Effect of the non peptide angiotensin II antagonist,GR117289C on the vasoconstrictor actions of angiotensin II in the human forearm

AIMS: GR117289C is a non peptide, selective angiotensin (AT1) receptor antagonist. The purpose of this study was to determine whether this agent, given orally, could attenuate the vasoconstrictor effects of angiotensin II(AII) infused locally into the forearm circulation in man. METHODS: Eight healthy male subjects were studied on four occasions in a randomized, double-blind, placebo controlled, crossover study. Five hours (approximate time of peak dynamic effect) following dosing with GR117289C (300 mg, 100 mg, 10 mg or placebo), A II was infused in incremental doses (0, 0.1, 0.4, 1.6, 6.2, 25 and 100 pmol min-1) into the left brachial artery, each for 10 min. Forearm blood flow was measured using venous occlusion plethysmography. RESULTS: GR117289C inhibits the vasoconstrictor effects of A II in a dose dependent manner. The active treatment: placebo ratios of forearm blood flow in the infused arm during the highest dose of AII (100 pmol min-1) were: GR117289C 10 mg, 1.12 (95% C.I. 0.81-1.55; P = 0.478), 100 mg, 1.43 (95% C.I. 1.01-2.01; P = 0.042) and 300 mg, 1.62 (95% C.I. 1.17-2.24; P = 0.006). There was no significant difference in blood pressure between each of the treatment groups and placebo. CONCLUSIONS: GR117289C is a pharmacologically active, oral A II antagonist in healthy men.     

The angiotensin-converting enzyme gene polymorphism and responses to angiotensins and bradykinin in the human forearm

The deletion (D) allele of the angiotensin-converting enzyme (ACE) is associated with high ACE levels. Subjects homozygous for the D allele should therefore exhibit enhanced angiotensin I-induced vasoconstrictor responses and diminished bradykinin-induced vasodilator responses as compared with subjects homozygous for the insertion (I) allele. In eight II and eight DD normotensive male subjects, angiotensin I, bradykinin, and angiotensin II were infused in the forearm. Changes in forearm blood flow were registered with venous occlusion plethysmography. Blood was sampled to quantify angiotensin I to II conversion. Plasma ACE levels were 60% higher, and DD subjects showed an enhanced response to angiotensin I infusion (p < 0.05). No differences in angiotensin I to II conversion, angiotensin H vasoconstriction, and bradykinin vasorelaxation were found. The ACE-inhibitor enalaprilate inhibited angiotensin I-induced vasoconstriction, but did not significantly affect bradykinin-induced vasodilation. The AT1-receptor antagonist losartan (3,000 ng/kg/min) inhibited angiotensin II-induced vasoconstriction. In conclusion, subjects with the DD genotype display an enhanced vasoconstrictor response to angiotensin I, which cannot be explained on the basis of a similarly enhanced angiotensin I to II conversion rate or a difference in vascular reactivity. Possibly therefore, differences in angiotensin I to II conversion occur within the vascular wall only, at a site that does not readily equilibrate with blood plasma.     

Angiotensin converting enzyme inhibition does not affect the response to exogenous angiotensin II in the human forearm.

Suppression of endogenous levels of angiotensin II by angiotensin converting enzyme inhibition, may result in up-regulation of vascular AT1 receptors. We have evaluated the effects of orally administered enalapril on angiotensin II induced vasoconstriction in the human forearm. Subjects received in random order, enalapril (20 mg) or matched placebo daily for 2 weeks. Forearm blood flow response to increasing doses of angiotensin II was measured using venous occlusion plethysmography at the beginning of the study and at the end of each 2 week treatment period. Treatment with enalapril significantly reduced plasma angiotensin II levels and supine blood pressure compared with placebo. The percentage reductions in forearm blood flow in the infused arm, in response to the maximum dose of angiotensin II (50,000 fmol min-1) were 48.1 +/- 3.6% at baseline, 57.5 +/- 3.6% on placebo and 54.5 +/- 4.2% on enalapril. The differences were not significantly different. This demonstrates that suppression of plasma angiotensin II for a 14 day period does not enhance the response to exogenous intra-arterial angiotensin II in the human forearm of healthy salt replete subjects.     

