Acute hypoxia effects the renin-angiotensin-aldosterone system (RAAS) and may change renal function. In previous studies from our laboratory a reproducible decrease in plasma renin activity, angiotensin II (Ang II), and plasma aldosterone concentration (PAC) during three hours of hypoxia was observed (1, 2). In addition, it was found, that the decrease in PRA is adenosine mediated (1). Since renin release from juxtaglomerular cells (JGC) of the kidney is facilitated by an increase in intracellular calcium concentration, we hypothesized that the acute administration of the short acting dihydropyridine calcium channel blocker nifedipine may inhibit the hypoxia-induced decrease in PRA.
Plasma renin acitvity (PRA) has been found to either increase or decrease during
acute hypoxia in humans as well as in animals (3-5). Among the reasons for these
contradictory results are, e.g., lacking differentiation between resting states
and exercise (4), uncontrolled salt- and water intake (5), and/or different
experimental procedures such as CO
2 inhalation
to prevent the fall in PCO
2 caused by hypoxia
induced hyperventilation (see discussion section for further details).
Nifedipine is currently being used as an adjunct treatment of high-altitude pulmonary edema (HAPE) if supplemental oxygen is unavailable and descent is impossible (6), or if prophylaxis of HAPE is recommended (7), since nifedipine has been shown to reduce pulmonary arterial pressure and pulmonary vascular resistance during acute hypoxia. However, the possible inhibition of the hypoxia-induced decrease in PRA and Ang II concentration by nifedipine could be disadvantageous if it was to reduce urinary output.
Therefore, the objective of the present study was to find out whether nifidepine would inhibit the decrease in PRA, AngII, and PAC during acute hypoxia in conscious, resting dogs on a controlled salt and water intake. This was investigated together with the changes in hemodynamics and renal function that ensue from such a treatment.
MATERIALS AND METHODS
Animals, maintenance, and diets
A total of 16 experiments was performed on eight purebred female Beagle dogs (body weight (wt) 12.2 ± 0.7 kg), two experiments on each dog. The intervals between the two experiments on the same dog were at least 14 days. The dogs were obtained from the Central Animal Facilities of the Humboldt-University in Berlin. The permission to perform the experiments was obtained from the Governmental Animal Protection Committee (AZ 0183/97).
A permanent tracheotomy was performed four to five weeks prior to the experiments
(for details see Ref. 2). Thereafter, the dogs were trained to lie quietly on
their right side on a padded animal table for at least 4 hours. The dogs were
kept under standardized environmental conditions (for details see Ref.8). They
were fed a low sodium diet, starting at least 7 days before the experiments.
The diet consisted of minced beef (12 g), and boiled rice (58 g), and contained
0.5 mmol sodium, 91 ml water, and 3.5 mmol potassium (all values given per kg
body weight per day). To ease the detection of small decreases in PRA, we stimulated
the RAAS by a low sodium diet (0.5 mmol Na·kg bodywt
-1·day
-1),
which was given for seven days before the experiments. If food intake is uncontrolled
or rich in sodium, PRA and PAC values are often very low, and changes in PRA
due to hypoxia and/or nifedipine infusion may be less apparent.
At least eight days prior to an experiment, 100 ml of the dog's own blood was
collected via puncture of a foreleg vein and stored in a blood bag at 4°C (Biopack
®,
Biotrans, Dreieich, Germany). This blood served to replace the blood withdrawn
for analysis during the experiments. No further fluid was administered during
the experiment.
