Vascular effects of angiotensin II in humans have been studied predominantly in the arterial system, revealing a marked vasoconstrictor potency of angiotensin II, which is inhibited by the angiotensin II type 1 (AT1)-receptor antagonist losartan (1,2). We previously found that losartan, infused intraarterially, and thus independent of the formation of the active metabolite Exp3174, appeared a potent inhibitor even of highly dosed angiotensin II (3). Angiotensin II at 10 ng/kg/min caused a vasoconstriction of ≤80%, which was antagonized by losartan in a dose-dependent manner in the dose range of 0.3-3 μg/kg/min. Venous-occlusion plethysmography performed during intraarterial drug infusion is recognized as a useful method of studying the functional effects of angiotensin II antagonism in human vasculature. However, responses to angiotensin II or the receptors involved have been studied little in the human venous system. Intravenously infused angiotensin II causes a reduction in venous volume (4), whereas locally injected angiotensin II induces constriction of human dorsal hand veins (5-8). The presence of AT1-receptors has been shown in the venous system of several animal models (9,10) and in the isolated human saphenous vein (11), where AT1-receptor antagonists were found to inhibit the contractile responses to angiotensin II.
The arterial constrictor effects of angiotensin II are assumed to be caused by an increase in intracellular calcium (Ca2+) in the vascular smooth-muscle cells, although the source of the Ca2+ may vary. Previous studies have shown that the intracellular Ca2+ may originate from influx via calcium channels or from the release from intracellular calcium stores (12,13). In human arteries, the responses to angiotensin II were abolished by L-type calcium channel blockers (14,15), and in human veins, the contractile responses to endothelin were partially inhibited by nicardipine (16).
From the studies mentioned, performed mostly in arteries and in different species, it appears that both AT1-receptor antagonists and calcium channel blockers are able to influence angiotensin II-induced vasoconstriction. These findings suggest that the contractile response of vascular smooth-muscle cells is dependent mainly on an AT1-receptor-mediated influx of Ca2+, which, however, appears to be dependent on the vessels and species studied. In contrast, it has not yet been investigated in any detail whether the effects of angiotensin II on human forearm veins are mediated by AT1-receptors and are sensitive to L-type calcium channel blockers.
In this study, we investigated (a) the constrictor responses of the forearm venous system to angiotensin II; (b) whether those venoconstrictor responses are AT1-receptor mediated by determining the inhibitory effect of losartan; and (c) whether the constrictor responses to angiotensin II in the arterial and venous systems are dependent on Ca2+ influx by determining the influence of nicardipine. All drugs used were infused into the brachial artery of human volunteers, which allows a comparative study of the arterial and venous responses to angiotensin II, the receptors involved, and their effector pathway in the human forearm vascular system.
The study was performed in 19 male volunteers with a mean age of 23 ± 1 (SEM) years. The subjects were included in the study after informed consent was obtained and after their medical history, physical examination, and routine laboratory tests revealed no abnormalities. None of the subjects took any medication for ≥2 weeks before the study. Subjects were instructed to refrain from alcohol, caffeine, licorice, and cigarettes for ≥12 h before the experiment. The protocol of the study was approved by the Medical Ethics Committee of the Leiden University Medical Center.
Subjects were studied in the supine position in a quiet room at ambient temperature (22-24°C). One-lead ECG was registered continuously. After local anesthesia with lidocaine 1%, the brachial artery of the nondominant arm was cannulated. The cannula (1.0 × 45 mm) was connected to a Statham P23ld pressure transducer (Gould, Oxnard, CA, U.S.A.). Drugs were infused into the brachial artery by using volumetric precision pumps (Harvard 22; Harvard Apparatus, Edenbridge, Kent, U.K.). Both arms were instrumented with mercury-in-silastic strain gauges, connected to a Hokanson EC-2 plethysmograph (Hokanson, Issaquah, WA, U.S.A.) for the measurement of forearm blood flow (FBF; 17) and of maximal venous outflow (MVO; 18-20). Heart rate (HR), intraarterial (i.a.) blood pressure (BP), and left and right FBF and MVO were recorded on a polygraph (Gould) and a personal computer (Dell, Limerick, Ireland). Both upper arms were instrumented with pressure cuffs, connected to a Hokanson E-10 rapid cuff inflator. For measurement of FBF, R-wave-triggered cuff inflation (at 40 mm Hg) for venous-occlusion plethysmography was controlled by the personal computer. FBF was measured 4 times per minute, and the average of the last six measurements at the end of each dose step of drug infusion was used for further analysis. MVO was determined according to previously described methods (18). In short, the upper arm cuffs were inflated manually to a pressure of 40 mm Hg, which was maintained until the forearm volume reached its maximum. Subsequently, the cuffs were rapidly deflated. A straight line was drawn as a tangent to the first portion of 0.2 s of the deflation curve (18,20). MVO was calculated from the slope of this tangent line. Both hands were continuously excluded from the circulation during infusion experiments by inflating wrist cuffs to ≥40 mm Hg above systolic BP to avoid the influence of the predominantly cutaneous perfusion of the hands.