Inhibition of neutral endopeptidase by thiorphan does not modify coronary vascular responses to angiotensin I, angiotensin II and bradykinin in the isolated guinea pig heart

Both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) are involved in the regulation of renin-angiotensin and kallikrein-kinin systems. The aim of the present study was to assess the role of NEPand ACE in the regulation of vascular responses to angiotensin I (Ang I), angiotensin II (Ang II) and bradykinin (Bk) in the coronary circulation. For this purpose we used typical inhibitors of ACE and NEP, perindoprilate (1 microM) and thiorphan (1 micromM and 10 microM), respectively, and analyzed their effects on the coronary vasoconstrictor responses to Ang I and Ang II and coronary vasodilator responses to Bk in the isolated guinea pig heart. Perindoprilate abolished coronary vasoconstriction induced by Ang I and potentiated coronary vasodilation evoked by Bk. Thiorphan at a concentration of 1 muM slightly reduced response to Ang I without a significant effect on the responses to Ang II and Bk. However, thiorphan at a concentration of 10 muM abolished coronary vasoconstrictor response to Ang I and enhanced Bk-induced vasodilation. Importantly, in the presence of perindoprilate, addition of thiorphan (10 microM) did not modify further either responses to Ang I, Ang II or to Bk. In conclusion, vascular responses induced by Ang I, Ang II and Bk in the isolated guinea pig heart are regulated by ACE but not by NEP. Moreover, thiorphan is not a perfect tool to asses functional role of NEP as it displays ACE inhibitory activity.     

The effect of HN-65021 on responses to angiotensin II in human forearm vasculature.

We studied the effect of (2-butyl-4-chloro-1[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]methyl]-1H-imadazole-5-carboxylic acid,-1-(ethoxycarbonyloxy) ethyl-ester (HN-65021), on angiotensin II induced vasoconstriction in forearm vasculature of eight healthy men. Placebo and HN-65021 (5, 10 and 100 mg) were administered orally. Forearm blood flow was measured by venous occlusion plethysmography during rising dose brachial artery infusions of angiotensin II (0.3-1000 pmol min-1) 2 h after dosing. HN-65021 inhibited angiotensin II, causing a shift to the right of the dose-response curve. Angiotensin II (100 pmol min-1) decreased mean blood flow in the infused arm by 63.1 +/- 3.2% when infused following placebo and by 49.9 +/- 4.3%, 50.7 +/- 3.5% and 36.4 +/- 2.8% following HN-65021 doses of 5.10 and 100 mg respectively. These results demonstrate that HN-65021 antagonises angiotensin II receptor mediated vasoconstriction in human forearm resistance vessels.     

Acute simultaneous stimulation of nitric oxide and oxygen radicals by angiotensin II in humans in vivo

Angiotensin II is a powerful vasoconstrictor and proatherogenic factor. It was recently suggested that the endothelium may influence the actions of angiotensin II by production of, for example, nitric oxide and superoxide. By using venous occlusion plethysmography, forearm blood flow was measured in 26 healthy subjects during intraarterial cumulative infusion of angiotensin II. In 14 subjects, the interaction between angiotensin II and NO was studied by infusion of angiotensin II before and after clamping NO availability at a fixed basal level by using N(G)-monomethyl-L-arginine (L-NMMA) and nitroprusside. During a "free" NO system, blood flow decreased on angiotensin II infusion from 2.70+/-0.30 ml/100 ml forearm/min to 1.38+/-0.15 ml/100 ml forearm/min, whereas during NO-clamp vasoconstriction was significantly enhanced (blood flow from 2.56+/-0.25 to 1.19+/-0.13; p<0.05 saline vs. NO clamp). In 12 other subjects, the interaction between angiotensin II and superoxide was evaluated by comparison of the effects of angiotensin II before and after coinfusion of vitamin C. Angiotensin II-induced vasoconstriction was significantly attenuated by vitamin C at higher dosages of angiotensin (saline, blood flow from 3.08+/-0.33 to 1.12+/-0.09; vitamin C, blood flow from 3.01+/-0.23 to 1.61+/-0.13; p<0.05 saline vs. vitamin C). Vitamin C had no effect on baseline forearm blood flow. In conclusion, this study demonstrates that the constrictor actions of angiotensin II are enhanced during NO clamp and attenuated during vitamin C, suggesting direct angiotensin II-associated stimulation of endothelial NO and of oxygen radicals, respectively, in humans in vivo.     

