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. 1996 May;118(1):93–104. doi: 10.1111/j.1476-5381.1996.tb15371.x

Baroreflex resetting but no vascular tolerance in response to transdermal glyceryl trinitrate in conscious rabbits.

A P Serone 1, J A Angus 1, C E Wright 1
PMCID: PMC1909489  PMID: 8733581

Abstract

1. We investigated whether acute (5 h) and chronic (3 days) transdermal glyceryl trinitrate (GTN) patches could cause the development of tolerance in terms of haemodynamics and vascular reactivity in the conscious rabbit. The effects of haemodynamic tolerance were assessed on arterial pressure, heart rate and the baroreflex control of heart rate, while hindquarter vascular reactivity in response to dilator and constrictor drugs and reactive hyperaemia were used to assess vascular tolerance. 2. Seven days prior to experiments, an inflatable cuff, a pulsed Doppler flow probe and an indwelling intra-aortic catheter (for i.a. agonist infusions) were implanted around the lower abdominal aorta. 3. In acute experiments, the effects of 0-5 h treatment with transdermal GTN (0 Sham), 10 or 20 mg 24 h-1) on MAP, HR and the baroreflex were examined. Chronic experiments were performed on three separated days (days 0 - before, 4 - with GTN patch and 8 - recovery). On each day, the baroreflex, reactive hyperaemic responses and hindquarter vascular dose-response curves to i.a. GTN, adenosine, acetylcholine, S-nitroso-N-acetylpenicillamine (SNAP) and methoxamine were assessed. On days 1-4, GTN was administered transdermally via a patch(es) (10 mg 24 h-1 (low dose) or 20 mg 24 h-1 (high dose); renewed every 24 h). 4. Acute treatment with 20 mg GTN 24 h-1, but not with 0 (n = 4) or 10 mg GTN 24 h-1 (n = 4), caused a significant fall in MAP (8 +/- 1 mmHg; n = 4) and resetting of the baroreflex by 5 h. Chronic GTN caused a significant fall in MAP of 8 +/- 2 and 8 +/- 2 mmHg on day 4 with low (n = 8) and high dose (n = 8), respectively, with no change in HR. There was no significant change to hindquarter vascular reactivity to i.a. infusion of GTN, nor were there any significant differences in the reactivity to i.a. adenosine, acetylcholine, SNAP or methoxamine with either low or high doses of GTN. 5. Chronic GTN treatment with low and high dose patches caused a parallel leftward shift ('resetting') of the baroreflex on day 4. By day 8, the baroreflex had still not recovered from this leftward shift 6. In the rabbit, chronic exposure to clinical nitrate patches caused haemodynamic compensation and baroreflex resetting but no evidence of vascular reactivity tolerance. Novel NO donor drugs and delivery regimens which provide intermittent dosing may prevent the development of haemodynamic resetting rather then preventing vascular tolerance, a commonly perceived difficulty in chronic nitrate therapy.

