Renal side-effects of cyclo-oxygenase-type-2 inhibitor use.
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Aged↗
Biomedical subjects
G A Riegger
Publications and source records attributed to G A Riegger.
Lipoprotein lipase gene polymorphism, cholesterol subfractions and myocardial infarction in large samples of the general population.
OBJECTIVE: Genetic variants of the lipoprotein lipase gene have been associated with dyslipidemia and coronary artery disease. However, data have been inconsistent and are mainly based on selected predominantly male patient groups. METHODS: We evaluated the influence of the HindIII restriction fragment length polymorphism on lipid levels in the general population (1361 participants of a large population-based survey from Augsburg, Germany; 50% women) as well as the association of this polymorphism with the risk of myocardial infarction (MI; genotype frequencies in 1159 patients with documented MI under 60 years of age). RESULTS: In the population-based survey, a highly significant association between the frequent H2H2 genotype and unfavorable cholesterol subfraction levels was observed in men and in postmenopausal women whereas no significant association was observed in premenopausal women (uni- and multivariate analysis). Such unfavorable lipid levels in homozygotes for the H2 allele may be expected to be associated with a 19-25% increased risk to suffer from myocardial infarction (MI). Nevertheless, genotype and allele frequencies in the general population were not different from those in patients with previous MI (H2H2 genotype frequency 51.3% vs. 53.2%, respectively; P=0.63). CONCLUSION: This large study shows that the H2H2 genotype of the lipoprotein lipase gene polymorphism is associated with unfavorable lipid levels. Estrogen status may modulate this association in women. The effects of the genotype on lipid levels were apparently not strong enough to reveal a significant association with MI.
Adult↗
Effects of chronic hypoxia on renal renin gene expression in rats.
BACKGROUND: The effects of hypoxia on renin secretion and renin gene expression have been controversial. In recent studies, we have demonstrated that acute hypoxia of 6 h duration caused a marked stimulation of renin secretion and renal renin gene expression. This hypoxia-induced stimulation of the renin-angiotensin system might contribute, for example, to the progression of chronic renal failure and to the development of hypertension in the sleep-apnoea syndrome. For this reason, we were interested in the more chronic effects of hypoxia on renal renin gene expression and its possible regulation. METHODS: Male rats were exposed to chronic normobaric hypoxia (10% O(2)) for 2 and 4 weeks. Additional groups of rats were treated with an endothelin ET(A) receptor antagonist, LU135252, or a NO donor, molsidomine, respectively. Systolic blood pressure and right ventricular pressures were measured. Renal renin, endothelin-1 and endothelin-3 gene expression were quantitated using RNAase protection assays. RESULTS: During chronic hypoxia, haematocrit increased to 72+/-2%, and right ventricular pressure increased by a mean of 26 mmHg. Renal renin gene expression was halved during 4 weeks of chronic hypoxia. This decrease was reversed by endothelin receptor blockade (105 or 140% of baseline values after treatment for weeks 3-4 or 1-4). Furthermore, there was a trend of increasing renal endothelin-1 gene expression (to 173% of baseline values) after 4 weeks of hypoxia. Systolic blood pressure increased moderately during 4 weeks of chronic hypoxia from 129+/-2 to 150+/-4 mmHg. This blood pressure increase was higher in rats treated for 4 weeks with an endothelin receptor antagonist (196+/-11 mmHg). CONCLUSIONS: Chronic hypoxia (in contrast to acute hypoxia) suppresses renal renin gene expression. This inhibition presumably is mediated by endothelins.
Animals↗
Effects of growth hormone on renal renin gene expression in normal rats and rats with myocardial infarction.
BACKGROUND: Published data regarding effects of growth hormone (GH) on the renin system are controversial. The aim of this study therefore was to evaluate the effects of GH on the renin system in normal rats and rats with myocardial infarction (MI). METHODS: Normal rats received 2, 5, or 10 IU GH/kg/day or vehicle subcutaneously for 4 weeks. Furthermore rats with MI were randomized to receive 2 IU GH/kg/day or vehicle for 4 weeks. Subdivision into MI groups (mild, moderate, and large) was by histological determination of infarct size. Renal renin gene expression was assessed by RNAase protection assay and plasma renin activity by radioimmunoassay. In addition, isolated mouse juxtaglomerular cells were exposed to GH for 20 h, and renin secretion rates were assessed. RESULTS: GH treatment in normal rats for 4 weeks increased body weight, and kidney weight to body weight ratio, but did not affect renin secretion and renal renin gene expression. In rats with large MI, renal renin gene expression increased about fourfold, but was unchanged in rats with small and moderate MI as compared to normal rats. In rats with MI, body weight decreased and this decrease was partially reversed by GH treatment. GH treatment did not change renal renin gene expression, and renin secretion in rats with MI. Renin secretion of isolated juxtaglomerular cells was unaffected by GH. CONCLUSIONS: Our study demonstrates that GH treatment has no significant effect on renin secretion and on renal renin gene expression in normal rats and in rats with stimulated renin system due to MI in vivo. In isolated juxtaglomerular cells in vitro, renin secretion was also unaffected by GH.
