Chronic Converting Enzyme Inhibition Research Articles

Chronic inhibition of angiotensin converting enzyme lowers blood pressure in spontaneously hypertensive rats by attenuation of sympathetic tone: The role of enhanced baroreflex sensitivity

Spontaneously hypertensive rats (SHR) are characterized by sympathetic hyperactivity and insufficient parasympathetic activity, and their high blood pressure (BP) can be lowered by long-term inhibition of the renin-angiotensin system. The aim of our study was to determine the influence of chronic inhibition of angiotensin converting enzyme (ACE) by captopril on cardiovascular regulation by the sympathetic and parasympathetic nervous system. Implanted radiotelemetric probes or arterial cannulas were used to measure mean arterial pressure (MAP), heart rate (HR), and arterial baroreflex in adult SHR and Wistar-Kyoto (WKY) rats under basal or stress conditions. MAP and the low-frequency component of systolic blood pressure variability (LF-SBPV, marker of sympathetic activity) were greater in SHR than in WKY rats. Under basal conditions chronic captopril treatment reduced both parameters more effectively in SHR, and the same was true during acute restraint stress. HR was similar in control rats of both strains, but WKY rats showed greater heart rate variability (HRV), indicating higher parasympathetic activity. Captopril administration increased HR in both strains, whereas HRV was decreased only in WKY. Chronic captopril treatment improved the impaired baroreflex-HR control in SHR by increasing the sensitivity but not the capacity of vagal arm of arterial baroreflex. Captopril treatment attenuated BP changes elicited by dimethylphenylpiperazinium (DMPP, agonist of nicotinic acetylcholine receptors), especially in SHR, indicating that sympathetic nerve transmission is facilitated by angiotensin II more in hypertensive than in normotensive animals. Thus, chronic ACE inhibition improves baroreflex sensitivity and lowers BP through both central and peripheral attenuation of sympathetic tone.

Ontogenetic role of angiontensin-converting enzyme in rats: Thirst and sodium appetite evaluation

We investigated the influence of captopril (an angiotensin converting enzyme inhibitor) treatment during pregnancy and lactation period on hydromineral balance of the male adult offspring, particularly, concerning thirst and sodium appetite. We did not observe significant alterations in basal hydromineral (water intake, 0.3 M NaCl intake, volume and sodium urinary concentration) or cardiovascular parameters in adult male rats perinatally treated with captopril compared to controls. However, male offspring rats that perinatally exposed to captopril showed a significant attenuation in water intake induced by osmotic stimulation, extracellular dehydration and beta-adrenergic stimulation. Moreover, captopril treatment during perinatal period decreased the salt appetite induced by sodium depletion. This treatment also attenuated thirst and sodium appetite aroused during inhibition of peripheral angiotensin II generation raised by low concentration of captopril in the adult offspring. Interestingly, perinatal exposure to captopril did not alter water or salt intake induced by i.c.v. administration of angiotensin I or angiotensin II. These results showed that chronic inhibition of angiotensin converting enzyme during pregnancy and lactation modifies the regulation of induced thirst and sodium appetite in adulthood.

Effect of chronic inhibition of converting enzyme on proximal tubule acidification

