subtype and not linked to a GTP-binding protein. [3H]-DHA binding to liver plasma membranes was also rapid, of high affinity, saturable and stereospecific with a Bmax 96.5 +/- 10.3 fmol mg-1 of protein of receptors. Computer aided analysis of the displacement curve of ICI 118,551, a subtype selective beta 2-antagonist (IC50 = 62 +/- 2 nM), indicated a one-site binding, thus, showing that beta adrenergic receptors are of the beta 2 subtype. The displacement curve of [3H]-DHA for (-)-isoproterenol was right shifted by GTP indicating that beta 2 adrenergic receptors are linked to a GTP-binding protein in human liver. These results indicate that alpha 1- and beta 2-receptors co-exist in human liver but only beta 2-receptors are linked to a GTP-binding protein.

Metoclopramide increases vasopressin secretion.

The possibility that metoclopramide (MCP), a potent stimulator of aldosterone secretion, might influence vasopressin secretion in man was studied. MCP (10 mg, iv) increased plasma vasopressin (mean +/- SD) from 1.3 +/- 0.1 to 2.4 +/- 0.1 pg/ml at 10 min and to 2.65 +/- 0.1 pg/ml at 20 min (P less than 0.01) in 10 recumbent normal subjects. No changes in plasma osmolality or peripheral hemodynamics, which might have accounted for the increase in vasopressin, were found. Sulpiride (100 mg iv), haloperidol (2 mg, iv), and domperidone (20 mg, iv), three chemically unrelated antidopaminergic agents, as well as TRH (200 micrograms, iv), failed to modify plasma vasopressin, thus suggesting that the MCP effect on vasopressin is not linked to its antidopaminergic and/or PRL-releasing properties. MCP also was effective in releasing vasopressin in 5 dehydrated subjects, in whom plasma vasopressin increased from 1.9 +/- 0.2 to 3.1 +/- 4 pg/ml (P less than 0.05), and in 5 subjects during steady state water diuresis, in whom free water excretion decreased from 9 to 1 ml/min (P less than 0.01) and plasma vasopressin increased from 0.3 +/- 0.1 to 1.2 +/- 0.2 pg/ml (P less than 0.05). No changes in either vasopressin secretion or free water excretion occurred in 4 patients with severe central diabetes insipidus. These results suggest that MCP stimulates the release of biologically active vasopressin in man.