Dopamine negatively modulates its own blood pressure increasing action

To evaluate the mechanisms of the hypertensive action of dopamine and its dependence on its metabolic patterns we infused a borderline hypertensive dose of free dopamine into healthy subjects. The moderate rise in systolic and diastolic blood pressure with an expected considerable increase of plasma free dopamine concentrations was associated within 30 minutes with an increase in plasma free norepinephrine and huge increases in plasma 3-4-dihydroxyphenylacetic acid, homovanillic acid and dopamine sulfate, the latter mostly between 60 and 180 minutes of infusion when diastolic blood pressure decreased. The overall pre-, per- and postinfusion changes in systolic blood pressure were negatively correlated with corresponding changes of free dopamine and dopamine sulfate. Reproducible patterns of blood pressure responses to the dopamine infusion made possible a subdivision into those who were blood pressure responders (who generated dopamine sulfate with delay) and non responders (who generated dopamine sulfate immediately). The data suggests that the 4 micrograms/kg/min dopamine infusion rate raises blood pressure indirectly via norepinephrine. Free dopamine and dopamine sulfate (the velocity of generation of which may be an inherited trait) are probably negative modulators of this action.     

Is there a correlation between serum dopamine level and blood pressure during upright posture?

In the face known antihypertensive action of small dopamine (DA) concentrations, serum free and conjugated dopamine levels were determined during orthostatic impulse. It was also estimated, whether correlation between blood pressure changes and serum dopamine concentration existed under those conditions. 9 patients with borderline hypertension, 8 with fixed hypertension and 5 healthy volunteers (control group) underwent the 10 minute passive tilt up test. It caused significant decrease of free DA concentration in healthy men as well as in those with borderline hypertension and conjugated DA level in both groups of patients with primary hypertension. Blood pressure increased only in patients with borderline hypertension. Most expressed changes in dopamine concentration were also observed in those patients and they only had increased serum DBH activity. Blood pressure changes inversely correlated with changes of serum free and/or conjugated DA levels in the control group and in patients with primary hypertension. Authors stated basing on this study results, that serum DA level lowering caused by the orthostatic impulse can be one of phenomenons enable adaptation for a vertical position.     

Intestinal lipoprotein production is stimulated by an acute elevation of plasma free fatty acids in the fasting state: studies in insulin-resistant and insulin-sensitized Syrian golden hamsters

It is not known whether intestinal lipoprotein production is stimulated by an acute elevation of plasma free fatty acids (FFA). We examined the effect of an intralipid and heparin infusion on the intestinal lipoprotein production rate (PR) in insulin-sensitive [chow-fed (CHOW)], insulin-resistant [60% fructose (FRUC) or 60% fat-fed (FAT)], and insulin-sensitized [FRUC or FAT plus rosiglitazone (RSG)-treated] Syrian Golden hamsters. After 5 wk of treatment, overnight-fasted hamsters underwent in vivo Triton WR-1339 studies for measurement of apolipoprotein B48 (apoB48) PR in large (Svedberg unit, >400) and small (Svedberg unit, 100-400) lipoprotein fractions, with an antecedent 90-min infusion of 20% intralipid and heparin (IH) to raise plasma FFA levels approximately 5- to 8-fold vs. those in the saline control study. IH markedly increased apoB48 PR in CHOW by 3- to 5-fold, which was confirmed ex vivo in pulse-chase experiments in primary cultured hamster enterocytes. Oleate, but not glycerol, infusion was associated with a similar elevation of apoB48 PR as IH. In FRUC and FAT, basal (saline control) apoB48 PR was approximately 4-fold greater than that in CHOW; there was no additional stimulation with IH in vivo and only minimal additional stimulation ex vivo. RSG partially normalized basal apoB48 PR in FAT and FRUC, and PR was markedly stimulated with IH. We conclude that intestinal lipoprotein production is markedly stimulated by an acute elevation of plasma FFAs in insulin-sensitive hamsters, in which basal production is low, but minimally in insulin-resistant hamsters, in which basal production is already elevated. With RSG treatment, basal PR is partially normalized, and they become more susceptible to the acute FFA stimulatory effect.     

