Effects of hyperventilation and hypocapnic/normocapnic hypoxemia on renal function and lithium clearance in humans.

BACKGROUND: Using the renal clearance of lithium as an index of proximal tubular outflow, this study tested the hypothesis that acute hypocapnic hypoxemia decreases proximal tubular reabsorption to the same extent as hypocapnic normoxemia (hyperventilation) and that this response is blunted during normocapnic hypoxemia. METHODS: Eight persons were studied on five occasions: (1) during inhalation of 10% oxygen (hypocapnic hypoxemia), (2) during hyperventilation of room air leading to carbon dioxide values similar to those with hypocapnic hypoxemia, (3) during inhalation of 10% oxygen with the addition of carbon dioxide to produce normocapnia, (4) during normal breathing of room air through the same tight-fitting face mask as used on the other study days, and (5) during breathing of room air without the face mask. RESULTS: Hypocapnic and normocapnic hypoxemia and hyperventilation increased cardiac output, respiratory minute volume, and effective renal plasma flow. Glomerular filtration rate remained unchanged on all study days. Calculated proximal tubular reabsorption decreased during hypocapnic hypoxemia and hyperventilation but remained unchanged with normocapnic hypoxemia. Sodium clearance increased slightly during hypocapnic and normocapnic hypoxemia, hyperventilation, and normocapnic normoxemia with but not without the face mask. CONCLUSIONS: The results indicate that (1) respiratory alkalosis with or without hypoxemia decreases proximal tubular reabsorption and that this effect, but not renal vasodilation or natriuresis, can be abolished by adding carbon dioxide to the hypoxic gas; (2) the increases in the effective renal plasma flow were caused by increased ventilation rather than by changes in arterial oxygen and carbon dioxide levels; and (3) the natriuresis may be secondary to increased renal perfusion, but application of a face mask also may increase sodium excretion.

Dopamine natriuresis in salt-repleted, water-loaded humans: a dose-response study.

AIMS: The purpose of the present study was to define the dose-response relationship between exogenous dopamine and systemic haemodynamics, renal haemodynamics, and renal excretory function at infusion rates in the range 0 to 12.5 microg kg(-1) min(-1) in normal volunteers. METHODS: While undergoing water diuresis, eight subjects were infused with 0, 1, 2, 3, 5, 7.5, 10 or 12.5 microg of dopamine kg(-1) min(-1) over 2 h in a randomized and double-blind fashion. On each study day, renal clearance studies were performed during a 1 h baseline period and subsequently during the second 1 h infusion period. Lithium clearance (CL(Li)) was used to estimate proximal tubular outflow. RESULTS: Cardiac output increased with the four highest doses. Mean arterial pressure followed a biphasic pattern with a decrease during the two lowest doses and a dose-dependent increase from the 7.5 microg kg(-1) min(-1) dose onwards. Effective renal plasma flow increased with all doses of dopamine, but peaked with the 3 microg kg(-1) min(-1) infusion rate [from 617 (585-649) ml min(-1) with placebo to 915 (824-1006) ml min(-1) (means with 95% CI, P<0.001)]. None of the doses changed glomerular filtration rate (GFR). Sodium clearance (CL(Na)) and CL(Li) were elevated with the four lowest doses but increased further from 7.5 microg kg(-1) min(-1) onwards. Compared with placebo, the percentage increase in CL(Na) with increasing dose was 77 (5-159), 93 (13-172), 107 (24-190), 121 (60-181), 253 (65-441), 284 (74-494), and 212 (111-312) %, respectively. There were only small, inconsistent decreases in absolute proximal reabsorption rate (APR = GFR-CL(Li)). Fractional distal reabsorption of sodium (FDR(Na) = (CL(Li)-CL(Na))/CL(Li)) decreased with all doses, reaching its nadir with 7.5 microg kg(-1) min(-1) [from 95.9 (94.6-97.2) % with placebo to 91.5 (90.0-93.0) % (P<0.01)] whereafter a flat dose-response curve was observed. CONCLUSIONS: In conclusion, the renal vasodilating effect of dopamine was maximal with 3 microg kg(-1) min(-1). The dose-dependent attenuation seen with higher doses is consistent with an increased alpha-adrenergic stimulation opposing the effect on dopaminergic receptors. The present CL(Li) studies confirm that dopamine increases proximal tubular outflow. The results suggest that the natriuretic effect of depressor doses of dopamine was primarily caused by attenuation of the increase in distal sodium reabsorption normally seen after an increase in proximal tubular outflow. Pressor doses further increased sodium excretion, indicating the presence of pressure natriuresis at these high doses.

No effect of the calcium antagonist, isradipine, on plasma catecholamines in irreversible chronic obstructive pulmonary disease (COPD). A randomized, double-blind, placebo-controlled study.

