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Cardiovascular Research 1998 40(2):402-409; doi:10.1016/S0008-6363(98)00124-2
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Copyright © 1998, European Society of Cardiology

Divergent effects of ACE-inhibition and calcium channel blockade on NO-activity in systemic and renal circulation in essential hypertension

Lioe-Ting Dijkhorst-Oei, Jaap J. Beutler, Erik S.G. Stroes, Hein A. Koomans and Ton J. Rabelink*

Department of Nephrology and Hypertension, University Hospital, Utrecht, The Netherlands

* Corresponding author. Tel.: +31 (30) 250 7329; Fax: +31 (30) 254 3492; E-mail: t.rabelink@digd.azu.nl

Received 11 February 1998; accepted 31 March 1998


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: Nitric oxide is a vasodilating and blood pressure lowering substance. To investigate whether calcium antagonists or angiotensin-converting enzyme (ACE) inhibitors increase vascular nitric oxide activity, we assessed systemic and renal vascular sensitivity to nitric oxide synthase inhibition in hypertensives on and off medication. Methods: Ten essential hypertensive patients, aged 22–51 years, were studied 3 times: ≥4 weeks off medication, after 3 weeks treatment with enalapril 20 mg twice a day and after 3 weeks nifedipine 60 mg/day. Each time, 24-h blood pressure registration was performed, followed by a clearance study to obtain a 3-h dose-response curve for intravenously infused NG-monomethyl-L-arginine (L-NMMA, respectively 0.75, 1.5 and 3.0 mg/kg/h). Results: L-NMMA dose-dependently increased mean arterial pressure with 5±2 mmHg and systemic vascular resistance with 24±5% at maximum dose, whereas cardiac output decreased (all P<0.001). Enalapril and nifedipine treatment decreased blood pressure, while the L-NMMA-induced increase in systemic vascular resistance was potentiated (enalapril: 45±7% and nifedipine: 46±8%; both P<0.01). L-NMMA also dose-dependently decreased renal blood flow by 58±8% at maximum dose (P<0.001), but neither drug potentiated these effects. Conclusion: These results indicate that, in essential hypertensives, antihypertensive therapy with enalapril or nifedipine increases nitric oxide dependency of systemic vascular tone, which may play a role in the blood pressure lowering effect of these drugs. However, this phenomenon cannot be observed in the renal circulation, suggesting a different regulation of endothelium-dependent vasomotion in the hypertensive kidney.

KEYWORDS Essential hypertension; Nitric oxide; L-NMMA; Angiotensin; Converting enzyme inhibitor; Calcium channel blocker; Systemic vascular resistance; Renal hemodynamics


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Nitric oxide (NO) has been identified as a vasodilating substance. It is continuously released from the endothelium, keeping the vasculature in a state of basal relaxation. It has been suggested that patients with essential hypertension have an impairment of NO activity. Forearm studies have shown an impaired stimulated NO release, assessed as impaired NO-mediated vasodilation upon infusion of acetylcholine [1–3]. Also basal NO-activity has been shown to be reduced, as exemplified by a reduced vasoconstrictor response to the NO synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA) [4]in hypertensive patients compared with normotensive controls. Basal systemic NO production may also be reduced in essential hypertensive patients, as assessed by urinary excretion of the NO metabolite nitrate [5].

Some forearm studies have claimed amelioration of stimulated and/or basal NO activity in the forearm circulation after treatment with angiotensin-converting enzyme inhibitors (ACEi) or calcium channel blockers (CCB) in hypertensive patients [6–8], although contrasting findings have been reported [9–13]as well. It is not known whether these effects of antihypertensive treatment on local basal and stimulated NO activity in forearm resistance vessels can be extrapolated to other vascular beds or total systemic vasculature. We have previously shown in healthy volunteers that the kidney is more sensitive to intravenous infusion of a NOS inhibitor than total systemic vascular tone, suggesting that basal NO activity is specifically important in maintaining a low basal renal vascular resistance [14]. Therefore, we investigated in patients with essential hypertension the effect of antihypertensive treatment with either a CCB or an ACEi on basal NO activity as assessed by the systemic and renal vasoconstrictor response to NOS inhibition


