Circulation, kidney function, and volume-regulating hormones during prolonged water immersion in humans.

To investigate whether prolonged water immersion (WI) results in reduction of central blood volume and attenuation of renal fluid and electrolyte excretion, these variables were measured in connection with 12 h of immersion. On separate days, nine healthy males were investigated before, during, and after 12 h of WI to the neck or during appropriate control conditions. Central venous pressure, stroke volume, renal sodium (UNaV) and fluid excretion increased on initiation of WI and thereafter gradually declined but were still elevated compared with control values at the 12th h of WI. Atrial natriuretic peptide (ANP) concentration in plasma initially increased threefold during WI and thereafter declined to preimmersion levels, whereas plasma renin activity, plasma aldosterone, and norepinephrine remained constantly suppressed. It is concluded that, compared with the initial increases, central blood volume (central venous pressure and stroke volume) is reduced during prolonged WI and renal fluid and electrolyte excretion is attenuated. UNaV is still increased at the 12th h of WI, whereas renal water excretion returns to control values within 7 h. The WI-induced changes in ANP, plasma renin activity, plasma aldosterone, and norepinephrine may all contribute to the initial increase in UNaV. The results suggest, however, that the attenuation of UNaV during the later stages of WI is due to the decrease in ANP release.     

Age dependence of the levels of plasma norepinephrine, aldosterone, renin activity and urinary vanillylmandelic acid in normal and essential hypertensives

In the present study the upper reference limits (URLs) for resting plasma norepinephrine, epinephrine, serum aldosterone, plasma renin activity, aldosterone/renin activity ratio, as well as urinary vanillylmandelic acid in healthy Egyptian normotensive subjects over a range of ages (5-60 yr) were established. There was a significant age effect on plasma norepinephrine, UVMA, serum aldosterone and PRA, whereas a single URL for plasma epinephrine level is satisfactory. In uncomplicated untreated essential hypertensive subjects (5-60 yr), the average prevalence of elevation in the plasma norepinephrine, epinephrine and urinary vanillylmandelic acid above their corresponding URLs was 85.10, 62.15 and 83.20%, respectively. This suggests that elevation in plasma catecholamine concentrations is more likely a common consequence than playing a possible role in the pathogenesis of hypertension, supported by insignificant correlation coefficients between the plasma catecholamine levels and resting systolic and diastolic blood pressure values (SBP & DBP) in all hypertensive age groups. Primary hyperaldosteronism was not detected among the normokalemic essential hypertensives at any age using aldosterone/plasma renin activity ratio as a primary screening method. In the present study, 7 statistically significant positive coefficient correlations are reported for SBP or DBP values with UVMA levels in hypertensive children and adolescents, serum aldosterone in old hypertensives, and PRA in adult hypertensives.     

Plasma free and sulfate conjugated catecholamine levels during acute physiological stimulation in man

The responses of plasma free and sulfate-conjugated catecholamines to acute physiological stimulation was examined in normal male subjects. Catecholamines were measured with a sensitive radioenzymatic assay incorporating simultaneous hydrolysis of sulfate conjugates and O-methylation of free norepinephrine and epinephrine. Following 20 minutes recumbency after venepuncture 30 +/- 3% of norepinephrine and 16 +/- 5% of epinephrine was in thr free form. Free catecholamines generally increased during standing, cold immersion and isometric handgrip, but sulfates did not change. Bicycle ergometry markedly increased free catecholamines which rapidly returned to basal levels at the end of exercise. In contrast, sulfated norepinephrine decreased substantially with exercise in all subjects but returned to basal levels 3 minutes after stopping exercise. Epinephrine sulfate varied considerably between subjects but showed a similar, although smaller, fall with exercise. Thus, during physiological stimulation, which caused increases in free norepinephrine and epinephrine levels in plasma, the only consistent change in sulfated catecholamines was a marked fall in norepinephrine sulfate after bicycle exercise. This may indicate saturation of sulfotransferase activity, substrate inhibition or impaired tissue conjugation.     