Animals↗
Evaluation of brain natriuretic peptide as marker of left ventricular dysfunction and hypertrophy in the population.
OBJECTIVE: To evaluate brain natriuretic peptide (BNP) as marker of left ventricular (LV) dysfunction and hypertrophy in a population-based sample of 610 middle-aged subjects (50-67 years) who were further characterized with respect to hemodynamic and anthropometric parameters and by echocardiography. RESULTS: Left ventricular (LV) systolic function, LV mass-index, age, gender, heart rate, and medication with beta adrenergic receptor blockers were significant and independently correlated with BNP (multivariate analysis, P < 0.05 each). As compared to subjects with normal LV function and mass-index (control), subjects with LV dysfunction (LV fractional shortening < 28%) or hypertrophy (LV mass-index > 110 g/m2 in women and > 134 g/m2 in men) were characterized by increased BNP. The increase in BNP associated with LV hypertrophy (n = 69, +101% versus control, P < 0.0001) was similar in magnitude to that associated with LV dysfunction (n = 39, +98% versus control, P < 0.03). These increases were markedly exceeded in subjects with severe LV dysfunction (n = 11, LV fractional shortening < 22%, BNP +197% versus control, P < 0.01), particularly in the presence of concomitant hypertrophy (n = 7, +227%, P < 0.01). The predictive values of BNP varied considerably with the degree of LV dysfunction and the presence or absence of concomitant LV hypertrophy. With 0.81, the highest area under the receiver operator characteristic curve was obtained for the detection of severe LV dysfunction and concomitant hypertrophy and sensitivity, specificity, positive and negative predictive value for this condition were 71, 86, 7 and 99.5%, respectively, for a cut-off of 34 pg/ml. CONCLUSIONS: The current study provides new insight into regulation and diagnostic value of BNP in middle-aged subjects and demonstrates important independent effects of LV function and mass upon BNP plasma concentrations. Although measurement of BNP cannot be recommended for the detection of marginally impaired LV function in the population, it may be helpful to suggest or exclude severe LV dysfunction with concomitant hypertrophy.
Analysis of Variance↗
Overexpression of chloride channel CLC-K2 mRNA in the renal medulla of Dahl salt-sensitive rats.
OBJECTIVE: The present study aimed to characterize the influence of salt intake on the gene expression of the kidney specific chloride channels CLC-K1 and CLC-K2 in the kidneys of salt-resistant and salt-sensitive Dahl rats. DESIGN: For this purpose Dahl salt-resistant (Dahl-R) and Dahl salt-sensitive rats (Dahl-S) were fed a low (0.02%), normal (0.6%) or high (4%) salt diet for 19 days and CLC-K1 and -K2 mRNA expression was semiquantitated in cortex, outer and inner medulla. METHODS: Kidneys were macroscopically dissected, total RNA was isolated according to the guanidinium-thiocyanate-phenol-chloroform method and messenger RNAs for the kidney specific chloride channels CLC-K1 and CLC-K2 were measured by ribonuclease protection assay. RESULTS: Systolic blood pressure in high salt-treated Dahl-S rats increased to 204 +/- 5 mmHg versus 150 +/- 7 mmHg in Dahl-S controls. Dahl R and low salt Dahl-S rats showed no increase in blood pressure. For CLC-K1 mRNA we found an order of abundance inner medulla >> outer medulla >> cortex. There was no difference in mRNA abundance between Dahl-R and -S, nor any effect of the rate of salt intake on CLC-K1 mRNA abundance in the different kidney zones. CLC-K2 mRNA expression in cortex and outer medulla was similar between Dahl-R and -S rats. In the inner medulla, however, CLC-K2 mRNA was 1.7-fold higher in Dahl-S than in Dahl-R rats. In the cortex we found no influence of salt intake on CLC-K2 mRNA. In outer and inner medulla of Dahl-R rats and Dahl-S rats high salt diet led to a marked downregulation of CLC-K2 mRNA expression. Consequently, CLC-K2 gene expression in the inner medulla was 2.2-fold higher in Dahl-S than in Dahl-R rats in states of high salt diet. CONCLUSION: Given that the CLC-K2 chloride channel in the outer and inner medulla contributes to salt reabsorption, our findings would suggest that Dahl-S rats have an increased medullary salt reabsorption. This may contribute to the inability of these animals to excrete an increased salt load at a normal renal perfusion pressure leading to the development of hypertension.
