(Hypertension. 1997;29:1192-1198.)
© 1997 American Heart Association, Inc.
Articles |
Nifedipine Attenuates Systemic and Renal Vasoconstriction During Nitric Oxide Inhibition in Humans
From the Department of Nephrology and Hypertension, University Hospital Utrecht (Netherlands).
Correspondence to Lioe-Ting Dijkhorst-Oei, Department of Nephrology and Hypertension, University Hospital Utrecht, Room F03.226, PO Box 85500, 3508 GA Utrecht, Netherlands. E-mail t.j.rabelink{at}digd.azu.nl
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Abstract |
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Abstract Clinical states associated with nitric oxide deficiency are often accompanied by vasoconstriction. We studied the effects of prolonged infusion of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on systemic and renal hemodynamics in humans and the reversibility of the established vasoconstriction by calcium channel blockade with nifedipine. Seven healthy men underwent three 7-hour clearance studies. During one study, L-NMMA (3 mg/kg priming dose plus 3 mg·kg-1·h-1) was infused during hours 2 through 5, and during another study, nifedipine (0.015 mg/kg priming dose plus 0.015 mg·kg-1·h-1) was coinfused during hours 4 and 5. A third study served as time control. L-NMMA elicited reproducible systemic and renal vasoconstriction that was stable during the 4 hours of infusion. Systemic vascular resistance index, calculated from bioimpedance-derived cardiac index, increased from 22±1 to 29±2 mm Hg·min·m2·L-1 (P<.05). Mean arterial pressure rose by 4±1 mm Hg (P<.05), and heart rate, stroke index, and cardiac index decreased. Renal blood flow, calculated from renal plasma flow, decreased from 1182±101 to 785±53 mL/min, and renal vascular resistance increased from 73±5 to 115±6 mm Hg·min·L-1 (P<.05). Glomerular filtration rate decreased from 114±6 to 104±6 mL/min (P<.05), and filtration fraction increased. Sodium excretion fell from 89±9 to 32±7 µmol/min (P<.05). Nifedipine completely reversed systemic vasoconstriction. Nifedipine caused partial restoration of renal vascular resistance and complete normalization of glomerular filtration rate and sodium excretion but left the elevated filtration fraction unaltered. We conclude that sustained nitric oxide deficiency in humans is accompanied by strong systemic and renal vasoconstriction, decreased glomerular filtration rate, and sodium retention. Nifedipine can reverse most of these effects, suggesting a role for calcium channel blockade in pathological states of impaired nitric oxide activity.
Key Words: L-NMMA • blood pressure • glomerular filtration rate • calcium channel blockers
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Introduction |
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Endothelial release of NO, a vasodilator synthesized from L-arginine by the constitutive cytoplasmic enzyme NOS, plays a key role in circulatory control. Numerous animal studies have demonstrated systemic and renal effects of NOS blockade using L-arginine analogues. Acute and chronic systemic administration of a NOS blocker results in an increase in arterial blood pressure and widespread vasoconstriction in several regional vascular beds.1 2 3 The renal hemodynamic effects of NOS inhibition in these animals consist of dose-dependent decrease in renal plasma flow and GFR, usually accompanied by sodium retention.1 4 In humans, information on the renal effects of NOS blockade is still limited. One recent study reported a small sustained decrease in renal perfusion and urinary sodium excretion after intravenous bolus administration of L-NMMA.5 This suggests a role for NO in the human renal circulation as well.
Impaired NO activity probably plays a role in a large number of pathological conditions, such as essential hypertension,6 hypercholesterolemia,7 preeclampsia,8 renal artery stenosis,9 acute and chronic renal failure,10 11 and cyclosporine treatment.12 These conditions are all associated with peripheral and renal vasoconstriction. From a clinical point of view, it is relevant to know whether vasoconstriction induced by NOS blockade can be reversed pharmacologically. Calcium channel blockers may be effective, because they interfere with the common signal transduction pathway of endogenous vasoconstrictors,13 which are left unopposed during NOS inhibition.14 15 Indeed, calcium channel blockers can antagonize systemic and renal vasoconstrictive actions of NOS inhibition in rats.16 17 18 19 20 However, one of these studies also showed that a calcium channel blocker cannot reverse renal vasoconstriction by NOS inhibition once this has been established.17 Notably, NO deficiency in patients will generally present itself as an established condition.