Experimental protocols
Preparation for the experiments started at 7:30 AM with the recording of the dog's body temperature and body weight. Thereafter, a foreleg vein was punctured and a creatinine infusion started for assessment of glomerular filtration rate (GFR) (exogenous creatinine clearance: priming dose 1.4 g for 30 min, maintenance infusion 4.7 mg/min). Urine was collected via a self retaining bladder catheter inserted through the urethra. An arterial line - for continuous blood pressure monitoring and blood sampling - and a pulmonary artery catheter were inserted using local anesthesia (for details see Ref. 8). After these procedures, the awake dog was placed on a padded animal table and positioned on its right side. The pressure transducers were adjusted to the level of the right atrium. The distance between transducer and table was recorded and also used for the next experiment in this individual dog. Finally, the tracheal tube was inserted, the cuff inflated, and the dog connected to the ventilator set to CPAP mode (CPAP level 4 mmHg). We used the widest tube that would fit the tracheostoma (mostly 8 mm I.D.) in order to decrease respiratory resistance. Thereafter, the conscious dogs were given 60 min to calm down and adjust to the experimental situation.
Each of the 8 dogs underwent two protocols in randomized order: control experiments
(
Control) and nifedipine experiments (
Nifedipine). In Control
experiments the dogs breathed room air (21 % O
2,
79 % N
2; normoxia) for one hour, followed by
breathing a gas mixture containing 10 % O
2 and
90 % N
2 for two hours (hypoxia). In the
Nifedipine
experiments, the dogs also breathed room air for one hour (normoxia), after
which time they were infused nifedipine (Adalat
®,
Bayer AG, Leverkusen, Germany; 1.5 µg·kg body wt
-1·min
-1)
for 30 min before the two hours of hypoxia were started. During hypoxia the
nifedipine infusion was continued at the same rate. The nifedipine solution
was protected from light at all time. The additional sodium intake through the
nifedipine solution was 0.02 mmol Na·kg body wt
-1·h
-1.
Heart rate (HR), mean arterial blood pressure (MAP), and central venous pressure (CVP) were measured continuously and the data stored on a personal computer. Cardiac output was measured using the thermodilution technique (5 ml injection volume at 5 - 10°C). Five consecutive measurements were performed and the highest and lowest values rejected. The mean cardiac output was calculated from the remaining three determinations and taken for calculation of systemic vascular resistance (SVR) by the standard formula.
Blood samples were taken at the end of each experimental hour to determine arterial blood gases, plasma electrolytes, creatinine, osmolarity, and hormone concentrations. The blood withdrawn was immediately replaced with an equal amount of the dog's own stored blood using a blood filter (TNSB-3, Biotest, Alzenau, Germany).
Urinary sodium, water, potassium, and creatinine excretions and osmolarity were measured hourly after complete evacuation of the urinary bladder (air washout). Exogenous creatinine clearance was calculated by the standard formula to assess glomerular filtration rate (GFR) (see above).
Assays
Blood samples for hormone analysis were collected into precooled Na-EDTA vials, and centrifuged at 4°C. The plasma was separated and stored at -22°C until analysis. Commercially available radioimmunoassay kits were used to measure plasma renin activity (PRA), concentration of angiotensin II (Ang II), aldosterone (PAC), atrial natriuretic peptide (ANP), antidiuretic hormone (ADH = vasopressin), and angiotensin converting enzyme activity (ACE) (for details see 2).
Plasma and urinary sodium and potassium concentrations were measured by flame photometry (Photometer Eppendorf, Hamburg, Germany), and creatinine with a creatinine analyzer (modified Jaffé reaction, Beckmann Instruments, Brea, USA). Plasma and urinary osmolarity was measured by cryoscopy (Osmometer, Roebling, Berlin, Germany). Blood gas analysis was performed at hourly intervals (ABL 505, Radiometer, Copenhagen, Denmark).
Statistical analysis
All values are given as means ± SE (n = 8). Intergroup comparison, i.e., Control vs. Nifedipine during the respective normoxia and hypoxia period, was performed using Student's t-test. For intra-group comparison (time course) a general linear model of analysis of variance (GLM ANOVA) for repeated measures was used (SPSS 9.0, Chicago, IL, USA). Post-hoc testing of means was performed with Student's t-test with Bonferroni correction for multiple comparisons. Statistical significance was considered at P < 0.05 (* = significant vs. normoxia, § = significant vs. Controls).