Inhibition of angiotensin converting enzyme with enalapril maleate in infants with congestive heart failure.

We studied the inhibition of angiotensin converting enzyme (ACE) in eight infants with congestive heart failure (CHF) poorly controlled with digoxin and diuretics, treated orally with 0.25 mg kg-1 enalapril maleate once a day. Baseline ACE activities were compared between these infants and control children without CHF or ACE inhibitor. Except for one infant who vomited, inhibition of ACE activity was 75.5 +/- 12.2%, 75.5 +/- 10.5% and 51.7 +/- 12.2%, at 4, 12 and 24 h after drug intake respectively. There was no correlation between postnatal age and inhibition of ACE activity. In infants with CHF, mean baseline ACE activity was significantly higher than in control infants (36.4 +/- 7.2 mu ml-1 vs 26.9 +/- 6.9 mu ml-1, P < 0.05). These results were very similar to those seen in adults.     

Statin therapy increases vascular sensitivity to angiotensin II in hypercholesterolaemic patients.

Cross-talk between various cardiovascular risk factors has been suggested by a number of studies. This study examines the interaction between hypercholesterolaemia and the renin-angiotensin system in vivo in man. METHODS: We performed a randomised, placebo-controlled, double-blind crossover study on 40 hypercholesterolaemic patients, comparing cholesterol-lowering therapy with a statin for six months versus placebo. Brachial artery function was assessed by bilateral venous occlusion plethysmography using intra-arterial infusions of the endothelial-dependent vasoconstrictors, angiotensin I (Ang I) and angiotensin II (Ang II), to measure vascular angiotensin-converting enzyme (ACE) and Ang II receptor response respectively. The endothelial-independent vasoconstrictor, noradrenaline, was used as a control vasoconstrictor. Results were analysed by multiple analysis of variance and statistical significance was taken as a p value <0.05. RESULTS: Cholesterol-lowering treatment with a statin significantly reduced the mean total cholesterol level to 5.71 mmol/L vs. 7.57 mmol/L on placebo (p<0.0001). Hypercholesterolaemia significantly increased the vasoconstriction response to noradrenaline (placebo versus statin treatment; p=0.046). In hypercholesterolaemia, there was a strong trend towards a reduction in the vasoconstriction response to Ang I (placebo versus statin treatment; p=0.089). In hypercholesterolaemia, the vasoconstriction response to Ang II was significantly reduced (placebo versus statin treatment; p=0.01). CONCLUSIONS: Our in vivo results show that, unlike some other previous work, hypercholesterolaemia is associated with down-regulation of the vasoconstrictor response to Ang II and that statin therapy up-regulates the local vasoconstrictor response to Ang II. The possibility now arises that, in man, statins alter the balance between AT(1)-receptors and AT(2)-receptors.     

