HORMONAL AND CARDIOVASCULAR RESPONSES TO DDAVP IN MAN

Hormonal and cardiovascular responses to 1-desamino-8-D-arginine vasopressin (DDAVP) were investigated in six normal adult volunteers. After overnight fluid deprivation, an intravenous injection of either DDAVP (0.4 microgram/kg) or the same volume of normal saline was administered. One hour later an intravenous infusion of hypertonic saline was commenced and continued over two hours. Five minutes following the DDAVP injection, facial flushing, a fall in diastolic blood pressure by an average of 13% and a rise in pulse rate by an average of 18% were observed. There was a significant increase in plasma renin activity and plasma cortisol concentration, but no significant changes were observed in plasma concentrations of LH, FSH, TSH, prolactin or GH. Following osmotic stimulation by hypertonic saline plasma AVP rose to the same extent in both the DDAVP and control studies. DDAVP (0.4 microgram/kg) was also administered to five subjects with cranial diabetes insipidus. Again facial flushing, increased facial temperature, a fall in diastolic pressure and a rise in heart rate were all observed, suggesting that DDAVP exerts its cardiovascular actions by a mechanism other than antagonism of circulating endogenous AVP.     

Association of arginine vasopressin and arterial blood pressure in a population-based sample

BACKGROUND: The role of arginine vasopressin (AVP) in the development and maintenance of arterial hypertension is controversial. Furthermore, it remains unclear whether chronic treatment with antihypertensive agents modulates levels of AVP, with potential secondary effects on vascular tone and fluid homeostasis. OBJECTIVE: To investigate the relation between plasma AVP and arterial blood pressure in a population-based sample of 534 middle-aged subjects. RESULTS: Overall, levels of AVP were higher in hypertensive subjects (2.15 +/- 0.26 pg/ml; n = 289) than in normotensive subjects (1.45 +/- 0.15 pg/ml; n = 245; P < 0.05). (Hypertension was defined as systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 95 mmHg, or receiving antihypertensive medication.) In untreated individuals, plasma levels of AVP were found to be correlated with both systolic (r = 0.15, P = 0.002) and diastolic (r = 0.14, P = 0.005) blood pressure. The differences between the lowest and highest quartile of AVP levels were 5.1 mmHg (P = 0.03) and 2.6 mmHg (NS) for systolic and diastolic blood pressure, respectively, after adjustment for age and sex. Moreover, it appeared that the relation between AVP and blood pressure was particularly strong in subjects with low levels of renin (< 10 mU/l; n = 118; systolic blood pressure r = 0.24, P = 0.007; diastolic blood pressure r = 0.19, P = 0.03). Specifically, patients receiving monotherapy with diuretics (n = 39) or beta-blockers (n = 54) displayed elevated plasma levels of AVP (2.93 +/- 0.98 pg/ml and 2.74 +/- 0.74 pg/ml respectively); however, only in patients taking diuretics was this finding apparently independent of confounding variables. Other monotherapies with angiotensin-converting enzyme inhibitors (n = 9) or Ca(2+)-antagonists (n = 19) were not associated with levels of AVP. CONCLUSION: The data suggest that plasma levels of AVP display a discernible relationship with arterial blood pressure and hypertension, particularly when renin levels are low. In addition, with the exception of diuretics, no modulation of AVP levels is attributable to the intake of antihypertensive agents as it occurs in a population-based sample.     

Urinary excretion of the aquaporin-2 water channel exaggerated in pathological states of impaired water excretion

