Abstract
Inhibition of the angiotensin converting enzyme (ACE) with ramipril was studied in male Wistar rats during long-term inhibition of nitric oxide (NO) synthase by NG-nitro-l-arginine methyl ester (l-NAME). Chronic treatment with l-NAME in a dose of 25 mg/kg per day over 6 weeks caused myocardial hypertrophy and a significant increase in systolic blood pressure (245 ± 16 mmHg) as compared to controls (155+4 mmHg). Animals receiving simultaneously l-NAME and ramipril were protected against blood pressure increase and partially against myocardial hypertrophy. L-NAME caused a significant reduction in glomerular filtration rate (GFR: 2.56+0.73 ml·kg−1·min−1) and renal plasma flow (RPF: 6.93±1.70ml·kg−1·min−1) as compared to control (GFR: 7.29±0.69, RPF: 21.36±2.33ml·kg−1·min−1). Addition of ramipril prevented l-NAME-induced reduction in GFR and renal plasma flow. l-NAME produced an elevation in urinary protein excretion and serum creatinine and a decrease in potassium excretion which was antagonised by ramipril. L-NAME-induced increase in plasma renin activity (PRA) was further elevated with ramipril treatment. Isolated hearts from rats treated with l-NAME showed increased post-ischaemic reperfusion injuries. Compared to controls duration of ventricular fibrillation was increased and coronary flow reduced. During ischaemia the cytosolic enzymes lactate dehydrogenase and creatine kinase, as well as lactate in the venous effluent were increased. Myocardial tissue values of glycogen, ATP, and creatine phosphate were decreased, whereas lactate was increased. Coadministration of ramipril reversed these effects. l-NAME treatment reduced the cyclic GMP content in urine and renal arteries, and was not changed by additional ramipril-treatment. In the kidney hyalinosis of arterioles and of glomerular capillaries, as well as mesangial expansion and tubular atrophies seen after long-term inhibition of NO synthase were reduced by coadministration of ramipril. In conclusion, long-term ACE inhibition by ramipril prevented l-NAME-induced hypertension and cardiac hypertrophy, and attenuated functional and morphological changes in the kidneys. In addition, cardiac-dynamic and -metabolic deterioration induced by L-NAME was normalised by co-treatment with ramipril.
Similar content being viewed by others
References
Arnal J-F, Warin L, Michel J-B (1992) Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxide synthase. J Clin Invest 90:647–652
Bartels H, Bohmer M, Heierli C (1972) Serum Kreatininbestimmung ohne Enteiweissen. Clin Chim Acta 37:193–197
Baylis Ch, Mitruka B, Deng A (1992) Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest 90:278–281
Becker RHA, Wiemer G, Linz W (1991) Preservation of endothelial function by ramipril in rabbits on a long-term atherogenic diet. J Cardiovasc Pharmacol [Suppl 2] 18:S110-S115
Bonin P (1897) Etudes sur l'évolution normale et l'involution du tube seminifère. Arch d'Anat Mier 1:225–339
El karib AO, Sheng J, Betz AL, Malvin RL (1993) The central effects of a nitric oxide synthase inhibitor (Nω-nitro-l-arginine) on blood pressure and plasma renin. Clin Exp Hypertens 15(5):819–832
Förstermann U, Mülsch A, Bohme E, Busse R (1986) Stimulation of soluble guanilate cyclase by an acetylcholine-induced endotheliumderived factor from rabbit and canine arteries. Circ Res 58:531–538
Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376
Gardiner Sheila M, Compton AM, Bennett T, Palmer RMJ, Moncada S (1990) Control of regional blood flow by endothelium-derived nitric oxide. Hypertens 15:486–492
Hackenthal E, Paul M, Ganten D, Taugner R (1990) Morphology, physiology and molecular biology of renin secretion. Physiol Rev 70: 1067–1116
Katsuki S, Arnold W Mittal C, Murad F (1977) Stimulation of guanilate-cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J Cycl Nucleot Res 3:23–35
Linz W, Schölkens BA, Han YF (1986) Beneficial effects of the converting enzyme inhibitor ramipril in ischaemic rat hearts. J Cardiovasc Pharmacol [Suppl 10] 8:591-S99
