Summary
Recent studies suggest endothelium to be involved in the vasorelaxation of calcium antagonists of the 1,4-dihydropyridine type, which may at least in part be mediated by endothelium-derived relaxing factor (EDRF=NO). To study this effect further, the influence of L-NG-nitro arginine (L-NNA), a specific inhibitor of EDRF-synthesis, on nitrendipine-induced vasorelaxation was examined in different isolated porcine arteries. Coronary, basilary, and tail arteries were bathed in Krebs-Henseleit solution and endothelial function was verified by means of substance P, and EDRF releasing neuropeptide. Vasorelaxation of nitrendipine in PGF2α-precontracted arteries was studied in the presence and absence of L-NNA. Nitrendipine-induced vasorelaxation was markedly reduced by the addition of L-NNA in all vessels studied. Tachyphylactic effects of nitrendipine could be excluded. The obtained results may be explained by an enhancement of nitrendipine action by basally released EDRF, alternatively, by an increased EDRF-release induced by this calcium antagonist. Therefore, in a second series of experiments the release of EDRF was studied in isolated coronary arteries under cumulative application of nitrendipine. Using the nitric oxide scavenging properties of oxyhemoglobin, EDRF release was measured spectrophotometrically by means of methemoglobin formation. The application of nitrendipine resulted in a concentration-dependent increase in the extinction rate, indicating an increased release of NO which could be inhibited by preincubation with L-NNA. It may be concluded that, in functionally intact vessels, vasorelaxation induced by nitrendipine may additionally be mediated by an increased release of EDRF.
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References
Adeagbo ASO, Triggle CR (1991) Effects of some inorganic divalent cations and protein kinase C inhibitors on endothelium-dependent relaxation in rat isolated aorta and mesenteric arteries. J Cardiovasc Pharmacol 18:511–512
Busse R, Lückhoff A, Winter I, Pohl U (1988) Fendiline and calmidazolium enhance the release of endothelium-derived relaxant factor and of prostacyclin from cultured endothelial cells. Naynyn-Schmiedebergs Arch Pharmacol 337:79–84
Busse R, Pohl U, Lückhoff A (1989) Mechanisms controlling the production of endothelial autacoids. Z Kardiol 78, Suppl 6:64–69
Feelisch M, Noack EA (1987) Correlation between NO formation during degradation of organic nitrates and activation of guanylate-cyclase. Eur J Pharmacol 139:19–30
Förstermann U, Mülsch A, Böhme E, Busse R (1986) Stimulation of soluble guanylate cyclase by an acetylcholine induced endothelium-derived factor from rabbit and canine arteries. Circ Res 58:531–538
Furchgott RF (1988) Endothelium-dependent relaxation in systemic arteries. In: Vanhoutte PM (ed) Relaxing and contracting factors. Humana Press, Clifton, pp 1–26
Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the ralaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376
Günther J, Dhein S, Rösen R, Klaus W, Fricke U (1991) Endothelium derived relaxing factor (NO) erhöht den vasodilatatorischen Effekt von Nitrendipin an isolierten Arterien des Schweines. Pharm UZ 20:122
Ignarro L (1989): Biological actions and properties of endothelium-derived nitric oxide formed and released from artery and vein. Circ Res 65:1–21
Ignarro, L, Byrus RE, Buga GM, Wood KS (1987) Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res 61:866–879
Ignarro L, Kadowitz PJ (1985) The pharmacological and physiological role of cGMP in vascular smooth muscle. Ann Rev Pharmacol Toxicol 25:171–191