OBJECTIVE The present study was undertaken to determine whether the hydro‐osmotic action of arginine vasopressin (AVP) is exaggerated in pathological states of impaired water excretion by measuring urinary excretion of the aquaporin‐2 (AQP‐2) water channel. PATIENTS AND MEASUREMENTS Eighteen hyponatraemic patients with impaired water excretion and 12 control subjects were studied during an acute oral water load (20 ml/kg body weight). RESULTS In the patient group plasma AVP levels were 1·6 pmol/l, relatively high compared to plasma osmolality of 279·8 mmol/kg. Urinary excretion of AQP‐2 under ad libitum water drinking was 41·1 fmol/umol creatinine in the patient group, a value significantly greater than that of 21·7 fmol/μmol creatinine in the control subjects. The acute water load verified the impairment in water excretion in the patient group, as the excretion of the water load was only 28·2% (control, 77·3%, P < 0·001) and the minimum urinary osmolality was as high as 437·3 mmol/kg (control, 122·9 mmol/kg, P < 0·001). Also, the minimum urinary excretion of AQP‐2 was significantly greater in the patient group than that in the control. There was a positive correlation between plasma AVP levels and urinary excretion of AQP‐2 in the control subjects (r = 0·56, P < 0·01). In contrast, the urinary excretion of AQP‐2 was exaggerated compared to the respective plasma AVP levels in the patient group, and thus the positive correlation disappeared. CONCLUSION These results indicate that hydroosmotic action of AVP is exaggerated more than that expected from plasma AVP levels in pathological states of impaired water excretion, with non‐suppressible, but normal, arginine vasopressin levels in spite of the hypo‐osmotic condition.     

α-HUMAN ATRIAL NATRIURETIC POLYPEPTIDE REDUCES THE PLASMA ARGININE VASOPRESSIN CONCENTRATION IN HUMAN SUBJECTS

The synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) was infused into six normotensive, euvolaemic, healthy volunteers to examine the effect on the plasma arginine vasopressin (AVP) concentration. The intravenous administration of alpha-hANP (0.1 microgram/kg/min, 20 min) led to a remarkable reduction in mean blood pressure (-10 mmHg, P less than 0.05), and there was an increase in pulse rate (+10 bpm, P less than 0.05), in each subject. The urinary volume, sodium excretion and cyclic 3',5'-guanosine monophosphate (cyclic-GMP) excretion were increased to 3.5 (P less than 0.05), 2.5 (P less than 0.05) eight-fold (P less than 0.01), respectively, during the alpha-hANP infusion. The dose and duration of the synthetic alpha-hANP in the present study was sufficient to induce these cardiovascular and renal effects. The plasma AVP concentrations decreased from 0.39 +/- 0.09 pg/ml to the undetectable level during the alpha-hANP administration. After infusion, the plasma concentrations of the AVP promptly returned to preinfusion levels (0.46 +/- 0.14 pg/ml). However, there was no significant change in plasma AVP concentration during placebo infusion. The marked suppression in plasma AVP concentration may account for the remarkable diuresis, in addition of the direct renal effects of the synthetic alpha-hANP.     

Effect of head-up tilt on vasopressin secretion and arterial pressure in anesthetized rats

The effect of 45 or 60 degrees head-up tilt on plasma arginine vasopressin (AVP) concentration, mean arterial pressure, and heart rate was studied in inactin-anesthetized rats. In all rats, there was a fall in blood pressure that was maximal within about 20-40 s and then returned toward normal. After 45 degrees head-up tilt for 30 min, AVP was increased from 7.0 +/- 1.7 to 21.0 +/- 5.9 pg/ml. Sixty-degree head-up tilt increased AVP at 5, 15, and 30 min, respectively, from 10.6 +/- 2.9 to 22.1 +/- 4.8 pg/ml, from 10.6 +/- 2.5 to 28.5 +/- 5.3, and from 16.1 +/- 4.7 to 62.6 +/- 10.3 pg/ml. After bilateral cervical vagotomy, 60 degrees head-up tilt for 30 min increased AVP, but the change was significantly reduced compared to intact animals. Bilateral sinoaortic denervation increased basal values of AVP, and there was no further increase during tilt. Bilateral electrolytic lesions of the hypothalamic paraventricular nuclei caused only a moderate reduction in the AVP response to tilt. When the effect of endogenous angiotensin II was antagonized by saralasin or its production was blocked by enalapril, the AVP response to tilt was reduced. The mean arterial pressure fell during the 1st min, but recovered rapidly when rats treated with a V1 vasopressin receptor antagonist were tilted. The data indicate that head-up tilt increases AVP secretion in anesthetized rats, that the response is mediated by the vagus and particularly by the arterial baroreceptors, and that circulating angiotensin II contributes to the response. However, the increased circulating AVP is not necessary for the maintenance of arterial pressure.     