The first aim of our study was to characterize the renal effects of sustained NOS blockade by continuous infusion of a NOS blocker to obtain a "steady state" of NO deficiency. For this purpose, healthy volunteers underwent clearance studies during 4 hours of L-NMMA infusion. We also monitored systemic hemodynamics to assess the relative importance of NO in maintaining a vasodilator tone in the kidney compared with the peripheral circulation. Our second aim was to explore whether calcium channel blockade can reverse the vasoconstriction caused by impaired NO activity in humans. To this end, we examined the efficacy of acute calcium channel blockade with nifedipine to reverse vasoconstriction established by sustained NOS blockade.
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Methods |
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Subjects
Studies were carried out in seven healthy men (age range, 20 to 25 years). Their health status was assessed by medical history, physical examination, and routine laboratory investigation. All participants gave their written informed consent after extensive explanation of the protocol. The study protocol was approved by the University Hospital Ethics Committee for Studies in Humans.
In each subject, two clearance studies were carried out with L-NMMA infusion and one with vehicle as a time control study because of the long duration of the experiment. During one of the L-NMMA infusion clearance studies, the effect of nifedipine addition was assessed. The order of these three studies was randomized. The studies were performed after at least 5 days of a diet containing 200 mmol sodium. To test the blockade of NO synthesis, we compared urinary nitrate plus nitrite excretion before, during, and after L-NMMA infusion alone with urinary nitrate plus nitrite excretion during the time control experiments. For this purpose, subjects started with a nitrate-restricted diet 5 days before the L-NMMA and time control experiments and fasted for 12 hours before the clearance study. During the experiments, subjects consumed only nitrate-free water.
Procedures
Adherence to the diet was monitored by 24-hour urine
collections. The clearance studies were performed after subjects had
fasted overnight and were in the seated position. After oral water
loading sufficient to allow spontaneous voiding every 20 to 30 minutes,
adequate diuresis was maintained by subjects drinking amounts
of water matching urine output. An antecubital vein was catheterized
bilaterally for separate blood sampling and infusions. At 9
AM, a priming dose of a solution containing 10% inulin,
for measurement of GFR, and 2.5% para-aminohippuric acid, for
measurement of ERPF, was given, followed by continuous infusion of this
solution throughout the remainder of the study. After at least 1 hour
of equilibration, three 20-minute baseline urine collections were
obtained by spontaneous voiding. Blood specimens were drawn at the
midpoint of each collection period.
Hereafter, infusion of either L-NMMA or vehicle (normal saline) was started. L-NMMA (Institut für Pharmazie, Universität Leipzig [Germany]) was dissolved in normal saline (5 mg/mL) and infused as a priming dose of 3 mg/kg body wt, followed by a maintenance infusion of 3 mg·kg-1·h-1 during 4 hours. This scheme, during which L-NMMA infusion was continued over a longer period and at a higher accumulative dose than previously reported in human studies,5 21 22 23 was chosen because we aimed to achieve a brief steady-state period, for two reasons: First, a steady state is more appropriate for the study of effects in the kidney by means of clearance techniques, and second, we wanted to assess the effects of calcium channel blockade during an established state of NO deficiency. In pilot studies, we explored the effects of stepwise increases in the duration of L-NMMA infusion on systemic and renal hemodynamics, at the dose of 3 mg/kg previously reported to affect systemic hemodynamics in humans.21 The pilot studies revealed full recovery of the L-NMMA–induced vasoconstriction within a few hours after the infusion was stopped, and no adverse effects were observed. In the final study, the 4-hour L-NMMA infusion period was followed by a 2-hour recovery period.
In the calcium antagonist experiments, nifedipine (Bayer BV) administration was started after 2 hours of L-NMMA infusion. Via a separate antebrachial vein, nifedipine was administered as a priming dose of 0.015 mg/kg in 5 minutes. Subsequently, nifedipine was infused at 0.015 mg·kg-1·min-1 for the remainder of the L-NMMA infusion period. Nifedipine was coinfused with 5.0% glucose to prevent local discomfort. The volume of glucose infusion, approximately 100 mL, was corrected for in the oral water intake.
