Effects of carbidopa and of intravenous saline infusion into normal and hypertensive subjects on urinary free and conjugated dopamine.

OBJECTIVE: To investigate the possible role played by endogenous dopamine as a modulator of renal sodium (Na+) reabsorption after a combined Na+ and volume load. DESIGN: A randomized placebo-controlled study. METHODS: Ten healthy volunteers and four hypertensive patients were subjected to intravenous infusions of 21 0.9% saline (308 mmol Na+) administered from 1000 to 1300 h after oral administration of placebo or of carbidopa, a dopamine decarboxylase inhibitor. RESULTS: Studies on control subjects after placebo showed that natriuresis occurred during the 6 h after commencement of the saline infusion, with falls in plasma albumin concentration, plasma renin activity and plasma aldosterone concentration; in comparison with results of mock infusion (6 mmol Na+) there was no change in the urinary excretion of dopamine and noradrenaline (In their free or conjugated forms). There was, however, a marked surge in excretion of urinary conjugated dopamine and in the dopamine: noradrenaline ratio from 1300 to 1600 h, after either type of infusion. Administration of carbidopa before the saline infusion resulted in a marked decrease in excretion of urinary free dopamine, but had no effect on the surge in excretion of urinary conjugated dopamine. Saline infusion decreased proximal fractional Na+ reabsorption. Administration of carbidopa delayed but did not prevent this decrease. The effects of saline infusion and of carbidopa on the urinary excretion of dopamine and noradrenaline from hypertensive patients were similar to those observed with the healthy volunteers. CONCLUSIONS: These findings indicate that volume expansion by intravenous saline infusion has no appreciable effect on the urinary free dopamine excretion from normal or hypertensive humans; with any apparent increase, it is important to exclude the possibility of conversion of conjugates to free dopamine in vitro. Furthermore, that carbidopa administration did not inhibit the afternoon surge of conjugated dopamine suggests that administration of carbidopa is deficient as a tool to investigate the functional role of the renal dopamine system.

Efficacy of an angiotensin II receptor antagonist in managing hyperaldosteronism.

OBJECTIVE: To determine whether an angiotensin II receptor antagonist decreases blood pressure in patients with hyperaldosteronism and hypertension who are taking other antihypertensive agents. DESIGN: A double-blind randomized placebo-controlled crossover study. PATIENTS AND METHODS: Blood pressure and hormonal responses to 2-week courses of placebo/irbesartan (150 mg/day given by mouth at 08.05 h) were assessed in 10 patients with hyperaldosteronism. Clinic blood pressure was measured by sphygmomanometer, and plasma concentrations of aldosterone, cortisol, angiotensin II, electrolytes and renin activity (PRA) were determined weekly. Automated 24 h ambulatory blood pressure recordings were made at the end of the active and placebo phases. RESULTS: Irbesartan caused a post-dose decrease in ambulatory blood pressure (systolic, P = 0.02; diastolic, P = 0.05) in the period from 10.00 h to 20.00 h. Clinic blood pressure, measured at trough, was not significantly decreased. Plasma aldosterone decreased (P < 0.03) and PRA increased (P < 0.04) in the first week of active treatment with irbesartan, but differences between the placebo and active-treatment groups were not significant in the second week. There were no significant changes in plasma concentrations of angiotensin II, cortisol or potassium in either week. In the second week of irbesartan treatment, there were associations between change in plasma aldosterone and maximal change in ambulatory blood pressure (systolic and diastolic). CONCLUSION: Irbesartan has a role in combination antihypertensive treatment of patients with hyperaldosteronism.

Erythrocyte cation fluxes in the normotensive and hypertensive clients of a health screening clinic.

Erythrocyte cation transport was measured in vitro using 22Na+ and 86Rb+ uptake techniques in Caucasian men with newly-detected hypertension and in male control groups. The Na+, K+ cotransport [determined by ouabain-resistant frusemide-sensitive (ORFS) components of Na+ or Rb+ influx], sodium pump activity (determined by ouabain-sensitive Rb+ influx) and erythrocyte Na+ and K+ concentrations were not significantly altered in hypertensive men. The total Na+ influx in hypertensives (n = 59) was significantly greater (P less than 0.001) than in controls. The difference was mainly attributable to an increase in the ouabain-resistant frusemide-resistant component of this flux. The total Rb+ influx in hypertensives (n = 39) was also greater (P less than 0.005) than in controls. Overall, both total Na+ influx and total Rb+ influx were positively correlated (P less than 0.01) with diastolic blood pressure and with habitual dietary intake of alcohol. Multivariate analyses after controlling for the effect of blood pressure showed that mean corpuscular volume (MCV) and alcohol intake were statistically significant predictor variables for total Rb+ influx, although not for total Na+ influx. The results are compatible with increased diffusion of cations across the erythrocyte membrane in hypertension, but raise the question of a possible role of alcohol intake in mediating this effect.