Different effects of low and high doses of endothelin on haemodynamics and hormones in the normotensive conscious dog.

The effects of low-dose endothelin on systemic haemodynamics and vasoactive hormones were examined in conscious dogs. In addition, we examined the effects of endothelin on pressor responses to noradrenaline and angiotensin II and the baroreflex regulation of heart rate in conscious dogs. Continuous infusion of 40 fmol/kg per min endothelin for 40 min induced a mild but significant reduction in mean arterial pressure from 89.1 +/- 1.7 to 82.7 +/- 2.0 mmHg (P less than 0.05), associated with decreases in total peripheral resistance 20 min later. A 400 fmol/kg per min dose of endothelin, on the other hand, induced a gradual elevation of mean arterial pressure from 89.2 +/- 2.3 to 96.8 +/- 2.0 mmHg (P less than 0.05), associated with increases in total peripheral resistance over 30 min. The 40 fmol/kg per min dose of endothelin infusion induced a significant reduction in plasma arginine vasopressin (AVP; P less than 0.05) and elevations of plasma atrial natriuretic peptide (ANP; P less than 0.05), plasma prostaglandin E2 (PGE2; P less than 0.05) and plasma 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha; P less than 0.05). The 400 fmol/kg per min dose produced elevations of AVP, ANP, PGE2 and 6-keto-PGF1 alpha (P less than 0.05). Pressor responses to noradrenaline and angiotensin II were significantly attenuated during continuous infusion of 40 fmol/kg per min endothelin, whereas 400 fmol/kg per min endothelin did not induce any significant changes compared with the control. Furthermore, baroreflex sensitivity was attenuated with 40 fmol/kg per min endothelin but did not show any significant changes at 400 fmol/kg per min.(ABSTRACT TRUNCATED AT 250 WORDS)     

PLASMA IMMUNOREACTIVE β-ENDORPHIN IS ELEVATED IN URAEMIA

Plasma immunoreactive-(IR) beta-endorphin (beta-EP) and beta-lipotrophin (beta-LPH) levels were measured in 15 adult uraemic patients on chronic haemodialysis. The presence of immunoreactivity eluting in the position of beta-EP was demonstrated following submission of pooled extracts of uraemic plasma to gel permeation chromatography on Sephadex G-50. To separate beta-EP from beta-LPH, pre-dialysis plasma extracts from six individual patients, and three pools of three patients each, were submitted to sequential immune-affinity chromatography and levels were measured by radioimmunoassay. In all cases, plasma IR beta-EP concentrations were markedly increased compared with normal subjects (m +/- SEM fmol/ml; 64.4 +/- 13.7 vs. 2.3 +/- 0.2). IR beta-LPH concentrations were also increased (m +/- SEM fmol/ml; 55.7 +/- 13.2 vs. normal 6.1 +/- 0.8). In addition, post-dialysis concentrations of plasma IR beta-EP and beta-LPH were lower than pre-dialysis levels (n = 4).     

RISE IN PLASMA GROWTH HORMONE IN RESPONSE TO EXOGENOUS LRH IN KLINEFELTER'S SYNDROME

In a group of sixteen patients with Klinefelter's syndrome (KS) aged from 2 years 8 months to 31 years, a study was made of the plasma growth hormone (hGH) response to LRH (50 μg/m² i.v.; n= 16), TRH (200 μg i.v.; n= 14) and insulin-induced hypoglycaemia (0·1 u R.I,/kg i.v.; n= 6). There was a rise in hGH following LRH from a level below 5 ng/ml during fasting to a level above 8 ng/ml (P < 0·001) in nine (56·3%) of the sixteen patients tested; a similar response was found in only one of a control group of fifteen boys matched for age. TRH stimulation led to a rise in hGH in one of the fourteen KS patients tested, with none in the control group. Insulin-induced hypoglycaemia elicited a normal response of hGH in the six KS patients tested, from 1·8 ± 0·7 to 16·5 ± 3·7 ng/ml, (M ± SD, P < 0·001). Basal prolactin (PRL) levels were normal in the KS patients (9·4 ± 4·1 ng/ml, M ± SD) but the response to TRH stimulation was significantly higher (63·3 ± 40 ng/ml; P < 0·01) than that of the control group (30 ± 15 ng/ml). Plasma gonadotrophin levels and the response to LRH stimulation were increased in all of the KS patients except those below the age of 13. Plasma TSH levels and the response to TRH stimulation as well as the levels of serum thyroxine were found to be normal in all the KS patients tested. The abnormal rise of hGH following LRH stimulation and of PRL following TRH stimulation suggests a disturbance in the neuroendocrine regulation mechanisms of these hormones in KS.     