Animals↗
Comparative coronary anatomy in six twin pairs with coronary artery disease.
OBJECTIVE: To compare the coronary anatomy and the location of coronary lesions in monozygotic and dizygotic twin pairs affected with coronary artery disease. DESIGN: Coronary angiographic findings were compared with respect to the distribution of coronary blood supply and the location of coronary lesions. MAIN OUTCOME MEASURES: Distribution of coronary blood supply, diameters and length of proximal coronary arteries. RESULTS: The lumen diameters of the left main coronary artery, the left anterior descending coronary artery, the circumflex artery, and the right coronary artery, as well as the lengths of the left main coronary artery, showed similar variability within monozygotic and dizygotic twin pairs. With respect to the dominance pattern of coronary blood supply, two of three monozygotic twin pairs differed, while all dizygotic twin pairs were concordant. Concordant and discordant locations of stenoses were found with similar frequency in monozygotic and dizygotic twin pairs. CONCLUSIONS: The dominance pattern of coronary blood supply and the location of coronary lesions are not strictly hereditary. The high concordance of premature coronary artery disease found in monozygotic twin pairs may largely be related to factors that are independent of the macroanatomic distribution of the coronary blood supply.
Adult↗
Activation of cardiorenal and pulmonary tissue endothelin-1 in experimental heart failure.
Endothelin-1 (ET-1) is a peptide that has been implicated in congestive heart failure (CHF). Although increased concentrations of circulating ET-1 have been repeatedly demonstrated, the activation of local ET-1 in target tissues of CHF remains poorly defined. Our objective was to characterize ET-1 tissue concentrations and gene expression of prepro ET-1 in myocardial, renal, and pulmonary tissue in rapid ventricular pacing-induced canine CHF. Progressive rapid ventricular pacing (38 days) resulted in impaired cardiovascular hemodynamics, increased atrial and left ventricular mass, decreased renal sodium excretion, and increased ET-1 plasma concentrations (all P < 0.05). Tissue analysis revealed significant increases in local ET-1 during CHF in left ventricular, renal, and pulmonary tissue, whereas a moderate increase in left atrial ET-1 did not reach statistical significance. In contrast, prepro-ET-1 gene expression was increased more than threefold in pulmonary tissue and more than twofold in left atrial myocardium with no increase in left ventricular or renal gene expression. The present studies demonstrate a differential pattern of ET-1 activation in cardiorenal and pulmonary tissue with a strong accumulation of ET-1 in kidney and lung during CHF. Although the observed increase in left ventricular and renal ET-1 in association with unaltered gene expression is consistent with increased uptake, pulmonary and atrial tissue may contribute to increased circulating and local ET-1 in CHF.
Animals↗
Store-operated calcium influx inhibits renin secretion.
On the basis of evidence that changes in the extracellular concentration of calcium effectively modulate renin secretion from renal juxtaglomerular cells, our study aimed to determine the effect of calcium influx activated by depletion of intracellular calcium stores on renin secretion. For this purpose we characterized the effects of the endoplasmatic Ca(2+)-ATPase inhibitors thapsigargin (300 nM) and cyclopiazonic acid (20 microM) on renin secretion from isolated perfused rat kidneys. We found that Ca(2+)-ATPase inhibition caused a potent inhibition of basal renin secretion as well as renin secretion activated by isoproterenol, bumetanide, and by a fall in the renal perfusion pressure. The inhibitory effect of Ca(2+)-ATPase inhibition on renin secretion was reversed within seconds by lowering of the extracellular calcium concentration into the submicromolar range but was not affected by lanthanum, gadolinium, flufenamic acid, or amlodipine. These data suggest that calcium influx triggered by release of calcium from internal stores is a powerful mechanism to inhibit renin secretion from juxtaglomerular cells. The store-triggered calcium influx pathway in juxtaglomerular cells is apparently not sensitive to classic blockers of the capacitative calcium entry pathway.
