Background: Substantial evidence has accumulated for the intrarenal generation of func tionally important quantities of angiotensin II (Ang II). To assess the possibility that Ang II generation occurs beyond a barrier to diffusion from the vascular compartment, six angiotensin-converting enzyme (ACE) inhibitors varying widely in their lipid solubility were employed in the spontaneously hypertensive rat (SHR) and their normotensive con trols (WKY). The biological end points were renal blood flow and its response to Ang II.
Results: Two ACE inhibitors, ramipril and captopril, induced a larger increase in renal blood flow and enhanced the renal vascular response to Ang II substantially more than did enalapril and lisinopril. The two prodrugs, enalapril and ramipril, which are substantially more lipophilic than the respective active drugs, enalaprilat and ramiprilat, showed equiva lent responses. The partial agonist saralasin virtually abolished the renal vasodilator response to ramipril. The pattern of response was similar in WKY, but the responses were substantially smaller.
Conclusions: The results support the concept that a functionally important compartment for intrarenal Ang II formation exists in the healthy rat and that this process is amplified in the SHR.
Leveng NR, Peach MJ, Carey RMRole of the intrarenal-angiotensin system in the control of renal function . Circ Res48:157,1981
2.
Navar LG, Rosivall L.Contribution of the renin-angiotensin system to the control of intrarenal hemodynamic. Kidney Int25:857, 1984
3.
Schnermann N., Briggs JPFunction of the juxtaglomerular apparatus: local control of glomerular hemodynamics . In Seldin DW, Gicbisch G (eds). The Kidney: Physiology and Pathophysiology . Raven Press, New York. pp. 1249-1289, 1992
4.
Johns EJRole of angiotensin II and the sympathetic nervous system in the control of renal function. J Hypertens7:695, 1989
5.
Navar LG, Saccomani G., Mitchell KDSynergistic intrarenal actions of angiotensin on tubular reabsorption and renal hemodynamics. Am J Hypertens4:90, 1991
6.
Williams GH, Braley LM, Menachery A.Decreased adrenal responsiveness to angiotensin II: a defect present in spontaneously hypertensive rats; a possible model of human essential hypertension . J Clin Invest69:31, 1982
7.
Arendshorst WJ, Chatziantoniou C., Daniels FHRole of angiotensin in the renal vasoconstriction observed during the development of genetic hypertension . Kidney Int30: 92,1990
8.
Guidi E., Hollenberg NKDifferential pressor and renal vascular reactivity to angiotensin II in spontaneously hypertensive and Wistar-Kyoto rats. Hypertension9:581, 1987
9.
Hollenberg NK , Coletti C., Passan D.Hypertension, volume and vasoconstriction: studies on the renal blood supply in SHR, WKY, and DOCA-salt rat models. Hypertens Res15:3, 1992
10.
Matsushima Y., Kawamura M., Akabane S., Imanishi M., Kuramochi M., Ito K., Omae T.Increases in renal angiotensin II content and tubular angiotensin II receptors in prehypertensive spontaneously hypertensive rats. J Hypertens6:791, 1988
11.
Rettig R., Strauss H., Folberth C., Ganten D., Waldherr R., Unger T.Hypertension transmitted by kidneys from stroke-prone spontaneously hypertensive rats. Am J Physiol257:F197,1989
12.
Dilley JR, Steir CT, Arendshorst WJAbnormalities in glomerular function in rats developing spontaneous hypertension . Am J Physiol246:F12, 1984
13.
Harrap SB, Doyle AEGenetic co-aggregation of renal hemodynamics and blood pressure in the spontaneously hypertensive rats. Clin Sci74:63, 1988
14.
Allan DR, McKnight JA, Kifor I., Coletti CM, Hollenberg NKConverting enzyme inhibition and renal tissue angiotensin II in the rat. Hypertension24:516,1994
15.
Lew MJ, Rivers RJ, Duling BRArteriolar smooth muscle responses are modulated by an intramural diffusion barrier. Am J Physiol257:H10, 1989
16.
Lew MJ, Duling BRArteriolar reactivity in vivo is influenced by an intramural diffusion barrier . Am J Physiol259:H574,1990
17.
Lew MJ, Duling BRAccess of blood-borne vasoconstrictors to the arteriolar smooth muscle . J Vasc Res640:1, 1992
18.
Vasmant D., Bender N.The renin-angiotensin system and ramipril, a new converting enzyme inhibitor . J Cardiovasc Pharmacol14:46,1989
19.
Ondetti MAStructural relationships of angiotensin converting enzyme inhibitors to pharmacologic activity. Circulation77:74, 1988
20.
Johnston CI. Fabris B., Yamada H., Mendelsohn Fao, Cubela R., Sivell D., Jackson B.Comparative studies of tissue inhibition by angiotensin converting enzyme inhibitors. J Hypertens7(Suppl 5):S11, 1989
21.
Grima M., Welsch C. Michel B, Barthlmebs M., Imbs JLIn vitro tissue potencies of converting enzyme inhibitors: prodrug activation by kidney esterase. Hypertension17: 492,1991
22.
Ranadive SA , Chen AX, Serajuddin Atm.Relative lipophilicities and structural-pharmacological considerations of various angiotensin-converting enzyme (ACE) inhibitors. Pharm Res9: 1480. 1992
23.
Genès N., Lemoine G.Duguet A., Vaur L., Moreau G., Etrillard C., Soullier F.Lipophilie comparée du trandolapril et des autres inhibiteurs de l'enzyme de conversion. Therapie50:131, 1995
24.
Zusman RMRenin and non-renin-mediated antihypertensive actions of converting enzyme inhibitors. Kidney Int25:969.1984
25.