The Role of the Hypothalamic-Pituitary-Adrenal (HPA) Axis in the Regulation of Blood Pressure

The role of the HPA axis in blood pressure regulation was examined in 6 normal male volunteers by comparing haemodynamic and hormonal effects of placebo, captopril, and dexamethasone given in random order for two days. The average 24-hour systolic and mean arterial pressures on placebo (135±6 and 93±2mmHg respectively) were significantly higher than on captopril (118±1 and 85±1mmHg respectively, p < 0.05) but there were no significant changes on dexamethasone compared with placebo (128±3 and 89±3mmHg respectively). There were no differences in the average 24-hour diastolic blood pressures or heart rates, nor the day-night differences, night:day ratios or percentage changes in blood pressure and heart rate between treatments. Captopril significantly increased active plasma renin concentration, whilst dexamethasone decreased cortisol concentration. These results confirm the role of the renin-angiotensin system in the regulation of blood pressure in normal subjects but suggest that the HPA axis does not play a major role in determining ambulatory blood pressure or day-night variability in the short term.     

Partial nephrogenic diabetes insipidus caused by a novel mutation in the AVPR2 gene

Objective To identify the molecular basis and clinical characteristics of X‐linked congenital nephrogenic diabetes insipidus (CNDI) presenting with an unusual phenotype characterized by partial resistance to AVP. Subjects The proband was admitted at the age of 4 years with a history of polydipsia and polyuria since infancy. Initial clinical testing confirmed a diagnosis of diabetes insipidus (DI). Urine osmolarity rose during fluid deprivation and after 20 µg of intranasal desmopressin [1‐deamino‐8‐d ‐arginine‐vasopressin (dDAVP)]. A similar DI phenotype was found in his brother. Methods The coding regions of the AVP gene and the AVP receptor 2 (AVPR2) genes were sequenced in two affected and three unaffected family members. Clinical studies included a fluid deprivation test, intranasal dDAVP challenge, infusion of graded doses of dDAVP and AVP, and measurements of 24‐h urine output before and at the end of a 7‐day therapeutic trial of intranasal dDAVP. Results A novel missense mutation (1454C > A) in exon 3 of the AVPR2 gene predicting a Ser329Arg substitution was identified in the X‐chromosome of the two affected brothers and in one of the X‐chromosomes in the mother. The AVPR2 gene was normal in two unaffected siblings. Under basal conditions, the 24‐h urine volumes of the two affected boys were 5·5 l (229 ml/kg) and 3·5 l (192 ml/kg), the urine osmolalities were 78 and 90 mosm/kg, and plasma AVP 13·5 and 19·0 pg/ml. Urine osmolalities increased to 573 and 720 mosm/kg while plasma AVP levels were practically unchanged, 13·6 and 8·8 pg/ml, during fluid deprivation. Infusion of AVP resulted in urine osmolalities of 523 and 623 mosm/kg at plasma AVP levels of 58 and 42 pg/ml. Infusion of dDAVP had a similar effect, while treatment with standard doses of intranasal dDAVP had no effect on urine output. Discussion The affected members of this Belgian kindred have CNDI with partial resistance to AVP caused by a mutation in the AVPR2 gene that differs from any of the six mutations reported previously to produce this phenotype. Because the resistance to AVP is partial, this form of CNDI can be difficult to distinguish by indirect diagnostic tests from partial pituitary and dipsogenic DI.     

