To determine whether or not rat plasma inactive renin is prorenin, specific antibodies were raised against two 15-amino acid peptides, Pro-NH2 and Pro-COOH, which contained the NH2-terminal and COOH-terminal sequences, respectively, of the prosegment of rat prorenin. Inactive renin was measured after trypsin treatment. Immunoaffinity chromatography of normal rat plasma on anti-Pro-NH2 and anti-Pro-COOH immunoglobulin G (IgG)-Sepharose showed that about one-half the amount of inactive renin was prorenin, whereas the rest was neither prorenin nor renin. Thus trypsin treatment of the unfractionated plasma does not provide measurement of the concentration of prorenin. However, fractionation of plasma by high-performance liquid chromatography on G3,000SW columns followed by trypsin treatment led to the measurement of prorenin. Prorenin and active renin concentrations in the normal plasma of conscious rats were 44.3 +/- 5.8 and 13.3 +/- 1.4 (SE) ng ANG I.h-1.ml-1, respectively (n = 10). On the other hand, plasma inactive renin from rats at 24 h after bilateral nephrectomy bound to neither anti-Pro-NH2 nor anti-Pro-COOH IgG immunoaffinity columns, and the enzymatic activity after trypsin treatment was not inhibited by anti-mature renin IgG. These results demonstrate that inactive renin from nephrectomized rats was not prorenin. Thus the kidney is the primary source of circulating prorenin in rats.

Background: It is well known that angiotensin converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor blockers (ARBs) prevent left ventricular (LV) remodelling after myocardial infarction (MI). However, it is still not clear whether inhibition of the AT1 receptor is enough to prevent LV remodelling after MI. Objective: To elucidate the effects of ACE inhibitors that are not mediated by the AT1 receptor on LV remodelling, MI was experimentally induced in wild-type (WT-MI) mice and AT1 receptor knockout (KO-MI) mice. Methods: Mice were divided into six groups: WT-control, KO-control, WT-MI, KO-MI, WT-MI treated with an ACE inhibitor, and KO-MI treated with an ACE inhibitor. Four weeks after MI, cardiac function was assessed by Doppler echocardiography and non-infarcted myocardial mRNA expression by northern blot analysis. Results: Cardiac function decreased significantly in the MI groups compared with the sham operated groups. Additionally, in the MI groups end diastolic dimension, E wave velocity, the ratio of peak velocity of E wave to A wave, deceleration rate of E wave, and mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, and collagens I and III increased significantly compared with the sham groups. LV remodelling after MI was prevented in KO-MI mice compared with WT-MI mice. ACE inhibitor administration significantly attenuated progressive LV remodelling in both WT and KO-MI groups. Conclusion: ACE inhibitors can prevent the LV remodelling process that accompanies cardiac dysfunction after MI, even in AT1 KO mice. These findings suggest that ACE inhibitors prevent LV remodelling after MI by mechanisms other than inhibition of angiotensin AT1 receptor mediated effects.

Summary Background : Mitogen‐activated protein (MAP) kinases, including extracellular signal‐regulated kinases (ERK),c‐Jun NH2‐terminal kinases (JNK) and p38 MAP kinase (p38 MAPK) are important intermediates of the signal‐transduction pathway from the cell surface to the nucleus. Expression of cyclooxygenase (COX)‐2, associated with proliferation, apoptosis or both of gastrointestinal cancer cells, is mediated through MAP kinase families. However, the correlation between respective MAP kinase signals and COX‐2 in the proliferation of gastric and colon cancer cells has not been well elucidated. Aim : We examined the effect of selective inhibitors of MAP kinases and COX‐2 on serum‐induced proliferation of gastric (MKN45) and colon (HT29) cancer cells. Methods : After 24‐h serum starvation, cancer cells were stimulated with 2% serum and COX‐2 inhibitors (NS398 10 µmol/L, or etodolac 100 µmol/L) or 1 h after preincubation with inhibitors for ERK (PD98059 20 µmol/L) or p38 MAPK (SB203580 10 µmol/L). Phosphorylated MAP kinases and COX‐2 protein were evaluated by Western blotting, and the proliferation of cancer cells was estimated by 3H‐thymidine incorporation. Transcription factors nuclear factor‐κB and CREB were assayed by an electorophoretic mobility shift assay. Results : Serum increased the proliferation of MKN45 and HT29 cells by 280% and 200%, respectively, compared with the control levels (100%). In both cancer cells, phosphorylated MAP kinases were increased within 30 min after stimulation. PD98059 and SB203580 inhibited the serum‐induced proliferation of MKN45 by 21% and 51% and of HT29 by 81% and 69%, respectively. NS398 and etodolac inhibited the proliferation of HT29 by 21% and 41%, respectively, but not that of MKN45. PD98059 and SB203580 also suppressed serum‐induced expression of COX‐2 protein in HT29 cells. In addition to the activation of MAP kinases and COX‐2, activities of nuclear factor‐κB and CREB were also increased during HT29 cell proliferation. Conclusions : These results suggest that the correlation of MAP kinases with COX‐2 induction for cell proliferation differs between MKN45 and HT29 cells.

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Highly purified 125I-labeled rat renal renin (125I-renin) was given intravenously to conscious rats to study the fate of circulating renin. Specific antirat renin antiserum was used to identify the labeled renin molecules. In sham-operated rats, the disappearance of 125I-renin from the plasma showed two exponential components with a half-life of 6.7 +/- 0.4 min for the rapid component and 65.1 +/- 5.7 min for the slow component. The metabolic clearance rate was 11.4 +/- 1.0 ml X min-1 X kg-1. In bilaterally nephrectomized rats, the metabolic clearance rate of 125I-renin was reduced by 55%, but the half-life of the slow component remained unchanged. Seventy percent hepatectomy caused a 54% decrement in the metabolic clearance and prolonged the half-life of the slow component. Five minutes after injection of 125I-renin, approximately 59 and 11% of the administered 125I-renin had accumulated in the liver and the kidneys, respectively, and at later time points the 125I-renin was highly concentrated in these organs. High-performance liquid chromatographic analysis of the liver and kidney extracts demonstrated that 125I-renin was catabolized by these organs. Biliary excretion of 125I-renin was negligible. Urinary excretion of 125I-renin up to 120 min was approximately 2% of the injected dose. We conclude that both the liver and the kidney are responsible for the clearance of circulating renin, with participation of the liver being predominant.