Post-exercise reduction in blood pressure in hypertensive subjects: effects of angiotensin converting enzyme inhibition

1. Much attention has been given to the effects of various classes of antihypertensive drugs on blood pressure and haemodynamics. The effects of a single bout of exercise on post-exercise blood pressure have also been studied by several investigators. However, the combined effects of prior exercise and antihypertensive medication has drawn less attention. 2. We examined the separate and combined effects of a single bout of exercise and of angiotensin converting enzyme (ACE) inhibition with a new ACE inhibitor (fosinopril, 20 mg day(-1)) on post-exercise blood pressure and systemic and regional haemodynamics. Ten patients with mild-to-moderate hypertension were studied with a double-blind, randomized crossover, placebo- and rest period-controlled study design. 3. At rest, mean arterial pressure (MAP, -10 +/- 2 mm Hg), total peripheral resistance (TPR, -11 +/- 5%) and forearm vascular resistance (FVR, -17 +/- 8%) were significantly (P < 0.05) reduced during ACE inhibition as compared with the placebo phase. 4. During the placebo phase, MAP (-3 +/- 1 mm Hg), TPR (-10 +/- 4%) and FVR (-9 +/- 4%) were lower after exercise as compared with the control rest period. 5. During ACE inhibition, MAP (-3 +/- 1 mm Hg) and TPR (-8 +/- 4%) were lower, but FVR (+32 +/- 15%) was increased after exercise as compared with the control rest period. 6. Thus, blood pressure and TPR decreased similarly after exercise during the placebo phase and during ACE inhibition. However, differences in post-exercise forearm haemodynamics during the placebo phase and during ACE inhibition indicate that underlying regional haemodynamics are modified.     

Effects of the angiotensin type I receptor antagonist, losartan, on systemic and regional vascular responses to lower body negative pressure in healthy volunteers.

1. The effects of a single oral dose (50 mg) of the angiotensin II AT1-receptor antagonist, losartan, on the systemic and regional vascular responses to simulated orthostatic stress by the lower body negative pressure (LBNP) technique were investigated in nine healthy volunteers, in a double-blind, placebo-controlled crossover study. 2. Arterial blood pressure remained unchanged throughout the study. Three hours after its administration and before LBNP, losartan selectively increased renal blood flow (PAH clearance) by 8.3% (3.5 to 13.1%, 95% CI) from 1.25 +/- 0.08 l min-1 (P < 0.05) and decreased plasma aldosterone levels by 58% (29 to 87%, 95% CI) from 22 +/- 3 ng 100 ml-1 (P < 0.05). 3. LBNP at -10 and -20 mm Hg induced a progressive and significant decrease in central venous pressure and increases in forearm (plethysmography) and splanchnic (indocyanine green clearance) vascular resistances which were similar after losartan and placebo administrations. Losartan blunted the LBNP-induced increase in renal vascular resistance observed at -20 mm Hg after placebo but a similar increase in glomerular filtration rate (inulin clearance) was observed at LBNP -10 and -20 mm Hg after losartan and placebo. Calculated filtration fraction increased after placebo (LBNP -10 mm Hg) and losartan (LBNP -20 mm Hg). Finally, LBNP-induced changes in biological parameters were similar after losartan and placebo at all levels of LBNP. 4. Thus, losartan does not interfere with the adaptive forearm and splanchnic vascular responses and preserves renal haemodynamics during orthostatic stress simulated by LBNP in healthy volunteers.     

High dietary sodium blunts affects of angiotensin-converting enzyme inhibition on vascular angiotensin I-to-angiotensin II conversion in rats

High sodium intake blunts the efficacy of angiotensin (Ang)-converting enzyme (ACE) inhibition (ACEi), but the underlying mechanism is incompletely characterized. High sodium has been reported to increase vascular expression and vascular activity of ACE. To investigate whether high-dietary sodium-induced effects on vascular conversion of Ang I might be involved in the sodium-induced blunting of the response to ACEi, the authors studied the vasoconstrictor responses to Ang I and Ang II of isolated aortic rings from healthy rats on low dietary sodium (LS: 0.05% NaCl) and high dietary sodium (HS: 2.0% NaCl) after 3 weeks of ACEi (lisinopril 75 mg/L) or vehicle (CON). Blood pressure was similar in LS and HS in CON, but HS blunted the blood pressure response to ACEi. Functional conversion of Ang I was assessed as the difference in dose-response curves to Ang I and Ang II in parallel aortic rings. Sodium intake did not affect the dose-response curves to Ang I and Ang II in CON. In the ACEi groups, a significant difference was present between the curves for Ang I and Ang II on LS (deltaEC50, 6.7 nM; range, 2.2-13 nM; P < 0.01) but not on HS (deltaEC50: 1.3 nM; range, 0.0-4.1 nM, median [interquartile range], NS). Thus, HS blunts the ACEi-induced reduction of functional vascular Ang I conversion compared with LS. Whether the blunted functional vascular conversion is causally related to the blunted blood pressure response remains to be elucidated.     