Role of sympathetic cardiovascular tone in control of arterial pressure in rats with cirrhosis

Abstract: Although an increase in sympathetic nervous activity has been recognized in cirrhosis, the contribution of this overactivity to the regulation of arterial pressure is unknown. The arterial pressure response to increasing doses of hexamethonium (0.05 to 3.2 mg · kg^-1 · min^-1), a ganglionic blocker that decreases sympathetic cardiovascular tone, was explored in normal rats and in two models of portal hypertension, i.e., rats with cirrhosis and rats with portal vein stenosis. Changes in plasma norepinephrine concentrations were greater in rats with cirrhosis (356±50 vs 166±30 pg/ml, p=0.04) than in normal rats (186±23 vs 86±31 pg/ml, p=0.06) and rats with portal vein stenosis (103±37 vs 93±5 pg/ml, p=0.10). The maximum decrease in arterial pressure was obtained at a dose of 1.6 mg · kg^-1 · min^-1 in each group. However, the decrease in arterial pressure was significantly greater in rats with cirrhosis (-25±2%) than in normal rats (-11±1%) and in rats with portal vein stenosis (-13±2%) (p=0.04). In conclusion, the results of this study suggest that the sympathetic cardiovascular tone is more important for the maintenance of arterial pressure in rats with cirrhosis than in normal rats and in rats with portal vein stenosis.     

Acute hemodynamic effect of a vascular antagonist of vasopressin in patients with congestive heart failure

To assess the role of arginine vasopressin (AVP) in congestive heart failure (CHF), 10 patients with CHF refractory to conventional treatment were studied before and 60 minutes after intravenous administration of 5 micrograms/kg of d(CH2)5Tyr(Me)AVP, a specific antagonist of AVP at the vascular receptor level. Heart rate, systemic arterial pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, cardiac index by thermodilution and cutaneous blood flow by laser-Doppler technique were measured. In 9 patients with no significant hemodynamic and cutaneous blood flow response to the AVP antagonist, baseline values (mean +/- standard deviation) were: heart rate, 77 +/- 14 beats/min; systemic arterial pressure, 120/79 +/- 18/8 mm Hg; pulmonary arterial pressure, 42/21 +/- 12/8 mm Hg; pulmonary capillary wedge pressure, 19 +/- 7 mm Hg; cardiac index, 2.2 +/- 0.6 liters/min/m2; plasma AVP, 2.3 +/- 0.8 pg/ml; and plasma osmolality, 284 +/- 14 mosm/kg H2O. The tenth patient had the most severe CHF. His plasma AVP level was 55 pg/ml and plasma osmolality was 290 mosm/kg. He responded to the AVP antagonist with a decrease in systemic arterial pressure from 115/61 to 79/41 mm Hg, in pulmonary arterial pressure from 58/31 to 33/13 mm Hg and in pulmonary capillary wedge pressure from 28 to 15 mm Hg. Simultaneously, cardiac index increased from 1.1 to 2.2 liters/min/m2 and heart rate from 113 to 120 beats/min; cutaneous blood flow increased 5-fold.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alteration of plasma ghrelin levels associated with the blood pressure in pregnancy

Ghrelin, an endogenous ligand for the growth hormone secretagogues, was originally isolated from rat stomach. It stimulates the release of growth hormone from primary pituitary cell cultures. We investigated the plasma concentration of ghrelin peptide in 16 nonpregnant women, 18 normal pregnant women, 20 patients with pregnancy-induced hypertension, and 10 postpartum women. The plasma concentration of ghrelin in nonpregnant women was 239.5+/-16.9 fmol/mL. The plasma concentration of ghrelin in normal pregnant women at the third trimester was 127.1+/-5.6 fmol/mL. There was negative correlation between plasma ghrelin concentration and systemic blood pressure in normal pregnant women (systolic: r=-0.564, P<0.05; diastolic: r=-0.610, P<0.01). Pregnant women with pregnancy-induced hypertension (177.9+/-14.6 fmol/mL, P<0.05) also had significantly higher levels of ghrelin compared with those of normal pregnant women. In addition, there was a significant correlation between plasma ghrelin levels and systemic blood pressure (systolic: r=-0.482, P<0.05; diastolic: r=-0.466, P<0.05). These results suggest for the first time that ghrelin might have some role in cardiovascular control during normal pregnancy and in pathophysiological conditions in pregnancy, such as pregnancy-induced hypertension.     

