Angiotensin II and Sympathetic Activity in Sodium-Restricted Essential Hypertension
Abstract Angiotensin II (Ang II) potentiates sympathetic neurotransmission by presynaptic facilitation of norepinephrine release. We investigated whether endogenous Ang II modulates peripheral sympathetic activity in sodium-depleted essential hypertensive patients. We evaluated the effect of intrabrachial infusion of saralasin, an Ang II antagonist (5 μg/100 mL forearm tissue per minute), and benazeprilat, an angiotensin-converting enzyme inhibitor (2 μg/100 mL forearm tissue per minute), on forearm vasoconstriction (measured by strain-gauge venous plethysmography) induced by the application of lower body negative pressure (−10 mm Hg for 5 minutes). Both saralasin and benazeprilat (n=6 for each group) blunted the vasoconstrictor action of lower body negative pressure, suggesting that circulating Ang II modulates peripheral sympathetic activity. In addition, since β-adrenoceptor stimulation can activate the production of vascular Ang II, the effect of saralasin and benazeprilat on lower body negative pressure application was evaluated in the presence of isoproterenol (0.09 μg/100 mL forearm tissue per minute) and propranolol (10 μg/100 mL forearm tissue per minute). In two other groups of hypertensive patients, isoproterenol infusion increased the release of Ang II in the forearm vasculature (arteriovenous values measured by radioimmunoassay). Furthermore, isoproterenol potentiated lower body negative pressure–induced vasoconstriction. This facilitating effect was abolished by either saralasin or benazeprilat (n=6 for each group). In contrast, in two further groups of patients (n=6 for each group), in the presence of the β-blocker propranolol, saralasin and benazeprilat did not alter the vasoconstrictor action of the endogenous sympathetic stimulus. The present data suggest that in sodium-depleted essential hypertensive patients, endogenous Ang II, activated by the stimulation of β-adrenergic receptors, can potentiate peripheral sympathetic neurotransmission.
A general agreement exists that angiotensin II (Ang II), in addition to its direct vasoconstrictor action, can enhance sympathetic neurotransmission through presynaptic facilitation of norepinephrine release.1 This effect is demonstrated by several observations derived from experiments in different vascular tissues,2 3 4 5 including skeletal muscle resistance vessels.6 In humans, the possibility that Ang II facilitates norepinephrine release by a presynaptic mechanism is suggested by evidence showing that exogenous Ang II infused into the brachial artery increases the forearm vasoconstrictor effect7 8 9 and norepinephrine spillover8 9 induced by sympathetic nervous system activation. In addition, intrabrachial administration of the angiotensin-converting enzyme (ACE) inhibitor captopril reduces the norepinephrine release caused by β-adrenoceptor stimulation through isoproterenol.9 However, no data are available in humans concerning the effect of endogenous Ang II on peripheral sympathetic activity.
In the present study, we tested the hypothesis that endogenous Ang II can modulate sympathetic neurotransmission in essential hypertensive patients by evaluating the effects of saralasin, an Ang II antagonist, and benazeprilat, the active metabolite of the ACE inhibitor benazepril, on peripheral sympathetic activity. In addition, since evidence is increasing that a local renin-angiotensin system may participate in vascular control,10 11 we extended our investigation to look at any possible role for vascular Ang II in modulating peripheral sympathetic neurotransmission.
Forty-two inpatients (24 men and 18 women; mean age, 43.7±7.6 years) with mild to moderate uncomplicated essential hypertension were recruited for the studies. Patients with hypercholesterolemia (total cholesterol >5.2 mmol/L), diabetes mellitus, cardiac and/or cerebral ischemic vascular disease, impaired renal function, or other major pathologies were excluded from the study. The study protocol was approved by the local ethics committee, and all patients were aware of the investigational nature of the study and gave written consent. All experimental procedures followed were in accordance with institutional guidelines. Patients discontinued any treatment for at least 2 weeks before admittance to the ward.
Essential hypertensive patients were recruited from among the newly diagnosed cases in our outpatient clinic. In all cases, patients reported the presence of a positive family history of essential hypertension. Patient supine arterial blood pressure (after 10 minutes of rest) measured by mercury sphygmomanometer three times at 1-week intervals was consistently found to be greater than 140/90 mm Hg. Secondary forms of hypertension were excluded from the study by routine diagnostic procedures. To exclude the presence of renovascular disease, all patients underwent a Doppler examination of the renal arteries. In addition, 18 of 42 underwent renal arteriography. On admission to the ward, patients were maintained on a normocaloric diet with moderately low sodium (60 to 80 mmol/d) and normal potassium chloride (60 to 80 mmol/d) intake so that a constant sodium excretion rate was obtained, usually on the fifth day of hospitalization. On attainment of sodium equilibrium, peripheral venous samples for plasma renin activity (PRA) measurement were obtained after patients had been standing for 1 hour.12 Only patients with PRA values greater than 1 pmol Ang I/mL per hour were admitted to the study.