Dopamine-beta-hydroxylase in dog lymph--effect of sympathetic activation

In anesthetized dogs baroreceptor denervation and electrical stimulation of the left stellate ganglion caused marked arterial hypertension and tachycardia. These were associated with a 4-10-fold increase in the total output of dopamine-β-hydroxylase (DβH) in the thoracic duct lymph. Serum DβH activity was lower than that in man and changes during sympathetic activation were inconsistent. These results suggest that a major portion of DβH released from adrenergic nerve terminals is transported in the lymph before it enters the circulating blood.     

Fluid-electrolyte shift and renin-aldosterone responses to exercise under hypoxia

In order to describe fluid-electrolyte shift and endocrine response to exercise under moderate acute hypoxia, 8 healthy male subjects (24 +/- 3 years old) were evaluated at 40, 60, 80 and 100% VO2 max in normoxic (N) and hypoxic (H) conditions (14.5% O2). VO2 max decreased from 55.5 +/- 1.3 to 45.8 +/- 1.4 ml/kg X min in H condition. Plasma volume reductions with increasing relative workloads were similar in N (9.4%) and H (9.9%) conditions. The rise in plasma osmolality was in part related to blood lactate accumulation which occurred in both conditions. However, variations in plasma solute content and osmolality suggested that exercise under hypoxia results in a greater electrolyte loss from vascular space and in a greater K+ loss from working skeletal muscles. Increase in catecholamine concentrations were similar in normoxic and hypoxic conditions except for lower maximal norepinephrine concentration under hypoxia. Finally, although plasma renin activity increased with workload in both conditions, plasma aldosterone did not significantly change. This dissociation between renin and aldosterone suggest that aldosterone release during exercise might depend upon other factors. However, changes in plasma potassium concentration do not appear as an important stimulus for aldosterone secretion during exercise.     

Marathon run: effects on plasma renin activity, renin substrate, angiotensin converting enzyme, and cortisol

Altogether 33 Finnish amateur runners were studied before and after a non-competitive Marathon run over the classical itinerary in Athens in 1976 (n = 8), 1977 (n = 14) and 1978 (n = 11). Plasma renin activity (PRA) rose 3-fold in all runs, whereas plasma renin substrate (RS) concentration did not change significantly. Serum angiotensin converting enzyme (ACE) activity was not changed. Serum cortisol concentration was increased 2-3 fold. The unchanged plasma RS concentration, in spite of increasing PRA, indicates that plasma RS is kept within normal limits during prolonged strenuous physical exercise. One contributing mechanism may be stimulation of RS biosynthesis by cortisol. Low PRA levels in two old runners, 65 and 83 years old, may indicate a decreased ability to respond with renin release to the stimuli of physical exercise.     

Effect of head-down tilt on basal plasma norepinephrine and renin activity in humans

The effects of loading cardiopulmonary baroreceptors on basal norepinephrine and renin activity were studied in six normal subjects. Loading of cardiopulmonary baroreceptors was accomplished by a 60-min 30 degrees head-down tilt with small supplemental saline infusions. Central venous pressure was measured continuously by intrathoracic catheter; arterial pressure was measured indirectly by cuff. During the tilt, central venous pressure increased from 5.1 +/- 1.3 to 8.9 +/- 1.7 mmHg (P less than 0.001), whereas arterial pressure was unchanged. Plasma norepinephrine (185 +/- 85 pg/ml) and plasma renin activity (3.9 +/- 5.7 ng . ml-1 . h-1) did not change. Moderate sustained loading of cardiopulmonary baroreceptors is therefore without effect on unstressed plasma norepinephrine and renin activity in normal humans, suggesting that the tonic inhibitory effects of these receptors on these neurohumoral control systems are not readily increased in the basal state.     