Meggs LGKatzberg RW, DeLeeuw P, Hollenberg NK. Specific desensitization of the canine renal vasculature to angiotensin II despite cyclo-oxygenase inhibition . Yale J Biol Med58:453,1985
26.
Wong PCZimmerman BGMechanism of captopril induced renal vasodilatation in anesthetized dogs after non-hypotensive hemorrhage. J Pharmacol Exp Ther215:104, 1980
27.
Wong PC, Zimmerman B., Kraft E.Pharmacological evaluation in conscious dogs of factors involved in the renal vasodilator effect of captopril. J Pharm Exp Ther219:646, 1981
28.
Hollenberg N., Passan D.Specificity of renal vasodilation with captopril: saralasin prevents the response in the DOCA-treated salt-loaded rabbit. Life Sci31:329, 1982
29.
Mattson DL, Roman RJRole of kinins and angiotensin II in the renal hemodynamic response to captopril . Am J Physiol260:F670,1991
30.
Wang Y., Gavras I., Lammek B., Bresnahan M., Gavras H.Effects of bradykinin and prostaglandin inhibition on systemic and regional hemodynamics in conscious normotensive rats. J Hypertens9:805, 1991
31.
Haij-ali AF , Zimmerman BGKinin contribution to renal vasodilator effect of captopril in rabbit. Hypertension17:504, 1991
32.
Nasjletti A. , Colina-Chourio J., MoGiff JCDisappearance of bradykinin in the renal circulation of dogs: effects of kininase inhibition. Circ Res37:59, 1975
33.
Clappison BH , Warwick AP, Johnston CIRenal hemodynamics and renal kinins after angiotensin converting enzyme inhibition. Kidney Int20:615, 1981
34.
Roman RJ, Kaldunsky ML, Scicli AG, Carretero OAInfluence of kinins and angiotensin II on the regulation of papillary blood flow. Am J Physiol255:F690, 1988
35.
Li T., Zimmerman BGIntrarenal converting enzyme inhibition in rabbit. J Cardiovasc Pharmacol10(Suppl 7): S133, 1986
36.
Zimmerman BG , Goering JL, Raich PCResistance to blockade by saralasin of effect of ACE inhibitors in conscious sodium restricted dog . Am J Physiol255:F944, 1988
37.
Guidi E., Hollenberg NKRcnovascular responses to angiotensin II in SHR: effect of prostaglandin synthesis blockade. Kidney Int34(Suppl 25):S149, 1988
38.
Seikaly MG, Arant BS, Seney FDEndogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat. J Clin Invest86:1352, 1990
39.
Wilcox CS, Dzau VJEffect of captopril on the release of the components of the renin-angiotensin system into plasma and lymph. J Am Soc Nephrol2:1241, 1992
40.
Lipnick RL, Filov VANikolai Vasilyevich Lazarev, toxicologist and pharmacologist, comes in from the cold. TIPS13:56, 1992
41.
Simionescu M., Simionescu N., Palade GESegmental differentiations of cell junctions in the vascular endothelium: arteries and veins. J Cell Biol68:705, 1976
42.
Simionescu N., Simionescu M., Palade GEStructural basis of permeability in sequential segments of the microvasculature of the diaphragm . Microvasc Res15:17, 1978
43.
Okuda T., Yamamoto T.The ultrastructural basis of the permeability of arterial endothelium to horseradish peroxidase. Cell Tissue Res231:117, 1983
44.
Rosivall L. , Razga Z., Ormos J.Morphological characterization of human juxtaglomerular apparatus. Kidney Int39(Suppl 32):S9, 1991
45.
Bucher O., Reale E.Zur elektronenmikroskopischen Untersuchung der juxtaglomerularen. Spezialenrichtungen die Niere. Z Zellforsch Mikrosk Anat64:167, 1961
46.
Celio MR, Inagami T.Angiotensin II immunoreactivity coexists with renin in the juxtaglomerular granular cells of the kidney. Proc Natl Acad Sci U S A78:3897, 1981
47.
Naruse K., Inagami T., Celio M., Workman RJ, Takii Y.Immunocytochemical evidence that angiotensin I and II are formed by intracellular mechanism in juxtaglomerular cells. Hypertension4(Suppl II):II-70, 1982
48.
Taugner R., Manner E., Nobiling R., Buhrle CP, Hackenthal E., Ganten D., Inagami T., Schroder H.Coexistence of renin and angiotensin II in epithelioid cell secretory granules of rat kidney. Histochemistry81:39, 1984
49.
Inagami T. Mizuno K, Higashimori K.Juxtaglomerular cells as a source of intrarenal angiotensin II production. Kidney Int39(Suppl 32):S20, 1991
50.
Laher MSDonohue JF, Kelly JG, Doyle GDAntihypertensive and renal effects of lisinopril in older patients with hypertension . Am J Med85(Suppl 3B):38, 1988
51.
Skidgel RA, Erdos EGBiochemistry of angiotensin I-converting enzyme. In Robertson JIS, Nicholls MG (eds). The Renin-Angiotensin System. Mosby-Year Book, London, Europe Ltd, pp 10.1-10.10, 1993
52.
Paula RDLima CV, Khosla MC, Santos Ras.Angiotensin (1-7) potentiates the hypotensive effect of bradykinin in conscious rats. Hypertension26:1154, 1995
53.
Dzau VJColucci WS, Williams GH, Curfman G., Meggs L., Hollenberg NKSustained effectiveness of converting-enzyme inhibition in patients with severe congestive heart failure. N Engl J Med302:1373, 1980