Urine and blood sampling continued at 30-minute intervals throughout the study. Blood pressure was recorded at 5-minute intervals by an automated oscillometer (Omega 1400, Invivo Research Laboratory Inc). Bioimpedance-derived cardiac output, stroke volume, and heart rate were measured continuously (NCCOM3, BoMed Medical Manufacturing Ltd) and recorded automatically at 2-minute intervals. Blood and urine samples were analyzed for sodium by flame photometry and inulin and para-aminohippurate by photometry as described previously.24 25 Urinary nitrate was assayed after conversion into nitrite with nitrate reductase. The conversion was performed by incubation of urine samples with anerobically grown Escherichia coli bacteria (which contain nitrate reductase) and ammonium formate.26 Total nitrite (representing endogenous nitrite and reduced nitrate) was assayed colorimetrically by a modification of the Griess reaction (formation of a purple dye with sulfanilamide and N-naphthylethylenediamine). The Griess reaction was modified in that the pH was adjusted to 2.9, because at this pH, the absorbance signal is twice as high as without pH adjustment.
Calculations and Statistics
Systemic hemodynamic data are presented
as averages per 15 minutes and kidney function data as averages per
hour, after thorough evaluation of the data revealed that no
information would be lost in this way. Weighed averages of two urine
collection periods (three during baseline) were taken as individual
clearance values per hour. Mean arterial blood pressure was
calculated as the sum of one third of systolic pressure and two
thirds of diastolic pressure. Renal blood flow was
calculated by dividing ERPF by (1-packed cell volume). Mean
arterial pressure was divided by cardiac index and renal
blood flow, respectively, for estimation of SVRI and RVR.
Results are expressed as mean±SE. For statistical analysis, all results were averaged per hour and subjected to two-way ANOVA for repeated measures, followed by post hoc multiple comparisons with the Student-Newman-Keuls test if variance ratios reached statistical significance. A value of P<.05 was considered significant.
Data Presentation
To improve clarity, the data presented in the tables are
limited to the baseline hour (hour 1), the second and fourth hour of
L-NMMA or vehicle infusion (hours 3 and 5), and the second hour of the
recovery period (hour 7). This also allows a clear view of the effects
of nifedipine, which in one of the series was infused
during the third and fourth hours of L-NMMA (hour 2 of
nifedipine infusion accords with hour 5 in the tables).
Note that the results of statistical analysis given in these
tables include all seven hourly periods.
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Results |
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General
Twenty-four-hour urinary sodium excretions were 165±18, 172±35, and 194±35 mmol on the days before the time control study, the L-NMMA control study, and the L-NMMA with nifedipine study, respectively. L-NMMA infusion was well tolerated. Two subjects experienced a somewhat heavy sensation in the forearm, but this occurred only during the bolus injection of the first L-NMMA study and disappeared readily when the elbow was stretched to allow unobstructed venous drainage. Subjects experienced no other sensations or side effects from either L-NMMA or nifedipine infusion.
Comparison of the baseline data showed no differences for systemic hemodynamics or renal function parameters among the three series of experiments.
Effects of Sustained L-NMMA Infusion
Systemic hemodynamic data are presented in
Fig 1
and Table 1. During the time
control study, no changes occurred. L-NMMA alone caused blood pressure
to rise significantly by 4±1 mm Hg and to remain constantly
elevated during the further time of infusion. Heart rate decreased
concomitantly. Both parameters recovered after the infusion
was discontinued. Cardiac index decreased by 19±2% compared with
baseline, as a result of both the decrease in heart rate and the
significant decrease in stroke volume index. Calculated SVRI increased
considerably by 32±5%. Recovery was almost complete at 2 hours after
L-NMMA infusion was stopped.
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indicates time control study; 
,
L-NMMA alone; 
, L-NMMA with subsequent coinfusion of
nifedipine; MAP, mean arterial pressure; HR,
heart rate; CI, cardiac index; and SVRI, systemic vascular resistance
index. For significant differences, see Table 1
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Fig 2 and Table 2 show the effects of
L-NMMA on kidney function. Compared with the time control experiment,
L-NMMA infusion suppressed GFR, ERPF, and sodium excretion.
