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K. A. Rolls P. A. Phillips K. Aldred K. J. Hardy 《Clinical and experimental pharmacology & physiology》1994,21(3):227-230
1. Since plasma renin activity is increased in cyclosporin A (CsA)-induced hypertension in the rat, the role of the vascular renin-angiotensin system (RAS) in CsA-induced hypertension was investigated in rat mesenteric resistance vessels. 2. Female Wistar rats received CsA (10 mg/kg per day, s.c.) or vehicle for 30 days. CsA treatment increased tail-cuff systolic blood pressure (CsA treated 135 ± 3 mmHg vs control 125 ± 1 mmHg, P<0.0001). 3. Mesenteric resistance arteries (200–300 μm) were isolated and mounted in a microvessel myograph. Concentration-response curves to tetradecapeptide renin substrate (10-11-10?6 mol/L), angiotensin I (10-l1-10?6 mol/L) and angiotensin II (10-12-10?6 mol/L) showed no differences between CsA-treated and control groups. 4. Mesenteric vascular angiotensin-converting enzyme (ACE) characteristics were determined by radioligand binding. There were no differences in the content or affinity of ACE between CsA-treated and control rats. 5. These results suggest that the mesenteric vascular RAS does not play a major role in CsA-induced hypertension in the rat. 相似文献
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EFFECTS OF CHRONIC CONVERTING ENZYME INHIBITION ON THE VASCULAR RENIN-ANGIOTENSIN SYSTEM 总被引:3,自引:0,他引:3
Hiroshi Saito Mitsuaki Nakamaru Hiromi Rakugi Hiroshi Mikami Toshio Ogihara Tadashi Inagami 《Clinical and experimental pharmacology & physiology》1990,17(11):745-753
1. The effects of chronic oral administration of inhibitors of angiotensin converting enzyme (ACE) on the vascular renin-angiotensin system were studied. 2. Male Sprague-Dawley rats were treated orally with five ACE inhibitors, captopril, enalapril, ramipril, cilazapril and CS-622 (10 mg/kg per day), for periods of 1-2 weeks. Their mesenteric arteries were then isolated and perfused in vitro with Krebs'-Ringer solution, and the angiotensin II (AII) released into the perfusate was measured under unstimulated and isoproterenol-stimulated conditions. The vascular renin activity was also determined after treatments with ACE inhibitors. 3. Treatment with captopril for 1 week suppressed the isoproterenol-stimulated increase in AII release, but had little effect on the baseline release. Oral treatment with captopril for 2 weeks or with other ACE inhibitors for 1 week markedly inhibited both the unstimulated and stimulated release of AII from the mesenteric vasculature. 4. Both the vascular renin activity and the plasma renin activity increased on captopril treatment, but their changes with time were different. 5. These results indicate that virtually complete inhibition of the vascular renin-angiotensin system can be achieved after prolonged treatment with ACE inhibitors, and suggest that the chronic antihypertensive action of ACE inhibitors is not solely due to inhibition of the plasma renin-angiotensin system. 相似文献
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Jørgen Jacobsen Knud Poulsen 《Clinical and experimental pharmacology & physiology》1990,17(6):445-451
1. Combined high performance liquid chromatography (HPLC) and radio-immunoassays were used to study the in vivo kinetics of the renin-angiotensin system in the rat. The HPLC-verified plasma concentrations of angiotensin I (AI) were 1.0 nmol/L (0.52-1.6) in anaesthetized normal and 4.2 nmol/L (2.5-7.0) in salt-depleted rats. The plasma concentrations of angiotensin II (AII) were 0.07 nmol/L (0.04-0.13) in anaesthetized normal and 1.0 (0.60-1.6) nmol/L in salt-depleted rats. 2. The fate of injected AI and AII passing through the vascular bed of the lungs was determined. Two-thirds of the injected AI was converted to AII and one-third was unchanged after a single passage through the lungs. Only trace amounts of angiotensin III (AIII), the only other metabolite, were demonstrated. 3. This verifies that the majority of AI is metabolized through AII. Injected AII disappeared from the circulation with formation of only trace amounts of AIII, the half-life being about 10 s. This corresponds to a calculated in vivo generation rate of AII of about 12 nmol/L per h in normal rats. It is in agreement with the AI generation rate (plasma renin activity) measured as 9.5 nmol/L per h in vitro. 相似文献
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Ian G. Crozier M. Gary Nicholls Hamid Ikram Eric A. Espiner Tim G. Yandle 《Clinical and experimental pharmacology & physiology》1989,16(5):417-424