Low-dose bradykinin infusion reduces endogenous glucose production in surgical patients

The systemic effect of low-dose bradykinin infusion on total body glucose production and arterial substrate concentrations was examined during D5W infusion (1.0 mg/kg/min) in five normal-weight postsurgical subjects and compared to the response in four saline infused control patients, well matched for age, weight, and degree of postoperative stress. The primed-constant infusion of 6,6-d2-glucose was used to determine the rate of endogenous glucose production. After a basal period of 90 minutes, subjects in the study group were infused with bradykinin at increasing rates of 2.0 and 4.0 micrograms/kg/h, each infusion rate lasting for 90 minutes, whereas in controls corresponding amounts of saline were given. After 75 minutes of bradykinin, endogenous glucose production was significantly reduced as compared to basal values (1.63 +/- 0.21 mg/kg/min, P less than .0125 v 2.20 +/- 0.35 basal). This was accompanied by a significant reduction in arterial concentrations of glucose, lactate, pyruvate, and alanine. Corresponding concentrations of insulin, glucagon, glycerol, free fatty acids, and ketone bodies, as well as mean arterial blood pressure and heart rate was not affected by bradykinin. In the control group no significant changes in substrate and hormone concentrations, or the rate of glucose production were observed. The higher bradykinin infusion rate did not further affect substrate metabolism or systemic hemodynamics. These results demonstrate the inhibitory effect of low-dose bradykinin on glucose production in surgically stressed patients. The stimulation of hepatic prostaglandin synthesis by bradykinin may explain the results since prostaglandins are known to exert an inhibitory effect on hormone stimulated gluconeogenesis and glycogenolysis in liver tissue.     

Baroreceptor influences on oxytocin and vasopressin secretion

The objective of these studies was to investigate the role of arterial baroreceptors in the control of neurohypophyseal secretion. The effect of sinoaortic denervation on basal and osmotic-induced release of oxytocin and vasopressin and on blood pressure was determined. Hypertonic or isotonic saline was infused intravenously into sham-operated or denervated rats 3 days after surgery. Plasma oxytocin and vasopressin were measured at 5 and 15 minutes after the infusion. The control levels of oxytocin were increased in the denervated rats, but vasopressin levels were not significantly altered. The vasopressin and oxytocin responses to hypertonic saline were greater after baroreceptor denervation. Plasma oxytocin was increased from 4.7 +/- 0.9 to 72.2 +/- 8.7 pg/ml in the denervated rats and from 1.8 +/- 0.3 to 39.9 +/- 6.7 pg/ml in the sham-operated control group at 5 minutes after the infusion (p less than 0.01). The plasma vasopressin response to hypertonic saline was 7.1 +/- 0.6 pg/ml in the sham-operated versus 11.1 +/- 1.6 pg/ml in the denervated rats (p less than 0.05). There was no difference between sham-operated and denervated rats in the effect of hypertonic saline on plasma sodium and hematocrit. Mean arterial blood pressure was increased after sinoaortic denervation (116.3 +/- 4.2 mm Hg in the sham-operated vs. 138.2 +/- 8.3 mm Hg in the denervated rats, p less than 0.05); however, there was no difference in the pressor response to hypertonic saline. These results show that the baroreceptor system influences the secretion of both oxytocin and vasopressin, with effects on basal secretion as well as the response to an osmotic stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)     

The coefficient of variation of RR intervals (CVRR) on electrocardiogram in patients with essential hypertension with reference to aging, hemodynamics and sympatho-adrenomedullary function]

To evaluate the significance of parasympathetic nerve activity in essential hypertension, we measured the coefficients of variation of RR intervals (CVRR) on electrocardiogram and examined the relationships between CVRR and aging, hemodynamics and sympatho-adrenomedullary function in normotensive subjects (NT) and in patients with essential hypertension (EHT). Mean arterial pressure (MAP), heart rate (HR), plasma noradrenaline concentration (pNA), plasma adrenaline concentration (pAd) and CVRR resting in a supine position were simultaneously measured in 37 NT (33.8 +/- 2.0 years) and 47 mild-to-moderate EHT (51.3 +/- 1.5 years). In both NT and EHT, significantly negative correlations between CVRR and age (NT: r = -0.54, p less than 0.001, EHT: r = -0.41, p less than 0.005) were observed, however, CVRR correlated with neither MAP, HR nor pAd. CVRR tended to correlate negatively with pNA (r = -0.27, p less than 0.1) in NT, unlike in EHT. The mean value of CVRR in EHT (n = 10, age: 38.3 +/- 1.6 years, CVRR: 3.61 +/- 0.37%) was significantly (p less than 0.005) lower than in age-matched NT (n = 10, age: 38.3 +/- 2.5 years, CVRR: 5.76 +/- 0.45%). These results indicate that the parasympathetic tone suggested by CVRR may be related to aging and sympathetic nerve activity, and that parasympathetic function might be impaired in EHT.     