All studies were performed at 8 am after an overnight fast with the patients lying supine in a quiet air-conditioned room (22° to 24°C). A polyethylene cannula (21 gauge, Abbott) was inserted into the brachial artery under local anesthesia (2% lidocaine) and connected through stopcocks to a pressure transducer (model MS20, Electromedics) for monitoring of systemic mean blood pressure (1/3 pulse pressure+diastolic pressure) and heart rate (model VSM1, Physiocontrol) and for intra-arterial infusions. Another cannula (6 cm long) was advanced into an ipsilateral deep forearm vein retrogradely. Forearm blood flow (FBF) was measured in both forearms (cannulated and contralateral) by strain-gauge venous plethysmography (LOOSCO, GL LOOS).13 Cannulated FBF modifications were used to evaluate the vascular response to our experimental intervention. Contralateral FBF was used to monitor possible aspecific time-dependent modifications in vascular tone. Arterial and deep venous blood samples were taken simultaneously at timed intervals. Circulation to the hand was excluded 1 minute before each sampling or FBF measurement by inflating a pediatric cuff around the wrist at suprasystolic blood pressure. Details concerning the sensitivity and reproducibility of the method as performed in our laboratory have already been published.14
Forearm volume was measured by the water displacement method. Drug infusion rates were normalized for 1 dL tissue by adjusting infusion speed to the desired infusion rates. Drugs were infused at systemically ineffective rates through separate ports via three-way stopcocks.
Endogenous sympathetic activation was obtained by application of lower body negative pressure (LBNP) at −10 mm Hg for 5 minutes. This maneuver reduces venous return and deactivates cardiopulmonary inhibitory pathways. In addition, it causes sympathetic discharge and peripheral vasoconstriction without changes in systemic blood pressure and heart rate.15 16
For the LBNP experiments, the inferior limbs were placed up to the waist in an airtight, Plexiglas container (Tecnoglas) sealed by rubber flaps around the waist. Negative pressure (−10 mm Hg), quantified by a U-shaped mercury manometer connected to the inside of the apparatus, was generated by means of a vacuum cleaner (Bosch).
Effect of Local Saralasin on Ang II–Mediated Vasoconstriction
This experimental series was designed first to titrate a saralasin infusion rate effective in antagonizing Ang II–induced vasoconstriction and second to exclude the possibility of intrinsic activity of the compound. In six hypertensive patients, exogenous Ang II was infused into the brachial artery at three log unit increments (3, 9, and 30 ng/100 mL forearm tissue per minute for 3 minutes for each dose) in the presence of saline (0.2 mL/min). The procedure was then repeated in the presence of intra-brachial saralasin at 5 μg/100 mL forearm tissue per minute. The infusion was started 10 minutes before the beginning of the second dose-response curve to Ang II and was continued throughout.
Effect of Ang II Receptor Blockade or ACE Inhibition on Endogenous Sympathetic Activation
To evaluate the effect of circulating Ang II on endogenous sympathetic activation, we tested whether either Ang II receptor blockade by saralasin or Ang II production inhibition by benazeprilat might interfere with the vasoconstrictor effect and norepinephrine release (only in the saralasin group) caused by LBNP. Thus, in a first group of six essential hypertensive patients, the sympathetic stimulus was applied in control conditions (intrabrachial saline at 0.2 mL/min) and repeated during saralasin infusion at 5 μg/100 mL forearm tissue per minute. Arterial and venous samples for norepinephrine and epinephrine were collected at the fifth minute of each LBNP application. Moreover, in a second group of patients (n=6), the above-reported experimental design was repeated in the presence of intrabrachial infusion of benazeprilat at 2 μg/100 mL forearm tissue per minute. Arterial and venous samples were collected before and during benazeprilat administration for Ang II determination.