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Selected References

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  1. Ahlner J., Andersson R. G., Torfgård K., Axelsson K. L. Organic nitrate esters: clinical use and mechanisms of actions. Pharmacol Rev. 1991 Sep;43(3):351–423. [PubMed] [Google Scholar]
  2. Angus J. A., Brazenor R. M. Relaxation of large coronary artery by verapamil, D600, and nifedipine is constrictor selective: comparison with glyceryl trinitrate. J Cardiovasc Pharmacol. 1983 Mar-Apr;5(2):321–328. doi: 10.1097/00005344-198303000-00026. [DOI] [PubMed] [Google Scholar]
  3. Armstrong P. W., Moffat J. A. Tolerance to organic nitrates: clinical and experimental perspectives. Am J Med. 1983 Jun 27;74(6B):73–84. doi: 10.1016/0002-9343(83)90857-4. [DOI] [PubMed] [Google Scholar]
  4. Bauer J. A., Fung H. L. Effects of chronic glyceryl trinitrate on left ventricular haemodynamics in a rat model of congestive heart failure: demonstration of a simple animal model for the study of in vivo nitrate tolerance. Cardiovasc Res. 1990 Mar;24(3):198–203. doi: 10.1093/cvr/24.3.198. [DOI] [PubMed] [Google Scholar]
  5. Beaufort-Krol G. C., Suichies H. E., Aarnoudse J. G., Okken A., Jentink H. W., Greve J. Postocclusive reactive hyperaemia of cutaneous blood flow in premature newborn infants. Acta Paediatr Scand Suppl. 1989;360:20–25. doi: 10.1111/j.1651-2227.1989.tb11277.x. [DOI] [PubMed] [Google Scholar]
  6. Berdeaux A., Drieu la Rochelle C., Richard V., Giudicelli J. F. Differential effects of nitrovasodilators, K(+)-channel openers, and nicorandil on large and small coronary arteries in conscious dogs. J Cardiovasc Pharmacol. 1992;20 (Suppl 3):S17–S21. doi: 10.1097/00005344-199206203-00005. [DOI] [PubMed] [Google Scholar]
  7. Boesgaard S., Aldershvile J., Poulsen H. E., Loft S., Anderson M. E., Meister A. Nitrate tolerance in vivo is not associated with depletion of arterial or venous thiol levels. Circ Res. 1994 Jan;74(1):115–120. doi: 10.1161/01.res.74.1.115. [DOI] [PubMed] [Google Scholar]
  8. Brown I. P., Thompson C. I., Belloni F. L. Role of nitric oxide in hypoxic coronary vasodilatation in isolated perfused guinea pig heart. Am J Physiol. 1993 Mar;264(3 Pt 2):H821–H829. doi: 10.1152/ajpheart.1993.264.3.H821. [DOI] [PubMed] [Google Scholar]
  9. Cheesman A. R., Benjamin N. Lack of tolerance in forearm blood vessels in man to glyceryl trinitrate. Br J Clin Pharmacol. 1994 May;37(5):441–444. doi: 10.1111/j.1365-2125.1994.tb05711.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cloarec-Blanchard L., Funck-Brentano C., Carayon A., Jaillon P. Rapid development of nitrate tolerance in healthy volunteers: assessment using spectral analysis of short-term blood pressure and heart rate variability. J Cardiovasc Pharmacol. 1994 Aug;24(2):266–273. [PubMed] [Google Scholar]
  11. Curry S. H., Kwon H. R., Perrin J. H., Culp J. R., Pepine C. J., Yu W. C., Stevens J. L. Plasma nitroglycerin concentrations and hemodynamic effects of sublingual, ointment, and controlled-release forms of nitroglycerin. Clin Pharmacol Ther. 1984 Dec;36(6):765–772. doi: 10.1038/clpt.1984.255. [DOI] [PubMed] [Google Scholar]
  12. Dorward P. K., Andresen M. C., Burke S. L., Oliver J. R., Korner P. I. Rapid resetting of the aortic baroreceptors in the rabbit and its implications for short-term and longer term reflex control. Circ Res. 1982 Mar;50(3):428–439. doi: 10.1161/01.res.50.3.428. [DOI] [PubMed] [Google Scholar]
