Control of Carotid Vasomotor Tone by Local Renin–Angiotensin System in Normotensive and Spontaneously Hypertensive Rats
Role of Endothelium and Flow
Abstract To investigate the relation between the tissue renin–angiotensin system (RAS) and the local vasomotor tone of large arteries, we used in vitro isolated carotid arteries from 14-week-old Wistar-Kyoto rats (WKY; n=80) and spontaneously hypertensive rats (SHR; n=80). Diameters were measured with the use of an ultrasonic echo-tracking system (12 MHz) under flow (2 mL/min) (F+) or no-flow (Fo) conditions, with intact endothelium (Endo+) or after endothelium removal (Endo−). The role of tissue RAS was assessed by incubating isolated carotid arteries with an angiotensin-converting enzyme inhibitor (ACE I; lisinopril, 10−6 mol/L) or with a specific antagonist of angiotensin II AT1 receptors (AT1A; losartan, 10−6 mol/L). In addition, maximal dilation of carotid arteries was measured after poisoning with KCN (100 mg/L). In all experiments, KCN significantly increased carotid diameters (WKY, 23±0.9%; SHR, 19±0.8%; P<.001 versus control conditions). In intact carotid arteries, flow caused significant dilation in WKY (7±0.5%, P<.001) but had no effect in SHR. In the presence or absence of flow, ACE I and AT1A induced similar dilations in both strains, and a specific antagonist of bradykinin B2 receptors (Hoe 140, 10−7 mol/L) had no effect on ACE I–induced dilation. After endothelium removal, carotid artery diameters were significantly increased (P<.001) in both strains, although more in SHR (13±0.8%) than in WKY (8±1.1%) (P<.001). Also, flow did not modify the diameter of deendothelialized vessels and ACE I had no effect in either strain. In contrast, AT1A increased diameters further (WKY, 4±0.4%; SHR, 3±0.6%; P<.01). The results of the present study suggest that in in vitro isolated intact carotid artery, (1) the endothelium exerts a basal vasoconstrictor effect that is larger in SHR than in WKY, which could participate in the relative insensitivity to flow in SHR; (2) in the absence of exogenous substrate the vessel wall is able to produce angiotensin II, which is active locally on the vascular tone; and (3) inhibition of angiotensin II formation, not degradation of bradykinin, appears to be responsible for the local relaxing effect of ACE inhibition.
Ang II plays an important role in the homeostasis of blood pressure, electrolyte balance, and cardiovascular hypertrophy.1 The classic view of the RAS is that it is primarily a circulating system. However, from recent molecular and biochemical studies, all compounds of the RAS have been reported within the vessel wall, suggesting the existence of a vascular RAS.2 3 ACE, essentially localized within and at the luminal surface of endothelial cells, catalyzes the generation of Ang II and the degradation of bradykinin. These two peptides produce potent vasoactive effects that are either dependent on or modulated by the endothelium. Comparative studies of WKY and SHR have revealed an increased ACE tissue concentration in SHR despite a normal ACE plasma concentration.4 In a previous study,5 we reported that local inhibition of the RAS by incubation with an ACE inhibitor had an endothelium-dependent effect on the compliance of in situ isolated carotid arteries in both WKY and SHR. Furthermore, there is considerable evidence of endothelium-dependent control of the vascular tone by flow.6 However, there is no information about the possible influence of flow on the relation between local RAS and local vasomotor tone. Therefore, the aim of the present study was to determine, under Fo and F+ conditions, the role of the local RAS regarding the vasomotor tone of intact or deendothelialized carotid arteries from WKY and SHR.
