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. 1995 Dec;116(8):3237–3242. doi: 10.1111/j.1476-5381.1995.tb15130.x

Exposure and characterization of the action of noradrenaline at dopamine receptors mediating endothelium-independent relaxation of rat isolated small mesenteric arteries.

P H Van der Graaf 1, P R Saxena 1, N P Shankley 1, J W Black 1
PMCID: PMC1909169  PMID: 8719802

Abstract

1. Previously, we reported that noradrenaline (NA), in addition to its alpha 1-adrenoceptor-mediated contractile effect, may relax the rat small mesenteric artery (SMA) in order to account for steep Schild plots obtained with compounds classified as alpha 1-adrenoceptor antagonists. In this study, a relaxant action of NA has been exposed in the rat isolated, endothelium-denuded SMA precontracted by the thromboxane A2-mimetic, U46619. 2. NA, but not the selective alpha 2-adrenoceptor agonist, UK14304, produced concentration-dependent contraction of the SMA (pEC50 = 5.7 +/- 0.1). After precontraction with 0.1 microM U46619, 10 nM-30 microM NA produced a further contraction (pEC50 = 6.1 +/- 0.2), while higher concentrations of NA produced small, but significant, relaxant responses. 3. In the presence of 1 microM prazosin, 0.1-30 microM NA produced concentration dependent relaxation (pIC50 = 5.9 +/- 0.1) after precontraction with 0.1 microM U46619. The NA relaxation concentration-effect curve was completely inhibited by 1 microM of the beta 1/beta 2-adrenoceptor antagonist, timolol. However, when the concentration of prazosin was increased by 10 fold (10 microM), NA once again produced concentration-dependent relaxation (pIC50 = 4.5 +/- 0.2). This relaxation concentration-effect curve was not blocked by a 10 fold higher concentration of timolol (10 microM), nor by the presence of idazoxan (10 microM), cyanopindolol (10 microM), NG-nitro-L-arginine methyl ester (L-NAME, 100 microM), indomethacin (10 microM) or sulpiride (1 microM). However, haloperidol (10 microM) and (+/-)-SCH-23390 (10 nM) produced significant inhibition of the relaxation, suggesting the involvement of dopamine D1 receptors. 4. Dopamine also produced concentration-dependent relaxation following U46619 precontraction (pIC50 = 5.4 +/- 0.1) which was significantly inhibited by haloperidol and (+)-SCH-23390. Pretreatment with 10 microM phenoxybenzamine for 60 min produced a significant inhibition of the dopamine and NA relaxation curves and application of the operational model of agonism yielded estimates of the affinity (pKA = 5.3 +/- 0.2 and 4.4 +/- 0.2) and efficacy (log gamma = 0.06 +/- 0.11 and 0.01 +/- 0.10) for dopamine and NA, respectively, at D1 receptors. 5. HV723 (0.1 and 1 microM), a ligand that yielded a Schild plot slope parameter of unity as an antagonist of NA in the contractile assay, produced concentration-dependent inhibition of the NA-mediated relaxation (pA2 approximately 8). 6. The results of this study indicate that NA can activate D1 receptors mediating relaxation in the rat SMA at concentrations which were encountered in our previous receptor classification experiments using competitive alpha 1-adrenoceptor antagonists.