Vascular effects of quinapril completely depend on ACE insertion/deletion polymorphism.

INTRODUCTION: The angiotensin-converting enzyme (ACE) DD-genotype is associated with increased plasma and myocardial ACE-activity. The influence of the ACE insertion/deletion (I/D) polymorphism on the effects of ACE-inhibition on vascular responses has not been previously described. MATERIALS AND METHODS: In the randomised, double-blind QUinapril On Vascular ACE and Determinants of Ischemia Study (QUO VADIS), 149 patients undergoing coronary bypass surgery were randomised to receive either the ACE inhibitor, quinapril, or placebo. In 82 patients, we obtained ACE-genotype, and measured vascular responses to angiotensin II (Ang II) in left internal mammary arteries. RESULTS: In the placebo group, the mean maximal vasoconstriction to Ang II was significantly lower in patients with the DD-genotype than in those with the ID/II genotype (36.2+/-5.11% [n=13] vs. 55.6+/-4.57% [n=25]; p=0.01). In the quinapril group, the mean maximal vasoconstriction to Ang II was similar between DD- and ID/II-genotype (59.6+/-9.19% [n=8] vs. 57.7+/-4.07% [n=35]; p=0.85). CONCLUSIONS: DD-genotype patients showed decreased vascular responses to Ang II but treatment with quinapril completely restored the decreased vascular response in DD-genotype patients to the same level as II/ID-genotype patients, while no effect of quinapril was demonstrated in the II/ID-genotype patients.     

C-peptide has no effect on forearm blood flow during local hyperinsulinaemia in healthy humans

BACKGROUND: C-peptide increases forearm blood flow (FBF) in patients with Type 1 diabetes, probably by interaction with insulin, but not in healthy subjects. It is unclear if the vasodilating effect is sealed at normal fasting insulin concentrations. METHODS: The effects of C-peptide alone and during local hyperinsulinaemia were studied in healthy young men. Subjects received intra-arterial insulin at 6 pmol min-1 (low dose) or placebo for 60 min with subsequent coinfusion of C-peptide at increasing doses of 2-60 pmol min-1 in a double-blind crossover study (n = 8). In control experiments insulin at 30 pmol min-1 (high dose) was coinfused with C-peptide (n = 3). FBF was measured by strain-gauge plethysmography. RESULTS: Placebo had no effect on FBF (mean percentage change from baseline at 50 min -3.1%, 95% confidence interval [CI]-14.9, + 8.7). Insulin infusion slightly enhanced FBF by + 10.2% (95% CI -6.8, + 27.2; low dose) and + 17.6% (95% CI -38.8, + 74.0; high dose), respectively. The mean individual difference of the change in FBF between low-dose insulin and placebo was + 13.3% (95% CI -6.0, + 32.7; P = NS). Infusion of C-peptide increased local C-peptide concentrations from 1.8 +/- 0.1 ng ml-1 to 6.1 +/- 2.8 ng ml-1, but had no effect on FBF during placebo or hyperinsulinaemia (mean difference vs low dose insulin -16.0%, 95% CI -38.9, + 6.9). CONCLUSION: The vasodilating effect of C-peptide seen in Type 1 diabetes is not detectable during fasting or hyperinsulinaemia in the forearm vasculature of healthy subjects. This suggests saturation of its vasodilating potency at insulin concentrations within the normal or in the supraphysiological range.     

Anti-atherosclerotic effects of an angiotensin converting enzyme inhibitor and an angiotensin II antagonist in Cynomolgus monkeys fed a high-cholesterol diet.