  13. Du Z. Y., Dusting G. J., Woodman O. L. Effect of tolerance to glyceryl trinitrate on vascular responses in conscious rabbits. Clin Exp Pharmacol Physiol. 1991 Jun;18(6):439–447. doi: 10.1111/j.1440-1681.1991.tb01476.x. [DOI] [PubMed] [Google Scholar]
  14. Dupuis J., Lalonde G., Lemieux R., Rouleau J. L. Tolerance to intravenous nitroglycerin in patients with congestive heart failure: role of increased intravascular volume, neurohumoral activation and lack of prevention with N-acetylcysteine. J Am Coll Cardiol. 1990 Oct;16(4):923–931. doi: 10.1016/s0735-1097(10)80342-0. [DOI] [PubMed] [Google Scholar]
  15. Förster S., Woditsch I., Schröder H., Schrör K. Reduced nitric oxide release causes nitrate tolerance in the intact coronary circulation. J Cardiovasc Pharmacol. 1991 Jun;17(6):867–872. doi: 10.1097/00005344-199106000-00002. [DOI] [PubMed] [Google Scholar]
  16. Ghio S., de Servi S., Perotti R., Eleuteri E., Montemartini C., Specchia G. Different susceptibility to the development of nitroglycerin tolerance in the arterial and venous circulation in humans. Effects of N-acetylcysteine administration. Circulation. 1992 Sep;86(3):798–802. doi: 10.1161/01.cir.86.3.798. [DOI] [PubMed] [Google Scholar]
  17. HERD J. A., BARGER A. C. SIMPLIFIED TECHNIQUE FOR CHRONIC CATHETERIZATION OF BLOOD VESSELS. J Appl Physiol. 1964 Jul;19:791–792. doi: 10.1152/jappl.1964.19.4.791. [DOI] [PubMed] [Google Scholar]
  18. Haywood J. R., Shaffer R. A., Fastenow C., Fink G. D., Brody M. J. Regional blood flow measurement with pulsed Doppler flowmeter in conscious rat. Am J Physiol. 1981 Aug;241(2):H273–H278. doi: 10.1152/ajpheart.1981.241.2.H273. [DOI] [PubMed] [Google Scholar]
  19. Head G. A., McCarty R. Vagal and sympathetic components of the heart rate range and gain of the baroreceptor-heart rate reflex in conscious rats. J Auton Nerv Syst. 1987 Dec;21(2-3):203–213. doi: 10.1016/0165-1838(87)90023-3. [DOI] [PubMed] [Google Scholar]
  20. Henry P. J., Drummer O. H., Horowitz J. D. S-nitrosothiols as vasodilators: implications regarding tolerance to nitric oxide-containing vasodilators. Br J Pharmacol. 1989 Nov;98(3):757–766. doi: 10.1111/j.1476-5381.1989.tb14603.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Henry P. J., Horowitz J. D., Louis W. J. Determinants of in vitro nitroglycerin tolerance induction and reversal: influence of dose regimen, nitrate-free period, and sulfhydryl supplementation. J Cardiovasc Pharmacol. 1989 Jul;14(1):31–37. doi: 10.1097/00005344-198907000-00007. [DOI] [PubMed] [Google Scholar]
  22. Henry P. J., Horowitz J. D., Louis W. J. Nitrate tolerance induced by nicorandil or nitroglycerin is associated with minimal loss of nicorandil vasodilator activity. J Cardiovasc Pharmacol. 1990 Mar;15(3):365–370. doi: 10.1097/00005344-199003000-00004. [DOI] [PubMed] [Google Scholar]
  23. Henry P. J., Horowitz J. D., Louis W. J. Nitroglycerin-induced tolerance affects multiple sites in the organic nitrate bioconversion cascade. J Pharmacol Exp Ther. 1989 Feb;248(2):762–768. [PubMed] [Google Scholar]