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Selected References

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  1. Amenta F., Ricci A., Napoleone P., Vyas S. J., Lokhandwala M. F. Anatomical localization of the binding and functional characterization of responses to dopexamine hydrochloride in the rat mesenteric vasculature. Pharmacology. 1991;42(4):211–222. doi: 10.1159/000138800. [DOI] [PubMed] [Google Scholar]
  2. Bevan J. A., Bevan R. D., Shreeve S. M. Variable receptor affinity hypothesis. FASEB J. 1989 Apr;3(6):1696–1704. doi: 10.1096/fasebj.3.6.2564831. [DOI] [PubMed] [Google Scholar]
  3. Black J. W., Leff P. Operational models of pharmacological agonism. Proc R Soc Lond B Biol Sci. 1983 Dec 22;220(1219):141–162. doi: 10.1098/rspb.1983.0093. [DOI] [PubMed] [Google Scholar]
  4. Crooks R. J., Martin G. R. An isolated vascular tissue preparation showing a specific relaxant effect of dopamine [proceedings]. Br J Pharmacol. 1979 Nov;67(3):474P–474P. [PMC free article] [PubMed] [Google Scholar]
  5. Dupont A. G., Lefebvre R. A., Vanderniepen P. Influence of the dopamine receptor agonists fenoldopam and quinpirole in the rat superior mesenteric vascular bed. Br J Pharmacol. 1987 Jul;91(3):493–501. doi: 10.1111/j.1476-5381.1987.tb11242.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Goldberg L. I., Volkman P. H., Kohli J. D. A comparison of the vascular dopamine receptor with other dopamine receptors. Annu Rev Pharmacol Toxicol. 1978;18:57–79. doi: 10.1146/annurev.pa.18.040178.000421. [DOI] [PubMed] [Google Scholar]
  7. Graves J., Poston L. Beta-adrenoceptor agonist mediated relaxation of rat isolated resistance arteries: a role for the endothelium and nitric oxide. Br J Pharmacol. 1993 Mar;108(3):631–637. doi: 10.1111/j.1476-5381.1993.tb12853.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hall A. S., Bryson S. E., Ball S. G., Balmforth A. J. Phenoxybenzamine mediated inhibition of the vascular dopamine D1 receptor. Eur J Pharmacol. 1993 Nov 15;247(3):249–255. doi: 10.1016/0922-4106(93)90192-c. [DOI] [PubMed] [Google Scholar]
  9. Hall A. S., Bryson S. E., Vaughan P. F., Ball S. G., Balmforth A. J. Pharmacological characterization of the dopamine receptor coupled to cyclic AMP formation expressed by rat mesenteric artery vascular smooth muscle cells in culture. Br J Pharmacol. 1993 Oct;110(2):681–686. doi: 10.1111/j.1476-5381.1993.tb13865.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Heesen B. J., De Mey J. G. Effects of cyclic AMP-affecting agents on contractile reactivity of isolated mesenteric and renal resistance arteries of the rat. Br J Pharmacol. 1990 Dec;101(4):859–864. doi: 10.1111/j.1476-5381.1990.tb14171.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hughes A. D., Sever P. S. The action of dopamine and vascular dopamine (DA1) receptor agonists on human isolated subcutaneous and omental small arteries. Br J Pharmacol. 1989 Jul;97(3):950–956. doi: 10.1111/j.1476-5381.1989.tb12036.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Leff P., Prentice D. J., Giles H., Martin G. R., Wood J. Estimation of agonist affinity and efficacy by direct, operational model-fitting. J Pharmacol Methods. 1990 May;23(3):225–237. doi: 10.1016/0160-5402(90)90066-t. [DOI] [PubMed] [Google Scholar]
  13. Martin P. L., Kelly M., Cusack N. J. (-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0923), a selective D2 dopamine receptor agonist demonstrates the presence of D2 dopamine receptors in the mouse vas deferens but not in the rat vas deferens. J Pharmacol Exp Ther. 1993 Dec;267(3):1342–1348. [PubMed] [Google Scholar]
  14. Mulvany M. J., Aalkjaer C. Structure and function of small arteries. Physiol Rev. 1990 Oct;70(4):921–961. doi: 10.1152/physrev.1990.70.4.921. [DOI] [PubMed] [Google Scholar]
  15. Mulvany M. J., Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res. 1977 Jul;41(1):19–26. doi: 10.1161/01.res.41.1.19. [DOI] [PubMed] [Google Scholar]
  16. Muramatsu I., Ohmura T., Kigoshi S., Hashimoto S., Oshita M. Pharmacological subclassification of alpha 1-adrenoceptors in vascular smooth muscle. Br J Pharmacol. 1990 Jan;99(1):197–201. doi: 10.1111/j.1476-5381.1990.tb14678.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nichols A. J., Hiley C. R. Identification of adrenoceptors and dopamine receptors mediating vascular responses in the superior mesenteric arterial bed of the rat. J Pharm Pharmacol. 1985 Feb;37(2):110–115. doi: 10.1111/j.2042-7158.1985.tb05017.x. [DOI] [PubMed] [Google Scholar]
  18. Nielsen H., Mulvany M. J. The divergence in the excitation-contraction coupling of rat mesenteric resistance arteries lies distal to the receptor site. Eur J Pharmacol. 1990 Apr 10;179(1-2):1–7. doi: 10.1016/0014-2999(90)90395-m. [DOI] [PubMed] [Google Scholar]
  19. Nyborg N. C., Bevan J. A. Increased alpha-adrenergic receptor affinity in resistance vessels from hypertensive rats. Hypertension. 1988 Jun;11(6 Pt 2):635–638. doi: 10.1161/01.hyp.11.6.635. [DOI] [PubMed] [Google Scholar]
  20. Perretti F., Nediani C., Manzini S. IP66 (1[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxy-phenyl)piperazine) enhances beta-adrenoceptor-induced vasodilatation in rat mesenteric vascular bed. Arch Int Pharmacodyn Ther. 1990 Jul-Aug;306:87–99. [PubMed] [Google Scholar]
  21. Rees D. D., Palmer R. M., Schulz R., Hodson H. F., Moncada S. Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol. 1990 Nov;101(3):746–752. doi: 10.1111/j.1476-5381.1990.tb14151.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Vanderheyden P., Ebinger G., Kanarek L., Vauquelin G. Epinephrine and norepinephrine stimulation of adenylate cyclase in bovine retina homogenate: evidence for interaction with the dopamine D1 receptor. Life Sci. 1986 Mar 31;38(13):1221–1227. doi: 10.1016/0024-3205(86)90177-3. [DOI] [PubMed] [Google Scholar]
  23. Wanstall J. C., O'Donnell S. R. Vasodilator responses to dopamine in rat perfused mesentery are age-dependent. Br J Pharmacol. 1989 Sep;98(1):302–308. doi: 10.1111/j.1476-5381.1989.tb16895.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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