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Am J Physiol. 1999 May;276(5 Pt 2):H1664-71.
Effects of aminopeptidase P inhibition on kinin-mediated vasodepressor responses.

Kitamura S, Carbini LA, Simmons WH, Scicli AG.

Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan 48202, USA.

We studied in anesthetized rats whether aminopeptidase P (AMP) may be involved in bradykinin (BK) metabolism and responses. For this we inhibited AMP with the specific inhibitor apstatin (Aps). Studies were done with Aps alone or together with the angiotensin-converting enzyme inhibitor lisinopril (Lis). Aps increased the vasodepressor response to an intravenous bolus of BK (400 ng/kg): vehicle, -3.0 +/- 0.7 mmHg; Aps, -7.8 +/- 0.7 mmHg (P < 0.01 vs. vehicle); Lis, -23.8 +/- 1.8 mmHg; Aps + Lis, -37.5 +/- 1.9 mmHg (P < 0.01 vs. Lis). Aps did not affect the vasodepressor response to BK given into the descending aorta. Plasma BK increased only in Aps + Lis-treated rats (in pg/ml): control, 48.0 +/- 1.4; Lis, 57.5 +/- 7.6; Aps + Lis, 121. 8 +/- 30.6 (P < 0.05 vs. control or Lis), whereas in rats infused with BK (400 ng. kg-1. min-1 for 5 min), Aps increased plasma BK (in pg/ml): control, 51.9 +/- 2.5; Aps, 83.5 +/- 20.5; Lis, 725 +/- 225; Aps + Lis, 1,668 +/- 318 (P < 0.05, Aps vs. control and Lis vs. Aps + Lis). In rats with aortic coarctation hypertension, the acute antihypertensive effects of Aps plus Lis were greater than Lis alone (P < 0.01). Hoe-140, a BK B2-receptor antagonist, abolished the difference. We concluded that in the rat AMP contributes to regulation of BK metabolism and responses.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10330252&dopt=Abstract




Clin Sci (Lond). 1999 Jun;96(6):669-75.
Regulation of 11beta-hydroxysteroid dehydrogenase type 2 by diuretics and the renin-angiotensin-aldosterone axis.

Ricketts ML, Stewart PM.

Department of Medicine, The University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK.

In the kidney and colon 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) inactivates cortisol to cortisone, thereby protecting the non-selective mineralocorticoid receptor from cortisol. Deficiency of 11beta-HSD2 results in cortisol-mediated sodium retention and hypertension, suggesting that the physiological regulation of 11beta-HSD2 in mineralocorticoid target tissues may be important in modulating sodium homoeostasis and blood pressure control. Using the human epithelial colon cell line SW-620, reverse transcriptase-polymerase chain reaction and enzyme kinetic analysis indicated expression of only 11beta-HSD2 (Km for cortisol 66 nmol/l). Bradykinin (10(-8) to 10(-12) mol/l), frusemide (10(-4) to 10(-9) mol/l), benzamiloride hydrochloride (10(-5) to 10(-10) mol/l) and atrial natriuretic peptide (10(-6) to 10(-10) mol/l) had no effect on 11beta-HSD2 expression. Using a range of concentrations of angiotensin II (2x10(-8) to 2x10(-5) mol/l) a significant reduction in activity was seen but only at supra-physiological concentrations, [e.g. 2x10(-6) mol/l at 4 h pretreatment: 36.7+/-2.0 pmol cortisone. h-1.mg-1 (mean+/-S.E.M.) compared with 45.1+/-1.7 pmol.h-1.mg-1 in control; P<0.05]. The angiotensin-converting enzyme inhibitors captopril, enalapril, lisinopril, perindopril, quinapril and trandolapril at 10(-7) mol/l, but not fosinopril, significantly increased 11beta-HSD2 activity after pretreatment for 16 or 24 h (P<0.05-P<0.01 compared with control). No effects were seen at 4 h pretreatment. Hydrochlorothiazide (10(-7) mol/l) significantly decreased 11beta-HSD2 activity (P<0.05 compared with control) at 4 h pretreatment. Commonly used diuretics, atrial natriuretic peptide and physiological concentrations of angiotensin II and bradykinin do not alter 11beta-HSD2 activity. In contrast, a series of angiotensin-converting enzyme inhibitors significantly increase 11beta-HSD2 activity in vitro. This may explain how intrarenal infusions of angiotensin-converting enzyme inhibitors increase renal sodium excretion independent of circulating concentrations of angiotensin II. The interaction between angiotensin-converting enzyme inhibitors and 11beta-HSD2 may be an additional mechanism by which the former can lower blood pressure.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10334975&dopt=Abstract




Pharm Res. 1999 May;16(5):609-15.
Competitive inhibition of glycylsarcosine transport by enalapril in rabbit renal brush border membrane vesicles: interaction of ACE inhibitors with high-affinity H+/peptide symporter.

Lin CJ, Akarawut W, Smith DE.

College of Pharmacy and Upjohn Center for Clinical Pharmacology, The University of Michigan, Ann Arbor 48109, USA.

PURPOSE: To examine the inhibitory potential of enalapril [and other angiotensin converting enzyme (ACE) inhibitors] on glycylsarcosine (GlySar) transport by the high-affinity renal peptide transporter. METHODS: Studies were performed in rabbit renal brush border membrane vesicles in which the uptake of radiolabeled GlySar was examined in the absence and presence of captopril, enalapril, enalaprilat, fosinopril, lisinopril, quinapril, quinaprilat, ramipril and zofenopril. RESULTS: Kinetic analyses demonstrated that enalapril inhibited the uptake of GlySar in a competitive manner (Ki approximately 6 mM). Fosinopril and zofenopril had the greatest inhibitory potency (IC50 values of 55 and 81 microM, respectively) while the other ACE inhibitors exhibited low-affinity interactions with the renal peptide transporter. With respect to structure-function, ACE inhibitor affinity was strongly correlated with drug lipophilicity (r = 0.944, p < 0.001 for all ACE inhibitors; r = 0.983, p < 0.001 without enalaprilat, quinaprilat and quinapril). CONCLUSIONS: The data suggest that enalapril and GlySar compete for the same substrate-binding site on the high-affinity peptide transporter in kidney, and that ACE inhibitors can interact with the renal carrier and inhibit dipeptide transport.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10350000&dopt=Abstract












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