Abstract
We investigated the effect of NO/cyclic GMP pathway on the action of calcium antagonists (isradipine, nisoldipine, lacidipine, verapamil, diltiazem) in rat aorta exposed to 100 mM KCl. For this purpose constitutive NO synthase was blocked by using 100 μM Nω-nitro-l-arginine (l-NNA).
The steady-state contractile response evoked by 100 mM KCl was enhanced when the basal NO release had been blocked. The combined effects of basal NO release and calcium antagonists resulted in an inhibition greater than additive. Concentrations of calcium antagonists producing 50% inhibition of contraction were about 3-fold lower in the presence of the basal NO release than in its absence (P < 0.01). 45Ca2− influx stimulated by 100 mM KCl was not affected by the basal NO release, but was inhibited by isradipine and verapamil regardless of NO blockade. Thus, the facilitation of the action of calcium antagonists by NO/cyclic GMP pathway seemed not to be accompanied by a modification of their action on L-type calcium channels. To confirm this, we measured the contractile tension and the calcium signal in fura-2 loaded rings, pretreated with either verapamil or verapamil plus 8-bromo cyclic GMP (BrcGMP), and further exposed to increasing concentrations of extracellular Ca2− ([Ca2+]o) in 100 mM KCl solution. The increase in cytosolic Ca2+ ([Ca2+]cyt) evoked by increasing ([Ca2+]o) in rings pretreated with verapamil alone was not different from rings pretreated with verapamil plus BrcGMP. In contrast, the [Ca2+]o-contraction curve was significantly shifted to the right in rings pretreated with verapamil plus BrcGMP.
These results show that the NO/cyclic GMP pathway facilitates the inhibitory effect of calcium antagonists on 100 mM KCl-evoked contraction. This phenomenon is not related to a modification of calcium channel blockade, but could result from the reduction of the sensitivity of contractile machinery to Ca2+ by cyclic GMP.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bolotina VM, Najibi S, Palacino JJ, Pagano PJ, Cohen RA (1994) Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 368:850–853
Cremona G, Wood AM, Hall LW, Bower EA, Higenbottam T (1994) Effect of inhibitors of nitric oxide release and action on vascular tone in isolated lungs of pig, sheep, dog and man. J Physiol 481:185–195
Dhein S, Zhao Y, Simsek S, Salameh A, Klaus W (1995) Actions of 1,4-dihydropyridines in isolated mesenteric vascular beds. J Cardiovasc Pharmacol 26:784–791
Eglème C, Godfraind T, Miller RC (1984) Enhanced responsiveness of rat isolated aorta to clonidine after removal of the endothelial cells. Br J Pharmacol 81:16–18
Frombach R, Reil GH, Schütte C, Jost S, Gulba PR, Lichtlen PR (1990) Effects of nisoldipine in intact and endothelium-denuded vascular ring preparations. In: Lichtlen PR, Krayenbühl HP (eds) Nisoldipine. Schattauer, Stuttgart, pp 51–60
Chgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376
Gao Y, Zhou H, Raj JU (1995) Heterogeneity in role of endothelium-derived NO in pulmonary arteries and veins of full-term fetal lambs. Am J Physiol 268:H1586-H1592
Godfraind T (1976) Actions of nifedipine on calcium fluxes and contraction in isolated arteries. J Pharmacol Exp Ther 224: 443–450
Godfraind T (1986) FDRF and cyclic GMP control gating of receptor-operated calcium channels in vascular smooth muscle. Eur J Pharmacol 126:341–343
Godfraind T (1994) Calcium antagonists and vasodilatation. Pharmacol Ther 64:37–75
Godfraind T, Kaba A (1969) Blockade or reversal of contraction induced by calcium and adrenaline in depolarized arterial smooth muscle. Br J Pharmacol 36:459–460