PRELIMINARY ESTIMATES OF THE DOPAMINE β-HYDROXYLASE CONTENT AND ACTIVITY IN PURIFIED NORADRENERGIC VESICLES1

The dopamine β-hydroxylase (DβH) content and activity of large dense-core noradrenergic vesicles purified from bovine splenic nerve were determined using two assay procedures : enzymic activity expressed in Units per mg protein and homospecific activity based on radioimmunoassay expressed in Units per mg DβH antigen. Approximately two-thirds of the total enzyme activity is latent in these vesicles, even after various treatments designed to compromise vesicle integrity. DβH can be completely unmasked by brief treatment with 0.01-0.05% Triton X-100 and activity increases from 0.20 to 0.64 Units per mg vesicle protein. Calculations based on both assay methods suggested that an average of 7% (range 3-15%) of the total vesicle protein was DβH and that the average vesicle contained about 4 molecules of enzyme (range 2-9 molecules). The estimated homospecific activities indicated an average of 25 and 50% (range 18-72%) of the vesicle enzyme was inactive in the various samples using the two antibodies. The vesicle can synthesize up to 30 molecules of noradrenaline/s per molecule of DβH at near optimal substrate concentration, and 60-270 molecules of norepinephrine/s per vesicle. The assumptions used in the various calculations were critically analyzed and, based on the methods employed, it is tentatively considered to be unlikely that there could be more than 5-12 molecules of DβH per vesicle. The possibility that circulating DβH originates primarily, if not exclusively, from the large dense-core vesicle type is considered and the functional implications of the data support the concept of vesicle reuse during several cycles of exocytosis involving a quantal size equal to a fraction of the vesicle transmitter content.     

Immediate baroreflex-neuroendocrine interactions in humans during graded water immersion

Healthy male subjects underwent graded water immersion for a study of arterial baroreceptors and neuroendocrine responses. Blood samples were studied for plasma renin activity, aldosterone, arginine vasopressin, norepinephrine and epinephrine. Results showed that ten minutes of immersion was enough to suppress the release of arginine vasopressin, renin, and norepinephrine. The role of baroreceptors in the release of these substances is discussed.     

Modifications of arterial pressure and plasma renin: their effects on the norepinephrine content of hypothalamus and medulla oblongata.

The effects of the bilateral nephrectomy and acute hypotension caused by the cava vein ligature on the norepinephrine (NE) concentration in hypothalamus and medulla oblongata and on the plasma renin activity were studied in male rats. NE increased and plasma renin activity decreased in hypothalamus in 24 h nephrectomized rats with or without the ligatures of the cava vein. NE also decreased in medulla of groups with the ligatures only. The mean arterial pressure, did not correlate with the NE or plasma renin activity levels. The modifications of the NE in the central nervous system showed an inverse relationship with plasma renin activity and this, could be due to changes in the NE uptake and/or release caused by the plasma renin activity alterations. NE modifications do not seem to be caused directly through reflex of the arterial pressure.     

Hormonal responses to exercise during moderate cold exposure in young vs. middle-age subjects.

The influence of moderate cold exposure on the hormonal responses of atrial natriuretic factor (ANF), arginine vasopressin (AVP), catecholamines, and plasma renin activity (PRA) after exhaustive exercise was studied in 9 young and 10 middle-aged subjects. Exercise tests were randomly performed in temperate (30 degrees C) and cold (10 degrees C) environments. Heart rate, oxygen consumption, and peripheral arterial blood pressure were measured at regular intervals. Blood samples were collected before and immediately after exercise at 30 or 10 degrees C. Plasma sodium and potassium concentrations as well as hemoglobin and hematocrit were measured, and the change in plasma volume was calculated. At rest and during exercise, oxygen consumption was similar during exposure to both temperate and cold temperatures. During submaximal exercise intensities, the rise in heart rate was blunted while the increase in systolic blood pressure was significantly greater at 10 than at 30 degrees C. The increases in plasma sodium and potassium concentrations after exhaustion were similar between environments, as was the decrease in plasma volume. In both groups, all plasma hormones were significantly elevated postexercise, with the AVP response similar at 10 and 30 degrees C. However, the norepinephrine and ANF responses were significantly greater while the PRA response was significantly reduced at 10 degrees C. In the middle-aged subjects the epinephrine response to exercise was higher at 10 than at 30 degrees C. The greater ANF and reduced PRA responses to exercise in the cold may have resulted from central hemodynamic changes caused by cold-induced cutaneous vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurohumoral and cardiopulmonary response to sustained submaximal exercise in the dog