RESULTS
Minute ventilation, arterial blood gases, pH, plasma values
During hypoxia, arterial O
2 tension (Pa
O2)
decreased from ~95 Torr to 37 - 38 Torr and arterial carbon dioxide tension
(Pa
CO2) from ~35 to 24 - 27 Torr in both protocols
(P < 0.05) (
Table 1). Minute ventilation increased about 1 - 1.9 l/min
in both protocols during hypoxia (P < 0.05) (
Table 1). Standard bicarbonate
concentration (20 - 21.1 mmol/l), base excess (-4.5 – -5.7 mmol/l), plasma sodium
concentration (143 - 145 mmol/l) and plasma osmolarity (294 - 300 mosmol/l)
were not different between both protocols and remained unchanged during hypoxia.
Plasma potassium concentration decreased during hypoxia in both Control and
Nifedipine experiments (P < 0.05) (
Table 1).
Table
1. Arterial blood gases, pH, plasma potassium concentration, and minute
ventilation during Control and Nifedipine experiments. |
|
PaO2,
arterial oxygen tension; PaCO2, arterial
carbon dioxide tension; PK, plasma potassium
concentration; VE, minute ventilation.
Values measured during one hour of normoxia (21 % inspiratory O2
concentration) and two hours of hypoxia (10 % inspiratory O2
concentration). Means ± SE, n = 8; *P < 0.05 vs. normoxia. |
Hemodynamics
During hypoxia, MAP increased in
Controls (P < 0.05) and decreased in
Nifedipine experiments (P < 0.05) (
Fig. 1). Heart rate did not
change in Controls, but increased in Nifedipine experiments during hypoxia (P
< 0.05) (
Table 2). Cardiac output (CO) increased slightly during hypoxia
in Controls (2.2 ± 0.2 to 2.6 ± 0.2 l/min, P < 0.05). The CO increase in Nifedipine
experiments was more pronounced (2.2 ± 0.1 to 3.4 ± 0.3 l/min; P < 0.05) (
Table
2). Systemic vascular resistance did not change during hypoxia in Controls,
whereas it decreased in Nifedipine experiments (P < 0.05) (
Fig. 1). Central
venous pressure was similar in both protocols and remained unchanged throughout
the experiments (
Table 2).
|
Fig. 1. Mean arterial pressure,
and systemic vascular resistance during 1 h of normoxia (FiO2
= 0.21) and 2 h of hypoxia (FiO2
= 0.1) in Control and Nifedipine experiments. Values are
means ± SE (n = 8). * P< 0.05 vs. normoxia, § P < 0.05 vs. Control. |
Table
2. Hemodynamic parameters during Control and Nifedipine
experiments. |
|
HR, heart
rate; CO, cardiac output; CVP, central venous pressure. Values measured
during one hour of normoxia (21 % inspiratory O2
concentration) and two hours of hypoxia (10 % inspiratory O2
concentration). Means ± SE, n = 8; *P < 0.05 vs. normoxia, §P
< 0.05 vs. Control. |
Plasma hormones
PRA and Ang II decreased during hypoxia in
Controls (P < 0.05), but increased
in
Nifedipine experiments (P < 0.05) (
Fig. 2). PRA correlated
inversely with mean arterial pressure (MAP) in Controls (r = 0.71, P = 0.002),
but not in Nifedipine experiments (r = 0.089, p = 0.742) (
Fig. 3). In
Controls PAC decreased swiftly with hypoxia, whereas in
Nifedipine
experiments the decrease was delayed (P < 0.05) (Fig. 2). Plasma concentrations
of ANP (36 - 40 pg/ml), ACE (45 - 51 U/l), and ADH (0.2 - 0.6 pg/ml) were similar
in both protocols and did not change during hypoxia in either protocol.