  24. Hiremath A. N., Hoffman B. B., Blaschke T. F. Responsiveness of peripheral veins to transdermal and sublingual nitroglycerin in healthy male volunteers. J Cardiovasc Pharmacol. 1989 Oct;14(4):534–541. doi: 10.1097/00005344-198910000-00004. [DOI] [PubMed] [Google Scholar]
  25. Hiwatari M., Nolan P. L., Johnston C. I. The contribution of vasopressin and angiotensin to the maintenance of blood pressure after autonomic blockade. Hypertension. 1985 Jul-Aug;7(4):547–553. doi: 10.1161/01.hyp.7.4.547. [DOI] [PubMed] [Google Scholar]
  26. Hogan J. C., Lewis M. J., Henderson A. H. Chronic administration of N-acetylcysteine fails to prevent nitrate tolerance in patients with stable angina pectoris. Br J Clin Pharmacol. 1990 Oct;30(4):573–577. doi: 10.1111/j.1365-2125.1990.tb03815.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Husain M., Adrie C., Ichinose F., Kavosi M., Zapol W. M. Exhaled nitric oxide as a marker for organic nitrate tolerance. Circulation. 1994 Jun;89(6):2498–2502. doi: 10.1161/01.cir.89.6.2498. [DOI] [PubMed] [Google Scholar]
  28. Kalant H., LeBlanc A. E., Gibbins R. J. Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacol Rev. 1971 Sep;23(3):135–191. [PubMed] [Google Scholar]
  29. Katz R. J., Levy W. S., Buff L., Wasserman A. G. Prevention of nitrate tolerance with angiotension converting enzyme inhibitors. Circulation. 1991 Apr;83(4):1271–1277. doi: 10.1161/01.cir.83.4.1271. [DOI] [PubMed] [Google Scholar]
  30. Kojda G., Beck J. K., Meyer W., Noack E. Nitrovasodilator-induced relaxation and tolerance development in porcine vena cordis magna: dependence on intact endothelium. Br J Pharmacol. 1994 Jun;112(2):533–540. doi: 10.1111/j.1476-5381.1994.tb13106.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kojda G., Noack E. Nitric oxide liberating, soluble guanylate cyclase stimulating and vasorelaxing properties of the new nitrate-compound SPM 3672. J Cardiovasc Pharmacol. 1993 Jul;22(1):103–111. doi: 10.1097/00005344-199307000-00017. [DOI] [PubMed] [Google Scholar]
  32. Kukovetz W. R., Holzmann S. Mechanisms of nitrate-induced vasodilatation and tolerance. Eur J Clin Pharmacol. 1990;38 (Suppl 1):S9–14. doi: 10.1007/BF01417559. [DOI] [PubMed] [Google Scholar]
  33. Levy W. S., Katz R. J., Wasserman A. G. Methionine restores the venodilative response to nitroglycerin after the development of tolerance. J Am Coll Cardiol. 1991 Feb;17(2):474–479. doi: 10.1016/s0735-1097(10)80118-4. [DOI] [PubMed] [Google Scholar]
  34. Ludbrook J. Comparison of the reflex effects of arterial baroreceptors and cardiac receptors on the heart rate of conscious rabbits. Clin Exp Pharmacol Physiol. 1984 May-Jun;11(3):245–260. doi: 10.1111/j.1440-1681.1984.tb00262.x. [DOI] [PubMed] [Google Scholar]
  35. Ludbrook J. Repeated measurements and multiple comparisons in cardiovascular research. Cardiovasc Res. 1994 Mar;28(3):303–311. doi: 10.1093/cvr/28.3.303. [DOI] [PubMed] [Google Scholar]
  36. Molina C. R., Andresen J. W., Rapoport R. M., Waldman S., Murad F. Effect of in vivo nitroglycerin therapy on endothelium-dependent and independent vascular relaxation and cyclic GMP accumulation in rat aorta. J Cardiovasc Pharmacol. 1987 Oct;10(4):371–378. doi: 10.1097/00005344-198710000-00001. [DOI] [PubMed] [Google Scholar]
  37. Nakashima A., Angus J. A., Johnston C. I. Comparison of angiotensin converting enzyme inhibitors captopril and MK421-diacid in guinea pig atria. Eur J Pharmacol. 1982 Jul 16;81(3):487–492. doi: 10.1016/0014-2999(82)90114-5. [DOI] [PubMed] [Google Scholar]