Animals↗
Evaluation of the aldosterone synthase (CYP11B2) gene polymorphism in patients with myocardial infarction.
Left ventricular remodeling after myocardial infarction involves activation of the renin-angiotensin-aldosterone system. Recently, the biallelic -344T/C polymorphism of the aldosterone synthase gene was associated with increased aldosterone levels, arterial hypertension, diastolic dysfunction, and left ventricular dilatation. We hypothesized that this polymorphism may also affect left ventricular geometry and function after myocardial infarction. By using a standardized questionnaire, as well as anthropometric and echocardiographic measurements, we thus studied 606 patients (533 men and 73 women) who had a myocardial infarction before the age of 60 years. The aldosterone synthase gene polymorphism was analyzed after polymerase chain reaction amplification and restriction enzyme digestion. The results demonstrated that there was no association of the aldosterone synthase gene polymorphism with echocardiographically determined left ventricular dimensions, wall thicknesses, or indexes of systolic or diastolic function. Furthermore, anthropometric data, including blood pressure levels, were balanced between the different genotypes. Finally, the allele frequency was similar for patients with myocardial infarction and a sample group from the normal population (n=1675). The data indicate that the allele status of the aldosterone synthase gene polymorphism is not useful for the identification of patients with myocardial infarction who have impaired left ventricular function or unfavorable remodeling.
Alleles↗
Hormone replacement therapy and interrelation between serum interleukin-6 and body mass index in postmenopausal women: a population-based study.
Postmenopausal women are at increased risk to develop osteoporosis, coronary artery disease, heart failure, and hypertension. Interleukin-6 (IL-6) may be a pathogenetic element in these disorders. Serum IL-6 levels increase during aging and seem to be related to increased body fat mass. In the present retrospective study we aimed to investigate the role of hormone replacement therapy (HRT) on serum IL-6 levels and the interrelation of IL-6 and body fat mass. Parameters were assessed in a population-based sample of postmenopausal women (n = 302) and, for comparison, 245 men of the same age. Women with HRT (n = 92) had significantly lower serum IL-6 levels compared to subjects without HRT, which was independent of age, antihypertensive therapy, smoking habits, and blood pressure (1.5 +/- 0.1 vs. 2.9 +/- 0.6 pg/mL; P = 0.017). In women without HRT, the body mass index (BMI) was correlated with serum IL-6 levels (P < 0.001). Multivariate analysis controlling simultaneously for the effects of blood pressure and heart rate confirmed the positive correlation (P = 0.001). However, in subjects with HRT no such correlation between IL-6 and BMI was demonstrated, which was confirmed after controlling covariates. In male subjects, BMI correlated with serum IL-6 (P = 0.009), which was, however, blunted after controlling for blood pressure and heart rate, probably indicating an influence of the sympathetic nervous system on this interrelation. In conclusion, women receiving HRT display lower serum IL-6 levels and a blunted interrelation of IL-6 and BMI. As IL-6 may be a pathogenetic factor in age-related diseases, HRT-related inhibition of IL-6 secretion could be an important element for the favorable effects of HRT in postmenopausal women.
Aged↗
Extracorporal therapy with AN69 membranes in combination with ACE inhibition causing severe anaphylactoid reactions: still a current problem?
The negatively charged membrane AN69 is known to evoke anaphylactoid reactions both without and with concomitant ACE inhibition. Underlying reasons are mainly the induction of bradykinin release due to the negatively charged membrane and the reduced degradation of bradykinin due to ACE inhibition. This complication has been reported repeatedly, but anaphylactoid reactions still occur in clinical practice. We recently had to treat two patients who suffered anaphylactoid reactions during extracorporal therapy with an AN69 membrane and simultaneous ACE inhibition. The first incident occurred in a patient on hemodialysis, the second was in a patient on continuous venovenous hemofiltration. An anaphylactoid reaction induced by an AN69 membrane during continuous, extracorporal treatment in combination with ACE inhibition has not been reported so far. Our report intends to serve as a reminder that the potentially lethal combination of AN69 membranes with ACE inhibitor treatment should be avoided.
Acrylic Resins↗
Improvement in exercise tolerance and symptoms of congestive heart failure during treatment with candesartan cilexetil. Symptom, Tolerability, Response to Exercise Trial of Candesartan Cilexetil in Heart Failure (STRETCH) Investigators.