Linz W, Wiemer G, Scholkens BA (1992) ACE-inhibition induces NO-formation in cultured bovine endothelial cells and protects isolated ischemic rat hearts. J Mol Cell Cardiol 24:909–919
Liu SF, Crawley DE, Rohde JAL, Evans TW Barnes PJ (1992) Role of nitric oxide and guanosine 3′,5′-cyclic monophosphate in mediating nonadrenergic, noncholinergic relaxation in guinea-pig pulmonary arteries. Br J Pharmacol 107:861–866
Morton JJ, Beattie EC, Speirs A, Gulliver F (1993) Persistent hypertension following inhibition of nitric oxide formation in the young Wistar rat: role of renin and vascular hypertrophy. J Hypertens 11:1083–1088
Naess PA, Christensen G, Kirkebøen KA, Kiil F (1993) Effect on renin release of inhibiting renal nitric oxide synthesis in anaesthetized dogs. Acta Physiol Scand 148:137–142
Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526
Pollock DM, Polakowski JS, Divish BJ, Opgenorth TJ (1993) Angiotensin blockade reverses hypertension during long-term nitric oxide synthase inhibition. Hypertension 21:660–666
Rees DD, Palmer RMJ, Moncada S (1989) Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci 86:3375–3378
Ribeiro MO, Antunes E, de Nucci G, Lovisolo SM, Zatz R (1992) Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Hypertension 20:298–303
Salazar FJ, Pinilla JM, López F, Romero JC, Quesade T (1992) Renal effects of prolonged synthesis inhibition of endothelium-derived nitric oxide. Hypertension 20:113–117
Schelling P, Fischer H, Ganten D (1991) Angiotensin and cell growth: a link to cardiovascular hypertrophy? J Hypertens 9:3–15
Schricker K, Kurtz A (1993) Liberators of NO exert a dual effect on renin secretion from isolated mouse renal juxtaglomerular cells. Am J Physiol 34:F180-F186
Smith HW, Finkelstein N, Aliminosa L, Crawford B, Gräber M (1945) The renal clearances of substituted hippuric acid derivatives and other aromatic acids in dog and man. J Clin Invest 24:288–293
Toda N, Okamura T (1992) Mechanism of neurally induced monkey mesenteric artery relaxation and contraction. Hypertens 19:161–166
Toda N, Kitamura Y, Okamura T (1993) Neural mechanism of hypertension by nitric oxide synthase inhibitor in dogs. Hypertension 21:3–8
Togashi H, Sakuma I, Yishioka M, Kobayashi T, Yasuga H, Kitabatake A, Saito H, Gross SS, Levi R (1992) A central nervous system action of nitric oxide in blood pressure regulation. J Pharmacol Exp Ther 262:343–347
Tresham JJ, Dusting GJ, Coghlan JP, Whitworth JA (1991) Haemodynamic and hormonal effects of N-nitro-L-arginine, an inhibitor of nitric oxide biosynthesis, in sheep. Clin Exp Pharmacol Physiol 18:327–330
Walser M, Douglas G, Davidson G, Orloff J (1955) The renal clearance of alkali-stable inulin. J Clin Invest 34:1520–1523
Wiemer G, Scholkens BA, Becker RHA, Busse R (1991) Ramiprilat enhances endothelial autacoid formation by inhibiting breakdown of endothelium-derived bradykinin. Hypertension 18:558–563
Wiemer G, Schölkens BA, Linz W (1994) Endothelial protection by converting enzyme inhibitors. Cardiovasc Res 28:166–172
Wilcox ChS, Welch WJ, Murad F, Gross SS, Taylor G, Levi R, Schmidt HHHW (1992) Nitric oxide synthase in macula densa regulates glomerular capillary pressure. Proc Nall Acad Sci 88:11993–11997
Zatz R, de Nucci G (1991) Effects of acute nitric oxide inhibition of rat glomerular microcirculation. Am J Physiol 30:F360-F363
Author information
Authors and Affiliations
Additional information
Correspondence to: Max Hropot at the above address
Rights and permissions
About this article
Cite this article
Hropot, M., Grötsch, H., Klaus, E. et al. Ramipril prevents the detrimental sequels of chronic NO synthase inhibition in rats: hypertension, cardiac hypertrophy and renal insufficiency. Naunyn-Schmiedeberg's Arch Pharmacol 350, 646–652 (1994). https://doi.org/10.1007/BF00169370
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00169370