Neurohumoral, cardiovascular, and respiratory parameters were evaluated during sustained submaximal exercise (3.2 km/h, 15 degrees elevation) in normal adult mongrel dogs. At the level of activity achieved (fivefold elevation of total body O2 consumption and threefold elevation of cardiac output), significant (P less than 0.05) increases in plasma norepinephrine and epinephrine concentration (from 150 +/- 23 to 341 +/- 35 and from 127 +/- 27 to 222 +/- 31 pg/ml, respectively) were present, as well as smaller but significant increases in plasma renin activity and plasma aldosterone concentration (from 2.2 +/- 0.3 to 3.1 +/- 0.6 ng X ml-1 X h-1 and from 98 +/- 8 to 130 +/- 6 pg/ml, respectively). Plasma arginine vasopressin increased variably and insignificantly. The cardiovascular response (heart rate, systemic arterial and pulmonary arterial pressures, left ventricular filling pressure, and calculated total peripheral and pulmonary arteriolar resistance) closely paralleled that of human subjects. Increased hemoglobin concentration was induced by exercise in the dogs. The ventilatory response of the animals was characterized by respiratory alkalosis. These data suggest similarities between canine and human subjects in norepinephrine, plasma renin activity, and plasma aldosterone responses to submaximal exercise. Apparent species differences during submaximal exertion include greater alterations of plasma epinephrine concentration and a respiratory alkalosis in dogs.     

Catecholamines, cocaine toxicity, and their antidotes in the rat.

Acute lethal cocaine intoxication in the rat induces significant increases of plasma dopamine, norepinephrine, and epinephrine concentrations associated with cardiac functional and morphologic changes. Nitrendipine (a calcium channel antagonist) administered 5 min following cocaine administration lowers catecholamine concentration and restores cardiovascular function to normal, while preventing lethality, and so does enalaprilat (an enzyme-converting inhibitor) administration with diazepam. Cocaine cardiac toxicity in the rat appears to be associated with a significant stimulation of the sympathoadrenal and a sustained elevated plasma concentration of epinephrine. The renin angiotensin system also appears to be activated.     

Influence of cold, exercise, and caffeine on catecholamines and metabolism in men

Recently we found that caffeine ingestion did not enhance either thermal or fat metabolic responses to resting in cold air, despite an increase in plasma epinephrine and free fatty acids. Theophylline, another methylxanthine, has been shown to be effective during exercise but not at rest during cold stress. Therefore we hypothesized that caffeine ingestion before exercise in cold air would have a thermal-metabolic impact by increasing fat metabolism and increasing oxygen consumption. Young adult men (n = 6) who did not normally have caffeine in their diet performed four double-blind trials. Thirty minutes after ingesting placebo (dextrose, 5 mg/kg) or caffeine (5 mg/kg) they either exercised (60 W) or rested for 2 h in 5 degrees C air. Cold increased (P less than 0.05) plasma norepinephrine while both caffeine and exercise increased (P less than 0.05) epinephrine. Serum free fatty acids and glycerol were increased, but there were no differences between rest and exercise or placebo and caffeine. Caffeine had no influence on either respiratory exchange ratio or oxygen consumption either at rest or during exercise. The exercise trials did not significantly warm the body, and they resulted in higher plasma norepinephrine concentrations and lower mean skin temperatures for the first 30 min. The data suggest that skin temperature stimulates plasma norepinephrine while caffeine has little effect. In contrast, caffeine and exercise stimulate plasma epinephrine while cold has minimal effect. Within the limits of this study caffeine gave no thermal or metabolic advantage during a cold stress.     

