Search

This study examined the effect of the angiotensin converting enzyme (ACE) inhibitor, enalaprilat, on mesangial cell (MC) DNA synthesis induced by H2O2, IL-6 and PDGF. MC were incubated with enalaprilat (2.5-100 mumol/l) alone and together with combinations of H2O2 (3 daily pulses of 10(-6) mol/l), IL-6 (5 ng/ml) and PDGF (10 ng/ml). DNA synthesis was assessed after 72 h using [3H]thymidine (3H-TdR) incorporation. Enalaprilat alone had no effect on MC DNA synthesis. Stimulation of MC by H2O2, PDGF and IL-6 alone resulted in increases in 3H-TdR of 4936.6 +/- 1147.5, 5640.5 +/- 1537.6 and 4413.5 +/- 998.4 cpm, respectively (P < 0.05 above control). Only 2.5 mumol/l enalaprilat effected a significant reduction in IL-6 and PDGF-induced DNA synthesis. Incubation of MC with H2O2 + PDGF or H2O2 + IL-6 resulted in increases of 3H-TdR of 6471.9 +/- 1785.1 and 5507.2 +/- 1270 cpm, respectively (P < 0.05 above control). Addition of enalaprilat with either H2O2 + PDGF or H2O2 + IL-6 effected significant reductions in DNA synthesis over the range 2.5-100 mumol/l. These data demonstrate that ACE inhibitors modulate MC DNA synthesis induced by reactive oxygen species.

1. This study was designed to investigate whether the angiotensin converting enzyme (ACE) inhibitors, captopril, enalapril and fosinopril have a dose-dependent effect on the production of prostaglandin E2 (PGE2), prostaglandin I2 (prostacyclin, PGI2) and thromboxane A2 (TxA2) by glomeruli isolated from normotensive Wistar-Kyoto rats. 2. Measurements of glomerular prostanoid production were made under basal conditions and in the presence of excess exogenous arachidonic acid. 3. All three ACE inhibitors demonstrated dose-dependent effects upon glomerular prostanoid production which varied with the individual ACE inhibitor. 4. Enalapril induced a dose-dependent increase in the ratio of (PGE2 + PGI2)/TxA2, from 2.17 +/- 0.20 to 5.35 +/- 0.84 and to 10.0 +/- 1.16 with the low and high doses of enalapril respectively. In contrast, the high dose of captopril tended to reduce the ratio when compared to the low dose. 5. The results obtained in this study suggest that although all three ACE inhibitors appear to induce prostacyclin synthetase and/or modulate phospholipase A2 (PLA2) activity, these effects differ with the ACE inhibitor studied and the dose employed. 6. This study has demonstrated dose-dependent effects of three ACE inhibitors on glomerular prostanoid production which may be significant in modulating glomerular haemodynamics and growth characteristics of glomerular cells.

1. The effect of H2O2 (4.7 x 10(-9) -4.7 x 10(-3) M) on prostanoid production by isolated glomeruli from normotensive (WKY) and, spontaneously hypertensive rats (SHR) has been studied. 2. Oxidant stress significantly increased synthesis of prostaglandin E2 (PGE2), I2 (PGI2) and thromboxane A2 (TxA2) by glomeruli from both strains whereas the ratio (PGE2 + PGI2)/TxA2 increased in only SHR. 3. Pre-incubation of glomeruli with the angiotensin converting enzyme inhibitors captopril or lisinopril, had virtually no effect on H2O2-induced synthesis of individual prostanoids nor on the ratio (PGE2 + PGI2)/TxA2 by glomeruli from either WKY or SHR. 4. The findings suggest that H2O2-induced changes in glomerular function may be mediated, in part, by PGs but fail to support the suggestion that the ability of ACEI to protect glomeruli from H2O2-induced damage is determined by PGs.

1. This study was designed to examine the production of certain eicosanoids (prostaglandin E2), prostacyclin (as 6-keto-prostaglandin F1 alpha) and thromboxane A2 (as thromboxane B2) by glomeruli isolated from normotensive Wistar-Kyoto and spontaneously hypertensive rats both before and after the administration of one of three angiotensin-converting enzyme inhibitors, captopril, enalapril or fosinopril, for 10 days. 2. Measurements of glomerular eicosanoid production were made under basal conditions and in the presence of excess exogenous arachidonic acid. 3. The production of prostaglandin E2, 6-keto-prostaglandin F1 alpha and thromboxane B2 was greater by glomeruli from untreated spontaneous hypertensive rats (prostaglandin E2 2.24 +/- 0.41, 6-keto-prostaglandin F1 alpha 1.20 +/- 0.13 and thromboxane B2 2.75 +/- 0.43 ng 10 min-1 mg-1 of protein) than by those from Wistar-Kyoto rats (prostaglandin E2 1.41 +/- 0.28, 6-keto-prostaglandin F1 alpha 0.98 +/- 0.11 and thromboxane B2 1.29 +/- 0.24 ng 10 min-1 mg-1 of protein) under basal conditions. However, these differences only achieved statistical significance for thromboxane B2 (P less than 0.01). Similar strain-related differences were noted in the presence of arachidonic acid. 4. The ratio of glomerular (prostaglandin E2 + prostacyclin)/thromboxane A2 production was significantly lower in spontaneously hypertensive rats than in their normotensive counterparts under basal conditions with values of 1.3 +/- 0.18 and 2.2 +/- 0.20, respectively (P less than 0.01). 5. Angiotensin-converting enzyme inhibitors induced significant changes in the glomerular production of some eicosanoids, which differed both between strains and with the nature of the inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

The following study was designed to examine the effect of the angiotensin converting enzyme (ACE) inhibitors captopril and enalapril on certain biological and physiological activities of isolated preparations of glomeruli from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive SHR rats. The results suggest that the contractile response of glomeruli from SHR to exogenous angiotensin II (Ang II) is significantly enhanced by captopril whereas it has a different effect on those from normotensive (WKY) rats. These effects are unrelated to changes in glomerular Ang II binding or the level of plasma renin activity (PRA), but they do depend partially on the sodium status of the animal. Whereas captopril induced a modest increase in the basal rate of prostaglandin E2 (PGE2) synthesis by glomeruli from normotensive (WKY) but not by those from SHR, the reverse occurred in the presence of Ang II. Prostaglandin E2 synthesis was increased in both strains of rats in the presence of excess arachidonic acid. Further increases occurred with the addition of captopril, these increases being significantly greater by glomeruli from WKY rats than by those from SHR, while enalaprilat had no effect on PGE2 production. The glomerular synthesis of PGE2 was not influenced in either strain of rats by in vitro administration of captopril.