Effect of Local Vascular Ang II on Endogenous Sympathetic Activation
Previous evidence obtained in both animals and humans indicated that β-adrenoceptor stimulation can activate local vascular production of Ang II.8 17 18 Based on this possibility, we designed experiments to evaluate the effect of both saralasin and benazeprilat on endogenous sympathetic activation while local vascular Ang II concentrations were increased by β-adrenergic stimulation. Moreover, the effect of β-adrenoceptor blockade on local vascular Ang II production was also evaluated. Therefore, in four different groups of hypertensive patients (n=6 each group), the following experimental protocols were performed. In two groups of patients, LBNP was applied in control conditions, in the presence of intrabrachial infusion of the β-adrenergic agonist isoproterenol (at 0.1 μg/100 mL forearm tissue per minute started 10 minutes before the sympathetic stimulus and continued throughout), and subsequently during the simultaneous infusion of isoproterenol and either saralasin (one group) or benazeprilat (the other group). Arterial and venous samples for determination of norepinephrine and epinephrine were collected at the fifth minute of each LBNP application in the saralasin group. In addition, in both groups of patients, arterial and venous samples for the determination of Ang II were collected before and after isoproterenol to confirm the possibility of causing β-adrenoceptor–induced local Ang II release. Finally, in a further two groups of essential hypertensive patients, the above-described experimental design was repeated in the presence of β-adrenoceptor blockade by intrabrachial propranolol at 10 μg/100 mL forearm tissue per minute.
PRA (picomoles Ang I per milliliter per hour) was measured by radioimmunoassay after plasma had been incubated at pH 5.7 for 1.5 hours.19 Plasma Ang II (femtomoles per milliliter) was determined by radioimmunoassay after extraction of the peptide from plasma with Sep-Pak C18 cartridges.8 The procedure has been previously described8 and validated by measurement with high-performance liquid chromatography of purified Ang II.20 In our laboratory, the plasma level of purified Ang II in healthy subjects is 12.4±2.7 fmol/mL (range, 5.7 to 22.8 fmol/mL). In preliminary experiments, saralasin showed cross-reactivity with Ang II antiserum. Therefore, it was not possible to measure plasma Ang II during saralasin infusion. Catecholamine concentrations (picograms per milliliter) were measured by high-performance liquid chromatography21 and hematocrit by a micromethod.
Net forearm balance of Ang II was obtained as the product of the respective venous-arterial plasma concentration gradient and forearm plasma flow. Plasma flow rates were calculated as the product FBF by 1 minus hematocrit. For determination of local norepinephrine production, forearm norepinephrine extraction in arterial plasma was estimated through forearm epinephrine extraction according to the following equation22 :
where NEVe is venous norepinephrine; EpiVe is venous epinephrine; NEAr is arterial norepinephrine; and EpiAr is arterial epinephrine.
Since arterial pressure did not change significantly during the study, all data were analyzed in terms of FBF, and FBF increments or decrements were taken as evidence of local vasodilation and vasoconstriction, respectively. Raw data were analyzed by repeated-measures ANOVA. Duncan’s test was applied for multiple comparison testing. Wilcoxon’s test was used to check the statistical significance of the difference between nonparametric values (percent modifications). Results are expressed as mean±SD.
Saralasin acetate (Sarenin, Röhm Pharma GmbH), isoproterenol HCl (Isuprel, Winthrop-Breon), propranolol HCl (Inderal, ICI), and Ang II (Hypertensina Ciba, CIBA-GEIGY) were obtained from commercially available sources; benazeprilat was provided by CIBA-GEIGY. Drugs were diluted in fresh solutions to the desired concentrations by addition of normal saline.
Table 1⇓ shows demographic, hemodynamic, and humoral parameters of the study patients. As expected,15 16 LBNP application did not significantly alter basal intra-arterial blood pressure or heart rate (data not shown).
Exogenous Ang II–Mediated Vasoconstriction
Exogenous Ang II caused a dose-dependent FBF decrement in the infused forearm (from 3.6±0.9 to 2.7±0.8, 1.5±0.5, and 0.8±0.3 mL/100 mL forearm tissue per minute). Saralasin infusion slightly increased FBF but not significantly (from 3.6±0.8 to 3.8±0.8 mL/100 mL forearm tissue per minute) and abolished the exogenous Ang II–induced constrictor effect (from 3.8±0.8 to 3.6±0.7, 3.8±0.9, and 3.9±0.9 mL/100 mL forearm tissue per minute) (Fig 1⇓). Contralateral FBF did not change significantly during Ang II or saralasin infusion (data not shown).