BACKGROUND: The renin-angiotensin system plays an important part in the pathogenesis of congestive heart failure (CHF). This study evaluated the effect of an angiotensin II type 1 receptor antagonist on exercise tolerance and symptoms of CHF. METHODS AND RESULTS: In this multicenter, double-blind, parallel-group study, 844 patients with CHF were randomized to 12 weeks' treatment with placebo (n=211) or candesartan cilexetil 4 mg (n=208), 8 mg (n=212), or 16 mg (n=213) after a 4-week placebo run-in period. Changes in exercise time, Dyspnea Fatigue Index score, NYHA functional class, and cardiothoracic ratio were determined. Candesartan cilexetil produced a dose-related improvement in exercise time. For the intention-to-treat population, the increase produced by candesartan cilexetil 16 mg was significantly greater than that produced by placebo (47.2 versus 30.8 seconds, P=0.0463). All doses of candesartan cilexetil significantly improved the Dyspnea Fatigue Index score relative to placebo. NYHA class improved more frequently in the candesartan cilexetil groups; the differences relative to placebo were not significant. The decrease in cardiothoracic ratio with candesartan 4 to 16 mg was small but statistically significant compared with placebo (all P<0.05). In all candesartan cilexetil groups, plasma renin activity and angiotensin II levels increased from baseline and aldosterone levels decreased in the 8- and 16-mg treatment groups. Candesartan cilexetil was well tolerated at all doses. CONCLUSIONS: In summary, treatment with candesartan cilexetil demonstrated significant improvements in exercise tolerance, cardiothoracic ratio, and symptoms and signs of CHF and was well tolerated.
Adult↗
[ACE inhibitors or AT1 receptor antagonists?].
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Age Factors↗
Lack of association between a polymorphism of the aldosterone synthase gene and left ventricular structure.
BACKGROUND: Cardiac growth and function may be modulated in part by trophic effects of neurohormones. Specifically, aldosterone has been shown to stimulate the growth of cardiac myocytes and the accumulation of cardiac extracellular matrix proteins. Moreover, a variant of the aldosterone synthase gene (a cytosine/thymidine exchange at position -344 in the transcriptional regulatory region) has been associated with enlargement and disturbed filling of the left ventricle (LV) in a small sample of young white adults. The aim of the present study was to reinvestigate the implications of aldosterone synthase -344C/T allele status for serum aldosterone levels, blood pressure, and LV structure and function in large population-based samples. METHODS AND RESULTS: Individuals who participated in the echocardiographic substudy of the third MONICA (MONitoring trends and determinants in CArdiovascular disease) survey (n=1445) or in the second follow-up of the first MONICA survey (n=562) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for aldosterone synthase -344C/T allele status. In both surveys, the distribution of sex, age, arterial blood pressure, and body mass index was homogeneous in the aldosterone synthase genotype groups. Echocardiographic LV wall thicknesses, dimensions, and mass indexes were not significantly associated with a specific aldosterone synthase genotype. Likewise, no association was detectable with echocardiographic measures of LV systolic or diastolic function. Data were consistent in both samples and not materially different in subgroups defined by age, sex, or intake of antihypertensive medication. Finally, no significant association was observed for aldosterone synthase allele status and serum aldosterone levels in the group of 562 individuals. CONCLUSIONS: The data are not in favor of a significant contribution of the C/T exchange at position -344 in the aldosterone synthase transcriptional regulatory region to the variability of serum aldosterone levels, blood pressure, or cardiac size or function as found in 2 white population-based samples.
Adult↗
Evidence for a vasopressin system in the rat heart.
Traditionally, a hypothalamo-neurohypophysial system is thought to be the exclusive source of arginine vasopressin (AVP), a potent antidiuretic, vasoconstricting, and growth-stimulating neuropeptide. We have identified de novo synthesis of AVP in the heart as well as release of the hormone into the cardiac effluents. Specifically, molecular cloning of sequence tags amplified from isolated, buffer-perfused, and pressure-overloaded rat hearts allowed the detection of cardiac AVP mRNA. Subsequent experiments revealed a prominent induction of AVP mRNA (peak at 120 minutes, 59-fold, P<0. 01 versus baseline) and peptide (peak at 120 minutes, 11-fold, P<0. 01 versus baseline) in these isolated hearts. Newly induced vasopressin peptide was localized most prominently to endothelial cells and vascular smooth muscle cells of arterioles and perivascular tissue using immunohistochemistry. In addition to pressure overload, nitric oxide (NO) participated in these alterations, because inhibition of NO synthase by Nomega-nitro-L-arginine methyl ester markedly depressed cardiac AVP mRNA and peptide induction. Immediate cardiac effects related to cardiac AVP induction in isolated, perfused, pressure-overloaded hearts appeared to be coronary vasoconstriction and impaired relaxation. These functional changes were observed in parallel with AVP induction and largely prevented by addition of a V1 receptor blocker (10(-8) mol/L [deamino-Pen1, O-Me-Tyr2, Arg8]-vasopressin) to the perfusion buffer. Even more interesting, pressure-overloaded, isolated hearts released the peptide into the coronary effluents, offering the potential for systemic actions of AVP from cardiac origin. We conclude that the heart, stressed by acute pressure overload or NO, expresses vasopressin in concentrations sufficient to cause local and potentially systemic effects.