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Subjects
We carried out studies in ten patients (two women and eight men, age range, 22 to 51 years) with essential hypertension. The protocol was approved by the University Hospital Ethics Committee for Studies in Humans. All participants gave written informed consent after explanation of the protocol. The investigation conforms with the principles outlined in the Declaration of Helsinki. Patients were recruited from the outpatient clinics for hypertension and internal medicine of the University Hospital Utrecht. The diagnosis of essential hypertension was established before the study by the absence of any clinical evidence of secondary hypertension and normal serum electrolytes, creatinine, urinalysis and renal scintiscan.

2.2 Study design
Each subject started with a drug-free period of 4–5 weeks. At the end of this period, 24-h ambulatory blood pressure (monitor model No. 90207, SpaceLabs Inc., Redmond, Washington, USA) was recorded for documentation of hypertension. The criteria for acceptance into the study were a mean ambulatory diastolic pressure during daytime hours (7 AM to 11 PM) greater than 90 mmHg and a mean ambulatory systolic pressure greater than 145 mmHg.

All subjects underwent three clearance studies during which L-NMMA was infused. The first study was after the period off medication. The second and third studies were performed after 3 weeks of treatment with enalapril, 20 mg BID, or nifedipine GITS, 60 mg/day. The two treatment periods were separated by a 2-week washout period. The order of the treatment periods was randomized. At the end of each period, 24-h ambulatory blood pressure was monitored and 24-hour urine was collected to assess sodium balance; a clearance study took place on the next day. Subjects took their last medication on the morning of the clearance study, at 5 am.

The clearance studies were performed after a light breakfast at 7 AM, and with subjects in the supine position. After oral water loading sufficient to allow spontaneous voiding every 20–30 min, adequate diuresis was maintained by drinking amounts of water matching urinary output. An antecubital vein was catheterized bilaterally for separate blood sampling and infusions. At 09:00 am a priming dose of a solution containing 10% inuline, to measure glomerular filtration rate (GFR), and 2.5% para-aminohippuric acid, to measure effective renal plasma flow (ERPF), was given, followed by continuous infusion of this solution throughout the remainder of the study. After at least one hour equilibration, three 20-min baseline urine collections were obtained by spontaneous voiding. Blood specimens were drawn at the midpoint of each collection period. Hereafter infusion of L-NMMA was started. L-NMMA (Institut für Pharmazie, Universität Leipzig, Germany) was administered intravenously for 3 hours in stepwise increasing doses; steps consisted of a priming dose, followed by continuous infusion, which was maintained for 1 h. Doses were: I. bolus infusion of 0.75 mg/kg body wt in 3 min, followed by 0.75 mg/kg/hour; II. 0.75 mg/kg in 3 min, followed by 1.5 mg/kg/hour; III. 1.5 mg/kg in 6 min, followed by 3.0 mg/kg/hour. With this scheme we aimed to achieve a dose-response curve with brief periods of steady state, appropriate for studying effects in the kidney by means of clearance techniques. Recovery was observed for 1 hour after cessation of L-NMMA infusion.

Urine and blood sampling continued at 20-min intervals throughout the study. Blood pressure was recorded at 5-min intervals using an automated oscillometer device (Omega 1400, Invivo Research Laboratory Inc., Tulsa, Oklahoma, USA). Bioimpedance-derived cardiac output (indexed for body surface area, CI) was measured continuously (NCCOM3, BoMed Medical Manufacturer Ltd., Irvine, California, USA) and recorded automatically at 2-min intervals. In healthy volunteers the assessment of cardiac output with BoMed has been shown to be reproducible and particularly accurate for detecting changes [15, 16].

2.3 Biochemical analysis
Blood and urine samples were analyzed for inuline and para-aminohippurate by photometry as described previously [17, 18], for osmolality (Advanced Digimatic Osmometer) and for sodium by flame photometry. Cyclic GMP was measured in urine samples of the final portion at each infusion rate. The samples were put directly on ice and analyzed using a radioimmunoassay kit with tritium-labelled cyclic GMP (Amersham International plc, Buckinghamshire, UK). Plasma angiotensin-converting enzyme activity was measured using a colorimetric method by hydrolysis of the synthetic substrate L-Hip-His-Leu [19].