1. To determine the response of plasma atrial natriuretic peptide (ANP) to treatment with an angiotensin converting enzyme (ACE) inhibitor in heart failure, seven patients (NYHA Functional Class III-IV) were studied before and after the addition of ramipril to maintenance digoxin and diuretic treatment. 2. Baseline arterial ANP levels were raised, but fell during ramipril treatment in parallel with changes in both haemodynamic recordings (arterial pressure, pulmonary artery diastolic pressure, and right atrial pressure) and hormone levels (angiotensin II and aldosterone). 3. Coronary sinus ANP, measured in three patients, was greater than concomitant arterial levels, and the coronary sinus ANP secretion rate was calculated to be between 15 and 119 pmol/min. 4. These results demonstrate that improvement in haemodynamic function during ACE inhibitor treatment is associated with a decline in elevated ANP levels, and support the concept that atrial stretch or pressure regulates the secretion of atrial peptides in man. 相似文献
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W. P. Anderson S. E. Selig R. L. Woods A. I. Gilchrist 《Clinical and experimental pharmacology & physiology》1987,14(8):641-647
1. Angiotensin II was infused into the renal artery of unanaesthetized dogs at 0.4 and 2.0 ng/kg per min for 40 min each. 2. Indomethacin (3 mg/kg, and 1 mg/kg per h infusion i.v.) accentuated the angiotensin II-induced falls in glomerular filtration rate, renal blood flow and urine flow rate. Indomethacin did not alter the effects of angiotensin II on Na+ or K+ excretions. 3. Aspirin (35 mg/kg p.o. 2.5 h and 0.5 h prior to experiment) did not significantly change the renal effects of angiotensin II. 4. Both aspirin and indomethacin accentuated renal vasoconstriction during briefer (5 min) angiotensin II infusion. 5. Thus indomethacin and aspirin had markedly different effects on the actions of angiotensin II in the kidney. This suggests that at least one of these drugs has actions which affect angiotensin II-mediated vasoconstriction other than via cyclooxygenase inhibition. 相似文献
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1. Conscious rats which had undergone unilateral renal artery constriction were infused for 1 h with a specific antagonist of angiotensin II, 1-Sar-8-Ala-angiotensin II (P-113). 2. There was a highly significant correlation between the change in blood pressure induced by P-113 and the pre-infusion plasma renin concentration (PRC), regardless of initial blood pressure or the duration of stenosis. However, the blood pressure fall was not significantly greater in nineteen hypertensive rats than in eleven which remained normotensive. P-113 did not abolish the hypertension. 3. The extent to which angiotensin II supports blood pressure in rats with renal artery constriction is directly related to the PRC. 相似文献
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María Elena Ibarra-Rubio Cristino Cruz Edilia Tapia José Carlos Peña José Pedraza-Chaverrí 《Clinical and experimental pharmacology & physiology》1990,17(6):391-399
1. Serum angiotensin converting enzyme activity (ACEA) and plasma renin activity (PRA) were determined in rats under different experimental conditions such as: nephrotic syndrome (NS), bilateral nephrectomy (BN), renovascular hypertension (RH), dehydration (DEH), anaesthesia (AN), low sodium diet (LSD) and high sodium diet (HSD), and injection with propranolol (PRO) and isoprenaline (ISO). 2. PRA increased in LSD, AN, NS, RH, DEH and IPT groups, and decreased in HSD, BN, and PRO groups. Serum ACEA did not change in RH, HSD, IPT, DEH, AN, and PRO groups, increased in NS group, and decreased in LSD and BN groups. 3. Serum ACEA changed in the opposite direction to PRA only in the LSD group. This finding suggests that ACE may limit the full expression of the renin-angiotensin system in the LSD group, but not in the other groups. 相似文献
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A. E. Doyle S. B. Harrap J. Torresi 《Clinical and experimental pharmacology & physiology》1986,13(7):563-568
Treatment with the potent angiotensin converting enzyme inhibitor perindopril completely prevented any rise in blood pressure in the 2-kidney, 1-clip (2K1C) model of renal hypertension in rats. Withdrawal of this inhibitor was followed by a slow rise in blood pressure. In 2K1C rats treated with perindopril, pressor responses to angiotensin I fell during the treatment period, but returned to normal after the inhibitor was stopped. Pressor responses to angiotensin II (AII) increased during treatment with perindopril; this was presumably due to increased receptor sensitivity consequent on the falls in endogenous AII levels. Responses to AII fell to control levels after the inhibitor was stopped. It is concluded that an increased pressor sensitivity to AII is not the cause of the slowly developing hypertension in the 2K1C model of hypertension, and that the slow pressor response to AII must be due to other factors. 相似文献
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VASCULAR ACTIONS OF ENDOTHELIN IN THE RABBIT KIDNEY 总被引:6,自引:0,他引:6