Fourteen-week-old WKY (n=80) and age-matched SHR (n=80), weighing 410±12 and 370±15 g, respectively, were anesthetized with intraperitoneal sodium pentobarbital (50 mg/kg). After induction of anesthesia, the trachea was cannulated, and artificial respiration with room air was immediately started with the use of a rodent respirator (model 680, Harvard Apparatus). A midsternal thoracotomy and cervicotomy were performed. The roots of both left and right carotid arteries were carefully dissected and exposed. The distal end of each carotid artery was first ligated and then catheterized with a 9-gauge cannula and connected to a reservoir that was filled with Tyrode’s solution containing albumin (4%) and placed 130 cm above the animal. The presence of albumin in flushing and incubating solutions maintained a physiological osmotic pressure gradient across the arterial wall and preserved the endothelium integrity and functions.7 A second cannula, which pointed distal, was then inserted into the proximal ligated end of the carotid artery. With this procedure, a pressure of 130 cm H2O (≈100 mm Hg) was maintained within an isolated segment of carotid artery (20 to 23 mm long). The two cannulae were then clamped into a crossbar with two adjustable clamps that maintained the artery at its in vivo length and prevented shortening on excision. Removed carotid artery segments always pressurized were then immersed in a bath containing Tyrode’s solution (pH 7.4, 95% O2/5% CO2, 38°C). The isolated carotid artery was introduced into a closed hydraulic system and connected to a manometer pressurized to 100 mm Hg; to a peristaltic pump (Minipuls M312, Gilson), which can deliver a controlled nonpulsatile flow; and to a three-port reservoir filled with a controlled-pH albumin Tyrode’s solution (Fig 1⇓). Preliminary in vivo Doppler measurements indicated that the common carotid blood flow in 14-week-old WKY (n=8) and SHR (n=8) was 1.9±0.2 mL/min, with no difference between WKY and SHR. At the end of each experiment, the integrity of the carotid endothelium was tested by flushing Evan’s blue (0.03%) albumin solution into the vessel. Absence of blue staining of the luminal surface indicated that the endothelium remained unaltered. Experiments with damaged endothelium were discarded. Several series of experiments were performed in both WKY and SHR under Fo or F+ (2 mL/min) conditions and with intact or damaged endothelium. Endothelium was removed by gentle mechanical stripping with a blunt catheter guide (2F, 0.66 mm) introduced into the vessel. The carotid artery was then flushed to wash away the scraped endothelial cells. In preliminary experiments, we established that the medial layer was not damaged after removal of endothelium by ensuring that phenylephrine-induced (10−6 mol/L) contraction of the carotid before and after deendothelialization was unchanged and that acetylcholine-induced dilation was abolished.
Measurement of Arterial Diameter
Changes in the carotid artery diameter due to changes in transmural pressure were determined with an ultrasonic echo-tracking microdimensiometer (12 MHz) (Application Electronique Montreuil), which allowed continuous measurement of the arterial diameter. The arterial diameter was determined from the transit time of the pair of echoes given by the proximal and distal walls. This method allowed us to measure arterial diameter from 500 to 2000 μm, with an accuracy of measurement of more than 10 μm.
The isolated artery segment was first exposed to a pressure of 25 mm Hg for 5 minutes, and the diameter of the vessel was recorded. The artery then received stepwise increases in pressure of 25 mm Hg, from 25 to 200 mm Hg. Each pressure level was maintained for 5 minutes before the arterial diameter was noted. With the use of the diameter measurement at each pressure level, a pressure–diameter relation was constructed for each carotid segment.
In preliminary experiments, we tested the stability and reproducibility of our experimental model. Under control conditions, 20 minutes after installation of the segment of carotid artery into the experimental system, the diameter of the carotid maintained at a transmural pressure of 100 mm Hg remained unchanged for at least 2 hours, ie, longer than the duration of the experiments. Therefore, the effects of the tested pharmacological agents and of mechanical deendothelialization cannot be interpreted as a time effect on the experimental preparation.
The basic experimental design consisted of the measurement of the carotid diameter under control conditions after ACE I or AT1A and then after total abolition of smooth muscle tone by KCN poisoning. The procedure was applied to both WKY and SHR. Experimental conditions combining Fo or F+ conditions and intact or damaged endothelium were performed in groups of 10 SHR and 10 WKY.
Isolated carotid arteries from WKY (n=80) and SHR (n=80) were randomized into two groups: half were studied under Fo conditions (WKY, n=40; SHR, n=40), and half were perfused at a constant flow of 2 mL/min (F+) (WKY, n=40; SHR, n=40).
Each group of arteries (Fo and F+) was divided into two subgroups: arteries with intact endothelium (Endo+) and arteries with removed endothelium (Endo−).
In the first group (Endo+: WKY, n=20; SHR, n=20), diameter measurements were recorded under control conditions (Endo+) and after intraluminal incubation for 20 minutes with a non–sulfhydryl-containing ACE I (lisinopril, 10−6 mol/L) (Endo+/ACE I) or with a specific antagonist of AT1A (losartan, 10−6 mol/L) (Endo+/AT1A).8
In the second group (Endo−: WKY, n=20; SHR, n=20), after we recorded diameter measurements under control conditions (Endo+), the endothelium was removed. The artery was flushed, and diameters were measured 20 minutes after endothelium removal (Endo−) and then after 20 minutes of local incubation with lisinopril (10−6 mol/L) (Endo−/ACE I) or with losartan (10−6 mol/L) (Endo−/AT1A).