1. We investigated the relationship between angiotensin II formation and the development of atherosclerotic lesions in the aorta of monkeys (Macaca fascicularis) fed a high-cholesterol (4% cholesterol and 6% corn oil) diet for 6 months, and studied the effects of an angiotensin converting enzyme (ACE) inhibitor, trandolapril (10 mg kg-1 per day, p.o.), and an angiotensin II type 1 receptor antagonist, 2-butyl-4-(methylthio)-1-[[2'[[[(propylamino)carbonyl]amino]sulfonyl] (1,1'-biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate (HR 720; 20 mg kg-1 per day, p.o.). 2. The level of low-density lipoprotein was significantly increased by the cholesterol diet, whereas that of high-density lipoprotein was significantly decreased. The relative areas of the atherosclerotic lesions in the thoracic aorta in the normal and cholesterol-diet groups were 1.3+/-0.3 and 64+/-10%, respectively. 3. Plasma renin and ACE activities showed no differences between the normal and cholesterol-diet groups. ACE activity and the concentration of angiotensin II were significantly increased in the aorta of the cholesterol-fed monkeys. 4. Trandolapril and HR 720 decreased significantly the area of the atherosclerotic lesions in the thoracic aorta of cholesterol-fed monkeys, but not the mean blood pressure and the levels of low-density and high-density lipoproteins. 5. In plasma and aorta, trandolapril, but not HR 720, decreased significantly the ACE activities in the cholesterol-fed monkeys, while both of these drugs decreased significantly the angiotensin II levels. 6. In conclusion, blockade of angiotensin II function in vascular tissues by trandolapril or HR 720 may play an important role in preventing the development of atherosclerotic lesions.     

Effect of hypoxia on the conversion of angiotensin I to II in cultured porcine pulmonary endothelial cells

Earlier studies by other investigators have shown that acute exposure of cultured endothelial cells to hypoxic atmospheres inhibits the activity of the angiotensin converting enzyme in situ, resulting in severe but reversible depression of the rate of degradation of bradykinin. We exposed primary cultures of endothelial cells from the pulmonary artery of the pig to a range of hypoxic gas mixtures and measured the activity of the angiotensin converting enzyme in situ using angiotensin I as substrate. Each cell flask was exposed in random sequence to both hypoxic gas mixtures (PO2 29-69 torr) and room air for 40 min in Dulbecco's medium containing angiotensin I at concentrations of 1000 (N = 7), 500 (N = 8) or 100 ng/ml (N = 4). Angiotensin I disappearance rates and angiotensin II generation rates were linear. Recovery of immunoreactive peptide as either angiotensin I or II following 40 min of incubation was 86 +/- 17% (S.D.). The rate of increase in angiotensin II concentration in surface medium in room air experiments was 91 +/- 51 (S.D.) ng x ml-1 x hr-1. During hypoxia it was 85 +/- 42 ng x ml-1 x hr-1. The difference in rates was not significant by paired t analysis. The results of this study are consistent with earlier observations by the authors which suggest that hypoxia-induced depression of angiotensin I conversion in vivo is due to hemodynamic phenomena. Further studies are needed to clarify the role of cellular mechanisms in hypoxia-induced depression of angiotensin metabolism.     

Quantification of pulmonary capillary endothelium-bound angiotensin converting enzyme inhibition in man