K. M. Denton W. P. Anderson 《Clinical and experimental pharmacology & physiology》1990,17(12):861-872
1. The effect of two doses of endothelin, 10 and 50 ng/kg per min, i.v., on glomerular filtration rate (GFR), tubular stop flow pressure and pre- and post-glomerular vascular resistance have been studied in anaesthetized rabbits. 2. Blood pressure did not change significantly in response to 10 ng/kg per min endothelin or vehicle infusion, but rose steadily during infusion of 50 ng/kg per min endothelin, increasing 11.8 +/- 2.7 mmHg by 90 min of infusion. 3. Glomerular filtration fraction (3H-inulin extraction ratio) rose and remained elevated throughout the endothelin infusion at 50 ng/kg per min. GFR did not change significantly until 70-90 min of the infusion (50 ng/kg per min) when it decreased by about 35%. No significant changes were seen at 10 ng/kg per min endothelin. 4. Sodium excretion rate rose in response to the lower dose, due to an increase in fractional sodium excretion. No changes in sodium excretion were seen at the higher dose of endothelin. 5. Glomerular capillary pressure rose significantly in response to endothelin infusion (50 ng/kg per min). 6. Renal blood flow fell progressively in response to endothelin (50 ng/kg per min), to about one-third of the pre-infusion value. 7. Renal vascular resistance increased progressively with both doses of endothelin, by about 35% at 10 ng/kg per min and about 400% at 50 ng/kg per min after 70-90 min. Preglomerular resistance increased from 1.0 +/- 0.1 to 5.0 +/- 1.9 mmHg/mL per min in response to endothelin 50 ng/kg per min. Postglomerular resistance rose from 1.0 +/- 0.1 to 5.6 +/- 2.17 mmHg/mL per min. 8. Thus endothelin infusion caused progressive renal vasoconstriction with similar magnitude increases in both pre- and postglomerular vessels. The vasoconstriction of the kidney caused by endothelin occurred at a dose which did not effect systemic blood pressure. 相似文献
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A. Semplicini G. P. Rossi S. Bongiovì F. Perissinotto B. Samà M. G. Mozzato A. C. Pessina 《Clinical and experimental pharmacology & physiology》1986,13(1):17-24
Aldosterone suppression is said to play a major role in the long term hypotensive efficacy of angiotensin converting enzyme inhibitors. However, in previous reports from other laboratories, plasma volume has been found mostly increased and sodium balance sometimes positive. The effects of the angiotensin converting enzyme inhibitor enalapril (10-40 mg/day, p.o., for 6 weeks) on blood pressure, body fluid volumes, renal function and plasma aldosterone were compared to those of hydrochlorothiazide (50 mg/day, p.o.) alone for 2 weeks and in association with propranolol (80-160 mg/day, p.o.) for 4 more weeks during a randomized double-blind parallel study in 14 essential hypertensives. Hydrochlorothiazide alone and in combination with propranolol induced slight and not significant change in either blood pressure and body fluids. The maximum hypotensive response to enalapril was achieved only after 2 weeks of continuous treatment possibly because after 1 week the hypotensive efficacy was lessened by a significant (P less than 0.05) fluid retention secondary to a transient and not significant fall in renal perfusion. At this time aldosterone was not significantly changed compared to pretreatment values. After 6 weeks on enalapril, blood pressure was significantly reduced, plasma aldosterone further but not significantly decreased and extracellular fluid volume was normal. These findings indicate that aldosterone suppression contributes to the blood pressure lowering effect of enalapril by offsetting the salt and water retention observed on starting treatment and due to direct vasodilation. 相似文献
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1. Acute sodium loading causes a rapid decrease in the circulating concentration of angiotensin II (AngII), which is apparent from 5 min after sodium administration. This could result from an increase in AngII catabolism and/or a decrease in AngII synthesis/secretion. However, the major determinant of AngII synthesis is thought to be a change in plasma renin activity, which occurs over a longer time frame (15 min). 2. To investigate the mechanisms underlying the rapid decrease in plasma AngII engendered by sodium administration, we performed metabolic clearance studies in male New Zealand white rabbits before and after a hypertonic sodium load of 1.5 mmol/kg as 0.513 mol/L saline i.v. bolus. 3. The metabolic clearance rate of AngII increased significantly from 42.2 ± 9.0 mL/min per kg before sodium to 110.8±33.7 mL/min per kg after sodium administration (P<0.05). The calculated or theoretical secretion rate decreased from 1470.7±404.2 to 573.5 ± 139.5 fmol/min per kg (P<0.025) in response to sodium. 4. We conclude that an increase in AngII metabolism and a decrease in synthesis/secretion contribute to the reduction in circulating AngII, which occurs in the first 60–90 min after sodium loading. 相似文献