2.4 Calculations and statistics
Mean arterial blood pressure (MAP) was calculated as the sum of one-third of the systolic pressure and two-thirds of the diastolic pressure. Renal blood flow (RBF) was calculated by dividing ERPF by [1-packed cell volume]. MAP was divided by CI and RBF, respectively, to estimate systemic vascular resistance index (SVRI) and renal vascular resistance (RVR). Observations of the three 20-min baseline collection periods were averaged to obtain the baseline value on each visit. To make comparisons of the effects of L-NMMA between the different treatment regimens, the values of the last two 20-min collection periods at each infusion rate were averaged and expressed as change from baseline.

Effects of treatment on baseline values were explored using a paired t-test. We used one-way ANOVA for repeated measures to assess the effects of L-NMMA, their dose-dependency and the recovery. To assess the effects of treatment on L-NMMA responses, we performed two-way ANOVA for repeated measures, with the L-NMMA infusion dose and the presence of nifedipine or enalapril as independent variables. The interaction variance ratios obtained by this method indicate whether the response to L-NMMA is different between two studies. The L-NMMA-induced percentual increases in vascular resistance in the systemic versus renal circulation were compared using two-way ANOVA for repeated measures, with the L-NMMA infusion dose and the vascular bed as independent variables. If treatment variance ratios reached statistical significance, post-hoc multiple comparisons with the Student–Newman–Keuls test were performed. P<0.05 was considered significant. Results are expressed as mean±standard error.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Effects of L-NMMA during the control study
L-NMMA caused increments in systemic and renal vascular resistance, that showed partial recovery in the first hour after cessation of the infusion. At every infusion rate steady state was achieved within 20 minutes in the systemic circulation as well as in the kidney. In view of the achieved steady state, averaging the values of the last two 20-min collection periods at each infusion rate to compare effects before and after antihypertensive treatment was deemed justified.

L-NMMA dose-dependently elevated MAP (P<0.001), which increased by 5±2 mmHg at the highest dose (Fig. 1). CI decreased by 8±1, 11±2 and 15±3% (P<0.001), so that calculated SVRI significantly increased by 11±2, 16±4 and 24±5% (P<0.001), for the successive 3 doses (Fig. 2). Recovery of systemic hemodynamics was achieved within the hour. Renal hemodynamics were also dose-dependently affected by L-NMMA (Fig. 3). GFR decreased by 7.0±2.6, 12.2±2.4 and 17.4±3.5% (P<0.0001), successively. RBF showed a stronger decrease, by 11.8±2.9, 22.1±3.1 and 33.0±3.4% (P<0.001), so that RVR was calculated to increase substantially by 16.7±4.0, 33.0±5.9 and 58.1±7.9% (P<0.0001). L-NMMA increased RVR more than SVRI (P<0.01, two-way ANOVA), with percentage increase in vascular resistance becoming significantly different from dose II (II, P<0.05, and III, P<0.01). Partial recovery of renal hemodynamics was observed 1 hour after L-NMMA infusion had ended. Urinary cGMP excretion decreased dose-dependently (P<0.001) from 612±90 pmol/min at baseline to 374±36 pmol/min at dose III (Fig. 4).


Figure 1
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  		Fig. 1 Dose-dependent systemic hemodynamic effects of L-NMMA in patients with essential hypertension off medication (open circles), and after 3 weeks treatment with enalapril (hatched squares) or nifedipine (filled triangles). Both drugs potentiate the L-NMMA-induced increases in mean arterial pressure (MAP; P<0.01, enalapril vs off medication; P<0.01, nifedipine vs off medication, ANOVA) and in systemic vascular resistance index (SVRI; P<0.01, enalapril vs off medication; P=0.01, nifedipine vs off medication). Enalapril enhances the L-NMMA-induced decrease in cardiac index (CI; P<0.05, enalapril vs off medication; NS, nifedipine vs off medication). Treatment-induced reductions in baseline MAP and SVRI are thus largely overcome at maximum NOS inhibitor dose. Values are presented as mean±SE.