Effects of sustained intravenous diltiazem infusion in healthy persons

A 3-stage infusion of diltiazem was tested in 8 subjects for up to 48 hours: a bolus injection (10 mg over 3 minutes), a rapid loading infusion (20 mg over 30 minutes) and a maintenance infusion (10 mg/hour to the end of the study). This regimen produced stable median plasma diltiazem concentrations of approximately 150 ng/ml. The median half-life of elimination for diltiazem was 206 minutes (range 144 to 452) and median total clearance was 980 ml/min (range 665 to 1,907). The PR interval lengthened 10 to 18% during the maintenance infusion in 7 subjects; in 1 subject atrioventricular nodal Wenckebach conduction was recorded during the rapid loading infusion. Systolic blood pressure decreased from 124 +/- 7 mm Hg (mean +/- standard deviation) during the control period to 121 +/- 8 mm Hg during the rapid loading infusion (p = 0.03 compared with control) and to 117 +/- 7 mm Hg (p = 0.04 compared with control) during the maintenance infusion. Heart rate did not change. PR interval and blood pressure returned to control levels within 4 hours after the infusion was stopped. Loading and maintenance infusion may be an attractive method of administering diltiazem when stable drug concentrations are required for prolonged periods.     

Cholecystokinin is not a major hormonal regulator of lower esophageal sphincter pressure

Although injection of cholecystokinin can reduce resting lower esophageal sphincter pressure, the physiological significance of this finding has not been established. The purpose of this double-blind crossover study was to determine the effect of physiological plasma levels of cholecystokinin on resting lower esophageal sphincter pressure. Eighteen normal male volunteers were studied on two separate days. Following a 20-minute baseline period, subjects received infusions of saline or synthetic cholecystokinin-8 at increasing rates. Basal plasma cholecystokinin levels averaged 1.3 +/- 0.2 pmol/L (mean +/- SE) and increased to levels of 7.4 +/- 0.9 pmol/L, 12.1 +/- 2.4 pmol/L, and 23.1 +/- 3.8 pmol/L during cholecystokinin infusion rates of 21, 42, and 84 pmol/min, respectively. Lower esophageal sphincter pressure was recorded continuously with a sleeved catheter. Basal lower esophageal sphincter pressure averaged 19.9 mm Hg and did not change with the first infusion, which produced physiological peak postprandial plasma levels of cholecystokinin. Lower esophageal sphincter pressure declined only during the infusions that produced plasma cholecystokinin levels two to four times greater than normal peak postprandial levels. Since infusion of cholecystokinin to levels that reproduce physiological blood levels does not significantly decrease lower esophageal sphincter pressure, it was concluded that cholecystokinin is not a major hormonal regulator of lower esophageal sphincter relaxation.     

The pathophysiological role of renal dopaminergic activity in patients with essential hypertension

To evaluate the role of the renal dopaminergic system on renal water-sodium metabolism patients with essential hypertension (EHT), urinary excretion of dopamine, urinary excretion of sodium (UNaV) and fractional excretion of sodium (FENa) were all investigated before and after the administration of dopamine (3 micrograms/kg/min, intravenous infusion for 60 minutes), dopamine antagonist, metoclopramide (8 mg/m2 BSA, intravenous injection) or mild sodium loading in both normotensive subjects and benign EHT. In the basal values, no significant difference in urinary excretion of free (u-fDA), conjugated (u-cDA) or total dopamine (u-tDA) was found between normotensives and hypertensives. However, low renin EHT showed a pronounced reduction in u-fDA compared with normotensis subject and (NT) normal renin EHT. In this study, a significant reduction of u-cDA and of u-tDA was also found in those patients with low renin essential hypertension. In the normotensive and essential hypertensive groups UNaV or FENa showed a positive correlation with u-fDA (measured simultaneously), but not with u-tDA or u-cDA. The regression line between u-fDA and UNaV or FENa in EHT was shifted towards a lower u-fDA level than in NT. UNaV and FENa were increased by dopamine infusion and were decreased by metoclopramide injection in both NT and EHT. Changes of UNaV and FENa following dopamine or metoclopramide, showed a negative correlation with u-fDA measured immediately before the administration of these drugs. The enhanced natriuretic response to infused dopamine and the attenuated antinatriuretic response to injected metoclopramide were significant in low renin EHT, when compared with NT or normal renin EHT patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dopaminergic suppression of angiotensin II-induced aldosterone secretion in man: differential responses during sodium loading and depletion