Finally, in all groups, the carotid segments were incubated with a saline solution of KCN (100 mg/L). The KCN solution was maintained in the vessel for 30 minutes, a period sufficient for total abolition of smooth muscle tone by poisoning of vascular smooth muscle cells, and the pressure–diameter relation was determined as described. Results are expressed as percent of the maximal diameter obtained after KCN poisoning at 100 mm Hg in both strains.
Several additional series of experiments were performed under Fo conditions. First, to assess the possible role of cyclooxygenase and lipoxygenase pathways in the vascular tone, we used a cyclooxygenase inhibitor (indomethacin, 2.10−5 mol/L: WKY, n=5; SHR, n=5) and a 5-lipoxygenase inhibitor (REV 5901, 3.10−6 mol/L: WKY, n=5; SHR, n=5). Drugs were added intraluminally 20 minutes after ACE I incubation (lisinopril, 10−6 mol/L) in arteries with intact endothelium.
Second, to determine the possible role of bradykinin in the vasomotor tone after ACE inhibition, intact carotid arteries were incubated in the presence of a noncompetitive bradykinin B2 receptor antagonist (Hoe 140, 10−7 mol/L) for 20 minutes before (WKY, n=5; SHR, n=5) and after (WKY, n=5; SHR, n=5) the addition of the ACE I (lisinopril, 10−6 mol/L).
Last, we tested the local effect of captopril (10−6 mol/L), a sulfhydryl-containing ACE I, on the vasomotor tone of carotid arteries (WKY, n=5; SHR, n=5).
Solutions and Drugs
Tyrode’s solution contained the following (in mmol/L): NaCl 137, KCl 2.68, CaCl2 1.8, MgCl2 0.526, NaHCO3 11.9, NaH2PO4 0.333, and glucose 5.56. Lisinopril, a non–sulfhydryl-containing ACE I, and losartan were supplied by Zeneca Pharma and DuPont-Merck Pharmaceuticals, respectively. Hoe 140 was a gift from Hoechst. Captopril, a sulfhydryl-containing ACE I; purified bovine serum albumin; indomethacin; acetylcholine; and phenylephrine were purchased from Sigma Chemical Co, and REV 5901 was purchased from Cayman Chemical Co.
Values are given as mean±SEM. The experimental model allowed us to use analysis of variance to provide evidence of differences related to strains (WKY or SHR), to treatment (ACE I, AT1A, or KCN), to endothelium conditions (Endo+ or Endo−), and to flow (Fo or F+). Differences between groups were evaluated with the use of Newman-Keuls test. Values of P<.05 were considered significant.
The Table⇓ gives the absolute values of carotid diameters obtained under the different experimental conditions in WKY and SHR.
Experiments Under No-Flow Conditions
The pressure–diameter relations obtained in WKY and SHR groups with intact endothelium under control conditions (albumin Tyrode’s solution) (Endo+/control) are presented in Fig 2⇓. The curves were approximately sigmoid, concave to the diameter axis in the low-pressure range (from 25 to 100 mm Hg), had an inflection point at intermediate pressure values, and then changed concavity in the high-pressure range (from 100 to 200 mm Hg). Two-way analysis of variance with pressure and rat strain as tested factors showed that over the entire range of pressure, the diameters of carotid arteries from SHR were significantly larger than those from WKY (P<.05).
KCN poisoning was used to determine the maximal diameter at each pressure level. In both strains, KCN poisoning of vascular smooth muscle cells induced a significant increase in the diameter of intact carotid arteries (P<.001) (WKY, Fig 3A⇓; SHR, Fig 3B⇓), indicating that the arterial smooth muscle exerted a basal vasomotor tone that was capable of significantly opposing the pressure-induced distension of the carotid artery. In previous experiments, we ensured that local incubation with KCN for 1 hour did not induce further relaxation. Under our experimental conditions, sodium nitroprusside incubation induced arterial dilation that was always less than or equal to but less stable than that obtained after KCN incubation.