Effect of alpha-adrenergic stimulation on prostacyclin and renin release in the rat kidney

The relationship between renin secretion and PGI2 production, in response to intrarenal infusion of norepinephrine, was examined in the isolated perfused rat kidney. Infusion of norepinephrine in a dose which caused substantial vasoconstriction (100 ng/min), markedly increased urinary excretion of 6-keto PGF1 alpha, the stable derivative of PGI2, without significantly altering renin secretion measured in the effluent perfusate. No change in urinary 6-keto PGF1 alpha occurred when vasoconstriction was prevented by infusing the alpha-adrenoceptor blocking drug phenoxybenzamine (2 x 10(3) ng/min) alongside norepinephrine (100 ng/min). However, under these conditions there was marked stimulation of renin secretion which, as has been demonstrated previously, is mediated by a beta-adrenoceptor. There were significant increases in urine flow rates during both vasoconstrictor and non-vasoconstrictor infusions. These findings clearly indicate that in the rat kidney prostacyclin production and renin release in response to norepinephrine are dissociated.     

The effect of cold on adrenergic neurotransmission in canine saphenous arteries and veins

The effect of severe cold (5 to 10 degrees C) on adrenergic neurotransmission was compared in the isolated cutaneous (saphenous) artery and vein of the dog. The vein contracted to sympathetic nerve stimulation at temperatures as low as 10 degrees C; higher temperatures were needed for the artery to contract. Both blood vessels contracted to exogenous norepinephrine at temperatures as low as 5 degrees C. However, the contractile response to exogenous norepinephrine was less in the saphenous artery, and contractions to high K+ solution were depressed by cooling more in the artery than in the vein. During electrical stimulation of the sympathetic nerves in saphenous arteries and veins previously incubated with labeled norepinephrine, progressive cooling from 37 to 5 degrees C caused a sharp decline in overflow of [3H]norepinephrine and its metabolites. However, overflow of labeled norepinephrine in both blood vessels continued at very cold temperatures. Thus the inability of the saphenous artery to contract to sympathetic nerve stimulation at 10 degrees C can be explained by a greater sensitivity of the arterial smooth muscle to the direct depressant effect of cold, rather than to a differential release or metabolism or norepinephrine in the arterial wall or a loss of responsiveness to norepinephrine at very cold temperatures.     

The mechanism of aldosterone response to furosemide test in patients with Shy-Drager syndrome

We examined the renin-angiotensin-aldosterone system in seven patients with Shy-Drager syndrome by studying their response to the stimulation of 1 mg/kg furosemide injection followed by sitting for 1 hour. Six of the seven patients showed a low response of plasma renin activity to the stimulation. However, in five of the low responders, the plasma aldosterone levels after stimulation were observed to be similar to those of the control subjects; in addition, an increment in the plasma cortisol level appeared although no such increment was observed in normal subjects. Next, we studied the aldosterone response to angiotensin II. The five patients who showed a low plasma renin activity response and a normal aldosterone response to furosemide administration also showed low plasma aldosterone response to angiotensin II. Furthermore, in the patients who demonstrated a low plasma renin activity response and a normal aldosterone response to furosemide administration, the pretreatment with 2 mg dexamethasone for 2 days caused a marked inhibition of aldosterone response to the stimulation. These findings suggested that in most patients with Shy-Drager syndrome, the plasma aldosterone response to the stimulation of furosemide injection followed by sitting for 1 hour might be controlled by ACTH but not by plasma renin activity.     

Linkage analysis of plasma dopamine ��-hydroxylase activity in families of patients with schizophrenia