Effects of carotid occlusion and angiotensin II on vasopressin secretion in intact and vagotomized conscious rabbits

Experiments were performed in conscious rabbits with sectioned aortic depressor nerves to determine whether there is an interaction between angiotensin II (Ang II) and the baroreceptor reflexes in the control of arginine vasopressin (AVP) secretion. Baroreceptor reflexes were activated by a 5- or 10-min period of bilateral carotid occlusion with or without background infusion of Ang II at 10 or 20 ng/kg.min. Carotid occlusion increased mean arterial pressure, right atrial pressure, and heart rate, but did not change plasma AVP (PAVP) concentration. Infusion of Ang II at 10 ng/kg.min increased PAVP from 4.0 +/- 0.9 to 6.3 +/- 1.8 pg/ml (P less than 0.05). Carotid occlusion during Ang II infusion produced the same cardiovascular changes as before Ang II, but still failed to increase PAVP. Because increased atrial pressure can inhibit AVP secretion, the experiments were repeated in acutely vagotomized rabbits. Vagotomy increased heart rate but did not change mean arterial pressure or PAVP. Carotid occlusion after vagotomy increased PAVP from 2.2 +/- 0.2 to 3.3 +/- 0.5 pg/ml (P less than 0.05). Ang II infusion again increased PAVP but did not enhance the AVP response to carotid occlusion (2.9 +/- 0.4 to 3.9 +/- 0.7 pg/ml). These results provide further evidence for a role of the carotid sinus baroreceptors and vagal afferents in the control of AVP secretion and demonstrate that Ang II stimulates AVP secretion in rabbits. However, they do not reveal any interaction between Ang II and the baroreceptor reflexes in the control of AVP secretion.     

Cardiovascular and renal effects of growth hormone*

OBJECTIVE With the advent of recombinant human GH (rhGH), it has become possible in controlled clinical studies to explore the effects of GH replacement in adults with GH deficiency. The objective of this study was to determine cardiovascular and renal effects of GH replacement in adults with GH deficiency. PATIENTS We studied ten patients (one woman and nine men), mean age 47 years, with GH deficiency. DESIGN The patients were given s.c. rhGH (Humatrope, Ell Lilly) 0·5 U/kg/week or placebo in a 6-month double blind cross-over study. Cardiac and renal function was measured before drug administration (baseline), before cross-over (i.e. after 6 months), and before termination of drug administration (after another 6 months). Analysis of variance was used to compare measurements during GH replacement with baseline and placebo measurements. One patient was excluded because of atrial fibrillation. MEASUREMENTS Main outcome measures were glomerular filtration rate and Doppler-echocardiographic estimates of cardiac function and structure. Computerized exercise electrocardiogram, spirometry, and blood samples for analyses of plasma hormones were also obtained. RESULTS Left ventricular function was maintained during GH replacement. However, left ventricular mass increased from 211 to 249 g (P<0·05) mainly due to increased left ventricular dimension since wall thicknesses did not increase. The left atrium increased from 38 to 41 mm (P<0·05), possibly because stroke volume increased from 92 to 118 ml (P<0·0001) and cardiac output increased from 5·29 to 7·58 l/min (P<0·05). Total peripheral resistance decreased from 18·9 to 12·4 mmHg min/l (P<0·05), and diastolic blood pressure from 79 to 72 mmHg (P<0·05). Heart rate at rest increased from 58 to 70 beats/min. Systolic blood pressure at rest was unchanged, as was systolic blood pressure during dynamic exercise. GH replacement did not cause ST-abnormalities. Serum creatinine decreased from 91·4 to 85·3 μmol/l (P<0·05) and glomerular filtration rate increased from 89·6 to 99·8 ml/min (P<0·01). CONCLUSIONS Thus, GH replacement has favourable cardiovascular and renal effects including increase of stroke volume and glomerular filtration rate with reduction of peripheral resistance.     