The acute effect of angiotensin-converting enzyme inhibition (ACEi) on proximal convoluted tubule (PCT) function is well documented. However, the effect of chronic treatment is less known. The aim of this work was to evaluate the effect of chronic ACEi on PCT acidification (J(HCO(3)(-))). Rats received enalapril (10 mg.kg(-1).day(-1), added to the drinking water) during 3 mo. Micropuncture experiments were performed to measure the effect of chronic ACEi on J(HCO(3)(-)). Nitric oxide (NO.) synthesis in kidney cortex homogenates was assessed by quantifying the conversion of [(14)C]-L-arginine to [(14)C]-L-citrulline. Western blot analysis was performed to determine the abundances of V-H(+)ATPase and NHE3 isoform of the Na(+)/H(+) exchanger in proximal brush-border membrane vesicles (BBMV). Enalapril treatment induced an approximately 50% increase in J(HCO(3)(-)). Luminal perfusion with ethyl-isopropyl amiloride (EIPA) 10(-4)M or bafilomycin 10(-6)M decreased J(HCO(3)(-)) by approximately 60% and approximately 30%, respectively, in both control and enalapril-treated rats. The effect of EIPA and bafilomycin on absolute J(HCO(3)(-)) was larger in enalapril-treated than in control rats. Acute inhibition of NO. synthesis with N(G)-nitro-L-arginine methyl ester abolished the enalapril-induced increase in J(HCO(3)(-)). Cortex homogenates from enalapril-treated rats displayed a 46% increase in nitric oxide synthase (NOS) activity compared with those from untreated animals. Enalapril treatment did not affect the abundances of NHE3 and V-H(+)ATPase in BBMV. Our results suggest that PCT acidification is increased during chronic ACEi probably due to an increase in NO. synthesis, which would stimulate Na(+)/H(+) exchange and electrogenic proton transport.

Chronic converting enzyme inhibition normalizes QT interval in aging rats.

The aim of the present study was to investigate the effects of converting enzyme inhibition by captopril on ECG parameters in aged rats. Four-month-old male rats received captopril dissolved in tap water (0.5 mg/l) or tap water for 2 or 20 months. At the end of treatment, under anesthesia, RR and PR interval, P wave and QRS duration, QT and corrected QT interval were measured in all animals. On the following day, chronic ECG (lead II) recordings were performed to quantify supraventricular (SVPB) or ventricular premature beats (VPB). After sacrifice, the hearts were removed and weighed. RR interval was similar in young and untreated aged rats, but significantly larger in aged rats treated with captopril. P wave and QRS length did not differ among groups. PR interval was significantly larger in old than in young rats and was not affected by captopril. Corrected QT interval was larger in aged than in young rats (117 +/- 4 vs 64 +/- 6 ms, P<0.05) and was reduced by captopril (71 +/- 6 ms, P<0.05). VPB were absent in young rats and highly frequent in untreated old animals (8.4 +/- 3.0/30 min). Captopril significantly reduced VPB in old rats (0.3 +/- 0.1/30 min, P<0.05). The cardiac hypertrophy found in untreated aged rats was prevented by captopril (3.44 +/- 0.14 vs 3.07 +/- 0.10 mg/g, P<0.05). The beneficial effects of angiotensin converting enzyme inhibition on the rat heart during the aging process are remarkable.

Mechanisms of spontaneous baroreflex impairment in lyon hypertensive rats.

This experiment aimed at 1) comparing the spontaneous baroreflex sensitivity (SBRS) in Lyon genetically hypertensive (LH), normotensive (LN), and low blood pressure (LL) rats and 2) assessing some aspects of the mechanisms of its impairment in LH rats. Baroreflex was studied in control animals after an early chronic converting enzyme inhibition with perindopril and after a 4-wk infusion of ANG II in perindopril-treated rats. The SBRS was determined with a previously validated method, using statistical dependence between blood pressure (BP) and heart rate values recorded in freely moving animals. LH rats exhibited high BP, cardiac hypertrophy, and decreased SBRS (LH, 1.3 +/- 0.2; LN, 2.5 +/- 0.4; LL, 2.2 +/- 0.4 beats . min-1 . mmHg-1). Perindopril prevented the development of hypertension and cardiac hypertrophy and normalized SBRS. BP rose in LH and LL rats after ANG II infusion, but only LH rats, which developed a cardiac hypertrophy, had an impaired SBRS (LH, 1.1 +/- 0.2; LN, 2.5 +/- 0.2; LL, 2.8 +/- 0.3 beats . min-1 . mmHg-1). This impairment was partially reversed by an acute ANG II blockade with losartan. These results demonstrate that high BP does not account for the decreased SBRS in LH rats. SBRS impairment could result either from cardiac hypertrophy or from the direct effect of ANG II on the baroreflex loop.

787-1 ACE Inhibition Acutely Stimulates Sympathetic Tone and Improves Myocardial Contractility and Coronary Flow in Coronary Artery Disease. A Bradykinin-related Effect?