The infusion experiments (Fig. 1) were started ≥45 min after the cannulation of the brachial artery. Between the various infusion experiments, the wrist cuffs were deflated, and sufficient time (≥30 min) was allowed for recovery from hand ischemia and for the hemodynamic parameters to return to baseline levels.
Baseline levels of HR, BP, FBF, and MVO were measured (Table 1). Sodium nitroprusside (SNP; mean, 10 ± 1 ng/kg/min; range, 5-12.5 ng/kg/min) was infused intraarterially to predilate the forearm vascular system to facilitate flow measurements and to obtain comparable initial flow levels. Five minutes after the start of the SNP, angiotensin II infusion into the brachial artery was started for 4-5 min per dose step: 0.1, 1, and 10 ng/kg/min. MVO of the noninfused arm was not used as a control, because the duration of cuff inflation depended on stabilization of forearm volume of the infused arm, which may be different from the time required to reach a stable volume of the noninfused arm.
The effects of losartan (0.3 μg/kg/min, eight subjects; and 3 μg/kg/min, five subjects) on baseline MVO and on angiotensin II-induced venous constriction were determined. After measurement of baseline flow, losartan was infused for 5 min, after which SNP was added to the infusion. Subsequently the angiotensin II infusions were started and were thus performed during losartan and SNP infusion. This protocol is similar to that used in previously reported studies to determine the arterial effects of losartan and angiotensin II (3).
The effects of nicardipine (0.05 and 0.15 μg/kg/min) on baseline FBF and on angiotensin II-induced arterial constriction were determined in six subjects. Nicardipine infusions were started ≥10 min before angiotensin II infusions (15). Accordingly, the effects of nicardipine (0.15 μg/kg/min) on baseline MVO and on angiotensin II-induced venous constriction were determined (seven subjects).
All active substances were formulated as sterile pharmaceutical preparations in the Leiden University Hospital Clinical Pharmacy. Angiotensin II (Hypertensin; Ciba Geigy, Arnhem, The Netherlands), losartan potassium (DuP 753; The DuPont Merck Pharmaceutical Company, Wilmington, DE, U.S.A.), and nicardipine (Cardene; Sarva Syntex, Mijdrecht, The Netherlands) were dissolved in 0.9% saline. Sodium nitroprus-side (E. Merck, Darmstadt, Germany) was dissolved in 5% dextrose.
The arterial and venous effects of angiotensin II were expressed as a percentage change in FBF and MVO, respectively. The percentage changes in FBF and MVO were calculated relative to the values measured at baseline or during SNP, losartan, or nicardipine infusions. Drug effects on FBF and MVO were graphically expressed by means of dose-response curves. Paired Student's t test and repeated-measures analysis of variance (ANOVA) with a Dunnett multiple-comparisons post hoc test were used for statistical evaluation. Results are reported as means ± SEM. A p value of <0.05 was considered statistically significant.
Under baseline conditions, HR was 60 ± 3 beats/min and remained unchanged during the infusion protocols (Table 1; p > 0.05). Mean arterial pressure (MAP) was 87 ± 4 mm Hg during baseline and was unaffected by SNP, losartan, or nicardipine (p > 0.05), when infused into the brachial artery. Angiotensin II in doses <10 ng/kg/min did not change MAP, whereas the dose of 10 ng/kg/min increased MAP ≤93 ± 3 mm Hg (Table 1; p < 0.05). This small angiotensin II-induced increase in BP was maintained during the concomitant infusion of losartan or nicardipine. The FBF of the noninfused arm (FBFni) was slightly but significantly increased during the angiotensin II infusion (doses >1 ng/kg/min) under control conditions (Table 1). This increase in FBFni was present during the angiotensin II infusion of 10 ng/kg/min in the nicardipine experiments (p < 0.05).
Forearm blood flow
Sodium nitroprusside (10 ± 1 ng/kg/min) increased FBF of the infused arm (FBFi) from a baseline value of 3.56 ± 0.56 to 8.11 ± 1.15 ml/100 ml/min (p < 0.05). Angiotensin II decreased FBFi significantly and dose dependently (Fig. 2). The doses of 0.1, 1, and 10 ng/kg/min caused a decrease in FBF by 16 ± 10%, 60 ± 10%, and 79 ± 4%, respectively.