Calcium antagonists have been claimed to decrease the pulmonary artery pressure and increase oxygen uptake and cardiac output in patients with chronic obstructive pulmonary disease (COPD). This should tend to decrease the plasma levels of catecholamines. The purpose of the present study was to assess the effects of the vasodilating calcium antagonist, isradipine, on resting and exercise levels of catecholamines in patients with COPD. Eighteen patients with severe respiratory insufficiency (FEV1<1.01) were investigated. During maximum exercise, the baseline levels of plasma noradrenaline rose from 2.27 nmol/l (0.41-7.66: mean, range) to 3.86 nmol/l (1.3-12.2) (P = 0.0002) and plasma adrenaline rose from 0.39 nmol/l (0.07-1.02) to 0.64 nmol/l (0.07-1.77) (P = 0.0001). The patients were randomly allocated to receive either capsules of placebo or capsules of 5 mg of isradipine and were reinvestigated after 2 h and 3 months. There was no significant difference between the two groups concerning the change in plasma catecholamines, neither at rest nor at exhaustion. Furthermore, the increase in catecholamines during exercise in the two groups did not differ from each other, neither before administration of isradipine nor after. In conclusion, a vasodilating calcium antagonist did not alter the resting level or exercise induced increase in plasma catecholamines.

The transplanted human kidney does not achieve functional reinnervation.

1. Previous histological studies have demonstrated partial reinnervation of the human transplanted kidney. However, it remains unknown whether this reinnervation is of any functional significance. 2. The effects of noradrenaline infusion (2 micrograms h-1kg-1) and lower body negative pressure (-27 mmHg) on renal haemodynamics, sodium excretion and tubular function were investigated in 25 renal transplant recipients and 10 normal subjects. Sixteen of the transplant recipients had all been transplanted for more than 27 months, and nine had all been transplanted for less than 2 months. 3. After an overnight fast, the subjects were water-loaded, and clearance studies were performed with a 1 h baseline period, a 1 h period with noradrenaline infusion, another 1 h baseline period, and a final 1 h period with lower body negative pressure. 4. During noradrenaline infusion the relative decrease in effective renal plasma flow, glomerular filtration rate and clearance of lithium and sodium was significantly more pronounced in the long-term transplanted patients than in the control subjects. 5. Lower body negative pressure only depressed the glomerular filtration rate significantly in the control subjects. Further, the relative decrease in effective renal plasma flow and clearance of lithium and sodium was significantly greater in the control subjects than in the two groups of transplanted patients. 6. The present study thus demonstrated that in short- and long-term transplanted kidneys in man, supersensitivity to circulating noradrenaline and an inadequate response to lower body negative pressure was present. This strongly suggests that the human transplanted kidney remains functionally denervated.

Effects of acute beta-adrenoceptor blockade with metoprolol on the renal response to dopamine in normal humans.

The present study investigated the contribution of adrenergic beta 1-receptor stimulation to the cardiovascular and renal effects of low-dose dopamine in eight normal, water-loaded humans. Metoprolol (100 mg) or placebo was administered orally at 08.00 h in a randomized, double-blind fashion on two different days. Renal clearance studies were performed during a 1 h baseline period, two 1 h periods with dopamine infusion (3 micrograms kg-1 min-1), and a 1 h recovery period. Cardiac output was measured by an ultrasonic Doppler method, and lithium clearance (CLLi) was used to estimate proximal tubular outflow. Baseline values of heart rate, systolic pressure and mean arterial pressure decreased with metoprolol compared with placebo, but cardiac output, effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were not significantly changed. Metoprolol significantly decreased baseline CLLi and sodium clearance (CLNa) by 19% (P < 0.01) and 34% (P < 0.01), respectively. Metoprolol blunted the dopamine-induced increases in heart rate and systolic pressure, but cardiac output increased to the same extent on both study days by 26% (placebo, P < 0.05) and by 31% (metoprolol, P < 0.01), respectively. With and without metoprolol, dopamine did not significantly change GFR, and the percentage increases in ERPF were similar on the two study days (40% (P < 0.001) and 42% (P < 0.001), respectively). Dopamine increased CLLi and CLNa by 31% (P < 0.01) and 114% (P < 0.01), respectively, with placebo, and by 36% (P < 0.01) and 114% (P < 0.01), respectively, with metoprolol. Values during infusion remained significantly lower with metoprolol compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine, dobutamine, and dopexamine. A comparison of renal effects in unanesthetized human volunteers.