Importantly, stably decreased levels were found as early as the first
hour of L-NMMA infusion (Fig 2). The fall in GFR was small but
significant. On the other hand, a much larger decrease in ERPF was
observed, resulting in an increase in filtration fraction. Renal blood
flow decreased by 33±2% (from 1182±101 to 785±53 mL/min,
P<.001), so calculated RVR increased considerably by
58±7%. In the second hour after cessation of the L-NMMA infusion, RVR
had recovered by about half. During the time control study, absolute
and fractional sodium excretions gradually decreased over 7 hours.
L-NMMA, however, caused a much stronger depression in both
parameters immediately upon the start of infusion. In the
second hour of recovery, sodium excretion was not different from that
in the time control study. Urinary nitrate plus nitrite excretion
decreased from 545±36 nmol/min in the time control experiment to
337±45 nmol/min during the L-NMMA study in the fourth hour of infusion
(P<.01).
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Effects of Acute Calcium Channel Blockade With
Nifedipine During L-NMMA Infusion
In this experiment, we first infused only L-NMMA for 2 hours. This
caused the same effects in systemic circulation (Fig 1
, Table 1) and
kidney function (Fig 2, Table 2) as in the previous experiment. During
the next 2 hours, nifedipine was coinfused with L-NMMA.
This caused an immediate fall in SVRI to the pre–L-NMMA level,
accompanied by an increase in heart rate and a small but significant
rise in stroke volume index, so that cardiac output normalized to the
pre–L-NMMA level as well. The net effect of these changes was blood
pressure normalization. In the second hour of nifedipine
infusion, SVRI tended to increase slightly and heart rate to
increase further, so that blood pressure tended to rise. However,
average blood pressure in the second hour of nifedipine was
not different from the pre–L-NMMA infusion level (Table 1).
Importantly, throughout the nifedipine infusion period,
SVRI remained significantly lower and cardiac index significantly
higher than during L-NMMA alone, and in fact, they were maintained at
levels not different from the pre–L-NMMA levels.
Nifedipine fully reversed the effects of L-NMMA on GFR. ERPF, however, restored only partially, and the elevation of filtration fraction caused by L-NMMA was unaltered. Both renal blood flow and calculated RVR restored partially to an intermediate level. Nifedipine completely restored absolute and fractional sodium excretions to time control values.
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Discussion |
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In the present study, we show that continued infusion of L-NMMA in humans causes a sustained systemic and renal vasoconstriction, in association with strong sodium retention. Apparently, it is possible to achieve in humans a sustained, steady state of NO deficiency sufficient to reveal an important role of endogenous NO in the systemic and renal circulations. We also demonstrated for the first time that calcium channel blockade with nifedipine can antagonize these effects of acute NOS inhibition. Nifedipine fully reversed the effects of L-NMMA infusion on systemic vascular resistance, GFR, and urinary sodium excretion and partially restored RVR.
First of all, we found sustained elevation of arterial pressure during maintenance L-NMMA infusion. This was accompanied by a decrease in cardiac output, indicating a substantial rise in peripheral resistance. The mechanisms accounting for this peripheral vasoconstriction include the direct effect of withdrawal of the vasodilator NO, which leaves unopposed the action of vasoconstrictors such as endothelin-114 and angiotensin II.15 Studies in animals have suggested that systemic NOS inhibition may also raise sympathetic activity,27 but this could not be confirmed in humans.22 The presently found decrease in heart rate during NO inhibition does not indicate a generalized sympathoexcitatory effect of L-NMMA but rather a baroreflex-mediated sympathoinhibitory response to the increased arterial pressure. The associated decrease in stroke volume during NOS blockade has been observed previously in humans and may be attributed to increased afterload.21 23 A prolongation of ventricular diastolic relaxation time has been found as well, implying that impaired cardiac filling may also participate in the reduction of cardiac output.23
L-NMMA infusion also markedly increased RVR, indicating the importance of NO in maintaining a tonic vasodilation in the human kidney. Our observations are consistent with findings in rats,1 2 28 rabbits,29 and dogs,30 in which a reduction of 25% to 40% in renal blood flow has been achieved. However, in contrast to the present study, these studies usually have reported an increase in total peripheral resistance of 100% to 140%,2 28 whereas we found a relatively mild systemic constriction of 30%. The reason for this discrepancy may be species-determined or may indicate that NO blockade in our study was incomplete. We have not tested the degree of NO inhibition by constructing a dose-response curve. However, the aforementioned animal studies showed a similar reduction in renal blood flow while NOS was maximally blocked, as reflected by the absence of further reduction with higher doses of NOS blocker1 and the attenuation of the vasorelaxing response to acetylcholine.28 Thus, although we observed only a mild effect on systemic NO, the apparently maximal reduction in renal blood flow as well as the reduction of urinary nitrate plus nitrite excretion do suggest substantial renal NO inhibition.