Effects of dietary sodium deprivation on erythrocyte sodium concentration and cation transport in normotensive and untreated hypertensive subjects.

There is controversy about the effects of dietary sodium deprivation on cellular cation transport. Using washed erythrocytes for in vitro 22Na and 86Rb uptake studies, we studied the effects of a strict low-salt diet (20 mmol/day) for 4 days in 14 normotensive and 13 hypertensive subjects. Urinary sodium excretion fell from 147 +/- 13 to 18 +/- 3 mmol/24 h in the normotensive group and from 155 +/- 16 to 20 +/- 2 mmol/24 h in the hypertensive group. In both groups, there was a fall in plasma sodium concentration and activation of the renin-aldosterone axis. Both systolic and diastolic blood pressures fell in the hypertensive, but not the normotensive group. There were small but significant (P less than 0.025) decreases in cell cation concentrations and passive cation transport in the normotensive, but not the hypertensive group. No significant change in sodium pump activity or in Na+K+ cotransport was seen in either group. These observations provide no support for the concept that a decrease in dietary sodium intake can induce changes in cell cation transport, detectable in vitro, to which reduction in blood pressure may be attributed.

Double-blind crossover study of the interaction between perindopril and amlodipine on blood pressure and hormones related to fluid and electrolyte balance in patients with essential hypertension.

This study was to investigate the interaction between low doses of perindopril (2 mg daily) and amlodipine (2.5 mg daily) on ambulatory blood pressure (BP), clinic BP, serum angiotensin-converting enzyme (ACE), plasma levels of renin (PRA), angiotensin II (Ang II), aldosterone, and atrial natriuretic peptide (alpha-h ANP) in subjects with essential hypertension. The study design was a parallel, two-period, placebo-controlled, double-blind crossover design, with 11 subjects receiving perindopril and 10 receiving amlodipine during the run-in phase. The addition of amlodipine to perindopril had no effect on ambulatory BP, whereas the addition of perindopril to amlodipine reduced both systolic (P = 0.027) and diastolic (P = 0.049) ambulatory BP. By contrast, the opposite result was obtained for clinic BP at trough, whereby the addition of amlodipine to perindopril reduced erect systolic BP (P = 0.036) and both supine and erect diastolic BP (P = 0.038) whereas the addition of perindopril to amlodipine was without effect. The addition of perindopril to amlodipine decreased serum ACE by 72% and increased PRA two-fold, without change in plasma levels of Ang II, aldosterone or alpha-h ANP. The addition of amlodipine to perindopril increased plasma aldosterone 1.7-fold but did not affect serum ACE, PRA, Ang II, or alpha-h ANP. These interactions between perindopril and amlodipine may have been conditioned by the specific effects of the therapy first given, as well as by the different circumstances of BP measurement (ambulatory vs clinic).

Comparison of the effects on urinary sodium excretion of indomethacin and of carbidopa in normal volunteers given an intravenous saline infusion.

1. Dopamine and prostaglandins are putative endogenous natriuretic hormones. The role of each in facilitating natriuresis induced by intravenous saline infusion was examined in normal volunteers in relation to administration of carbidopa, a dopadecarboxylase inhibitor, and indomethacin, an inhibitor of prostaglandin synthetase. 2. In a placebo-controlled, randomized study, 13 subjects received carbidopa (100 mg) and 12 received indomethacin (50 mg). Proximal and distal renal tubular Na+ reabsorption were determined using exogenous lithium clearance. 3. On the control day, 2 litres of 0.9% saline (308 mmol Na+) given intravenously in 3 h, resulted in volume expansion and natriuresis. Carbidopa reduced the urinary dopamine/noradrenaline ratio but showed no anti-natriuretic effect and no effect on fractional Na+ reabsorption. Indomethacin diminished natriuresis and increased distal fractional Na+ reabsorption in proportion to the antinatriuretic effect. 4. The changes in plasma concentrations of albumin, aldosterone, atrial natriuretic peptide and renin activity associated with volume expansion were not modified by either carbidopa or indomethacin. Urinary prostaglandin E2 excretion was decreased transiently by indomethacin and was unaffected by carbidopa. 5. This study suggests that prostaglandins may modulate urinary Na+ excretion during saline-induced natriuresis through inhibition of distal tubular Na+ reabsorption. No role for free dopamine as a modulator of renal Na+ handling could be assigned on the basis of the findings with carbidopa.