The acute effects of ACE inhibition on neurohormonal activation are complex. Sympathetic tone decreases as a direct result of angiotensin II reduction; however, an increase in bradykinin may stimulate sympathetic tone. Consequently, divergent coronary and systemic hemodynamic effects may ensue. As these acute ACE inhibitor effects are incompletely identified in humans, 49 pts with significant ( &gt; 70%) CAD received enalaprilat, perindoprilat or captopril intravenously, which resulted in immediate ( ≤ 5’) 73% ACE inhibition and a 52% reduction in arterial angiotensin II. Twenty-two patients received placebo. During a 15-minute study protocol, placebo induced no changes. In the treated group, arterial norepinephrine (NE) increased at 5 and 15 minutes by 11% and 12%, respectively, and arterial epinephrine (E) by 11% and 14%, respectively. Heart rate did not change, but contractility (V MAX ) increased by 13% and 4%, respectively. Mean arterial pressure (MAP) decreased by 2% and 5% and systemic vascular resistance (SVR) decreased by 4% and 7%, respectively. Despite the reduction in coronary perfusion pressure, coronary blood flow (CBFj increased by 8% at 5 minutes, while coronary vascular resistance ICVR) decreased by 10% and 11%, respectively, at 5 and 15 minutes. Arterial 6-keto-F2α, the prostacyclin metabolite, was 52% higher compared to placebo, but increased late, at 15 minutes. Other prostaglandins and cardiac neurohormonal balances remained unaltered. Thus, in contrast to the well-known modulation of sympathetic activity by chronic converting enzyme inhibition, acute ACE inhibition results in an immediate increase in circulating catecholamines and improves myocardial contractility and coronary flow. The effect on sympathetic tone and contractility cannot be explained by changes in circulating angiotensin II and prostaglandins or cardiac renin-angiotensin, which suggests a bradykinin-related effect.

Effect of Chronic Converting-Enzyme Inhibition on Kidney Function of Senescent Hypertensive Rats

Effect of Chronic Converting-Enzyme Inhibition on Kidney Function of Senescent Hypertensive Rats

Chronic converting enzyme inhibition facilitates baroreceptor resetting to hypertensive levels.

We investigated the acute and chronic effects of converting enzyme inhibitors (captopril or enalapril) and of angiotensin II receptor blockade (DuP 753) on rapid (30-minute) baroreceptor resetting elicited by a prompt and sustained hypertensive response provoked by aortic constriction. Pressure-nerve activity curves, pressure at 50% of maximal baroreceptor activity, baroreceptor gain (slope of the curve), and systolic threshold pressure for baroreceptor activation were determined as indexes of baroreceptor function. A slight fall in mean arterial pressure after acute treatment with the converting enzyme inhibitor or DuP 753 was accompanied by a partial leftward curve shift, which is associated with a partial threshold shift and increase in gain. A maintained hypertensive stimulus caused a partial rightward curve shift and partial (49% to 56%) threshold shift to hypertensive levels in both acutely treated and control rats. The hypertensive stimulus provoked a partial rightward curve shift and complete (88% to 94%) threshold shift to hypertensive levels in chronically treated rats. The effect of enalapril on baroreceptor function was unaltered by the bradykinin antagonist Hoe 140. These data demonstrate that chronic inhibition of converting enzyme or blockade of angiotensin II receptors facilitates rapid resetting of the baroreceptors to hypertensive levels caused by partial aortic constriction without a change in baroreceptor sensitivity.