|
Fig. 2. Plasma renin activity,
angiotensin II concentration, and plasma aldosterone concentration during
1 h of normoxia (FiO2
= 0.21) and 2 h of hypoxia (FiO2
= 0.1) in Control and Nifedipine experiments. Values are
means ± SE (n = 8). * P< 0.05 vs. normoxia, § P < 0.05 vs. Control. |
|
Fig. 3. Plasma renin activity
of each dog in Control (n = 8) and Nifedipine (n = 8) experiments
during normoxia and hypoxia plotted against mean arterial pressure at
the same time. |
Renal function data
In Controls urine volume (P < 0.05) and urinary potassium excretion increased
~50 % during hypoxia (
Table 3). In
Nifedipine experiments urine
volume decreased during hypoxia (P < 0.05), whereas urinary potassium excretion
(P < 0.05) increased (
Table 3). In
Controls urinary sodium excretion,
fractional excretion of sodium and glomerular filtration rate did not change
during hypoxia (
Table 3). In
Nifedipine experiments glomerular
filtration rate also did not change, whereas urinary sodium excretion and fractional
excretion of sodium increased during hypoxia (P < 0.05) (
Table 3). Urinary
osmolarity decreased (P < 0.05) during hypoxia in
Controls, but increased
in
Nifedipine experiments (P < 0.05) (
Table 3).
Table
3. Renal excretion parameters during Control and Nifedipine
experiments. |
|
UV, urine
volume; UNaV, sodium excretion; UKV,
potassium excretion; Uosmol, urinary
osmolarity; FENa, fractional excretion
of sodium; GFR, glomerular filtration rate, all values given per kilogram
body weight (kg) and minute (min). Values were measured during one hour
of normoxia (21 % inspiratory O2 concentration)
and two hours of hypoxia (10 % inspiratory O2
concentration). Means ± SE, n = 8; *P < 0.05 vs. normoxia. §P
< 0.05 vs. Control. |
DISCUSSION
The aim of the present study was to find out, whether the calcium channel antagonist nifedipine would inhibit the hypoxia-induced decrease in plasma renin activity. The experiments were performed on eight conscious, tracheotomized Beagle dogs. In a three hour protocol, the dogs were breathing room air for one hour, and a hypoxic gas mixture for two hours. The results demonstrated that nifedipine is able to inhibit the hypoxia-induced decrease in PRA.
The present study describes basic physiological and pathophysiological mechanisms
during acute hypoxia in conscious, resting dogs with all their regulatory mechanisms
intact. The significance of the results obtained is a matter of speculation.
The decrease in PRA and AngII in
Controls may result in less peripheral
vasoconstriction and can be considered a physiological advantage to guarantee
tissue oxygenation during hypoxia. The decrease of PAC at the same time may
stimulate sodium and water excretion during hypoxia and improve oxygen transport
by the resulting hemoconcentration.
Hormones
In
Controls, plasma renin activity and angiotensin II concentration decreased
during hypoxia (
Fig. 1). This is in accordance with former studies from
our laboratory (1, 2, 8), but there are also studies, in which PRA increased
during acute hypoxia (4, 5). This can be explained by, e.g., uncontrolled sodium
and water intake (5) and/or not differentiating between resting states and exercise
(4). Furthermore, the experimental situation has to be taken into account, e.g.,
in some studies the arterial CO
2 tension during
hypoxia could not be reduced through hyperventilation by the subjects under
investigation, because the studies were performed during general anesthesia
with controlled mechanical ventilation, or CO
2
had been mixed to the inspiratory gas (9), or the degree of hypoxia was very
severe (F
iO
2
< 0.07). These conditions may all increase PRA and AngII levels, e.g., via a
very high degree of stress and consecutively sympathetic stimulation (10). With
our experimental setup (F
iO
2
= 0.1) and well trained conscious animals, who hyperventilated as a physiological
response towards hypoxia, we minimized these non-physiological conditions.
Many adaptive responses to hypoxia involve the regulation of specific genes.
These responses depend, e.g., on whether hypoxia is acute, chronic, or intermittent.