An aged case of orthostatic hypotension possibly due to parasympathetic neurodysfunction

94-year-old male patient, with orthostatic hypotension, possibly due to impairment of vasoconstriction and parasympathetic nervous system dysfunction was reported. This patient experienced faintness and lower muscle weakness on standing. The blood pressure was 180/90 mmHg in a supine position, while it significantly decreased to 100/58 mmHg in an upright position. There was no evidence indicating the presence of organic brain diseases, cardiovascular diseases, and endocrine diseases, plasma catecholamine, renin, aldosterone, and vasopressin levels at rest were within normal range. Thus, the cause of orthostatic hypotension of this patient was unknown. His systolic blood pressure decreased by 70 mmHg, and his diastolic blood pressure also decreased by 25 mmHg in response to a 70 degrees head-up tilting test (170/71-100/46 mmHg). Plasma vasopressin level significantly increased in response to this test (0.62-67.2 pg/ml). Plasma catecholamine levels also increased (Adr 0.01-0.10 ng/ml, Ndr 0.05-0.22 ng/ml). Other autonomic nervous system examinations revealed normal responses to mental arithmetic test, hyperventilation test, cold pressure test, and adrenalin test. However, the results of the carotid occlusion test, acetylcholine test, atropine test, phenylephrine test were considered to be abnormal. From these findings, we concluded that the functions of sympathetic nervous system were almost intact, while the parasympathetic functions were impared in this case. The orthostatic hypotension of the patient as effectively treated with fludrocortisone. This report suggests that impairment of vasoconstriction and parasympathetic neurodysfunction might be involved in the development of orthostatic hypotension in the elderly.     

The effect of moderate hypotension on vasopressin levels in normal humans

Isosmotic decreases in central venous pressure do not stimulate arginine vasopressin (AVP) secretion in normal humans, while symptomatic vasovagal hypotension produces large rises in plasma AVP levels. The effects of an asymptomatic fall in arterial pressure on plasma AVP in humans are poorly documented. Heart rate, mean arterial pressure, plasma osmolality, and plasma AVP were measured in seven healthy volunteers during infusion of sodium nitroprusside on two occasions, with and without central venous pressure measurements. On both study days, heart rate increases (5 +/- 3 and 8 +/- 4 beats/min) and mean arterial pressure reductions (12 +/- 3 and 13 +/- 2.0 mm Hg) were comparable. Plasma AVP (3.2 +/- 1.4 and 4.0 +/- 1.7 pg/ml at control) did not change on either study day after nitroprusside titration (30-40 minutes) or after an additional 90 minute observation on the first day. When measured on the second day, central venous pressure declined from 5.6 +/- 1.9 to 2.9 +/- 1.5 mm Hg, p less than .001. Osmolality was constant on both days at all times. Unloading of sinoaortic baroreceptors produced by asymptomatic hypotension, coupled with a moderate reduction in central venous pressure, does not, therefore, stimulate plasma AVP secretion in normal humans. This observation has relevance to understanding the mechanisms involved in the reported increases in plasma AVP during orthostatic stress and in various diseases.     

Hemodynamic and antianginal effects during rest and exercise of intravenous isradipine, a new dihydropyridine calcium antagonist

In an open randomized study, hemodynamic and antianginal effects of nifedipine and the new dihydropyridine derivative isradipine were compared in patients with stable, angiographically confirmed coronary heart disease. Right heart hemodynamics, systemic arterial blood pressure, ECG, and drug plasma concentrations were measured before medication at rest and exercise, after infusions of increasing doses at rest, and again after treatment at rest and exercise. A linear relationship between serum concentrations and cumulated dosages was obtained for both drugs. At rest, both drugs significantly increased cardiac output and heart rate. The reduction of arterial blood pressure was significantly greater after isradipine (systolic from 148 +/- 3 to 104 +/- 3 mmHg; diastolic from 90 +/- 4 to 58 +/- 2 mmHg) than after nifedipine (systolic 149 +/- 6 to 125 +/- 4 mmHg; diastolic 92 +/- 4 to 76 +/- 3 mmHg). The minimal effective plasma level of isradipine regarding blood pressure reduction was estimated at 5 ng/ml (nifedipine: 10-25 ng/ml). During exercise both medications significantly reduced mean pulmonary artery pressure (isradipine: 40 +/- 3 to 20 +/- 1 mmHg, nifedipine: 37 +/- 4 to 22 +/- 1 mmHg), pulmonary artery wedge pressure (isradipine: 23 +/- 3 to 10 +/- 1 mmHg, nifedipine 24 +/- 3 to 14 +/- 1 mmHg), and diastolic arterial pressure (isradipine: 103 +/- 3 to 73 +/- 4 mmHg, nifedipine: 99 +/- 3 to 91 +/- 2 mmHg), whereas systolic pressure was reduced by only isradipine (189 +/- 4 to 147 +/- 5 mmHg). Neither medication significantly changed electrocardiographic ST depression during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