Fig 4A⇓ shows that under Fo control conditions (Endo+/Fo: WKY, n=20; SHR, n=20 [albumin Tyrode’s solution]), mean carotid diameters measured at 100 mm Hg represented 78±1.4% and 82±1.2% of maximal values obtained after KCN poisoning in WKY and SHR, respectively. This result indicates that the reserve of diameter increase was significantly larger in WKY than in SHR (P<.01), even though absolute mean carotid diameters after KCN poisoning were significantly higher in SHR (1406±17 μm) than in WKY (1366±37 μm) (P<.01).
In intact carotid arteries (Endo+/Fo) (Fig 4A⇑), local incubation with ACE I (WKY, n=10; SHR, n=10) or AT1A (WKY, n=10; SHR, n=10) induced significant (P<.001) and similar dilations in both strains (WKY, 14±0.3% and 14±0.5%; SHR, 14±0.6% and 16±0.7%, respectively), but diameters remained significantly lower than those obtained after KCN poisoning in both strains (P<.001).
In both WKY and SHR, removal of the endothelium (Endo−/Fo: WKY, n=20; SHR, n=20) (Fig 4B⇑) induced significant relaxations (WKY, 8±1.1%; SHR, 13±0.8%; P<.001). Diameters in deendothelialized vessels remained significantly lower than those obtained after KCN poisoning (P<.001). Increases in diameter after endothelium removal were significantly larger in SHR than in WKY (P<.001).
In deendothelialized carotid arteries from both WKY and SHR, ACE I incubation (WKY, n=10; SHR, n=10) had no effect on the arterial diameter. In contrast, local incubation with AT1A (WKY, n=10; SHR, n=10) induced a further significant increase in carotid diameters compared with that obtained after endothelial removal (WKY, 4±0.4%; SHR, 3±0.6%; P<.01).
Experiments Under Flow (2 mL/min) Conditions
Perfusion of intact carotid arteries at a constant flow of 2 mL/min (Endo+/F+: WKY, n=20; SHR, n=20) significantly increased the diameter in WKY by 7±0.5% compared with Fo conditions (Endo+/Fo) (P<.001) but had no significant effect (1±0.2%) in SHR (Fig 5A⇓).
The maximal dilation obtained after KCN poisoning in both strains was not influenced by flow in intact or deendothelialized arteries (compared with the control diameter Endo+/Fo: WKY, 23±0.9%, P<.001; SHR, 19±0.8%, P<.001).
Local perfusion of carotid arteries with ACE I (WKY, n=10; SHR, n=10) or AT1A (WKY, n=10; SHR, n=10) induced further significant dilations in both strains (Fig 5A⇑) (WKY: 4±0.8%, P<.01, and 6±0.5%, P<.01, respectively; SHR: 7±0.4%, P<.001, and 6±0.7%, P<.001, respectively). In both strains, there was no significant difference between diameters obtained after either ACE I or AT1A incubation. However, because flow did not increase the diameter in SHR, the carotid dilation induced by ACE I or AT1A was significantly greater in SHR than in WKY (P<.01).
Perfusion had no effect on the diameter obtained after endothelium removal in either strain (WKY, n=20; SHR, n=20) (Fig 5B⇑), indicating the absence of flow-dependent dilation in deendothelialized carotid arteries.
In perfused deendothelialized vessels (Fig 5B⇑), the addition of ACE I (WKY, n=10; SHR, n=10) or AT1A (WKY, n=10; SHR, n=10) had no effect on the diameter in either WKY or SHR.
Additional Control Experiments Under No-Flow Conditions
Effect of Inhibition of Cyclooxygenase and 5-Lipoxygenase
In both strains, the combination of indomethacin (WKY, n=5; SHR, n=5) or REV 5901 (WKY, n=5; SHR, n=5) with ACE I did not modify the vasomotor effect of the ACE I alone. In WKY, the carotid diameter was 1272±18 μm after incubation with ACE I alone, 1281±21 μm after incubation with indomethacin and ACE I, and 1276±14 μm after incubation with REV 5901 and ACE I. In SHR, the diameter after incubation with ACE I alone was 1339±26 μm, 1342±21 μm after incubation with indomethacin and ACE I, and 1329±18 μm after incubation with REV 5901 and ACE I.
Effect of Bradykinin B2 Receptor Antagonist (Hoe 140)
In both strains, Hoe 140 did not significantly modify diameters measured after incubation of intact arteries with ACE I alone (WKY, 1210±22 μm after ACE I [n=5] and 1207±21 μm after ACE I plus Hoe 140 [n=5]; SHR, 1323±11 μm after ACE I [n=5] and 1325±12 μm after ACE I plus Hoe 140 [n=5]).