Previous studies have shown that aldosterone secretion may be inhibited by dopaminergic mechanisms in man. Dopamine does not inhibit aldosterone responses to angiotensin II in sodium-replete normal subjects. Since sodium deficiency is associated with a reduction in renal dopamine formation, we investigated the effect of dopamine on angiotensin II-induced aldosterone secretion in the sodium-depleted state. Six normal subjects in balance at 10 mEq sodium intake (UNaV 17 +/- 2 meq/24 hr) received dopamine 4 micrograms/kg/min or vehicle for 210 minutes on two consecutive days. After 60 minutes of the dopamine or vehicle infusion, the subjects received successive 30-minute infusions of angiotensin II in increasing doses of 0.5, 1, 2, 4 and 6 picomol/kg/min. Control plasma aldosterone concentrations before vehicle or dopamine were 15 +/- 3 (mean 1 +/- SE) and 25 +/- 3 ng/dL, respectively. Aldosterone responses to angiotensin II were greater with vehicle than dopamine at angiotensin II doses of 4 and 6 picomol/kg/min (P less than 0.025). The slope of angiotensin-aldosterone dose-response curve was steeper with vehicle (0.33) than with dopamine (0.16), P less than 0.01. Serum prolactin concentrations were lower with dopamine (1.6 +/- 0.8 ng/mL) than with vehicle (6.4 +/- 1.2 ng/mL, P less than 0.05) by 120 minutes of infusion and remained suppressed with dopamine for the remainder of the dopamine infusion. Diastolic blood pressure was higher (P less than 0.05) with vehicle than with dopamine at angiotensin II doses of 2, 4, and 6 picomol/kg/min. Dopamine administration was associated with an increase in plasma cortisol concentration from 90 to 150 minutes of infusion (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between urinary dopamine production and natriuresis after acute intravascular volume expansion with sodium chloride in dogs

The role of renal production of dopamine in mediating the natriuretic response to acute vascular volume expansion was investigated. The effect of infusion of 0.9% saline (30 ml/kg X h) over 2 h on urine excretion of sodium and catecholamines, as well as other hemodynamic and renal function parameters, was examined in seven dogs during control and carbidopa (1 mg/kg every 8 h for 24 h before saline infusion) treatment periods. Acute vascular volume expansion with saline resulted in a rise (P less than 0.01) in the renal excretion of dopamine and a depression (P less than 0.01) in renal excretion of norepinephrine which paralleled the natriuretic response to saline infusion. Epinephrine excretion was not altered by saline infusion. Carbidopa treatment was not associated with changes in left ventricular filling pressure, arterial blood pressure, glomerular filtration rate, renal blood flow, renal excretion of norepinephrine or epinephrine. However, carbidopa eliminated the increase in renal production of dopamine and markedly attenuated the natriuretic response to saline infusion. Since carbidopa blocks tissue conversion of dopa to dopamine, it appears that renal production of dopamine is an important mechanism mediating the natriuretic response to acute volume expansion.     