  38. Needleman P., Johnson E. M., Jr Mechanism of tolerance development to organic nitrates. J Pharmacol Exp Ther. 1973 Mar;184(3):709–715. [PubMed] [Google Scholar]
  39. Newman C. M., Warren J. B., Taylor G. W., Boobis A. R., Davies D. S. Rapid tolerance to the hypotensive effects of glyceryl trinitrate in the rat: prevention by N-acetyl-L- but not N-acetyl-D-cysteine. Br J Pharmacol. 1990 Apr;99(4):825–829. doi: 10.1111/j.1476-5381.1990.tb13014.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Park K. H., Rubin L. E., Gross S. S., Levi R. Nitric oxide is a mediator of hypoxic coronary vasodilatation. Relation to adenosine and cyclooxygenase-derived metabolites. Circ Res. 1992 Oct;71(4):992–1001. doi: 10.1161/01.res.71.4.992. [DOI] [PubMed] [Google Scholar]
  41. Parker J. D., Farrell B., Fenton T., Cohanim M., Parker J. O. Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin. Circulation. 1991 Dec;84(6):2336–2345. doi: 10.1161/01.cir.84.6.2336. [DOI] [PubMed] [Google Scholar]
  42. Parker J. D., Parker J. O. Effect of therapy with an angiotensin-converting enzyme inhibitor on hemodynamic and counterregulatory responses during continuous therapy with nitroglycerin. J Am Coll Cardiol. 1993 May;21(6):1445–1453. doi: 10.1016/0735-1097(93)90322-r. [DOI] [PubMed] [Google Scholar]
  43. Pohl U., Lamontagne D., Bassenge E., Busse R. Attenuation of coronary autoregulation in the isolated rabbit heart by endothelium derived nitric oxide. Cardiovasc Res. 1994 Mar;28(3):414–419. doi: 10.1093/cvr/28.3.414. [DOI] [PubMed] [Google Scholar]
  44. Shaffer J. E., Han B. J., Chern W. H., Lee F. W. Lack of tolerance to a 24-hour infusion of S-nitroso N-acetylpenicillamine (SNAP) in conscious rabbits. J Pharmacol Exp Ther. 1992 Jan;260(1):286–293. [PubMed] [Google Scholar]
  45. Slack C. J., McLaughlin B. E., Brien J. F., Marks G. S., Nakatsu K. Biotransformation of glyceryl trinitrate and isosorbide dinitrate in vascular smooth muscle made tolerant to organic nitrates. Can J Physiol Pharmacol. 1989 Nov;67(11):1381–1385. doi: 10.1139/y89-221. [DOI] [PubMed] [Google Scholar]
  46. Sumimoto T., Hamada M., Kawakami H., Suzuki M., Abe M., Matsuoka H., Shigematsu Y., Hiwada K. Effects of glyceryl trinitrate on blood pressure and arterial compliance. Angiology. 1993 Dec;44(12):951–957. doi: 10.1177/000331979304401205. [DOI] [PubMed] [Google Scholar]
  47. Torfgård K. E., Ahlner J. Effect of low dose of dipyridamole on glyceryl trinitrate tolerance in healthy volunteers. J Cardiovasc Pharmacol. 1993 Apr;21(4):516–521. doi: 10.1097/00005344-199304000-00002. [DOI] [PubMed] [Google Scholar]
  48. Wright C. E., Angus J. A., Korner P. I. Vascular amplifier properties in renovascular hypertension in conscious rabbits. Hindquarter responses to constrictor and dilator stimuli. Hypertension. 1987 Feb;9(2):122–131. doi: 10.1161/01.hyp.9.2.122. [DOI] [PubMed] [Google Scholar]
  49. Zimmermann T., Leitold M., Yeates R. A. Comparison of isobutyl nitrate and isobutyl nitrite: tolerance and cross-tolerance to glyceryl trinitrate. Eur J Pharmacol. 1991 Jan 3;192(1):181–184. doi: 10.1016/0014-2999(91)90088-8. [DOI] [PubMed] [Google Scholar]

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