Effect of a Sulfhydryl-Containing ACE Inhibitor (Captopril)
In both strains (WKY, n=5; SHR, n=5), there was no significant difference between carotid diameters obtained after incubation with captopril or lisinopril (WKY, 1245±22 μm after lisinopril incubation and 1253±26 μm after captopril incubation; SHR, 1348±19 μm after lisinopril incubation and 1329±24 μm after captopril incubation).
The ultrasonic echo-tracking system represents a valuable technique for determining the pressure–diameter relation in in vitro isolated carotid arteries, with an accuracy of measurement of more than 10 μm.9 The use of isolated carotid arteries maintained at their physiological length and diameter allowed us to measure variations in smooth muscle tone without the need for preconstriction by vasoactive agents, which could result in modification of the arterial response to the RAS blockade with ACE I or AT1A.
Under control conditions (albumin Tyrode’s solution), the carotid diameter was significantly larger in SHR than in WKY. This is in agreement with previous in vivo findings regarding carotid artery diameter from normotensive rats and SHR10 and with results obtained in normotensive and hypertensive patients.11 Poisoning of smooth muscle cells by KCN at all pressures induced significant increases in diameter, indicating the important contribution of smooth muscle cells in the control of arterial diameter. This contribution is even more important in small than in large arteries.12 Resistance arterioles have been shown to have a greater ability to dilate and constrict than large conduit arteries.13
Role of RAS in Intact Arteries
Under Fo conditions, inhibition of ACE with an ACE I and blockade of Ang II AT1 receptors with a specific AT1A, losartan, induced in both strains marked and similar dilations of carotid arteries. However, the dilations were smaller than those obtained after KCN poisoning, indicating that there was still a significant reserve of carotid dilation in both strains. Several studies have reported that under F+ conditions, NO contributes to the vasodilation evoked by an ACE I via the decrease of bradykinin degradation.14 15 However, the addition of Hoe 140, an antagonist of bradykinin B2 receptors,16 did not modify the dilation observed after incubation with the ACE I alone, suggesting a minor role of bradykinin in the dilation induced by ACE I under our experimental Fo conditions. Moreover, the ACE I–induced dilation was not specific to the ACE I used; in both strains, no difference was observed between the effects of captopril or lisinopril on the carotid diameters.
Exposing isolated vessels to physiological flow induced significant dilation of carotid arteries from normotensive rats, which is in agreement with previous findings showing the existence of flow-dependent dilations in large arteries.13 17 This flow-dependent dilation was mediated by the endothelium, since it was abolished after endothelial removal in WKY. Flow-related shear stress is known to induce the release of vasodilating endothelial mediators—in particular, NO—in endothelial cell cultures as well as in perfused arteries from normotensive animals.18 19 However, in the present study, flow did not significantly modify the arterial diameter of isolated carotid arteries from SHR. In essential hypertension, endothelium-dependent vasodilation in response to acetylcholine has been reported to be altered.20 Koller and Huang21 reported that in response to perfusate flow, arterioles of SHR exhibited reduced dilation compared with normotensive rats. Likewise, we reported that the flow-dependent dilation was markedly reduced in conductance mesenteric arteries from SHR.22 However, flow-dependent vasodilation has been found intact in the forearm circulation of hypertensive subjects, although the response to acetylcholine was diminished.23
Incubation of isolated carotid arteries with ACE I and AT1A induced smaller dilations under F+ conditions than under Fo conditions. This was probably due to the fact that the initial diameter values were already increased by flow. However, under F+ and Fo conditions, vasodilation induced by either ACE I or AT1A was similar in WKY and SHR. Taken together, these results suggest that the RAS plays a role in maintaining the basal vasomotor tone of the carotid arterial wall and the observed dilation after ACE I may be related to a direct action on the Ang II formation, not to a decrease in degradation of bradykinin by ACE I. Furthermore, our results suggest that the vessel wall, in the absence of exogenous substrates of the RAS, is capable of generating Ang II, whose formation or action can be inhibited by an ACE I or a specific AT1A, respectively. Although this issue remains controversial, a complete RAS has been described within the vessel wall.2 3 Prorenin mRNA has been found to be present in endothelial and vascular smooth muscle cells.24 Angiotensinogen mRNA has been detected in the media and adventitia of the rat aorta.25 26 However, evidence for translation of this mRNA into active products remains elusive. It has also been postulated that renin in vascular tissue is taken up from plasma.27 28 The experiments in the present study did not allow us to determine whether renin and angiotensinogen shown to be in the vascular wall were either synthesized locally or previously taken up from plasma and stored in the wall to generate Ang II in the tissue.