Angiotensin converting enzyme (ACE, kininase II) is an endothelial luminal ectoenzyme expressed abundantly on the pulmonary capillary endothelium and recognized as the site for the conversion of circulating angiotensin I to II. In the present study, we have applied recently developed methodologies for assaying pulmonary capillary endothelium-bound (PCEB) ACE activity in man, to estimate the interaction of an ACE inhibitor (enalaprilat) with PCEB ACE in human subjects. Trace amounts of the specific ACE substrate, 3H-benzoyl-Phe-Ala-Pro (3H-BPAP; 40 Ci or 2 nmol), was injected as a bolus into the subclavian vein and immediately blood was withdrawn from a radial arterial catheter. Plasma concentrations of surviving substrate and product (3H-benzoyl-Phe) were estimated and BPAP utilization was calculated during a single transpulmonary passage, at baseline (T(0)) and at 15 min (T(15)) and 2 h (T(120)) after intravenous administration of 1.5 g/kg enalaprilat in 12 normotensive subjects. This treatment had no significant effect on mean arterial pressure (91+/- 6 vs. 84 +/- 7 vs. 88 +/- 6 mm Hg for T(0), T(15) and T(120), respectively), but significantly decreased serum and PCEB ACE activities. When normalized to predrug (T(0)) activity levels, enalaprilat inhibited PCEB and serum ACE activities at T(15) 74 +/- 6% and 68 +/- 6%, respectively. However, 2 h after enalaprilat (T(120)), PCEB ACE inhibition was maintained at 66 +/- 7%, whereas serum ACE inhibition was reduced to 46 +/- 8% (P<.01 from PCEB ACE), suggesting a preferential PCEB ACE inhibitory effect of enalaprilat.     

Glucocorticoid induction of angiotensin converting enzyme

Angiotensin converting enzyme (ACE) converts angiotensin I (Angio I) to angiotensin II (Angio II) and inactivates bradykinin (BK). Glucocorticoids in the physiological range increase ACE in rabbit alveolar macrophages and bovine endothelial cells in culture. Since Angio I and BK are cleaved by ACE catalysis during passage through the pulmonary vasculature we have studied the steroid modulation of ACE in the rat lung. The conversion of Angio I to Angio II by isolated lungs from normal or adrenalectomized male Wistar rats has been evaluated. The initial conversion of Angio I to Angio II in lungs from normal rats was about 60%. In contrast the initial converting activity in lungs from adrenalectomized rats was about 30%. In both groups the converting activity progressively decreased. After 3 h it was about 30% in normal lungs and virtually undetectable in lungs from adrenalectomized rats. Dexamethasone infusion (1 microgram/ml) prevented the decrease in ACE activity observed in normal lungs and induced a gradual enhancement of converting activity in lungs from adrenalectomized animals up to the control level. The effect of dexamethasone was abolished by simultaneous infusion of cycloheximide (1 microgram/ml). These results demonstrate that glucocorticoids induce ACE synthesis in the rat lung. By this induction glucocorticoids promote the increase of both Angio II formation and BK degradation. Thus ACE induction may represent a possible mechanism whereby glucocorticoids might control vascular tone and permeability according to the general mode of action of steroid hormones.     

Cigarette smoking in men and vascular responsiveness

AIMS: Smoking is a major risk factor for developing atherosclerosis. In order to understand the vascular abnormalities observed in smokers, we investigated vascular responsiveness in cigarette smokers. METHODS: We performed two consecutive matched group comparative studies to investigate vascular responsiveness using venous occlusion plethysmography. The mean effects of three incremental doses of each vasoactive agent are presented. Both studies compared smokers with nonsmokers. RESULTS: The first investigated 68 subjects (smokers = 29; mean +/- s.d. ages; 24 +/- 6 vs 25 +/- 5 years; P = NS) and found smoking was associated with a significant blunting of the flow ratio between treated and untreated arms to endothelium-dependent vasodilatation to acetylcholine (mean +/- s.d., nonsmokers vs smokers) 4.07 +/- 2.18 vs 3.42 +/- 1.79 (P = 0.04, 95% CI 0.02, 1.12). By contrast, there was no significant difference in the responses to the endothelium-independent vasodilators sodium nitroprusside and verapamil. Smoking was also associated with a significant impairment in endothelium-dependent vasoconstriction induced by monomethyl-L-arginine (L-NMMA) 0.78 +/- 0.22 vs 0.87 +/- 0.21 (P = 0.006, 95% CI -0.14, -0.02) and a trend to blunted endothelium-independent vasoconstrictor responses to noradrenaline. In the second study we investigated the response to angiotensin I and II in 23 subjects (smokers = 12; mean +/- s.d. ages; 34 +/- 10 vs 32 +/- 11 years). There was significant impairment in smokers of the mean vasoconstrictor response to angiotensin I 0.51 +/- 0.15 vs 0.59 +/- 0.16 (nonsmokers vs smokers; P = 0.003, 95% CI -0.13, -0.03) and a nonsignificant trend towards impairment of the response to angiotensin II. CONCLUSIONS: Cigarette smoking in male volunteers is associated with blunted basal and stimulated nitric oxide bioactivity. Endothelial independent vasodilator responses (to nitroprusside and verapamil) were unaltered in smokers. A defect in the vasoconstrictor response to angiotensin I was also seen.     