Nicardipine caused an increase in FBFi by 124 ± 32% and 108 ± 41% (p < 0.05) compared with baseline, no difference (p > 0.05) between the doses of nicardipine of 0.05 and 0.15 μg/kg/min (Table 1)). Nicardipine in both doses significantly inhibited the angiotensin II-induced arterial vasoconstriction (Fig. 2). During nicardipine at 0.05 μg/kg/min, only the dose of 10 ng/kg/min of angiotensin II remained significantly effective, resulting in a maximal decrease in FBFi by 48 ± 4%. Lower doses of angiotensin II caused no vasoconstriction during nicardipine infusion. During nicardipine at 0.15 μg/kg/min, the maximal angiotensin II-induced decrease in FBFi was −6 ± 2%, indicating that the vasoconstrictor effect of angiotensin II was abolished (Fig. 2; p > 0.05).
Maximal venous outflow
Baseline MVO of the infused arm (MVOi) amounted to 131 ± 5 ml/100 ml/min. SNP increased MVOi to a value of 156 ± 8 ml/100 ml/min (Fig. 3; p < 0.05). Angiotensin II, 10 ng/kg/min, decreased MVOi by 28 ± 3% (p < 0.05); the lower doses caused no significant decreases in MVOi(Fig. 4).
Losartan did not change baseline MVOi(Fig. 3) but significantly inhibited the angiotensin II-induced decrease in MVOi. Both doses of losartan (0.3 and 3 μg/kg/min) completely abolished the venoconstrictor response to angiotensin II (Fig. 4).
Nicardipine at 0.15 μg/kg/min increased baseline MVOi from a baseline value of 146 ± 20 to 169 ± 18 ml/100 ml/min (Fig. 3; p < 0.05). Nicardipine at 0.15 μg/kg/min did not significantly influence the venous constriction by angiotensin II (Fig. 4; p > 0.05). The maximal decrease in MVOi by 34 ± 8% during nicardipine was not different from MVOi during control conditions (28 ± 3%).
The venous-occlusion plethysmography technique combined with the intraarterial infusion of different types of drugs into the forearm is widely recognized as a useful method of investigating the drug effects in the arterial (3,21) and venous systems in humans (18-20). After the intraarterial injection of drugs, a sufficient venous blood concentration will be reached to measure the influence on the venous system. For angiotensin II, a venous concentration of 66% of the arterial concentration was estimated to be achieved in the human forearm (22). As demonstrated by us, intraarterially infused losartan proved an effective antagonist of angiotensin II-induced arterial constriction, involving AT1-receptor blockade. This effect was caused by losartan itself and not by its active metabolite Exp3174 (3). In our study, the intrabrachial drug infusion performed together with flow measurements allowed the comparison of effects on the venous system with the relatively well known and more frequently studied influence on resistance vessels in the same region.
As described in the Results section, angiotensin II caused a slight but significant increase in BP, which reflects a mild systemic effect. This pressor effect was not influenced by the intrabrachially injected nicardipine, which is presumably explained by the fact that no effect on BP of infusion of nicardipine alone was observed.
Losartan did not influence baseline MVO, which indicates that endogenous angiotensin II does not play a role in maintaining venous tone. This finding is in line with our previous observation that endogenous angiotensin II appears not to play a role in maintaining arterial tone (3). Baseline FBF was markedly increased by nicardipine, which is in accordance with the well-known vasodilator effect of nicardipine, mediated by L-type calcium channels (23-25). Nicardipine also caused a moderate dilatation of the venous vascular bed, as reflected by the increase in MVO. The venodilatation caused by nicardipine was comparable to the dilatation induced by SNP, an effect previously reported by our group (20).
The main findings of this investigation may be characterized as follows: Angiotensin II caused constriction of the venous vascular bed, although higher doses were required for this effect than for the constriction of resistance (arterial) vessels. The venoconstriction caused by angiotensin II is mediated by AT1-receptors, as reflected by the inhibitory action of losartan, a selective AT1-receptor antagonist. In contrast to the constrictor effect of angiotensin II in the arterial vascular bed, nicardipine did not inhibit the angiotensin II-induced venoconstriction. Accordingly, the venous response to angiotensin II appeared AT1-receptor mediated but independent of calcium influx via L-type calcium channels.