Godfraind T, Miller RC, Wibo M (1986) Calcium antagonisms and calcium entry blockade. Pharmacological Rev 38:321–416
Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450
Hayashi T, Fukuto JM, Ignarro LJ, Chaudhuri G (1992) Basal release of nitric oxide from aortic rings is greater in female rabbits than in male rabbits: implications for atherosclerosis. Proc Natl Acad Sci USA 89:11259–11263
Kähönen M, Arvola P, Wu X, Pörsti I (1994) Arterial contractions induced by cumulative addition of calcium in hypertensive and normotensive rats: influence of endothelium. Naunyn-Schmiedeberg's Arch Pharmacol 349:627–636
Krippeit-Drews P, Morel N, Godfraind T (1992) Effect of nitric oxide on membrane potential and contraction of rat aorta. J Cardiovasc Pharmacol 20[Suppl 12]:S72-S75
Liu JJ, Johnston CI, Buxton BF (1994) Synergistic effect of nisoldipine and nitroglycerin on human internal mammary artery. J Pharmacol Exp Ther 268:434–440
Lowry OH, Rosebrough NJ, Farr A.L., Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193: 265–275
Lüscher TF, Yang Z (1993) Calcium antagonists and ACE inhibitors — Effects on endothelium and vascular smooth muscle. Drugs 46 [Suppl 2]:121–132
Martin W, Furchgott RE, Villani GM, Jothianandan D (1986) Phosphodiesterase inhibitors induce endothelium-dependent relaxation of rat and rabbit aorta by potentiating the effects of spontaneously released endothelium-derived relaxing factor. J Pharmacol Exp Ther 237:539–547
Moore PK, Al-Swaye OA, Chong NWS, Evans RA, Gibson A (1990) L-NG nitroarginine (L-NOARG), a novel, l-arginine-reversible inhibitor of endothelium-dependent vasodilatation in vitro. Br J Pharmacol 99:408–412
Mulsch A, Busse R (1990) Ng-nitro-l-arginine (N5-[amino (nitroamino)methyl]-L-ornithine) impairs endothelium-dependent dilations by inhibiting cytosolic nitric oxide synthesis from L-arginine. Naunyn-Schmiedeberg's Arch Pharmacol 341:143–147
Nakayama N, Ikezono M, Ohura M, Yabuuchi Y (1993) Effects of the new long-acting dihydropyridine calcium antagonist pranidipine on the endothelium-dependent relaxation in isolated rat aorta in vitro. Arzneim Forsch/Drug Res 43:1266–1270
O'Murchu B, Miller VM, Perrella MA, Burnett Jr JC (1994) Increased production of nitric oxide in coronary arteries during congestive heart failure. J Clin Invest 93:165–171
Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526
Rees DD, Cellek S, Palmer RMJ, Moncada S (1990) Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on vascular tone: an insight into endotoxin shock. Biochem Biophys Res Commun 173:541–547
Robertson BE, Schubert R, Hescheler J, Nelson MT (1993) cGMP-dependent protein kinase activates Ca2+-activated K channels in cerebral artery smooth muscle cells. Am J Physiol 265: C299-C303
Salomone S, Godfraind T (1993) Influence of spontaneous release of EDRF on the inhibition of vascular contraction by calcium antagonists. Br J Pharmacol 108:134P
Salomone S, Morel N, Godfraind T (1995) Effects of 8-bromo cyclic GMP and verapamil on depolarization-evoked Ca2+ signal and contraction in rat aorta. Br J Pharmacol 114:1731–1737
Taniguchi J, Furukawa KI, Shigekawa M (1993) Maxi K+ channels are stimulated by cyclic guanosine monophosphate-dependent protein kinase in canine coronary artery smooth muscle cells. Pflügers Arch 423:167–172
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Salomone, S., Silva, C.L.M., Morel, N. et al. Facilitation of the vasorelaxant action of calcium antagonists by basal nitric oxide in depolarized artery. Naunyn-Schmiedeberg's Arch Pharmacol 354, 505–512 (1996). https://doi.org/10.1007/BF00168443
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00168443