Increased vascular angiotensin II binding capacity and ET-1 release in young cardiomyopathic hamsters

Heart failure (HF) is a multifactorial and progressive disease that has been associated with multiple systemic and vascular alterations. Previous reports from our laboratory showed that in 2-month-old Bio-To2 Syrian cardiomyopathic hamsters (SCH) that have not yet developed the clinical manifestations of HF, the vascular contractility induced by 0.1 microM angiotensin II was approximately 35% greater than in control animals. This finding was observed concomitantly with an increased aortic ACE activity. To further evaluate the mechanisms underlying angiotensin II-enhanced vascular contraction, concentration-response curves for angiotensin II (0.01 nM-10 microM) were constructed before and after the addition of prazosin (alpha-1 blocker), NS-398 (selective COX-2 blocker) and BQ-123 (ET-1A-receptor antagonist) in aortic rings from 2-month-old SCH. The binding capacity and affinity of the AT-1 receptors were also evaluated in aortic homogenates using 125I-angiotensin II. Age-matched golden hamsters were used as controls (CT). Our results indicate that incubation with either 10 microM prazosin or 10 microM NS-398 did not modify EC50 or Emax values for angiotensin II indicating that norepinephrine and prostaglandins are not involved in the enhanced contractile action of angiotensin II. However, 10 microM BQ-123 reduced by 40% the contraction induced by 1.0 microM angiotensin II (from 1.05+/-0.04 to 0.6475+/-0.06 g/mg tissue, n = 5, P < 0.05), suggesting that in cardiomyopathic hamsters, the action of angiotensin II is mediated in part by ET-1. At lower angiotensin II concentration (0.1 microM), the ET-1-dependent contraction decreases to 29%. In addition, although dissociation constants for labeled angiotensin II were found to be similar in the aorta of SCH and control animals (K(D): CT = 7.8 nM and SCH = 5.1 nM), 125I-angiotensin II binding capacity was about 2-fold greater in SCH than in controls (Bmax: SCH = 1113 and CT = 605 fmol/mg protein). Altogether these results suggest that in 2-month-old SCH the enhanced response of angiotensin II in the vasculature is mediated both by an increased binding capacity for the hormone and facilitation of the ET-1 action.     

The effect of captopril on the superior mesenteric artery and portal venous blood flow in normal man.

1. Measurements of superior mesenteric artery and portal venous blood flow were made non-invasively along with systemic and other regional (cardiac index, forearm and cutaneous blood flow) vascular responses to acute ingestion of the ACE inhibitor captopril (50 mg) or placebo (50 mg vitamin C), in 12 healthy subjects while supine and during head-up tilt. 2. After captopril, superior mesenteric artery and portal blood flow rose markedly with a reduction in superior mesenteric artery vascular resistance. Supine blood pressure was unchanged but cardiac index and forearm blood flow rose; during head-up tilt, blood pressure fell in some subjects. 3. There was a rise in levels of plasma renin activity and a fall in levels of plasma angiotensin II after captopril. After placebo, there were no significant changes in splanchnic blood flow, systemic or other regional responses and in biochemical measurements, while supine. 4. Our studies indicate that captopril is a potent dilator of the splanchnic vascular bed and suggest that this action may contribute to its therapeutic effects. The studies indicate a role for angiotensin II in the control of this large vascular bed although other agents (bradykinin, prostacyclin) may contribute.