The venous constriction by angiotensin II, as indicated by a decrease in MVO, reflects an increase in venous resistance, because during measurements, the pressure in the upper arm cuff is kept constant. Our findings of angiotensin II-induced venoconstriction in the forearm vascular bed are in accordance with those obtained in the dorsal hand veins (5,6,26) and in isolated human saphenous vein (11,27). However, results obtained in the forearm vascular bed may be different from those obtained in the hand. Dilator and constrictor sensitivity of vessels of the largely cutaneous hand circulation will differ from that of the muscular forearm (28,29), as will their role in peripheral vascular resistance and venous return and their reflection of other systemic effects (7). The investigation of flow effects in the forearm allows a direct comparison of drug effects in the arteries and veins of the same tissue.
The use of venous-occlusion plethysmography to investigate forearm venous responses also has its limitations. Although locally infused, the drugs may cause systemic effects such as changes in BP or HR. For a drug such as losartan, systemic effects may also result from formation of its metabolite Exp3174 after liver passage. Although some influence is to be expected, these systemic effects will probably not importantly affect the results, mostly because the local direct effects will be much more prominent. The venous concentration of an intrabrachially infused drug is dependent on the metabolism of the drug in the forearm. However, for angiotensin II, it was shown that a sufficient drug concentration may be achieved in the venous system (22). Last, the measure of MVO requires the stabilization of the forearm volume at a certain cuff pressure, in contrast to the frequently repeated FBF measurements. Thus relatively fewer venous measurements may be obtained, which may to some extent affect the accuracy of the values measured. Nevertheless in our study, the results were very straightforward and will therefore not be influenced by a slightly reduced accuracy.
The dose of angiotensin II (10 ng/kg/min) required to induce venous constriction was relatively high compared with that causing the arterial constriction, in which an effect may already be observed at 0.1 ng/kg/min. The maximal flow reduction in the venous system of ∼30% versus ∼80% in the arterial system indicates that angiotensin II acts more potently on arteries, although some arteriovenous concentration gradient of angiotensin II should be considered (22).
As observed in previous studies (3), we observed angiotensin II-induced arterial constriction in the forearm vascular bed, which also was suppressed by losartan and therefore most likely to be mediated by AT1-receptors. In the arterial vascular bed, the inhibitory effect of nicardipine on angiotensin II-induced vasoconstriction was comparable to that of losartan. The comparable inhibitory actions of the AT1-receptor antagonist and the calcium channel blocker indicate that the forearm arterial constrictor responses are calcium-influx mediated, which is in accordance with findings described by Andrawis et al. (14) by using lower doses of angiotensin II and by Pedrinelli et al. (15) in patients with hypertension.
It appears of interest that the constrictor effect of angiotensin II in arteries is sensitive to calcium channel blockade, whereas that in the venous system is not. For this major discrepancy, several explanations can be suggested. For instance, angiotensin II may trigger alternative pathways to increase the intracellular calcium in smooth-muscle cells, such as by intracellular calcium release (12,30,31) rather than influx, or by triggering different types of receptors. In addition, a role of angiotensin II-induced presynaptic noradrenaline release (6,32) has been reported, as well as altered sensitivity to calcium (33), a role for extracellular sodium concentration (34), and for sodium/calcium exchange (35). Furthermore, certain anatomic and functional differences between resistance and capacitance vessels may explain the differences in the constrictor and dilator responses found by us (36,37). Apparently the mechanism of the increase in intracellular calcium is dependent on the stimulus (38,39), as well as on the species and vascularity studied, as confirmed in our study. It remains possible that an arterial constrictor effect may be elicited by higher doses of angiotensin II, as appears in Fig. 2. Whether in that case even higher doses of L-type calcium channel antagonists are necessary or other calcium channels or intracellular calcium release are involved cannot be concluded from this study.
These findings in the venous and arterial beds may have certain clinical implications for the treatment with angiotensin II-receptor antagonists. Losartan induces arterial dilation and reduces increased blood pressure and cardiac afterload. The venous system, containing the majority of intravascular blood, is an important regulator of cardiac preload by its capacitative function (36). Only a slight decrease in venous capacity may have a significant impact on preload and vascular volume (36), an effect that may be caused by angiotensin II (40,41). Thus the antagonistic effect of losartan on the angiotensin II-induced venous constriction, as found in this study, may play a role [e.g., in the case of essential hypertension, in which an increase in venomotor tone was found (42), or in heart failure (41), in which the renin-angiotensin-aldosterone system may be activated].
In conclusion, in the forearm of healthy subjects, angiotensin II exerts not only an arterial constrictor effect but also a less pronounced although significant venous response. Both the arterial and venous constrictor responses to angiotensin II are mediated by the AT1-receptor subtype. The arterial response appears to be completely dependent on the influx of extracellular calcium via L-type calcium channels, whereas the angiotensin II-induced venous constriction appears to be independent of those channels. The antagonistic effect of losartan on the arterial and venous constriction by angiotensin II may contribute to the therapeutic efficacy of the drug.
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