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EFFECTS OF LOSARTAN ON THE CARDIOVASCULAR SYSTEM, RENAL HAEMODYNAMICS AND FUNCTION AND LUNG LIQUID FLOW IN FETAL SHEEP 总被引:1,自引:0,他引:1
Kathleen M. Stevenson Karen J. Gibson Eugenie R. Lumbers 《Clinical and experimental pharmacology & physiology》1996,23(2):125-133
1. The angiotensin type 1 (AT1) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125–132 days gestation). Losartan reduced the fetal systolic (P < 0.01) and diastolic (P < 0.01) pressor response to 5 μg angiotensin II (AngII) i.v. from 27.4 ± 1.5 to 7.4 ± 0.9 and from 17.5 ± 1.3 to 5.4 ± 0.6 mmHg, respectively, after 1h and to 6.1 ± 0.5 and 4.4 ± 0.5 mmHg, respectively, after 2h. Maternal pressor responses to 5 μg AngII i.v. were unchanged. Fetal mean arterial pressure decreased (P < 0.05) after losartan administration, but fetal heart rate did not change. 2. Fetal haematocrit increased (P < 0.05), fetal PO2 decreased (P < 0.01), PCO2 did not change and pH decreased (P < 0.01), as did plasma bicarbonate levels (P < 0.01) following administration of losartan. Thus, losartan induced a fetal metabolic acidosis. 3. Fetal placental blood flow did not change following administration of losartan. In the fetal kidney, losartan caused a decrease in vascular resistance (P < 0.01) and an increase in blood flow (P < 0.05). Glomerular filtration rate decreased (P < 0.05); thus, filtration fraction decreased (P < 0.01). There was no change in the fractional reabsorption of sodium and glomerulotubular balance was maintained. Free water clearance decreased (P < 0.01) and became negative. Urine flow decreased (P < 0.01), the excretion rates of sodium, potassium and chloride did not change, but the urinary sodium:potassium ratio decreased (P < 0.05). There was a decrease in lung liquid flow (P < 0.05) following losartan. 4. It is concluded that the fetal renin-angiotensin system (RAS) is important in the maintenance of fetal arterial pressure, the regulation of fetal renal blood flow and is essential in the maintenance of fetal glomerular function. Further, these actions of AngII are mediated via functional AT1 receptors. These effects of losartan on the fetal cardiovascular system, renal blood flow and function are similar to those observed following captopril administration. Thus, the effects of angiotensin converting enzyme (ACE) inhibition in the foetus are due to the blockade of the fetal RAS and are independent of any direct effects on bradykinin or prostaglandin levels. 相似文献
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E. Marelyn Wintour J. R. Blair-West† Elizabeth H. Brown J. P. Coghlan† D. A. Denton† J. Nelson† Catherine J. Oddie† B. A. Scoggins† G. T. Whipp R. D. Wright† 《Clinical and experimental pharmacology & physiology》1976,3(4):331-342
1. The peripheral blood concentrations of aldosterone, corticosterone and cortisol were measured during pregnancy in conscious, undisturbed sheep. 2. Aldosterone levels did not change during pregnancy and the mean pregnant value, 1·2 s.d. 1·4 ng/100 ml (n= 12) was not significantly different from the non-pregnant value, 2·1 s.d. 1·7 (n= 16). 3. Cortisol levels likewise were unchanged by pregnancy–non-pregnant values were 0·56 s.d. 0·50 μg/100 mi (n= 12) compared with 0·46 s.d. 0·40 μg/100 ml (n= 16) in pregnant sheep. 4. Sheep of 110–140 days gestation had a 400 mmol greater total exchangeable sodium than non-pregnant sheep. Plasma volume and plasma renin concentration tended to be elevated near to term. 5. Very high aldosterone secretion rates and peripheral blood levels could be produced in pregnant sheep by stress, intravenous ACTH or angiotensin II infusions, and by sodium deficiency. It is suggested that the pregnant sheep may show increased sensitivity in contrast to non-pregnant sheep to these stimuli and the enlarged size of their adrenals may be a contributing factor. 相似文献
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Shelley A. Klemm Richard D. Gordon Terry J. Tunny Wendy L. Finn 《Clinical and experimental pharmacology & physiology》1990,17(3):191-195
1. Plasma potassium and chloride concentrations were raised and plasma renin activity, aldosterone, bicarbonate and arterial pH were reduced in two brothers with the syndrome of hypertension and hyperkalaemia with normal glomerular filtration rate (Gordon's syndrome), on unrestricted or moderately restricted sodium diets. 2. These abnormalities were corrected in both patients within 10 days of severe sodium restriction. 3. Pressor sensitivity to cold and angiotensin II decreased on low sodium diet, associated with a fall in blood pressure. 4. Increasing distal tubular sodium delivery by infusion of normal saline increased fractional excretion of potassium when aldosterone had been stimulated by severely restricted sodium diet, but not when aldosterone levels were low on unrestricted sodium diet. 5. These findings are consistent with excessive sodium reabsorption as the primary renal lesion in Gordon's syndrome, leading to volume expansion and suppression of renin and aldosterone. Severe dietary sodium restriction leading to volume contraction, by stimulating renin and aldosterone and promoting kaliuresis, corrects the abnormalities. 相似文献