Dopamine β-hydroxylase (DβH) catalyzes the conversion of dopamine to norepinephrine. DβH enters the plasma after vesicular release from sympathetic neurons and the adrenal medulla. Plasma DβH activity (pDβH) varies widely among individuals, and genetic inheritance regulates that variation. Linkage studies suggested strong linkage of pDβH to ABO on 9q34, and positive evidence for linkage to the complement fixation locus on 19p13.2-13.3. Subsequent association studies strongly supported DBH, which maps adjacent to ABO, as the locus regulating a large proportion of the heritable variation in pDβH. Prior studies have suggested that variation in pDβH, or genetic variants at DβH, associate with differences in expression of psychotic symptoms in patients with schizophrenia and other idiopathic or drug-induced brain disorders, suggesting that DBH might be a genetic modifier of psychotic symptoms. As a first step toward investigating that hypothesis, we performed linkage analysis on pDβH in patients with schizophrenia and their relatives. The results strongly confirm linkage of markers at DBH to pDβH under several models (maximum multipoint LOD score, 6.33), but find no evidence to support linkage anywhere on chromosome 19. Accounting for the contributions to the linkage signal of three SNPs at DBH, rs1611115, rs1611122, and rs6271 reduced but did not eliminate the linkage peak, whereas accounting for all SNPs near DBH eliminated the signal entirely. Analysis of markers genome-wide uncovered positive evidence for linkage between markers at chromosome 20p12 (multi-point LOD?=?3.1 at 27.2?cM). The present results provide the first direct evidence for linkage between DBH and pDβH, suggest that rs1611115, rs1611122, rs6271 and additional unidentified variants at or near DBH contribute to the genetic regulation of pDβH, and suggest that a locus near 20p12 also influences pDβH.     

Angiotensinergic and noradrenergic neurons in the rat and human heart

Although the physiological and pharmacological evidences suggest a role for angiotensin II (Ang II) with the mammalian heart, the source and precise location of Ang II are unknown. To visualize and quantitate Ang II in atria, ventricular walls and interventricular septum of the rat and human heart and to explore the feasibility of local Ang II production and function, we investigated by different methods the expression of proteins involved in the generation and function of Ang II. We found mRNA of angiotensinogen (Ang-N), of angiotensin converting enzyme, of the angiotensin type receptors AT(1A) and AT? (AT(1B) not detected) as well as of cathepsin D in any part of the hearts. No renin mRNA was traceable. Ang-N mRNA was visualized by in situ hybridization in atrial ganglial neurons. Ang II and dopamine-β-hydroxylase (DβH) were either colocalized inside the same neuronal cell or the neurons were specialized for Ang II or DβH. Within these neurons, the vesicular acetylcholine transporter (VAChT) was neither colocalized with Ang II nor DβH, but VAChT-staining was found with synapses en passant encircle these neuronal cells. The fibers containing Ang II exhibited with blood vessels and with cardiomyocytes supposedly angiotensinergic synapses en passant. In rat heart, right atrial median Ang II concentration appeared higher than septal and ventricular Ang II. The distinct colocalization of neuronal Ang II with DβH in the heart may indicate that Ang II participates together with norepinephrine in the regulation of cardiac functions: produced as a cardiac neurotransmitter Ang II may have inotropic, chronotropic or dromotropic effects in atria and ventricles and contributes to blood pressure regulation.     

Renin release by pentobarbital anesthesia in the rat: A role for vascular mechanisms

Studies were undertaken in intact rats to characterize the renin response to pentobarbital anesthesia and the mechanisms involved in this response. Aortic and peritoneal cavity cannulas were previously implanted to allow drug infusion, blood sampling and anesthesia to be performed without stress. A sustained 2–3- fold increase in plasma renin concentration (PRC) and a 10–15 mm Hg depression of mean arterial pressure were found in pentobarbital anesthesia. Circulating levels of epinephrine and norepinephrine were unchanged. Sympathetic stimulation by tyramine did not decrease and chronic renal denervation did not abolish the PRC rise by pentobarbital. Phenoxybenzamine given to conscious or anesthetized animals elevated PRC to similar levels. Propranolol was effective in suppressing PRC in anesthetized animals, regardless of the presence or absence of phenoxybenzamine. We concluded that the renin response to pentobarbital anesthesia is unrelated to changes in sympatho-adrenal activity. The response appears to be mediated by beta-adrenergic receptors. It is postulated that pentobarbital- induced relaxation of afferent arterioles or JG cells exposes previously concealed beta-receptor sites which increase the signal for the release of renin.