Discrepancy between Lithium and Free Water Clearance in Patients with Bartter’s Syndrome

Lithium and free water clearance (CLi and CH2O) were measured simultaneously in 5 patients with Bartter's syndrome (BS), and the results were compared with values obtained in a large group of healthy control subjects. In line with the literature, fractional diluting segment reabsorption estimated from CH2O appeared to be subnormal in BS (82.4 +/- 4.7 versus 89.4 +/- 4.4% in controls, p < 0.01). Fractional delivery to this segment, expressed as the maximum urine flow during water diuresis (Vmax/glomerular filtration rate, GFR), also appeared to be reduced (11.3 +/- 1.6 versus 13.8 +/- 2.5%, p < 0.05), suggesting compensatory increased proximal reabsorption. In disagreement with the latter, CLi/GFR, alleged to be a measure of fractional sodium and water output from the proximal tubules, was increased (36.2 +/- 1.8 versus 30.7 +/- 5.1% in controls, p < 0.01), suggesting that suppressed proximal reabsorption could be the primary reabsorption defect in BS. During chronic converting enzyme inhibition with enalapril, given to treat hypokalemia (3 patients), the concordance between the two methods was restored because CLi/GFR fell by approximately 50%, whereas VMax/GFR did not change; the alleged diluting segment reabsorption defect remained present. These contradictory results lead to the conclusion that one of the two methods reflected the pattern of tubular sodium handling in BS incorrectly. However, the present study does not unequivocally indicate which method yielded erroneous results in this condition.

Effect of Chronic Converting-Enzyme Inhibition on Kidney Function of Senescent Hypertensive Rats

The age-related changes in the structure and the function of the kidney and the effect of chronic inhibition of angiotensin-converting enzyme (ACE) activity on these alterations were assessed in senescent, genetically hypertensive rats. Mean blood pressure was unchanged between 6 and 21 months, being 136 +/- 10 and 135 +/- 21 mm Hg, respectively. Hypertrophy of the glomeruli with a high incidence of glomerulosclerosis was reported in the 21-month-old animals. Renal blood flow, glomerular filtration rate, and filtration fraction were reduced between 6 and 21 months, whereas albuminuria and cGMP excretion were markedly enhanced with aging. Chronic ACE inhibition by administration of 0.3 mg/kg/day trandolapril from 18-21 months increased the life expectancy of the animals without affecting their mean blood pressure. The incidence of glomerular lesions and the excretion of enzymes that reflected the integrity of tubular and glomerular cells were not altered by ACE inhibition. On the other hand, the filtration fraction was restored in the 21-month-old treated animals, and the age-related albuminuria and rise in cGMP excretion were prevented by ACE inhibition. These results indicated that ACE inhibitor administered at the end of the life of senescent hypertensive rats was able to prevent some of the age-related changes in kidney function when glomerulosclerosis was already present.

Effect on exercise performance of enalapril therapy initiated early after myocardial infarction

Objectives. The Nordic Enalapril Exercise Trial was a multicenter subtrial of the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS II) designed to evaluate the effect on maximal exercise performance of a 6-month period of enalapril treatment initiated early after myocardial infarction.Background. When begun early after myocardial infarction, converting enzyme inhibition therapy has been shown to attenuate infarct expansion and reduce left ventricular volume. Therapy has been associated with improved exercise performance.Methods. Three hundred twenty-seven men (mean age 63.3 ± 10.9 years) with documented acute myocardial infarction were randomized to treatment with enalapril or placebo on a double-blind basis. Intravenous enalaprilat or placebo therapy was initiated within 24 h after the onset of symptoms. Oral therapy was continued at a target dose of 20 mg/day. Patients exercised maximally at 1 month and 6 months after infarction to symptom-limited end points on a cycle ergometer with a 20 W/min incremental protocol.Results. The treatment and control groups were comparable in patient age, concurrent therapy and type and site of infarction. At 1 month, for all patients, mean total work performed was 34.9 ± 20.9 kJ in the enalapril group (n = 169) versus 28.5 ± 20.6 kJ in the placebo group (n = 158) (difference = 18.4%, p < 0.01). This between-group difference in favor of enalapril was greatest in patients >70 years old (difference = 41.4%, p < 0.01, n = 105) and those with clinical evidence of heart failure (difference = 33.0%, p < 0.01, n = 122). At 6 months for all patients, mean total work performed was 35.4 ± 23.8 kJ in the enalapril group versus 34.0 ± 23.9 kJ in the placebo group (difference = 4.1%, NS).Conclusions. This trial found that chronic converting enzyme inhibition initiated early after myocardial infarction was associated with significantly greater exercise capacity in men tested at 1 month. This difference was independent of type or site of infarction, patient age or the presence of clinical heart failure. The difference between the treatment and control groups was not significant at 6 months because of improvement in the placebo group. Further research is needed to elucidate the potential mechanisms involved, profile those patients most likely to profit from early therapy and establish the optimal timing and duration for intervention.