 

Figure 2
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  		Fig. 2 Systemic hemodynamic responses to L-NMMA, expressed as relative changes from baseline, in essential hypertensive patients off medication (empty bars), after 3 weeks enalapril (hatched bars) and after 3 weeks nifedipine (filled bars). Both enalapril and nifedipine significantly potentiate the systemic vasoconstrictor responses to L-NMMA. Values are presented as mean±SE. MAP indicates mean arterial pressure; CI, cardiac output index; SVRI, systemic vascular resistance index; *, P<0.05; **, P<0.01; NS, non-significant.

 

Figure 3
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  		Fig. 3 Dose-dependent renal hemodynamic effects of L-NMMA in patients with essential hypertension off medication (open circles), and after 3 weeks treatment with enalapril (hatched squares) or nifedipine (filled triangles). Irrespective of baseline levels, under the different treatment conditions L-NMMA causes similar decreases in glomerular filtration rate (GFR; NS, enalapril vs off medication; NS, nifedipine vs off medication, ANOVA) and renal blood flow (RBF; NS, enalapril vs off medication; NS, nifedipine vs off medication), and similar increases in renal vascular resistance (RVR; NS, enalapril vs off medication; NS, nifedipine vs off medication). Values are presented as mean±SE.

 

Figure 4
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  		Fig. 4 Baseline urinary cGMP excretion rates (U-cGMP) and L-NMMA-induced changes in essential hypertensive patients off medication (empty bars), after 3 weeks enalapril (hatched bars) and after 3 weeks nifedipine (filled bars). Enalapril or nifedipine treatment affects neither baseline U-cGMP nor L-NMMA-induced changes. Values are presented as mean±SE. *, P<0.05 vs baseline.

 
3.2 Effects of enalapril pretreatment
Ambulant blood pressure monitoring showed significant antihypertensive effects of enalapril (Table 1). Baseline CI was not affected and baseline calculated SVRI tended to decrease (P=0.07). Enalapril significantly lowered baseline RVR, while baseline RBF and GFR were not changed. Baseline cGMP excretion was also unchanged compared with off medication. Effective suppression of plasma ACE activity was verified on the day of the clearance study.


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  		Table 1 Baseline values off medication and after 3 weeks enalapril or nifedipine treatment

 
Enalapril pretreatment significantly potentiated the L-NMMA-induced increase in MAP, which increased at the successive doses by 4±1, 7±2 and 9±2 mmHg (P<0.01 vs off medication), and the decrease in CI (P<0.05; Fig. 2). Thus systemic vasoconstriction in response to L-NMMA was significantly potentiated (P<0.01 vs off medication), with SVRI increasing by 19±2, 30±5 and 45±7%, and the apparent difference in basal SVRI between the untreated condition and enalapril treatment was overcome by L-NMMA infusion (Fig. 1). In the kidney, L-NMMA again dose-dependently decreased GFR and RBF, and profoundly increased RVR (all P<0.001; Fig. 3). However, the responses in GFR (decreases of 8.0±2.4, 10.4±3.4 and 18.5±3.4% at doses I through III), RBF (decreases of 12.9±2.7, 20.8±3.1 and 32.7±2.2%) and RVR (increases of 19.7±4.1, 34.7±4.4 and 61.7±5.7%) were similar as during the drug-free period. L-NMMA-induced decreases in cGMP excretion during enalapril (P<0.001) were also not different compared to off medication (Fig. 4).

3.3 Effects of nifedipine pretreatment
Nifedipine lowered basal blood pressure significantly and to the same extent as enalapril (Table 1). Baseline CI remained unchanged. Calculated basal SVRI decreased from 40.5±3.3 to 34.7±3.0 mmHg*min*m2/l (P=0.05). These effects were not significantly different from the effects of enalapril treatment on systemic hemodynamics. In contrast, nifedipine significantly increased baseline RBF and GFR (both P<0.05 vs off medication; Fig. 3). As with enalapril, basal RVR significantly decreased on nifedipine treatment (P<0.01). No change was observed in urine cGMP excretion.