BACKGROUND: Recently, dopexamine (DX), which acts via adrenergic beta 2 and dopaminergic DA1 receptors, has been introduced in the treatment of low cardiac output states. However, the renal effects of DX have not been compared to those produced by equipotent inotropic doses of dopamine (DA), which predominantly stimulates DA1 and DA2 receptors, and of dobutamine (DB), which stimulates beta 1 but not DA receptors. The current study tested the null hypothesis that, with equal increases in cardiac output, DX, DA, and DB would have similar effects on renal function. METHODS: Each drug was given for 2 h on three different occasions to eight normal subjects in doses adjusted to produce a similar 30-35% increase in cardiac output. Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured as renal clearances of 131I-hippuran and 99mTc-DTPA, respectively. Lithium clearance (CLi) was used as an index of proximal tubular outflow. RESULTS: Doses of DA, DX, and DB were 2.90 +/- 0.19, 1.00 +/- 0.02, and 4.92 +/- 0.40 microgram.kg-1.min-1, respectively. Dopamine and DX increased ERPF by 23% and 10%, respectively, whereas ERPF remained unchanged during DB. The increase in ERPF was smaller during DX compared with DA. The GFR remained unchanged during DA and DB, but increased during DX (7%). The CLi increased by 35% and 30% during DA and DX, respectively, but was not changed by DB. Calculated absolute proximal reabsorption rate (APR = GFR--CLi) decreased by 13% during DA, but remained unchanged during DB and DX. Dopamine increased sodium clearance (CNa) by 103%, but the changes during DX and DB were not significant. Only DA decreased fractional distal reabsorption (FDRNa = 1--CNa/CLi). CONCLUSIONS: The findings are consistent with a specific, renal-vasodilating effect of DA and DX. However, in the current doses, this effect of DX was of lesser magnitude compared with that of DA. Only DA significantly increased CNa, and the decreases in APR and FDRNa indicate that an effect on tubular reabsorption rate contributed to the natriuresis.

Lithium clearance method and the renal response to low-dose dopamine in man: a randomized, controlled study.

1. The effect of a single dose of lithium on renal function before and during intravenous infusion of dopamine (3 micrograms min-1 kg-1) was investigated in 12 healthy males. In a double-blind and randomized design, 450mg or 600mg of lithium carbonate or placebo was administered orally at 22.00 hours on three different occasions. After an overnight fast, the subjects were water-loaded and clearance studies were started at 09.00 hours with a 1h baseline period and three 1h periods during dopamine infusion. 2. Baseline sodium clearance with placebo was 0.65 +/- 0.35 ml/min, but with lithium it increased to 1.25 +/- 0.44 (P < 0.001) and 1.17 +/- 0.46 ml/min (P < 0.01) after 450 and 600mg, respectively. Urine flow rates were unchanged compared with placebo. Lithium did not significantly affect glomerular filtration rate, but both doses slightly increased effective renal plasma flow by 7% (P < 0.05) and 10% (P < 0.01), respectively. 3. The maximal natriuretic and diuretic effects of dopamine were not reduced by lithium, but the percentage increases in sodium clearance were significantly diminished after 450mg (P < 0.01) and 600mg (P < 0.001) of lithium. Lithium had no effect on dopamine-induced changes in effective renal plasma flow, glomerular filtration rate or osmolal clearance. Neither lithium nor dopamine influenced plasma concentrations of renin, aldosterone or atrial natriuretic peptide. 4. In conclusion, single test doses of lithium, as normally used in lithium clearance studies, increase baseline values of sodium clearance and effective renal plasma flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Radioimmunoassay of endothelin in human plasma.

A specific and sensitive radioimmunoassay (RIA) for determination of endothelin-1 (ET-1) in human plasma has been developed. Antibodies were raised in rabbits using synthetic ET-1 conjugated to thyroglobulin as immunogen. The antibodies obtained were used at a final dilution of 1:300,000 yielding maximum binding of 61.7 +/- 3.0% (mean +/- 1 SD, n = 20) of 125I-ET-1. The ID50 (inhibitory dose 50%) was 4.5 +/- 0.6 fmol/100 microliters (mean +/- 1 SD, n = 20). The sensitivity of the RIA was 0.33 fmol/100 microliters standard solution. No cross reactivity was observed with endothelin-3, big-endothelin-1, atrial natriuretic factor, angiotensin I or angiotensin II. The cross-reactivity with endothelin-2 was 100%. Endothelin was extracted from acidified plasma with Sep-pak C18 cartridges and recovery of ET-1 added to normal plasma was 70.9 +/- 10.3% (mean +/- 1 SD, n = 12). The concentration of ET-1 in plasma from normal subjects was 1.5 +/- 0.4 pmol/l (mean +/- 1 SD, n = 11) ranging from 1.0 to 2.2 pmol/1. Extracts of normal human plasma subjected to high performance liquid chromatography on a reverse phase C18 column showed one peak of immunoreactivity co-eluting with the standard for ET-1. From these data it is concluded that the immunoreactive material measured in normal plasma with the present RIA is identical to ET-1.