Effect of Ang II Receptor Blockade or ACE Inhibition on Endogenous Sympathetic Activation
In the saralasin group, LBNP application caused an evident FBF decrease in both forearms (experimental, −34.3±8.4%; contralateral, 32.4±7.9%) (Fig 2⇓). Saralasin infusion caused a slight increase in basal FBF (from 3.2±0.6 to 3.6±0.7 mL/100 mL forearm tissue per minute). Compared with saline, LBNP-mediated vasoconstriction was significantly blunted (P<.01) by the presence of saralasin (−22.4±5.7%) (Fig 2⇓ and Fig 3⇓, left). In contrast, it was found to be unaltered in the contralateral forearm (35.3±8.4%) (Fig 2⇓). Similarly, norepinephrine spillover determined by LBNP application during saline (2.10±0.3 pmol/min) was significantly (P<.05) reduced by saralasin (1.60±0.3 pmol/min).
In the second group of patients, benazeprilat infusion reduced plasma Ang II (from 17.2±3.0 to 4.6±0.6 fmol/mL) in the forearm vein without affecting arterial values (from 19.1±3.9 to 20.2±4.2 fmol/mL), demonstrating blockade of Ang II production in the forearm vasculature. The ACE inhibitor increased basal FBF (from 3.6±0.5 to 4.4±0.7 mL/100 mL forearm tissue per minute) and significantly (P<.05) blunted the LBNP-induced vasoconstrictor effect (saline, −38.2±7.2%; benazeprilat, −26.4±8.7%). In the contralateral forearm, the first and second applications of LBNP caused a comparable amount of vasoconstriction (−39.6±8.7% and −41.3±9.2%) (Fig 2⇑). Details concerning FBF behavior are reported in Table 2⇓.
Effect of Local Vascular Ang II on Endogenous Sympathetic Activation
Isoproterenol administration increased venous Ang II without affecting arterial values (vein, from 16.5±3.1 to 23.1±3.9 fmol/mL; artery, from 18.7±3.4 to 18.2±3.2 fmol/mL), indicating a local release of the peptide in the forearm vascular bed (calculated net balance from −4.3±0.2 to 19.5±2.4 fmol/min). Compared with saline, isoproterenol significantly increased basal FBF (Fig 4⇓) and potentiated LBNP-mediated vasoconstriction (from −30.5±5.8% to −46.8±9.4%, P<.01) (Fig 3⇑, center), probably by increasing sympathetic discharge through activation of presynaptic β-adrenoceptors. This facilitating effect was abolished by saralasin (−21.8±5.5%, P<.01 versus saline or isoproterenol alone) (Fig 3⇑, center). In the contralateral forearm, the vascular response to LBNP application did not significantly change throughout the study (Fig 4⇓). Norepinephrine spillover caused by LBNP was increased by isoproterenol (from 1.62±0.2 to 2.95±0.5 pmol/min, P<.05), and this potentiating effect was blunted by saralasin (2.53±0.5 pmol/min, P<.05 versus isoproterenol alone).
In the benazeprilat study, isoproterenol infusion increased local Ang II release (vein, from 15.3±2.7 to 19.4±3.7 fmol/mL; artery, from 17.3±2.9 to 17.7±3.1 fmol/mL; net balance, from −4.0±0.2 to 9.6±1.7 fmol/min). As in the previous group of patients, forearm vasoconstriction induced by LBNP application (saline, −38.2±4.4%) was significantly (P<.05) augmented by isoproterenol (−45.9±7.8%). This potentiating effect was significantly (P<.05) blunted by benazeprilat (−24.9±9.5%). The effectiveness of the ACE inhibitor was limited to the forearm vascular bed, as demonstrated by the reduction of venous plasma Ang II (from 15.7±2.7 to 3.6±0.8 fmol/mL) without alterations in arterial values (from 17.5±2.8 to 17.8±2.9 fmol/mL). Vasoconstriction to LBNP did not change in the contralateral forearm during the time course of the experiment (data not shown). Details concerning FBF behavior are reported in Table 2⇑.
Intrabrachial propranolol increased LBNP-mediated vasoconstriction (saline, −28.2±4.7%; propranolol, −37.8±5.1%; P<.05) (Fig 3⇑, right and Fig 5⇓, center). It is likely that this effect is related to vasodilating postsynaptic β-adrenoceptor blockade. Saralasin did not alter the augmented response to LBNP caused by propranolol (−40.1±6.6%) (Fig 5⇓ and Fig 3⇑, right). In the contralateral forearm, the response to LBNP did not change significantly throughout the study (Fig 5⇓). Norepinephrine release caused by LBNP was not altered during our experimental interventions (saline, 1.90±0.3 pmol/min; propranolol, 1.76±0.3 pmol/min; propranolol plus saralasin, 1.89±0.4 pmol/min).