When L-NMMA infusion was repeated during nifedipine treatment, again dose-dependent effects on systemic hemodynamics were observed (all P<0.001). Moreover, responses were significantly stronger than before treatment (Fig. 2). MAP increased by 6±2, 9±2 and 13±2 mmHg (P<0.01 vs off medication) at the successive doses, and with the eventual 13±2 mmHg increase, MAP was not significantly different compared with MAP on the highest dose of L-NMMA off medication (NS, paired t-test; Fig. 1). The same was observed for SVRI, which also showed potentiated increments on L-NMMA infusion (P=0.01), of 16±4, 28±6 and 46±8% (Fig. 2). So compared to the untreated state, nifedipine-induced reductions in initial, basal MAP and SVRI were overcome by the maximum dose of L-NMMA (Fig. 1). Changes in CI were not significantly different compared to off medication. Nifedipine enhanced systemic hemodynamic responses to L-NMMA to a similar degree as enalapril (NS, two-way ANOVA). In contrast with the responsiveness of total systemic hemodynamics, nifedipine did not change the dose-dependent renal hemodynamic effects of L-NMMA (Fig. 3). GFR decreased by 5.8±2.2, 10.6±2.9 and 17.3±4.3%, RBF decreased by 9.1±4.6, 18.8±2.5 and 32.3±2.9%, and RVR increased by 17.5±5.2, 33.4±4.4 and 66.1±7.7% at the successive doses. L-NMMA-induced decreases in urinary cGMP excretion were also not changed by nifedipine (Fig. 4).


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
The key finding of the present study is that treatment with either nifedipine or enalapril equally decreased basal blood pressure and subsequently increased the L-NMMA dose-pressor response in essential hypertensive patients, implicating that, despite different modes of action, both antihypertensive agents increase NO dependency of blood pressure and systemic vascular tone.

Measurement of endothelial function in hypertension has yielded conflicting results. Agonist-stimulated NO-activity, mostly using acetylcholine and metacholine, demonstrated normal [20, 21]as well as impaired [1–3, 10, 22]endothelium-dependent vasodilation. Similarly, the results of anti-hypertensive therapy on endothelium-dependent vasodilation also varied greatly [6–13]. While short-term therapy with ACEi could improve stimulated NO-activity in hypertensive patients [6], most investigators found no effect of blood pressure lowering therapy on stimulated NO-activity [9–13]. In contrast basal NO-activity, assessed as the vasoconstrictor response to L-NMMA administration in the forearm [7, 8]or using the stable isotope dilution technique [5], has consistently been found to be decreased in hypertensive patients. Interestingly, whereas in atherosclerosis receptor dependent NO-activity is impaired before receptor independent NO-activity [23], it has been demonstrated that in hypertension basal (shear stress) activity of endothelial NO is already disturbed at a stage where agonist induced responses may still be intact [24].

The observation that L-NMMA induced systemic vasoconstriction is enhanced during blood pressure lowering medication may have several explanations: First, it could be a non-specific phenomenon, reflecting a more general enhancement of constrictor sensitivity secondary to predilation of the vasculature. This seems unlikely, since in previous experiments studying a similar patient group and using the same methodology, we observed that the response to another potent vasoconstrictor, i.e. endothelin-1, was reduced after predilation of the vasculature by enalapril or nifedipine [25]. The latter observation argues against a non-specific increase in vascular contractile response to vasoconstrictors in general after blood pressure lowering treatment with these drugs. Second, the increased vasoconstrictor response to L-NMMA could reflect enhanced effects of alternative vasoconstrictor mechanisms stimulated by L-NMMA, such as the sympathetic nervous system, vasopressin and the renin–angiotensin system. However, this explanation is not supported by other observations of L-NMMA infusion in humans. Acute L-NMMA infusion results in decreased, rather than increased sympathetic activity [26–28]. Also, L-NMMA has been demonstrated not to affect plasma vasopressin [29]. In addition, L-NMMA does not alter renin or aldosterone levels [29–31], whereas the vasoconstrictor response to L-NMMA in vivo has been shown to be independent of the renin–angiotensin system [32]. Therefore, we conclude that the enhanced constrictor response to L-NMMA reflects increased basal NO-activity.