It is interesting to compare the time course of the peripheral and renal vasoconstriction observed presently and in previous studies in humans in which bolus injections of L-NMMA were used. In the latter, the systemic vasoconstriction lasted for only minutes,5 21 whereas the renal vasoconstriction lasted for hours.5 Such a dissociation did not occur in the present protocol of continued L-NMMA infusion. Another obvious difference is that our infusion protocol caused much more renal vasoconstriction than was found previously after bolus injection of L-NMMA,5 indicating more complete blockade of renal endogenous NO production.
GFR was relatively preserved in our study, and filtration fraction increased. In animals, too, only a small reduction or no change in GFR was observed during systemic infusion of NOS blocker at a dose that already markedly affects renal blood flow.1 29 30 In vivo studies of single nephron function have shown that acute systemic NOS inhibition is followed by a decrease in filtration coefficient and increase in glomerular hydrostatic pressure, resulting in a net effect of increased filtration fraction.29 31 These studies also showed proportional increments of afferent and efferent resistances, the combination of which allows part of the increased systemic pressure to be transduced into the glomerular capillaries. Constriction of the efferent arteriole, which appears less conspicuous in in vitro conditions,32 has been ascribed to the unopposed effects of constrictors such as angiotensin II and endothelin.31 Indeed, there appears to be remarkable agreement between the presently observed effects of NOS inhibition and effects that we found previously in humans during infusion of angiotensin II33 and endothelin.34 Both peptides caused marked renal vasoconstriction, with relative preservation of GFR and increased filtration fraction, together with only modest systemic pressor effects.
The presently observed antinatriuresis was also stronger than observed previously after a single bolus injection of L-NMMA,5 suggesting a major role for NO in the regulation of sodium balance in humans. Animal studies have shown that NOS blockade at a dose that has little effect on blood pressure can cause strong antinatriuresis.1 4 The fall in fractional sodium excretion implies that NOS blockade stimulates tubular sodium reabsorption. This may involve an indirect renal hemodynamic effect, ie, increased filtration fraction and decreased medullary blood flow,35 or a direct interaction of NOS blockade with tubular sodium handling.36 Although our studies in humans cannot discern between these options, it is clear that the combination of such a strong increase in tubular sodium reabsorption and renal vasoconstriction implies major resetting of the renal pressure-natriuresis relationship35 and thus a major role of NO in long-term blood pressure regulation.
Our second goal was to examine whether calcium channel blockade with nifedipine is able to undo established effects of NOS inhibition. We show for the first time in humans that nifedipine can reverse the systemic and renal vasoconstriction caused by NOS inhibition. Although the increase in systemic vascular resistance caused by L-NMMA was quickly and effectively restored, the net depressor effect of nifedipine was offset by a simultaneous increase in heart rate and cardiac output, which is a well-known action of dihydropyridine calcium channel blockers.37 The (partial) restorations of stroke index and cardiac index reduced previously by L-NMMA are of potential clinical interest. We are not aware of other detailed data on the effect of calcium channel blockers on heart function during NOS inhibition. Given the present indirect methodology, further study is indicated.