In primary cultures of renal juxtaglomerular cells (JGC) of rats hypoxia per
se had no influence on renin secretion and renin gene expression (11). Thus,
other mediators have to play a role in regulating renin secretion from the juxtaglomerular
cells during acute hypoxia. One potential mediator is adenosine, which has recently
been suggested to mediate the renin decrease via inhibition of adenylate cyclase
(1). Beside adenosine, mechanisms such as the stimulation of guanylate cyclase
or phospholipase C can also mediate a decrease in PRA (12). Furthermore, ATP-sensitive
potassium channel stimulators increase and inhibitors decrease plasma renin
acitivity (13). A further intriguing feature of the control of renin secretion
is called the "calcium paradox" and describes the observation that a decrease
in cytoplasmatic calcium concentration increases the renin secretion from the
juxtaglomerular cells and vice versa (14, 15). Our present
Nifedipine
experiments support this notion, because PRA and Ang II increased after application
of the calcium channel antagonist instead of decreasing during hypoxia as in
Controls (
Fig. 1). The increase in PRA could be a direct effect of nifedipine
on the juxtaglomerular cells (16), since it has been shown that L-type calcium
channel blockade is able to stimulate renin release through a decrease in intracellular
calcium (14).
In addition, an increase in renal sympathetic nerve activity (RSNA) may trigger
the increase in PRA during hypoxia (17). In
Controls, hypoxia decreased
PRA, indicating that the RSNA was not significantly increased by hypoxia per
se. In contrast, nifedipine is known to stimulate the cardiac sympathetic nervous
system (e.g., tachycardia occurs) (18), and the renal sympathetic nervous system
indirectly (19).
Furthermore, a decrease in mean arterial pressure, and thus renal perfusion
pressure, may have increased PRA in
Nifedipine experiments. In conscious
dogs the threshold pressure for the pressure-dependent renin release has been
determined to be about 89 mm Hg (20). Since the lowest MAP during
Nifedipine
experiments in our study was about 83 mm Hg (
Fig. 1), it is unlikely
that this decrease alone can explain the striking increase in PRA from 6.5 to
12.1 ng AngI·ml
-1·h
-1
during hypoxia. If PRA is plotted against mean arterial pressure (
Fig. 3),
the correlation is high only in
Control experiments, whereas in
Nifedipine
experiments the mechanism of pressure-dependent renin release seems to be suspended,
i.e., there is no correlation at all. Indicating, that the increase in PRA during
hypoxia with simultaneous calcium antagonist treatment is mainly brought about
by factors other than the slight decrease in MAP (
Fig. 1).
Plasma aldosterone concentration decreased during hypoxia in both groups, but
the effect was less pronounced in
Nifedipine experiments (
Fig. 2).
The decrease of PAC in
Control experiments is most likely due to a direct
hypoxic inhibition of aldosterone secretion from the suprarenal glands (21).
In
Nifedipine experiments the increase in PRA and Ang II may counteract
the hypoxia induced decrease in PAC.
Renal excretion
In Control experiments, urine volume and potassium excretion increased about
fifty percent during hypoxia (
Table 3). This is in accordance with previous
data from our laboratory (8). Opposite to
Controls, urine volume decreased
during hypoxia in
Nifedipine experiments (
Table 3). The increase
in angiotensin II concentration in
Nifedipine experiments may partly
account for this finding (22). An increase in ADH seems not to be involved since
the ADH concentration did not differ between the normoxia and hypoxia period
(
see Results section).
The striking increase in potassium excretion during hypoxia in
Nifedipine
experiments (
Table 3) may partly be explained by the greater aldosterone
levels compared with
Controls.
The unchanged urinary sodium excretion in
Control experiments was accompanied
by an increase in urine volume, resulting in a decrease in urinary osmolarity
during hypoxia (
Table 3). This is in accordance with former data from
our laboratory obtained on a low sodium diet during hypoxia (1). Normally, a
decrease in PAC during hypoxia - as observed in
Controls - would be expected
to increase sodium excretion ("high altitude natriuresis"; i.e., 23). On a low
sodium diet, however, the organism has to defend against sodium losses and the
hypoxia-induced decrease in Ang II and plasma aldosterone concentrations in
Controls seems to be too small to bring about a measurable increase in
renal sodium excretion under these circumstances. Interestingly, in
Nifedipine
experiments an increase in urinary sodium excretion of about 85% was observed
during hypoxia (
Table 3). This increase in sodium excretion occurred
on the same low sodium diet as in
Controls and is probably brought about
by a direct tubular effect of nifedipine (24) since it occurred in the face
of an increase in FE
Na without any change in
the glomerular filtration rate (
Table 3). This nifedipine induced natriuresis
was not outweighed by the concomitant increase in Ang II and aldosterone concentrations
observed during the hypoxia period in
Nifedipine experiments.