Use of an intravenous sodium load in screening for primary hyperaldosteronism.

A sodium loading test was performed in 35 patients presenting with hypertension and hypokalemia. In 14 of these patients, intravenous administration of 0.9% saline (2 l in 4 h) on two consecutive days caused urinary aldosterone excretion to fall to values within the range for normal volunteers. The other 21 patients, in whom urinary aldosterone excretion did not decline following two days of saline loading, or in whom pronounced hypokalemia after the first day of loading precluded further saline infusion, were designated as having primary aldosteronism. Seventeen of this group underwent surgery and discrete adrenal adenomas were found in 16. When serum potassium concentration, plasma renin activity or the relationships of serum potassium to concurrent urinary potassium excretion or of urinary aldosterone excretion to plasma renin activity were used as alternative diagnostic criteria for primary aldosteronism, overlapping of the two groups occurred. It is concluded that measurement of urinary aldosterone excretion after intravenous sodium loading is a useful test in the test in the identification of primary aldosteronism due to aldosterone-producing adenoma. In this series the saline loading test was more specific in diagnosis than criteria based on serum and urinary potassium, plasma renin activity or unsuppressed aldosterone excretion.

Erythrocyte cation transport is sex-related and is modified by oral contraceptives.

Cation transport across the erythrocyte membrane was studied in normotensive male and female subjects, 20 to 45 years of age. Inward sodium-potassium cotransport was found to be significantly greater in men than in women who were not taking oral contraceptives. Intracellular potassium concentration was lower in men than in women, and was inversely correlated with cotransport. Women who were using oestrogen-progestogen oral contraceptives had higher cotransport than those who were not. It is concluded that a difference in cotransport exists between Caucasian men and women, which is not evident if women are taking oral contraceptives, and which could invalidate comparisons of cation transport between subject groups that are not sex-matched.

Humoral determinants of Na+ excretion after intravenous NaCl loading in normal volunteers.

1. Twelve healthy volunteers maintained on a 100 mmol/day Na+ diet, were given an intravenous infusion of 2L saline (0.9%) between 10.00 h on 2 study days at least 1 week apart. Urine collections (90 min) were made from 08.30 to 16.00 h. Either carbidopa 100 mg or indomethacin 50 mg was given orally at 07.45 h on one study day and placebo was given on the other (in random order). 2. On the placebo day, saline infusion caused significant decreases in plasma albumin concentration, plasma renin activity (PRA), plasma aldosterone concentration and urinary aldosterone excretion, with 2 to 3-fold increases in plasma atrial natriuretic peptide (ANP) concentration and urinary dopamine: noradrenaline ratio (DA:NA), whereas mean urinary kallikrein and prostaglandin E2 (PGE2) excretion rates were unchanged. Carbidopa decreased urinary DA:NA and indomethacin decreased urinary PGE2 excretion, compared with the placebo day. Excretion of sodium (Na+) decreased below baseline in two out of six carbidopa-treated subjects and in three out of six indomethacin-treated subjects, but showed little or no change in the remainder. 3. These preliminary observations suggest that some subjects in the early phase of natriuresis after an intravenous Na+ load can be identified as having prostaglandin-dependent or dopamine-dependent mechanisms for Na+ excretion.

Effects of 17 alpha-ethinyl oestradiol in vitro on erythrocyte cation transport in men and women.

The effects of 17 alpha-ethinyl oestradiol in vitro upon erythrocyte Na(+)-K+ cotransport were investigated in nine normal males and in eight normal females during the mid-follicular phase of the menstrual cycle. At a concentration of 10(-1) mmol/l, Na(+)-K+ cotransport was almost completely inhibited. At concentrations of 10(-12) to 10(-2) mmol/l, a minor concentration-related effect was observed in males but not females. In the same concentration range, there was a significant difference in Na(+)-K+ cotransport between sexes. Thus, erythrocyte Na+K+ cotransport is lower in females than males, probably due to chronic exposure of their erythrocytes to endogenous oestrogen.