Preventive effect of chronic converting enzyme inhibition on aortic stiffening induced by renovascular hypertension in conscious dogs

The aim was to assess the influence of the renin-angiotensin system on the geometrical and elastic properties of the aorta in conscious dogs, using a model of renovascular hypertension, and to examine the effects of inhibition of the system by the angiotensin converting enzyme inhibitor spirapril. The aortic elastic behaviour in response to renovascular hypertension was studied in 15 conscious dogs instrumented with a pressure microtransducer and a pair of ultrasonic diameter dimension gauges in the upper descending thoracic aorta. Renovascular hypertension was induced by surgical occlusion of one renal artery and stenosis of the other. One day after renal surgery, dogs were randomly assigned to two groups receiving for two months either the new angiotensin converting enzyme inhibitor spirapril (n = 8) or a placebo capsule (n = 7). The two groups of dogs were compared to a control group of normotensive dogs (n = 7). After two months of treatment the elastic properties of the aorta were studied by computation of the beat to beat pressure-diameter hysteresis loops obtained during transient increase of pressure induced by bolus doses of angiotensin. The aortic pressure-diameter (P-D) relationship, obtained over a wide range, was fitted by an exponential fit (P = alpha.e beta D), where beta is the stiffness index. A decomposition of the P-D curve according to a biphasic model of the parallel arrangement of elastin and collagen enabled two pressure-diameter elastic moduli to be obtained, one representing the resistance to stretch at low pressure levels (elastic fibres and smooth muscle), and the other representing the resistance to stretch at the highest pressures (collagen fibres). The pressure-diameter curve of the placebo group was shifted to the left compared to the curves of the control and spirapril groups, showing that renovascular hypertension was associated with isobaric reduction of aortic diameter. The stiffness index beta was higher (p < 0.05) in the placebo group [0.605(SD 0.304) mm-1] than in either the control group [0.362(0.126) mm-1] or the spirapril group [0.348(0.083) mm-1], suggesting that renovascular hypertension was associated with aortic stiffening. The biphasic analysis showed that the collagen pressure-diameter elastic modulus was unaffected by spirapril, whereas the elastin pressure-diameter elastic modulus was significantly reduced by converting enzyme inhibitor with respect to the placebo (p < 0.05). Chronic converting enzyme inhibition by spirapril prevents the isobaric aortic diameter reduction induced by renovascular hypertension in conscious dogs and decreases aortic stiffness, in particular by changing the elastic behaviour of the elastin fibres rather than of the collagen fibres.

Cardiovascular Pressor Reactivity After Chronic Converting Enzyme Inhibition

In addition to inhibiting the formation of angiotensin II, chronic converting enzyme inhibition may affect other blood pressure modulating factors. The influence of an 8 week treatment phase with cilazapril on the activity of the renin-angiotensin-aldosterone and sympathetic nervous systems, the pressor reactivity to infused angiotensin II or norepinephrine, the chronotropic response to isoproterenol, and body sodium and plasma atrial natriuretic peptide concentrations was assessed in 11 normal subjects and 12 patients with essential hypertension. As compared to a 4 week placebo phase, cilazapril decreased arterial pressure in both study groups (from 124/83 +/- 9/6 to 114/77 +/- 9/5 mm Hg and from 143/102 +/- 13/7 to 137/96 +/- 10/10 mm Hg; P less than .025); exchangeable sodium (-158 mmol and, respectively, -104 mmol) and upright plasma aldosterone (-24% and -15%) also tended to fall. Heart rate, the chronotropic response to posture or isoproterenol, plasma norepinephrine levels, the concentration/pressor response curve to norepinephrine, plasma atrial natriuretic peptide concentration, plasma angiotensin II and the responses of blood pressure or plasma aldosterone to angiotensin II were unchanged after 8 weeks of cilazapril. Plasma renin activity increased (+175% to +650%). These findings indicate that the blood pressure lowering effect of cilazapril in the stable phase of pharmacological intervention is not associated with modifications of sympathetic-dependent pressor reactivity or beta-adrenergic sensitivity. Plasma angiotensin II concentration and angiotensin II-dependent pathways including the pressor and aldosterone responsiveness to angiotensin II are also unchanged.