The fact that two pharmaceutical compounds with a totally different mode of action are both associated with an identical increase in L-NMMA-induced vasoconstriction, support the concept that blood pressure lowering per se, rather than the medication used is the main determinant for amelioration of basal NO activity [7, 8]. However, from the present study we cannot exclude the possibility that modulation of the L-arginine-NO pathway is a specific effect of both ACEi and CCB. In this respect, several studies have suggested an improvement of stimulated NO-activity during ACE-inhibition [33]or CCB [34], which occurred independent of the blood pressure lowering effect of these drugs. Several mechanisms could contribute to increased NO bio-availability during ACE-inhibition. ACE-inhibition inhibits the breakdown of bradykinin by ACE, which activates the L-arginine-NO pathway in human endothelial cells [35, 36]. In addition, angiotensin II activates endothelial NADH-oxidase, leading to increased superoxide production [37]. Superoxide is a major determinant of NO-availability and thus a reduction in angiotensin II levels may increase NO availability. Accordingly, superoxide has recently been shown to be responsible for part of the hypertensive effect of angiotensin-II in rats [38]. A similar mode of action could also be relevant to the observations with nifedipine. The molecular structure of dihydropyridines possesses several properties which are characteristic of anti-oxidants [39, 40]. Due to the high partition coefficient resulting in accumulation in lipid membranes, nifedipine has been shown to be efficient in scavenging free radicals [39, 40].

This is the first study in humans demonstrating that L-NMMA dose-dependently decreases renal blood flow. At every dose, renal vascular resistance increased more than total systemic vascular resistance, suggesting greater NO dependency of renovascular tone in hypertension. With blood flow to the kidneys comprising 20–25% of total cardiac output, the kidneys obviously have a relatively low vascular resistance. To maintain this basal vasodilated state, regulation of renal NO availability may be specifically aimed to counterbalance prevailing local constrictor activity, rendering basal renal hemodynamics highly dependent on NO activity. The effects of L-NMMA were unaffected by either ACEi and calcium channel antagonists. Accordingly, L-NMMA-induced renal vasoconstriction was unaffected by angiotensin-II type I receptor blockers as well as dihydropyridine CCB [41, 42]in normotensive humans as well as animal models. The potent renal vasoconstrion to NO-inhibition cannot be explained solely by unopposed action of endogenous angiotensin-II (which would respond to ACEi), nor to increased endothelin-1 action (which would be attenuated by CCB [25]), and hence most likely also reflects withdrawal of nitric oxide in the renal vasculature.

Strikingly, the unchanged renal vasoconstrictor response to L-NMMA during ACEi or CCB is in contrast with the significantly augmented systemic response to L-NMMA on these therapeutic regimens. One possible explanation is that reduction of constrictor tone by ACEi or CCB is accompanied by a simultaneous downregulation of NO activity in the kidney, leading to a similar L-NMMA response. However, we found that antihypertensive treatment did not alter basal urinary cyclic GMP excretion, which is assumed to be a measure of renal NO activity [43]. Alternatively, the kidney is characterized by abundant mRNA expression and enzymatic activity of other NO-synthase isoforms, such as brain-type NO-synthase (NOS-I) in the macula densa of animal [44, 45]as well as human [44]kidneys, and inducible NO-synthase (NOS-II) in both afferent and efferent arterioles of the rat juxta-glomerular apparatus [46]. Inhibition of these isoforms may enhance the renal vasoconstrictor response on L-NMMA, thus potentially masking any modulation of endothelial NO-activity in the kidney.

In summary, the infusion of L-NMMA causes dose-dependent increases in systemic and renal vascular resistance in patients with essential hypertension. Treatment with either enalapril or nifedipine potentiates the systemic vasoconstrictor responses, suggesting increased basal NO tone. However, this phenomenon cannot be observed in the kidney, suggesting a different regulation of peripheral and renal NO activity in hypertension.

Time for primary review 21 days


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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