Atrial natriuretic peptide (ANP) was suggested to initiate hypoxic natriuresis in conscious lambs (25). In our experiments, ANP concentrations did not change. Thus, ANP does not seem to play a pivotal role for acute hypoxic natriuresis in conscious dogs, which is in accordance with results in humans (26).
Hemodynamics
During the hypoxia period the
Nifedipine dogs showed a decrease in systemic
vascular resistance, a pronounced increase in cardiac output, a moderate decrease
in MAP, and a striking increase in heart rate, while in
Control experiments
the systemic vascular resistance remained stable during hypoxia, because the
slight increase in cardiac output paralleled the increase in mean arterial pressure
(
Fig. 1). It is speculated that the cardiovascular effects during hypoxia
are mainly due to sympathetic stimulation of the cardiovascular system in
Controls
(27). The pharmacological properties of nifedipine, e.g., on the sympathetic
nervous system (18), are able to modify and overrule the physiological cardiovascular
effects of hypoxia (
Fig. 1, Table 2).
We conclude that the hypoxia-induced decrease in PRA is among others a calcium dependent mechanism. The L-type voltage-dependent calcium channel antagonist nifedipine increases plasma renin activity during hypoxia possibly by decreasing intracellular calcium in the juxtaglomerular cells and/or by increasing renal sympathetic nerve activity.
Acknowledgment: The authors are indebted to Rainer
Mohnhaupt for help with the statistics, to Birgit Brandt and Daniela Bayerl
for expert technical assistance, and to April M. Kurzke for editorial help.
This study was supported by a grant from the Deutsche Forschungsgemeinschaft
to Gabriele Kaczmarczyk (Ka 526/5-2).
REFERENCES
- Höhne C, Krebs MO, Arntz E, Boemke W, Kaczmarczyk G. Evidence that the renin decrease during hypoxia is adenosine-mediated in conscious dogs. J Appl Physiol 2001; 90: 1842-1848.
- Krebs MO, Boemke W, Simon S, Wenz M, Kaczmarczyk G. Acute hypoxic pulmonary vasoconstriction in conscious dogs decreases renin and is unaffected by losartan. J Appl Physiol 1999; 86: 1914-1919.
- Keynes RJ, Smith GW, Slater JD, Brown MM, Brown SE, Payne NN, Jowett TP, Monge CC. Renin and aldosterone at high altitude in man. J Endocrinol 1982; 92: 131-140.
- Neylon M, Marshall J, Johns EJ. The role of the renin-angiotensin system in the renal response to moderate hypoxia in the rat. J Physiol (Lond) 1996; 491: 479-488.
- Skwarski KM, Morrison D, Barratt A, Lee M, MacNee W. Effects of hypoxia on renal hormonal balance in normal subjects and in patients with COPD. Respir Med 1998; 92: 1331-1336.
- Hackett PH, Roach RC. High-altitude illness. N Engl J Med 2001; 345: 107-114.
- Bärtsch P, Maggiorini M, Ritter C, Noti P, Oelz O. Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med 1991; 325: 1284-1289.
- Höhne C, Boemke W, Schleyer N, Francis RCE, Krebs MO, Kaczmarczyk G. Low sodium intake does not impair short-term renal compensation of hypoxia-induced respiratory alkalosis in conscious dogs. J Appl Physiol 2002; 92: 2097-2104.
- Malpas SC, Shweta A, Anderson WP, Head GA. Functional responses to graded increases in renal nerve activity during hypoxia in conscious rabbits. Am J Physiol 1996; 271: R1489-R1499.