Orthostatic hypotension: a posture-induced hyperdopaminergic state

To explore the role of dopaminergic mechanisms in orthostatic hypotension we compared the postural responses of 20 such patients to those of a control group by radioenzymatic determination of free and sulfated catecholamines and related indices. Patients with orthostatic hypotension, unlike control subjects, experienced an increase in total plasma dopamine (DA) (free + sulfate) in response to upright posture (p less than 0.01). Of the 20 patients with orthostatic hypotension, 16 were normo- or hyperadrenergic with normal basal and posture-responsive or hyperresponsive plasma free and total norepinephrine (NE). The other 4 were hypoadrenergic with low basal and posture-unresponsive NE. Hypoadrenergic patients had, in the upright position, no increase in pulse rate and more severe hypotension, less diuresis and natriuresis, lower urinary free and total DA, lower total NE excretion, and higher plasma and urinary total DA:total NE ratio than normo- or hyperadrenergic patients or control subjects. Normo- or hyperadrenergic patients had higher PRA and plasma aldosterone in the upright position than hypoadrenergic patients or control subjects (all p less than 0.05). We suggest that an excessive increase in free DA occurs in response to upright posture, perhaps representing a compensatory reaction of the remaining autonomic nervous system to an excessive fall in blood pressure. The free dopamine may be biologically active but it is so rapidly sulfoconjugated that it can be detected only as DA sulfate. These findings, combined with reports of orthostatic hypotension precipitated by administration of dopaminomimetic drugs and relieved by administration of dopaminergic antagonists, are consistent with the interpretation that excessive DA release may perpetuate, by its vasodilating and natriuretic action, the orthostatic hypotension.     

Small-volume resuscitation with hypertonic saline (2,400 mOsm/liter) during hemorrhagic shock

We compared small-volume resuscitation using either normal saline or hypertonic saline (2400 mOsm/liter) during hemorrhagic hypotension. Six unanesthetized sheep were bled to 50 mm Hg mean arterial pressure and maintained for 2 h. During this shock period cardiac output decreased 40-50% of baseline, while total peripheral resistance increased 20-30%. Then the response to a bolus injection of either hypertonic saline or normal saline, randomly chosen, was studied for an additional 2 h. The volume injected was 145-175 ml, equal to 10% of total shed blood volume. After data collection all shed blood was returned. Several days later, the protocol was repeated on each sheep with the alternate solution. After hypertonic saline the mean arterial pressure increased 48 mm Hg to 83% of control; with normal saline, mean arterial pressure increased 26 mm Hg. Cardiac output recovered to 95% of control immediately after infusion of hypertonic saline, while no significant increase was observed with normal saline. Ten minutes after injection of hypertonic saline, plasma volume increased approximately 360 ml, but with normal saline no increase was observed. We conclude that small-volume injection of hypertonic saline can dramatically improve circulatory function during hemorrhagic shock, as evidenced by expansion of plasma volume, increased cardiac output, and reduced peripheral resistance.     

Effects of dopamine infusion on the release of atrial natriuretic factor

We evaluated the effects of dopamine infusion (1.5 micrograms/Kg/min for 60 min) on secretion of atrial natriuretic factor before raised diuresis could affect extracellular fluid volume and hence peptide release. We investigated ten healthy subjects without cardiovascular, renal or endocrine disease and ten patients with congestive heart failure (New York Heart Association Classes III and IV). The study protocol required four 30 minute clearance periods: 1st basal, 2nd during placebo, 3rd and 4th during dopamine infusion. We measured diuresis, natriuresis, glomerular filtration rate, blood pressure, heart rate, central venous pressure and plasma concentrations of atrial natriuretic factor, noradrenaline, renin activity, aldosterone and antidiuretic hormone. Blood samples were drawn at the midpoint of each clearance period after measuring blood pressure, heart rate and central venous pressure. Atrial natriuretic factor was determined by radioimmunoassay after chromatographic extraction, noradrenaline was measured fluorometrically while plasma renin activity, aldosterone and antidiuretic hormone concentrations were obtained by radioimmunoassay. During dopamine infusion plasma atrial natriuretic factor plasma levels were significantly raised in healthy subjects while high basal values of the peptide in patients with congestive heart failure were significantly reduced; this trend was also evident for noradrenaline levels in both groups. Plasma renin activity, aldosterone and antidiuretic hormone values remained unchanged in healthy subjects, but plasma renin activity and aldosterone levels dropped significantly in congestive heart failure patients. Diuresis, natriuresis and glomerular filtration rate were significantly increased while blood pressure, heart rate and central venous pressure remained unchanged in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of epinephrine on norepinephrine release in essential hypertension