Animals↗
The cardiac endothelin system in established pressure overload left ventricular hypertrophy.
In normal hearts, endothelin-1 (ET-1) has been shown to initiate myocyte growth and to modulate cardiac function. However, regulation of the various components of the system and the functional effects of ET-1 in established left ventricular hypertrophy (LVH) are less clear. We thus studied ET-1, ET(A) receptor, and endothelin converting enzyme (ECE-1) mRNA regulation as well as the effects of ET-1 on coronary resistance, LV contractility and relaxation in hypertrophied rat hearts. Cardiac pressure overload, secondary to banding of the ascending aorta, resulted in a transient increase of cardiac ET-1 and ET(A) receptor mRNAs that reached a maximum at 2 days (+75% and +40%, respectively, P<0.05, each). ET-1 mRNA levels reached a second peak at 84 days of pressure overload (+60%, P<0.05), at the later time point in conjunction with elevated ECE-1 mRNA levels (+20%, P<0.05). The functional implications of ET-1 were examined in a study of isolated perfused hearts. Both hearts with established LVH and sham control hearts responded to ET-1 perfusion (10(-1)] to 10(-9) M) with an increase of coronary perfusion pressure (CPP; +85+/-15 and +75+/-8 mm Hg; P<0.001 each) and a slight decrease of LV systolic pressure (LVP; -12+/-9 and -9+/-7 mm Hg; P = NS). In contrast, ET-1 increased LV end-diastolic pressure (LVEDP) only in LVH hearts (+22+/-7 mm Hg, P<0.05 versus baseline and +20+/-7 mm Hg, P<0.05 versus sham). Direct stimulation of protein kinase C mimicked the effects of ET-1, whereas inhibition of this kinase or the Na+ -H+ exchanger blunted the effects of ET-1 on CPP, LVP, and LVEDP. Interestingly, coadministration of the vasodilator and the nitric oxide (NO) donor nitroglycerin not only prevented the increase of CPP and LVEDP, but also uncovered a slight positive inotropic effect of ET-1 in LVH hearts. Thus, the cardiac expression of ET-1, ET(A), and ECE-1 mRNAs displays a distinct pattern during early and advanced cardiac pressure overload. Furthermore, ET-1 mediates a slight depression of systolic, and a profound depression of diastolic, functional parameters in hearts with established LVH, effects that appear to be secondary to ET-1-related coronary vasoconstriction. The data suggest a functional role of the endothelin system in hearts with established pressure overload hypertrophy.
Amiloride↗
Chloride channel blockers attenuate the inhibition of renin secretion by angiotensin II.
The aim of this study was to assess the relevance of chloride channels to the inhibitory effect of angiotensin II (ANGII) on renin secretion. We thus examined the effects of the chloride channels blockers IAA-94 and niflumic acid, the Na-K-Cl cotransport blocker bumetanide and substitution of isethionate for extracellular chloride on the action of ANGII on renin secretion from isolated perfused rat kidneys. Renin secretion prestimulated by isoproterenol (10 nmol/l) was almost completely blocked by ANGII with a concentration yielding a half-maximal response (EC50) of around 150 nmol/l. In the presence of IAA-94 and niflumic acid the EC50 for ANGII was shifted to about 400 nmol/l. In the presence of bumetanide and isethionate renin secretion responded more sensitively to ANGII and the EC50 for ANGII was below 100 nmol/l. On the assumption that the chloride equilibrium potential in renin-secreting cells is more positive than the membrane potential, our findings would suggest that the inhibitory effect of ANGII is enhanced when chloride entry is blocked and attenuated when chloride efflux is impaired. Activation of chloride channels therefore probably contributes to the inhibitory action of ANGII on renin secretion.
Angiotensin II↗