Converting Enzyme Inhibition Prevents Postprandial Hyperfiltration in Rats With Renal Mass Ablation

Food restriction or chronic converting enzyme inhibition (CEI) both limit age-related glomerulosclerosis and the associated proteinuria which occurs spontaneously in rats with renal mass ablation. Since hyperfiltration consecutive to the decreased number of nephrons may be damaging to the kidney, we investigated how fasting and CEI compare in lowering glomerular filtration rate in partially nephrectomized rats. Male Wistar rats were subjected to 3/4 nephrectomy and chronically catheterized. A week after surgery, the animals were separated into two groups, one control and one treated with the converting enzyme inhibitor perindopril (1 mg/kg/24 h) for ten days. In the control untreated 3/4 nephrectomized rats, successive measurements of kidney function in the same animal showed that renal blood flow and glomerular filtration were 30 to 50% higher in fed than in fasted animals. In the group treated with perindopril, there was no longer any such difference in the renal blood flow and filtration rate. These results indicate that, by blunting postprandial hyperfiltration, chronic converting enzyme inhibition is as effective as food restriction in reducing the load delivered to the kidney.

Remodeling of Heart and Arteries by Chronic Converting Enzyme Inhibition in Spontaneously Hypertensive Rats

Hemodynamic and structural changes of the heart and large arterial vessels were studied in normotensive and spontaneously hypertensive rats following 12 weeks administration of converting enzyme inhibitor (perindopril, 2 mg/kg daily by gavage). In both strains, a significant blood pressure reduction was observed. In normotensive rats, the hemodynamic changes involved significant increase in systemic arterial compliance whereas slight changes in left ventricular weight and aortic medial thickness were observed. In hypertensive rats, the increase in compliance was relatively small, whereas there was a major reduction in medial thickness. Furthermore, the reduction of the media thickness was much more pronounced than that of the left ventricular hypertrophy. The present results suggest that the cardiac and arterial changes observed following long term converting enzyme inhibition do not strictly parallel the blood pressure changes in hypertensive rats. Dissociation between cardiac and arterial changes may be observed.

Cytosolic free calcium of aorta in hypertensive rats. Chronic inhibition of angiotensin converting enzyme.

Cytosolic free calcium concentration ([Ca2+]i) and muscle tension were simultaneously measured in aortic tissue isolated from spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto (WKY) rats, and SHR chronically treated with a novel angiotensin converting enzyme inhibitor, CS-622. In the presence of 2.5 mM Ca2+ in the bathing solution, aortic [Ca2+]i measured with fura-2 was higher in SHR than in WKY rats, and it was almost the same in CS-622-treated SHR and untreated WKY rats. Increase of external Ca2+ concentration from zero to 2.5 mM elicited a contraction in SHR aortas but not in aortas from both CS-622-treated SHR and untreated WKY rats. When the aortas were contracted by 60 mM K+, however, [Ca2+]i as well as developed tension was similar in the three groups. CGP-28392 (10(-6) M), a Ca2+ channel activator, induced a rhythmic activity superimposed on a gradual increase of [Ca2+]i and tension in SHR aortas but not in the aortas of CS-622-treated SHR or untreated WKY rats. Nicardipine (10(-7) M) decreased the resting [Ca2+]i and the resting tone in SHR aortas, but not in WKY rat aortas. These results suggest that SHR aortas have a higher myogenic tone due to increased [Ca2+]i than WKY rat aortas and that the increased [Ca2+]i is attributed to alterations of dihydropyridine-sensitive Ca2+ channels in SHR aortas. Further, the decrease of the vascular tone induced by long-term administration of the angiotensin converting enzyme inhibitor may be due to a reduction of increased [Ca2+]i in SHR.