Regarding the kidney, we found that nifedipine partially reversed the L-NMMA–induced vasoconstriction and fall in ERPF. Nonetheless, the restoration of GFR was complete, so the elevated filtration fraction was left unaltered. Substantial evidence shows that calcium channel blockers mainly affect the preglomerular vascular resistance.38 This implies that nifedipine reveals the effect of L-NMMA on the efferent arteriole. Comparison with the baseline data shows that the combination of nifedipine and L-NMMA results in an only slightly increased vascular resistance and decreased ERPF, with maintained GFR and high filtration fraction, which is compatible with selective efferent constriction. Previous studies in humans have shown that coinfusion of a calcium channel blocker during angiotensin II39 or endothelin40 causes a similar effect of impaired renal vasoconstriction but unimpaired elevation of filtration fraction. Nifedipine also completely restored the L-NMMA–induced antinatriuresis, similar to the way it restored endothelin-induced antinatriuresis in a previous study.40 This may be the result of the nifedipine-induced vasodilation. However, calcium channel blockade has also been shown to cause natriuresis by a direct tubular effect.41 In animals, the effect of calcium channel blockers on NO inhibition–induced changes in renal electrolyte handling has not been investigated.
Whereas nifedipine completely restored systemic hemodynamics, it only partially reversed renal vasoconstriction. Our data suggest a more effective NO inhibition in the renal circulation than in the systemic circulation. This would also imply that higher doses of nifedipine may be required to completely reverse the renal vasoconstriction. It also remains to be established whether nifedipine can counteract the hemodynamic changes induced by profound systemic NO inhibition. On the other hand, in clinical conditions such as essential hypertension,6 acute renal failure,10 and preeclampsia,8 NO activity is assumed to be only partially impaired.
The vasoconstrictive effect of NOS inhibition probably
involves elevation of intracellular free calcium by facilitated
cellular entry through voltage-gated calcium channels.42
This makes vascular smooth muscle cells more sensitive to
endogenous vasoconstrictors.14 15 In that
perspective, it is understandable that calcium channel blockers
interfere with the constrictive effects of NOS inhibition, as has been
shown in rats.16 17 18 19 20 Regarding the systemic
circulation, calcium channel blockers were shown to antagonize the
pressor response to acute16 17 18 and
prolonged20 NOS blockade and to reverse established
hypertension in chronic NOS inhibition.19 Interestingly,
some data suggest that the capacity of calcium channel blockers to
antagonize the pressor response to NOS inhibition is unique, as it is
unequaled by selective inhibition of angiotensin II,
-adrenoceptor, endothelin, or eicosanoid
activities.18 19 Regarding the kidney, vasorelaxing
responses to calcium channel blockers were found during acute and
chronic NOS inhibition,17 19 again with indications that
antagonists of single constrictor mechanisms are less
effective.19
Notably, in one of the aforementioned rat studies,17 verapamil could prevent renal vasoconstriction when given simultaneously with an acutely administered NOS inhibitor but remained without effect when given later. The relevance of this observation lies in the fact that NO deficiency in patients will generally present itself as an established condition. We therefore tested the antagonistic capacity of nifedipine in humans against a background of established preconstriction and found that nifedipine was quite effective. Whether pretreatment with calcium channel blockers can prevent effects of NOS inhibition in humans has yet to be studied. Also, we do not know whether selective angiotensin II or endothelin inhibitors can diminish vasoconstrictive actions of systemic NOS blockade in humans. This is particularly relevant in view of the possibility that calcium channel blockers cannot release the effects of NOS inhibition on the postglomerular arterioles. Whether these and other vasodilators are capable of reversing NOS inhibition–induced vasoconstriction in humans remains to be established.
In summary, continued infusion of a NOS blocker in humans results in a steady state of systemic and renal vasoconstriction as well as sodium retention. These effects may well be attributed to the unopposed actions of endogenous vasoconstrictors. The capability of nifedipine to reverse almost completely the established effects of NOS inhibition in humans can be explained by its interference with the common signal transduction pathway of such vasoconstrictors. The clinical relevance of our data pertains to pathological states associated with impaired NO activity. Most of these conditions, such as essential hypertension,6 acute renal failure,10 and cyclosporine treatment,12 are associated with peripheral and renal vasoconstriction and sodium retention. Since calcium channel blockade with nifedipine proved to have a beneficial effect on systemic hemodynamics as well as renal circulation during established NOS inhibition, its value in the management of disease states with impaired NO activity should be further considered.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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L.T. Dijkhorst-Oei is sponsored by the Dutch Kidney Foundation. T.J. Rabelink is sponsored by a fellowship of the Royal Dutch Academy of Sciences (KNAW).
Received August 13, 1996; first decision September 10, 1996; accepted November 8, 1996.
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