Similar results were obtained in the group of patients studied with benazeprilat. Forearm vasoconstriction induced by LBNP (−30.2±6.5%) was significantly (P<.05) increased by propranolol administration (−39.2±8.2%). Such an effect was not altered by the ACE inhibitor (−43.6±7.8%). Benazeprilat effectiveness was demonstrated by reduction of plasma Ang II in the forearm vascular bed (artery, from 22.4±3.3 to 21.2±3.5 fmol/mL; vein, from 20.3±3.1 to 5.3±0.7 fmol/mL). Details concerning FBF behavior are reported in Table 2⇑.
To investigate whether endogenous Ang II might facilitate sympathetic neurotransmission in the forearm vascular bed of patients with essential hypertension, we induced a reflex augmentation in sympathetic tone by application of LBNP, resulting in vasoconstriction in the forearm, and we blocked the effects of Ang II through either saralasin, an Ang II receptor antagonist, or benazeprilat, an ACE inhibitor. In our experimental conditions, both of these compounds reduced the LBNP-induced vasoconstrictor effect. Moreover, saralasin blunted norepinephrine spillover caused by the sympathetic stimulus. Since intra-arterial infusion of saralasin and benazeprilat rules out the possibility of systemic effects induced by these compounds, the present findings indicate that the local blockade of circulating Ang II receptors or synthesis blunts the vascular effects of sympathetic stimulation. This further suggests that endogenous Ang II can modulate peripheral sympathetic neurotransmission in patients with essential hypertension.
The present results confirm experimental data in various animal models1 2 3 4 5 6 indicating a presynaptic potentiating effect of Ang II on sympathetic neurotransmission. In addition, these findings are in agreement with previous results in humans indicating that an exogenous low dose of intrabrachial Ang II increases forearm vasoconstriction and LBNP-induced norepinephrine spillover.7 8 9 Thus, the evidence that Ang II, either exogenously administered or endogenously blocked, respectively increases or decreases the vascular and humoral effects of an endogenous sympathetic stimulus confirms that the peptide can modulate the sympathetic nervous system activity at a presynaptic level in humans. In fact, the possibility of Ang II–mediated postsynaptic potentiation of the constrictor effect of norepinephrine, as suggested by results obtained in certain animal models,23 24 is excluded in humans by the evidence that intrabrachial Ang II does not affect the vasoconstrictor action of exogenous norepinephrine.7 8
In recent years, growing experimental evidence has demonstrated the existence of a vascular renin-angiotensin system.10 11 Furthermore, animal findings suggest the possibility of activating production of local Ang II from arterial vessels.17 18 In agreement with these experimental results, we confirmed in a previous study8 that local β-adrenoceptor stimulation can increase the release of active renin and Ang II in the forearm vasculature of essential hypertensive patients. It was also shown that this effect is strictly related to the circulating renin profile.20 Therefore, in the present study, to investigate whether vascular Ang II plays any role in modulating peripheral sympathetic activity, we selected patients with circulating renin stimulated by sodium restriction and we activated local production of Ang II by isoproterenol. β-Adrenoceptor stimulation increased the norepinephrine spillover and vasoconstriction caused by LBNP application. This potentiating effect was found to be blunted by saralasin or benazeprilat. In contrast, during β-adrenoceptor blockade by propranolol, saralasin or benazepril did not exert any inhibition on the vascular and humoral effects of LBNP application. Taken together, these findings suggest that activation of β-adrenergic receptors is a determining condition for the facilitating effect of Ang II on sympathetic neurotransmission. Since β-adrenoceptors can induce the production of vascular Ang II,8 17 18 20 it is conceivable that sympathetic-mediated norepinephrine release stimulates β-adrenergic receptors to activate the vascular renin-angiotensin pathway and produce Ang II. This effect could in itself facilitate sympathetic neurotransmission at a presynaptic level. Such a hypothesis is in agreement with results obtained in rat mesenteric vascular preparations, indicating that both captopril and saralasin reduce the isoproterenol-induced enhancement of the pressor response to periarterial nerve stimulation.25 It also confirms evidence obtained in our laboratory in essential hypertensive patients showing that intrabrachial captopril reduces the norepinephrine spillover caused by local β-adrenoceptor stimulation.8
It is interesting to observe that both isoproterenol and propranolol led to an increase in the vasoconstrictor response induced by LBNP application. This apparent contradiction can be explained by the different functions exerted by presynaptic β-adrenoceptors, whose stimulation causes an increment in norepinephrine release, and postsynaptic β-adrenoceptors, whose activation or blockade determines vasodilation or vasoconstriction, respectively. Thus, it is likely that isoproterenol increases vasoconstriction to LBNP by facilitating norepinephrine release. On the other hand, the same vascular effect is exerted by propranolol through blockade of postsynaptic vasodilating β-adrenoceptors. However, our finding that both saralasin and benazeprilat did not alter the response to LBNP application in the presence of propranolol was unexpected because, even in the presence of β-blockade, the potentiating effect of circulating Ang II on sympathetic neurotransmission should be unaltered. A possible explanation for this discrepancy could be that β-blockade, ACE inhibition, or Ang II antagonism blunts sympathetic neurotransmission by a presynaptic inhibition of norepinephrine release. In the case of β-blockade, this inhibitory effect, which should determine reduced sympathetically mediated vasoconstriction, is masked by the simultaneous blockade of vasodilating postsynaptic β-receptors. When saralasin or benazeprilat is infused during propranolol administration, it is possible that the already present presynaptic inhibition of sympathetic neurotransmission exerted by β-blockade does not allow the ACE inhibitor or the Ang II antagonist to further inhibit sympathetic discharge.