The effects of endogenous epinephrine (E), released by glucagon injection, and exogenously infused E on plasma norepinephrine (NE) and cardiovascular responses before and after beta-blockade were studied in patients with essential hypertension and in age-matched normotensive controls. The resting plasma NE and E levels were significantly higher in the borderline hypertensive subjects (NE: 251 +/- 21 pg/ml [SEM], p less than 0.005; E: 57 +/- 5, p less than 0.05, n = 18) than in controls (NE: 129 +/- 12; E: 39 +/- 5, n = 18). An intravenous injection of glucagon (1.0 mg) induced a transient rise of both plasma catecholamine levels and blood pressure in every subject studied. Plasma E levels rose transiently and returned to the basal levels by 20 minutes after the injection, whereas plasma NE levels showed a more prolonged rise over 20 minutes. beta-Blockade with propranolol did not affect the plasma E response to glucagon, but inhibited the prolonged rise of plasma NE levels. An intravenous infusion of exogenous E (1.25-1.50 micrograms/min) for 30 minutes caused an apparent rise of both plasma NE levels and blood pressure, which lasted more than 60 minutes after stopping the E infusion. Propranolol did not affect the time course of plasma E but again inhibited the prolonged rise of both plasma NE levels and blood pressure. No significant differences could be observed in the cardiovascular or plasma NE responses to glucagon or to E infusion between normal and hypertensive subjects. These findings lend support to the view that plasma E can act physiologically as a sustained stimulator of presynaptic beta-adrenergic receptors, which leads to an enhanced NE release from peripheral sympathetic nerve terminals and a rise of blood pressure in humans.     

Effects of incremental infusions of atrial natriuretic factor on aldosterone, renin, and blood pressure in humans

To evaluate the physiological effects of human atrial natriuretic factor-(99-126) (ANF), we infused ANF, 0.1, 0.3, and 1.0 micrograms/min, or placebo for 125 minutes on different days into six sodium-deprived normal men. During the last 45 minutes of infusion, angiotensin II, 6 ng/kg/min, was infused. Blood pressure, heart rate, plasma concentrations of ANF, aldosterone, and cortisol, and plasma renin activity (PRA) were measured before and during infusion. Steady state mean plasma ANF levels during infusion were 26.2 (placebo), 68.8 (0.1 micrograms ANF/min), 221 (0.3 micrograms ANF/min), and 648 pg/ml (1.0 microgram ANF/min). Systolic blood pressure fell significantly (with 1.0 microgram ANF/min), and diastolic pressure tended to rise in a dose-dependent manner, while heart rate was unchanged. PRA and plasma aldosterone fell during ANF infusion in a dose-dependent manner (significant with 0.3 and 1.0 microgram ANF/min infused). The blood pressure-raising and aldosterone-stimulating effects of angiotensin II were blunted by ANF (significant only with 1.0 microgram ANF/min). It is concluded that effects of ANF on blood pressure and the renin-aldosterone system occur with plasma ANF levels close to the physiological range, as well as with slightly elevated ANF levels, as observed in congestive heart failure and renal insufficiency.     

Dopamine inhibits the aldosterone response to upright posture

Aldosterone secretion in man is stimulated by potassium, ACTH, and angiotensin II and is inhibited by dopamine (DA). In normal sodium-replete supine individuals, aldosterone secretion is under maximum tonic inhibition by DA. Dopaminergic control of aldosterone secretion is modified by dietary sodium depletion. To determine the physiological significance of dopaminergic inhibition of aldosterone secretion, we studied the effect of DA on the aldosterone response to upright posture. Twelve normal men were studied while eating an ad libitum sodium diet, and the effect of DA was determined in the supine and upright positions. Plasma aldosterone (PAC), plasma cortisol (F), plasma aldosterone-stimulating factor (ASF), PRA, and blood pressure were measured while the men were supine and after 4 h of upright posture during an infusion of 5% dextrose vehicle and during a DA infusion of 4.0 micrograms/kg X min. The men also were studied as a time control in the supine position while receiving vehicle or DA. PAC increased from a mean basal value of 20.4 +/- 3.2 ng/dl (+/- SE) by 25.9 +/- 5.1 ng/dl to a peak of 44.4 +/- 2.4 ng/dl in response to upright posture during vehicle infusion. The PAC response to upright posture was reduced to 7.4 +/- 1.8 ng/dl (P less than 0.05) when DA was infused. The increase in PRA with upright posture was 3.7 +/- 1.3 ng/ml X h during the vehicle infusion and 4.1 +/- 1.1 ng/ml X h (P = NS) during the DA infusion. ASF, F, and blood pressure were not altered by upright posture and DA. PAC did not change in the six men infused with DA while supine. Therefore, DA inhibits upright aldosterone responses without affecting PRA, ASF, or F.     