- Raff H, Roarty TP. Renin, ACTH, and aldosterone during acute hypercapnia and hypoxia in conscious rats. Am J Physiol 1988; 254: R431-R435.
- Ritthaler T, Schricker K, Kees F, Kramer B, Kurtz A. Acute hypoxia stimulates renin secretion and renin gene expression in vivo but not in vitro. Am J Physiol 1997; 272: R1105-1011.
- Jackson EK. ADENOSINE: A physiological brake on renin release. Annu Rev Pharmacol Physiol Toxicol 1991; 31: 1-35.
- Pratz J, Mondat S, Montier F, Cavero I. Effects of the K+
channel activators, RP52891, cromakalim and diazoxide, on the plasma insulin
level, plasma renin activity an blood pressure in rats. J Pharmacol Exp
Ther 1991; 258: 216-222.
- Hackenthal E, Paul M, Ganten D, Taugner R. Morphology, physiology, and molecular biology of renin secretion. Physiol Rev, 1990; 70:1067-1116.
- Wagner C, Krämer BK, Hinder M, Kieninger M, Kurtz A. T-type and L-type calcium channel blockers exert opposite effects on renin secretion and renin gene expression in conscious rats. Br J Pharmacol 1998; 124: 579-585.
- Schweda F, Riegger GAJ, Kurtz A, Krämer BK. Store-operated calcium influx inhibits renin secretion. Am J Physiol 2000; 279: F170-176.
- Denton KM, Shweta A, Anderson WP. Preglomerular and postglomerular resistance response to different levels of sympathetic activation by hypoxia. J Am Soc Nephrol 2002; 13: 27-34.
- Wenzel RR, Bruck H, Noll G, Schäfers RF, Daul AE, Philipp T. Antihypertensive drugs and the sympathetic nervous system. J Cardiovasc Pharmacol 2000; 35: 43-52.
- Huang BS, Leenen FH. Sympathoinhibitory effects of central nifedipine in spontaneously hypertensive rats on high versus regular sodium intake. Hypertension 1999; 33: 32-35.
- Finke R, Gross R, Hackenthal E, Huber J, Kirchheim HR. Threshold pressure for the pressure-dependent renin release in the autoregulating kidney of conscious dogs. Pflügers Arch 1983; 399: 102-110.
- Brickner RC, Jankowski B, Raff H. The conversion of corticosterone to aldosterone is the site of the oxygen sensitivity of the bovine adrenal zona glomerulosa. Endocrinology 1992; 130: 88-92.
- Keil J, Lehnfeld R, Reinhardt HW, Mohnhaupt R, Kaczmarczyk G. Acute effects of angiotensin II on renal haemodynamics and excretion in conscious dogs. Ren Physiol Biochem 1989; 12: 238-249.
- Swenson ER, Duncan TB, Goldberg SV, Ramirez G, Ahmad S, Schoene RB. Diuretic effect of acute hypoxia in humans: relationship to hypoxic ventilatory responsiveness and renal hormones. J Appl Physiol 1995; 78: 377-383.
- Cappuccio FP, Antonios TF, Markandu ND, Folkerd EJ, Sagnella GA, Sampson B, MacGregor GA. Acute natriuretic effect of nifedipine on different sodium intakes in essential hypertension: evidence for distal tubular effect? J Hum Hypertens 1994; 8: 627-630.
- Baertschi AJ, Teague WG. Alveolar hypoxia is a powerful stimulus for ANP release in conscious lambs. Am J Physiol 1989; 256: 990-998.
- Hildebrandt W, Otenbacher A, Schuster M, Swenson ER, Bärtsch P. Diuretic effect of hypoxia, hypocapnia, and hyperpnea in humans: relation to hormones and O2 chemosensitivity. J Appl Physiol 2000; 88: 599-610.
- Rowell L, Blackmon J. Human cardiovascular adjustments to acute hypoxemia. Clin Physiol 1987; 7: 349-376.