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DEVELOPMENT OF ANGIOTENSIN CONVERTING ENZYME IN FETAL LUNG AND PLACENTA OF THE RAT AND HUMAN 总被引:2,自引:0,他引:2
Angiotensin converting enzyme (ACE) activity in fetal lung and placenta was determined by the method of Cushman and Cheung (1971) during the second trimester of human pregnancy and throughout the rat gestation. The enzyme activity in the neonatal rat lung was also determined during the first 19 days of life. The enzyme activity in both tissues of both species increased with gestation. The activity in human fetal lung at the end of the second trimester was already 70% of that present in the adult human lung while rat fetal lung enzyme activity at term was only 15% of the adult value. The activity in the term placenta of the human and rat was respectively 13% and 5% that of the adult lung value. Developmental increases in enzyme activity continued in the neonatal rat lung till adult value at about 19 days postpartum. The pattern of fetal lung enzyme development in the rat resembled that of the rabbit fetal lung as determined by other investigators using different techniques but was different from that of the human. The findings support the suggestion that ACE in the lung and placenta play important roles in the maintenance of circulatory homeostasis during the latter part of gestation, at birth and early postpartum, albeit at a different extent in different species. 相似文献
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Erkadius J. Di Iulio F. Lucente C. Bramich T. Morgan R. Di Nicolantonio 《Clinical and experimental pharmacology & physiology》1994,21(3):239-242
1. To examine whether the uterine environment plays a role in the development of hypertension in the spontaneously hypertensive rats (SHR), we have compared fetal weight, placental weight, and amniotic fluid composition of SHR and Wistar-Kyoto (WKY) rats after 20 days of gestation. 2. Pregnant SHR and WKY were anaesthetized at 20 days of gestation and the uterus and embryonic sacs removed. Fetal and placental weights were recorded and amniotic fluid collected for measurement of volume, osmolality and electrolyte composition. 3. No significant difference was found in litter size and placental weight between SHR and WKY. Total embryonic sac weight and fetal weight of SHR were significantly lower than WKY. Amniotic fluid volume, sodium concentration and osmolality of SHR were significantly higher than WKY, while amniotic fluid potassium concentration of SHR was significantly lower than WKY. 4. Thus, the SHR foetus was significantly underweight compared to the WKY and was bathed in amniotic fluid with a significantly higher osmolality and sodium concentration. As the mature foetus is known to drink amniotic fluid, it is hypothesized that the elevated Na/K ratio in SHR amniotic fluid may instigate or accelerate the hypertensive process. 相似文献
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1. In two experiments severe hypertension (systolic blood pressure 180 mmHg) was induced in rats by constricting one renal artery with a silver clip (two-kidney, one clip hypertension; 2KIC). Blood pressure, plasma renin activity (PRA) and body weight were measured for 35 days after clipping. Plasma sodium concentration and carcass sodium content were measured at the conclusion of the experiment. To determine the relationship between sodium intake, PRA and the development of severe hypertension, half of the rats were given a normal diet and water to drink; the other half were given a low sodium diet and 0-9% saline to drink. 2. In both experiments, two patterns of responses were observed. Group (1) had reduced growth rate, and marked elevation of PRA. Some, but not all of these animals had histological evidence of malignant nephrosclerosis in the untouched kidney. In the other group (11), weight gain was normal and PRA was normal or only slightly elevated. 3. Group 1 animals drinking saline, had raised carcass sodium levels, whereas those drinking water had no increase in carcass sodium. 4. The results confirm that hypertension in the 2KIC model is not always associated with a raised PRA. 5. The coexistence of a raised PRA and increased total body sodium suggests that the PRA does not rise as a result of sodium depletion in this model. 相似文献