It is important to note that in patients recruited for the present study we activated circulating PRA by sodium restriction. The reason for this selection lies in the evidence that the vasodilating activity of short-term ACE inhibitor administration seems to be linked to the presence of a stimulated renin-angiotensin system. Creager et al26 demonstrated that short-term captopril administration caused a reduction in forearm vascular resistance in sodium-depleted but not in sodium-replete healthy subjects. In addition, Webb et al27 demonstrated that intrabrachial infusion of enalaprilat did not alter resting FBF and vasoconstriction to application of LBNP in normotensive subjects with normal sodium intake. In contrast, the ACE inhibitor caused vasodilation in the same subjects after sodium depletion. Moreover, we produced evidence in hypertensive patients that both the direct vasodilator effect of intrabrachial captopril (unpublished observations, 1994) and the release of vascular Ang II–induced β-adrenoceptor stimulation20 are strictly related to the renin profile. Therefore, this accumulated evidence prompted us to design experiments for patients with an activated renin-angiotensin system. However, we acknowledge that this kind of selection could represent a limitation for the clinical significance of the present results.
Another possible theoretical limitation of this study resides in the agonistic properties of saralasin.28 However, this possibility seems unlikely because intrabrachial saralasin at the concentrations used in the present study is devoid of a direct constrictor effect on basal FBF and abolishes the forearm vasoconstriction to exogenous Ang II.
The present data cannot provide information on the origin of vascular renin, the key enzyme that activates the enzymatic cascade leading to vascular Ang II production. However, the findings that in both animal and human skeletal muscle circulation the effect of isoproterenol on local Ang II formation depends on circulating renin18 20 29 support the possibility that the enzyme may be taken up from plasma into the vessel wall.
Finally, although previous evidence has already demonstrated that oral administration of ACE inhibitors such as captopril30 and benazepril31 attenuates endogenous sympathetic vasoconstriction, the present study provides new insights into the mechanisms through which these compounds exert this effect. Thus, in addition to the classic blockade of conversion of Ang I to Ang II, it has been proposed that at least part of the pharmacological action of ACE inhibitors can be attributed to potentiation of endogenous kinins, especially bradykinin.32 33 However, the finding that benazeprilat shares the same sympathomodulatory action as saralasin would appear to indicate that at least the effect of ACE inhibitors on sympathetic nervous system activity is mediated by blockade of Ang II production.
In conclusion, the present data confirm in humans that Ang II exerts a potentiating action on sympathetic neurotransmission, probably through a presynaptic facilitation of norepinephrine release. This finding could be important for an in-depth understanding of the mechanism of action of antihypertensive drugs, such as ACE inhibitors and Ang II antagonists, which exert their cardiovascular activity mainly through blockade, at different levels, of the renin-angiotensin system pathway.
We thank Prof Mario Motolese for the gift of benazeprilat. Art work from Moreno Rocchi and technical support from Pierluigi Menichini are acknowledged.
Reprint requests to Dr Stefano Taddei, I Clinica Medica, University of Pisa, Via Roma, 67, 56100 Pisa, Italy.
- Received May 3, 1994.
- Revision received June 15, 1994.
- Accepted December 7, 1994.
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