Preservation of the circadian rhythm of blood pressure and heart rate during chronic converting enzyme inhibition with quinapril in essential hypertension

Preservation of the circadian rhythm of blood pressure and heart rate during chronic converting enzyme inhibition with quinapril in essential hypertension

The role of tissue renin-angiotensin systems in hypertension and effects of chronic converting-enzyme inhibition

When inhibitors of the renin-angiotensin system (RAS) were initially developed, they were believed to act as antihypertensive agents mainly under pathophysiological conditions, in which an elevated plasma RAS contributed to the elevation and maintenance of high blood pressure (BP). However, evidence has accumulated from studies in hypertensive patients, as well as in animals, indicating that BP could be lowered by converting-enzyme inhibitors (CEIs) independently of whether or not the plasma RAS was stimulated. Several other effects had to be considered. It was thus discovered that converting enzyme (CE) is identical with the bradykinin-degrading enzyme, kininase II, and CEIs can therefore potentiate the vasodepressor effects of bradykinin and thereby interact with the prostaglandin system. Actions of CEIs possibly unrelated to inhibition of angiotensin and kininase also need to be considered. The actions of CEIs at the tissue level (brain, heart, blood vessels, kidney, adrenal gland) and their interference with the autonomic nervous system through central and peripheral actions may under certain conditions be more important than their inhibition of the circulating hormonal plasma angiotensin II. Recent clinical and experimental studies and new insights in the molecular biology of the RAS, especially gene expression of renin and angiotensinogen in tissues of the cardiovascular system, support this view. We have found that chronic CE inhibition with substances such as captopril, quinapril and lisinopril specifically affects angiotensinogen mRNA levels in cardiovascular tissues, and has marked effects on left ventricular hypertrophy, possibly through an action on cardiac angiotensin. These findings have consequences not only for the understanding of pharmacokinetics and pharmacodynamics of CEIs but also for their practical therapeutic use.

P-462 - Cytosolic free calcium of aorta in SHR: Effects of chronic inhibition of angiotensin converting enzyme

P-462 - Cytosolic free calcium of aorta in SHR: Effects of chronic inhibition of angiotensin converting enzyme

Chronic inhibition of angiotensin converting enzyme decreases Ca2+-dependent tone of aorta in hypertensive rats.

Long-term effects of a novel angiotensin converting enzyme (ACE) inhibitor, CS-622, on Ca2+-dependent tone in aortic smooth muscles of spontaneously hypertensive rats (SHR) were examined. CS-622 (3 or 10 mg/kg/day), when orally administered to SHR for 21 weeks, exhibited a dose-dependent antihypertensive action. In Krebs-Henseleit solution, removal of Ca2+ caused much greater relaxation in aortas excised from control SHR than those from SHR treated with CS-622. Restoration of Ca2+ from zero to 2.5 mM elicited a marked contraction in aortas from control SHR but only a small contraction in aortas from both CS-622-treated SHR and normotensive Wistar-Kyoto rats. These findings suggested that myogenic tone that resulted from increased Ca2+ permeability in aortas of SHR was suppressed by long-term treatment with CS-622. The aortic tone from the individual rats correlated well with systolic blood pressure in both CS-622-treated and control SHR. The exaggerated myogenic tone in aortas of SHR was attenuated in the medium containing nicardipine but was not altered in the presence of CS-622 diacid (active form of CS-622) at a concentration high enough to fully inhibit aortic ACE. The myogenic tone in normal Ca2+ concentration was not decreased in aortas excised from SHR treated with hydralazine (5 mg/kg/day) for 21 weeks. We conclude that after prolonged administration CS-622 reduced the high vascular tension resulting from increased Ca2+ permeability of vascular smooth muscle membrane in SHR and that the restoration of normal Ca2+ permeability of vascular smooth muscles may underlie long-term antihypertensive action of ACE inhibitors.