THE DEVELOPMENT OF A RADIOIMMUNOASSAY FOR THE MEASUREMENT OF HUMAN PLASMA ARGININE VASOPRESSIN

A radioimmunoassay for AVP capable of measuring human plasma AVP is described, Iodination was performed by the chloramine T method and purified by chromatography on Sephadex G-25. Specific activity of ¹²⁵I-AVP was 1710×155 Ci/mmol. Antiserum of high affinity (K_eq= 2.7×10¹¹l/mol) has been raised in rabbits, which shows slight cross-reactivity with LVP and negligible reactivity with oxytocin. The aqueous assay is capable of detecting 0.4 fmol of AVP/tube and it is highly reproducible. A Florisil extraction technique is described in detail and gives recovery of 70% of synthetic AVP added to plasma over a wide physiological range. The lowest detectable concentration of plasma AVP is 0.3 pmol/l. The method has been validated by studying changes in plasma AVP concentration following overnight dehydration (plasma AVP = 3.46×1.89 (SD) pmol/l), and water loading (plasma AVP = 1.54×0.59 pmol/l), P < 0.005, in normal subjects. A A highly significant positive correlation has been found between plasma AVP and plasma osmolality (r=+0.75). Plasma AVP concentration has also been determined in patients with DI and the syndrome of inappropriate ADH secretion. No effect was found on the level of plasma AVP in normally hydrated volunteers undergoing postural change but levels rose following strenuous exercise from basal concentrations of 1.57×0.59 pmol/l to 4.77×3.43 pmol/l, P < 0.01.     

Calcium stimulates vasopressin release

The association of acute hypercalcaemia with hypertension has long been known. Its mechanism has remained unexplained, however, since no significant pressor contribution from the renin-angiotensin system or the sympathetic nervous system has been detected. To assess the possible contribution of arginine vasopressin (AVP), we investigated the effect of a 2 h infusion of 2 ml isotonic calcium gluconate (0.46 mmol/ml Ca2+) on the mean blood pressure of anephric (n = 8) or intact (n = 7) rats and the blood pressure response to a specific vasopressin inhibitor (V1). In anephric rats, blood pressure rose by 30 +/- 3 mmHg (mean +/- s.e.m.) and plasma AVP levels rose to 34 +/- 9 pg/ml. In response to injection of the AVP inhibitor, blood pressure fell by 26 +/- 3 mmHg. In intact rats, blood pressure rose by 12 +/- 4 mmHg with plasma AVP levels 14.5 +/- 3.2 pg/ml (normal range 2.2 +/- 1.1 pg/ml), but did not respond consistently to AVP inhibition. Serum calcium levels at the end of the infusion were 25.0 +/- 4.3 mg/dl in anephric and 24.9 +/- 1.2 mg/dl in intact rats. In order to confirm that the calcium ion was indeed responsible for the AVP-dependent changes in blood pressure, another group of anephric rats (n = 8) received a 2 h infusion of CaCl2 (0.46 mmol/ml Ca2+) and exhibited a blood pressure rise of 35 +/- 3 mmHg, which responded to the AVP inhibitor with a blood pressure fall of 22 +/- 3 mmHg. Moreover, prior treatment with indomethacin greatly attenuated the pressor effect of calcium infusion and prevented the rise of AVP.(ABSTRACT TRUNCATED AT 250 WORDS)