Efficacy, electrocardiographic and renal effects of intravenous diltiazem for essential hypertension

The acute systemic blood pressure, electrocardiographic and renal function responses to an intravenous bolus infusion of diltiazem (0.2 to 0.5 mg/kg) were evaluated in 18 subjects with mild to moderate essential hypertension. Although a significant blood pressure response occurred within 5 minutes, blood pressure returned to pretreatment levels within 1 to 3 hours. After drug infusion, a variety of rhythm and conduction disturbances were noted; the most important were transient prolongation of the PR Interval (first-degree atrioventricular block), a single episode of second-degree atrioventricular block (Mobitz I) associated with T-wave inversion and a transient episode of junctional escape rhythm and atrioventricular dissociation. Intravenous diltiazem had no consistent effect on glomerular filtration rate or effective renal plasma flow. Natriuresis and kaliuresis were observed only at the highest infusion dose. It is concluded that an alternative dosing regimen will be required if intravenous diltiazem is to be used safely and effectively to control blood pressure in patients with hypertensive disease.     

Free and Conjugated Catecholamines in Plasma and Red Blood Cells of Normotensive and Hypertensive Patients

Plasma free and conjugated norepinephrine levels were found to he significantly increased in patients with labile and sustained hypertension whereas epinephrine levels were normal in these patients. While free NE and E levels increased significantly during postural change, conjugated NE and E levels were not altered by this stimulus suggesting that conjugated NE levels could be an index of chronic rather than acute changes in the sympathetic tone. In hypertensive patients, plasma free dopamine levels increased during postural change and conjugated DA levels tended to be higher suggesting a dysfunction in the dopamine metabolism. Red blood cells were also found to contain free and conjugated CA. While conjugated CA levels in red blood cells (RBC) were equal or lower than in the plasma, free CA were found in larger concentrations than in the plasma. In hypertensive patients conjugated CA levels in RBC were similar to those found in normotensive subjects but free NE and E levels were significantly higher in hypertensive patients. These studies demonstrate various abnormalities i n the metabolism of CA i n hypertensive patients. Each of these could contributeto the maintenance of hypertension by an alteration of the biological expression of the sympathetic tone at the cellular level of the sepatients.     

Central dopaminergic regulation of aldosterone secretion in sheep

Central dopaminergic mechanisms involved in the regulation of plasma aldosterone concentration were investigated in 16 conscious sheep following Na depletion with intramuscularly administered furosemide. Intracerebroventricular infusion of dopamine (20 micrograms/min) decreased plasma aldosterone significantly to 52 +/- 8% of basal level and increased plasma renin activity (PRA) significantly to 172 +/- 25% of basal level in this animal model. In addition, intracerebroventricular infusion of the dopamine antagonist metoclopramide (20 micrograms/min) in artificial cerebrospinal fluid vehicle significantly increased aldosterone levels to 144 +/- 14% of basal level and decreased PRA to 62 +/- 5% of basal value. Neither intracerebroventricular infusion of the vehicle nor intravenous infusions of metoclopramide or dopamine at the same doses changed aldosterone or PRA levels. Intracerebroventricular bolus injections of metoclopramide (20 micrograms/kg in 0.4 ml of vehicle) were also effective, increasing aldosterone levels to 266 +/- 22% of basal level and decreasing PRA to 70 +/- 12% of basal level. Intravenous bolus injections of the same dose of metoclopramide were ineffective. Dopamine was infused intracerebroventricularly into two uniadrenalectomized sheep with the remaining adrenal transplanted to the neck. Aldosterone levels were decreased to 49 +/- 10% of basal level, and PRA was increased to 157 +/- 10% of basal value. None of the infusions or injections changed arterial or intracranial pressure, or plasma K, Na, and cortisol levels. These data indicate that endogenous or exogenous dopamine may act on central dopamine receptors to decrease plasma aldosterone concentration by an unknown humoral mechanism. The known aldosterone regulators, plasma Na, K, angiotensin II, and adrenocorticotropic hormone, are not involved in the regulation.