Kelm M, Feelisch M, Schrader J (1989) Release of the free nitric oxide radical (NO) and EDRF from endothelial cells. Zeitschr f Kardiol 78, Suppl 6:70–74
Kojda G, Werner G, Klaus W, Fricke U (1990) Reduced reponses of nitrendipine in PGF2α precontracted porcine isolated arteries after pretreatment with methylene blue. Basic Res Cardiol 85:461–466
Kojda G, Klaus W, Werner G, Fricke U (1991) The influence of endothelium on the action of PGF2α and some dihydropyridine-type calcium antagonists in porcine basilar arteries. Basic Res Cardiol 86:254–265
Lüscher TF, Dohi Y, Tschudi MR, Criscione L, Pfeiffer K (1991) Effects of antihypertensive therapy on the endothelial L-arginine pathway in rat coronary and peripheral mesenteric resistance arteries. Biology of Nitric oxide. Second International Meeting, Biology of Nitric Oxide, London, Sept 30–Oct 2, 1991
Moore PK, al-Swayeh OA, Chang NWS, Evans RA, Gibson A (1990) L-NG-nitro arginine (L-NOARG), a novel, L-arginine-reversible inhibitor of endothelium-dependent vasodilation in vitro. Br J Pharmacol 99:408–412
Mügge A, Peterson T, Harrison D (1991) Release of nitrogen oxide from cultured bovine aortic endothelial cells is not impaired by calcium channel antagonists. Circulation 83:1404–1409
Mülsch A, Busse R (1990) NG-nitro-L-arginine impairs endothelium-dependent dilations by inhibiting cytosolic nitric oxide synthesis from L-arginine. Naunyn-Schmiedeberg's Arch Pharmacol. 341:143–147
Murad F, Rapoport RM, Fiscus R (1985) Role of cyclic-GMP in relaxations of vascular smooth muscle. J Cardiovasc Pharmacol 7, Suppl 3:S111–S118
Myers PR, Guera R, Harrison DG (1989) Release of nitric oxide and EDRF from cultured bovine endothelial cells. Am J Physiol 256:H1030–H1037
Nilius B, Riemann D (1990) Ion channels in human endothelial cells. Gen Physiol Biophys 9:89–112
Palmer RMJ, Ashton DS, Moncada S (1988) Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333:664–666
Palmer RMJ, Ferridge AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526
Pfitzer G, Hofmann F, Disalvo J, Ruegg JC (1984) cGMP and cAMP inhibit tension development in skinned coronary arteries. Pflügers Arch 401:277–280
Rubanyi G, Schwarz A, Vanhoutte PM (1985) The calcium agonists Bay K 8644 and (+)202,791 stimulate the release of endothelium derived relaxing factor from canine femoral arteries. Eur J Pharmacol 117:143–144
Rubanyi G, Schwarz A, Vanhoutte PM (1988) Calcium transport mechanisms in endothelial cells regulating the synthesis and release of endothelium-derived relaxing factor. In: Vanhoutte PM (ed) Relaxing and contracting factors; Humana Press Inc, Crescent Manor, pp 179–188
Teng CM, Yu SM, Chen CC, Huang YL, Huang TF (1990) EDRF-release and Ca++-blockade by magnolol, an antiplatelet agent isolated from Chinese herb magnolia officinalis, in rat thoracic aorta. Life Sci. 47:1153–1161
Vanhoutte PM (1988) Vascular endothelium and Ca2+ antagonists. J Cardiovasc Pharmacol 12, Suppl 6:S21–S28
Vilaine JP, Biondi ML, Feletou M, Peglion JL, Vanhoutte PM (1991) The calcium channel antagonist S 11568 causes endothelium dependent relaxation in canine arteries. Eur J Pharmacol 197(1):41–48
Werner G, Kojda G, Fricke U (1990) Influence of endothelium on vascular activity of structurally different calcium antagonists in porcine isolated basilary arteries. Naunyn-Schmiedebergs Arch Pharmacol 341 (Suppl):R44
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Günther, J., Dhein, S., Rösen, R. et al. Nitric oxide (EDRF) enhances the vasorelaxing effect of nitrendipine in various isolated arteries. Basic Res Cardiol 87, 452–460 (1992). https://doi.org/10.1007/BF00795057
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DOI: https://doi.org/10.1007/BF00795057