Effects of prazosin on blood pressure and plasma renin activity during onset and withdrawal of action in the anaesthetized rat.

1. The effects of single intramuscular injections of prazosin, 0.1 mg/kg, upon blood pressure, heart rate and plasma renin activity, were studied, over 24 h, in groups of anaesthetized rats, control rats receiving 0.9% saline. 2. Within 6 min of prazosin administration, heart rate fell by 50 beats/min (s.e.m = 19) and blood pressure by 40 mmHg (s.e.m. = 8). Starting levels were regained within 90 min and 16 h of injection, respectively, and thereafter both parameters remained unaltered. Plasma renin activity showed a slight though insignificant rise during the initial hypotension, but subsequently fell to 32% of the control level. 3. The hypotensive response to prazosin, unlike that to the centrally acting agents clonidine or guanfacine, was not followed by overshoots in blood pressure, heart rate or plasma renin activity. Instead, suppression of plasma renin activity was demonstrable after re-establishment of control blood pressure.

Erythrocyte cation fluxes in normal and hypertensive human subjects.

Intracellular cation concentrations ([Na]i, [K]i) and influxes of 22Na and 86Rb were determined in the erythrocytes of hypertensive and control groups of subjects. In both groups [Na]i showed a positive correlation with frusemide-resistant Na influx and was inversely correlated with ouabain-sensitive Rb influx, whereas [K]i was inversely correlated with frusemide-sensitive Na influx (FSNaI). No significant differences between groups were found in [Na]i, [K]i or frusemide-resistant Na influx. FSNaI was greater in males than females. FSNaI was slightly greater (P less than 0.06) in the hypertensive group, but the significance of the difference diminished with sex-matching. Ouabain-sensitive Rb influx was increased in the hypertensive group.

Concurrence of primary aldosteronism and renal artery stenosis.

1. An unusual clinical case is described in which renal artery stenosis (RAS) was found to coexist with adrenocortical hyperplasia, resulting in hypertension. 2. Partial relief of the hypertension was achieved by correction of RAS, and then further relief by extirpation of one adrenal gland affected by unilateral hyperplasia, in interventions 8 months apart. 3. Biochemical features typical of primary hyperaldosteronism were observed both before and after RAS repair but were not present after unilateral adrenalectomy. 4. The association of these two lesions could have occurred by chance, through genetic linkage, or by progression from RAS to tertiary aldosteronism.

Responsiveness of hypertensive subjects to prazosin.

1. Plasma drug levels and blood pressure changes produced by a single 2 mg oral dose of prazosin were determined in nine hypertensive patients. 2. Regression analysis showed that there was a high degree of correlation between plasma prazosin concentration and change in mean blood pressure. 3. There were marked differences between patients in their responsiveness to prazosin.

The beta-adrenoceptor controlling renin release.

The beta-adrenoceptor antagonists, atenolol, metoprolol and propranolol, administered intravenously to anaesthetized rats in doses producing equal beta1-adrenoceptor blocking effects, caused comparable suppression of plasma renin activity (PRA) despite the fact that, at these doses, atenolol and metoprolol exhibited no beta2-adrenoceptor blocking properties. Practolol, an agent specific for beta1-adrenoceptors but possessing intrinsic sympathomimetic activity, caused less marked suppression of PRA. When doses of atenolol, metoprolol, propranolol and butoxamine were selected to achieve equal beta2-blocking effects, PRA was again significantly suppressed by atenolol and metoprolol but not by propranolol or butoxamine. These results do not support the concept that adrenergic release of renin is mediated by beta2-adrenoceptors, but are compatible with the involvement of a beta1-adrenoceptor-mediated mechanism.

Erythrocyte cation fluxes during the menstrual cycle in normal female subjects.

1. Studies of erythrocyte cation transport mechanisms in vitro were performed on eight normotensive, premenopausal female subjects at the mid-points of the follicular and luteal phases of their menstrual cycles. Concurrent plasma concentrations of 17 beta-oestradiol, progesterone, aldosterone and renin activity were measured. 2. Ouabain-resistant, frusemide-resistant rubidium influx (an index of passive potassium diffusion) was significantly lower in the luteal than the follicular phase. 3. In further studies in four of the eight subjects, the mean rate constant of the rubidium influx measurement was also lower in the luteal than in the follicular phase. 4. There were no changes in Na+-K+ co-transport, sodium pump activity or intracellular cation concentrations throughout the cycle. 5. There was a tenfold fall in the mean plasma 17 beta-oestradiol/progesterone ratio, as well as increases in plasma aldosterone concentration and renin activity between the mid-follicular and mid-luteal phases. 6. We conclude that changes in plasma oestrogen/progesterone ratio during the menstrual cycle may be associated with alterations in passive potassium diffusion.