Role of RAS After Endothelium Removal
Endothelial cells modulate underlying vascular smooth muscle tone by releasing endothelium-derived relaxing factors and endothelium-derived contracting factors.29 In the present study, under Fo conditions, endothelium removal induced significant increases in carotid diameter in both strains, showing that in intact carotid arteries the endothelium exerted a predominant vasoconstrictive tone in both WKY and SHR. Furthermore, the increase in diameter after endothelium removal was markedly larger in SHR than in WKY, suggesting that the endothelium of SHR secretes more vasoconstrictive agents than that of WKY. In earlier studies, production of constricting endothelial factors was observed in arteries obtained from both SHR30 31 and WKY.32 Several studies have shown that arachidonic acid caused endothelium-dependent contractions in canine femoral and pulmonary veins,33 canine basilar arteries,34 and rabbit aorta,35 blocked by the cyclooxygenase inhibitor indomethacin. In the present study, rat carotid dilation induced by ACE I was not affected by indomethacin or by REV 5901, a 5-lipoxygenase inhibitor, suggesting that neither prostaglandin nor leukotriene pathways play a significant vasoconstrictive role under our experimental conditions.
After endothelium removal, ACE I no longer had an effect on the carotid diameter in either strain. Therefore, pharmacological inhibition of ACE by ACE I and mechanical removal of the endothelium, which is known to contain most of the ACE, appeared to have similar effects on the local formation of Ang II, probably through the inhibition of conversion of Ang I to Ang II, and thus on the carotid smooth muscle tone. In both strains, after endothelium removal, incubation with AT1A had a small but significant relaxing effect. Recently, Arnal et al36 described the location of ACE in medial and adventitial layers of the vascular wall. Indirect evidence for the presence of converting enzyme in vascular smooth muscle is supported by studies with [3H]captopril,37 in which specific binding was found in the intima and adventitia of aortic wall, with little binding in the media. Moreover, André et al38 found that in response to Ang I, endothelium-denuded rat aortic rings contract and intracellular Ca2+ concentration increases in primary cultures of vascular smooth muscle cells free of endothelial cells, suggesting extraendothelial conversion of Ang I to Ang II. On the contrary, Gohlke et al,39 with an in vitro model of thoracic rabbit aorta, reported that removal of the aortic endothelium before intraluminal incubation with Ang I completely abolished the conversion of Ang I to Ang II. Therefore, the evidence that ACE exists in smooth muscle cells of the whole vessel wall and that it has sufficient activity to exert a physiological role in Ang II generation remains controversial. In the present study, incubation of deendothelialized arteries with an AT1A induced a further relaxation compared with endothelium removal or with ACE I conditions. This can be accounted for by the presence of a residual quantity of Ang II displaced by the AT1A. It might also be due to the existence of a non–ACE-dependent Ang II generation pathway, revealed by the AT1 receptor blockade.
In conclusion, the present study suggests that (1) the endothelium of carotid artery exerts a basal vasoconstrictor action that is larger in SHR than in WKY. This larger vasoconstrictor role of endothelium in SHR might be related to a relative insensitivity of carotid artery to flow in hypertensive rats, (2) all compounds of the RAS might be present in the wall of the excised carotid artery, and (3) inhibition of Ang II formation, and not degradation of bradykinin, could be primarily responsible for the relaxing effect of ACE I on smooth muscle cell tone of in vitro intact carotid artery.
Selected Abbreviations and Acronyms
|ACE (I)||=||angiotensin-converting enzyme (inhibitor)|
|Ang I or II||=||angiotensin I or II|
|AT1A||=||Ang II AT1 receptor antagonist|
|SHR||=||spontaneously hypertensive rats|
|WKY||=||Wistar-Kyoto rats (normotensive)|
This work was supported in part by MSD-INSERM grant 312004. We thank Zeneca Pharma, in particular Dr Catherine Wimart, for their help.
- Received May 2, 1994.
- Accepted April 11, 1995.
- © 1995 American Heart Association, Inc.
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