Altered erythrocyte cation transport related to hypertension or oral contraception.

Intracellular cation concentrations (Nai, Ki), and the influx of Rb86 and of Na22 were measured in the erythrocytes of 22 normal women with no family history of hypertension, 16 women with untreated essential hypertension, and 14 normotensive women treated with hormonal contraceptives. Values for total Rb influx, and for its components denoting sodium pump activity (ouabain-sensitive) and Na, K co-transport (ouabain-resistant, frusemide-sensitive), were significantly greater in the hypertensive and contraceptive-treated groups than in the normal group. Na, K cotransport measured by Na influx (frusemide-sensitive) was found to be significantly increased in the contraceptive-treated but not the hypertensive group. Passive sodium diffusion (frusemide-resistant Na influx) and Ki did not differ significantly between groups. Nai was lower in the hypertensive group than in the other two groups. These findings support the hypothesis that hypertension or hormonal contraception are associated with increased leakage of K ions from erythrocytes, without a corresponding increase in passive Na influx: the change in cell membrane permeability is compensated for by increases in Na, K co-transport and sodium pump activity, adjusted to allow for altered differential permeability to K and Na ions.

Increase in serum total angiotensin-converting enzyme activity with enalapril therapy in humans: a controlled trial.

1. In a controlled, randomized double-blind trial, 15 patients with essential hypertension were treated with enalapril 5-20 mg/day, or doxazosin 1-8 mg/day, during a 7 week dose titration phase. This was followed by 7 weeks of combined treatment with doxazosin and enalapril. 2. Blood was taken after a 2 week placebo run-in phase, and at 3 and 7 weeks in the single-agent and combined treatment phases, for measurement of plasma renin activity (PRA), plasma angiotensin II (AII), plasma aldosterone and serum free and total angiotensin-converting enzyme (ACE) activities. 3. Doxazosin had no effect on serum free or total ACE activities. 4. Enalapril reduced serum free ACE activity and increased serum total ACE activity, which at 7 weeks was significantly greater than in patients receiving doxazosin. 5. In those patients who received enalapril, 10 mg/day for 3 weeks and then 20 mg/day for 4 weeks (n = 12), with or without doxazosin, mean serum total ACE activity increased by 51%. PRA was also increased in this group, but there were no changes in plasma AII or aldosterone concentrations.

Responsiveness to prazosin in renal failure.

1. The fall in blood pressure produced by a test dose of prazosin was greater in a group of patients with chronic renal failure than in a group with normal renal function. 2. This difference could not be attributed to increased reactivity, measured as the slope of the regression line relating mean blood pressure and plasma prazosin concentration, nor to retarded elimination of the drug. 3. The enhanced antihypertensive effect of prazosin in renal failure appears to reflect changes in the bioavailability or distribution of the drug, which result in higher drug concentrations for a given dose.

Withdrawal of clonidine: effects of varying dosage or duration of treatment on subsequent blood pressure and heart rate responses.

The influence of the dosage or duration of treatment on the incidence and severity of clonidine withdrawal responses was examined in normotensive rats. Clonidine (0.01 or 0.1 mg/kg i.m.) was administered either in single doses, or twice daily for 3 days or 3 weeks. Rats were then anesthetized and arterial catheters were inserted. Significant overshoots in blood pressure and heart rate, reaching peak values 16 to 26 hr after the last injection, occurred in all clonidine-treated rats, but in no control rats. The overshoots after single injections of clonidine were as great as those after suspension of sustained treatment. Moreover, withdrawal responses were as great after the low dose as they were after the 10-fold greater dose. Only plasma renin activity showed a significantly greater elevation during withdrawal of the high dose of clonidine. Since ganglionic blockade reduced blood pressures and heart rates to the same levels in rats with clonidine withdrawal hypertension as in control rats, the withdrawal overshoots appear to be nervously mediated. Neither the dosage nor the duration of treatment could be shown to determine the magnitude of the response to withdrawal of clonidine.