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Reduced Hemodynamic Responses to Physical and Mental Stress Under Low-Dose Rilmenidine in Healthy Subjects

  • Clinical Pharmacology and Drug Studies
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Summary

Activation of the sympathetic nervous system plays a major role in the pathogenesis and prognosis of cardiovascular diseases. Rilmenidine is an I1-imidazoline receptor agonist that reduces blood pressure by modulation of central sympathetic activity, but the effects of low-dose rilmenidine on the hemodynamic responses to physiological maneuvers that increase adrenergic drive is not known. To assess the effects of low-dose rilmenidine on the hemodynamic responses to stress, 32 healthy subjects (20–56 years old) underwent acute physical exercise (n = 15, individualized ramp protocol on treadmill) and mental stress (n = 17, word color Stroop and mental arithmetics tests) two hours after the oral administration of 0.5 mg of rilmenidine (RIL) or placebo (PLA) following a randomized, double-blind, placebo controlled crossover study. No subject complained of any side effect. Rilmenidine reduced peak exercise heart rate (PLA: 187 ± 7; RIL: 181 ± 9 bpm; P = 0.003), but did not modify peak aerobic power (VO2max — PLA: 41.7 ± 6.2; RIL: 42.3 ± 6.7 ml/kg/min; P = 0.26). During mental stress, rilmenidine inhibited the peak systolic (PLA: 123 ± 10; RIL: 114 ± 8 mmHg; P = 0.02) and diastolic (PLA: 86 ± 7; RIL: 81 ± 7 mmHg; P <0.05) blood pressure responses. In conclusion, rilmenidine reduced the hemodynamic response to physical and mental stress stimuli without limiting exercise capacity. These results support the concept that rilmenidine, at a dose lower than the ones recommended to treat hypertension, reduced the myocardial oxygen demand to stress and may carry potential clinical impact.

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References

  1. Brook RD, Julius S. Autonomic imbalance, hypertension, and cardiovascular risk. Am J Hypertens 2000;13(6 Pt 2):112S–122S.

    Article  PubMed  CAS  Google Scholar 

  2. Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation 2003;108:560–565.

    Article  PubMed  Google Scholar 

  3. Julius S, Valentini M. Consequences of the increased autonomic nervous drive in hypertension, heart failure and diabetes. Blood Press 1998;3(Suppl):5–13.

    PubMed  Google Scholar 

  4. Verrier RL, Antzelevitch C. Autonomic aspects of arrhythogenesis: the enduring and the new. Curr Opin Cardiol 2004;19:2–11.

    Article  PubMed  Google Scholar 

  5. Curtis BM, O’Keefe JH Jr. Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight. Mayo Clin Proc 2002;77:45–54.

    PubMed  Google Scholar 

  6. Hjalmarson A. Prevention of sudden cardiac death with beta blockers. Clin Cardiol 1999;22(Suppl 5):V11–15.

    PubMed  Google Scholar 

  7. De Ferrari GM, Salvati P, Grossoni M, et al. Pharmacologic modulation of the autonomic nervous system in the prevention of sudden cardiac death. A study with propranolol, methacholine and oxotremorine in conscious dogs with a healed myocardial infarction. J Am Coll Cardiol 1993;22:83–290.

    Google Scholar 

  8. Grabe-Guimaraes A, Alves LM, Tibirica E, Nobrega AC. Pyridostigmine blunts the increases in myocardial oxygen demand elicited by the stimulation of the central nervous system in anesthetized rats. Clin Auton Res 1999;9:83–89.

    Article  PubMed  CAS  Google Scholar 

  9. Castro RRT, Porphirio G, Serra SM, Nobrega ACL. Cholinergic stimulation with pyridostigmine protects against exercise induced myocardial ischaemia. Heart 2004;90:1119–1123.

    Article  PubMed  CAS  Google Scholar 

  10. Bousquet P, Feldman J. Drugs acting on imidazoline receptors: a review of their pharmacology, their use in blood pressure control and their potential interest in cardioprotection. Drugs 1999;58:799–812.

    Article  PubMed  CAS  Google Scholar 

  11. Tibiriçá E, Feldman J, Mermet C, Gonon F, Bousquet P. An imidazoline-specific mechanism for the hypotensive effect of clonidine: a study with yohimbine and idazoxan. J Pharmacol Exp Ther 1991;256:606–613.

    PubMed  Google Scholar 

  12. Tibiriçá E, Feldman J, Mermet C, Monassier L, Gonon F, Bousquet P. Selectivity of rilmenidine for the nucleus reticularis lateralis, a ventrolateral medullary structure containing imidazoline-preferring receptors. Eur J Pharmacol 1991;209:213–221.

    Article  PubMed  Google Scholar 

  13. Bousquet P, Feldman J, Schwartz J. Central cardiovascular effects of alpha-adrenergic drugs: Difference between catecholamines and imidazolines. J Pharmacol Exp Ther 1984;230:232–236.

    PubMed  CAS  Google Scholar 

  14. Reis DJ, Regunathan S, Wang H, Feinstein DL, Meeley MP. Imidazoline receptors in the nervous system. Fund Clin Pharmacol 1992;6:23S–29S.

    Article  Google Scholar 

  15. Chan CK, Sannajust F, Head GA. Role of imidazoline receptors in the cardiovascular actions of moxonidine, rilmenidine and clonidine in conscious rabbits. J Pharmacol Exp Therap 1996;276:411–420.

    CAS  Google Scholar 

  16. De Sarro GB, Ascioti C, Froio F, Libri V, Nistico G. Evidence that locus coeruleus is the site where clonidine and drugs acting at alpha1- and alpha2-adrenoceptors affect sleep and arousal mechanisms. Br J Pharmacol 1987;90:675–685.

    PubMed  CAS  Google Scholar 

  17. Reid JL. Update on rilmenidine: Clinical benefits. Am J Hypert 2001;14(11 Pt 2):322S–324S.

    Article  CAS  Google Scholar 

  18. van Zwieten PA, Peters SL. Central I1-imidazoline receptors as targets of centrally acting antihypertensive drugs. Clinical pharmacology of moxonidine and rilmenidine. Ann N Y Acad Sci 1999;881:420–429.

    Article  PubMed  CAS  Google Scholar 

  19. van Zwieten PA. The renaissance of centrally acting antihypertensive drugs. J Hypertens 1999;17(Suppl 3):S15–S21.

    CAS  Google Scholar 

  20. Reid JL, Panfilov V, MacPhee G, Elliott HL. Clinical pharmacology of drugs acting on imidazoline and adrenergic receptors. Studies with clonidine, moxonidine, rilmenidine, and atenolol. Ann N Y Acad Sci 1995;763:673–678.

    PubMed  CAS  Google Scholar 

  21. Roegel JC, Yannoulis N, De Jong W, Monassier L, Feldman J, Bousquet P. Inhibition of centrally induced ventricular arrhythmias by rilmenidine and idazoxan in rabbits. Naunyn Schmiedebergs Arch Pharmacol 1996;354:598–605.

    Article  PubMed  CAS  Google Scholar 

  22. Poisson D, Christen MO, Sannajust F. Protective effects of I(1)-antihypertensive agent moxonidine against neurogenic cardiac arrhythmias in halothane-anesthetized rabbits. J Pharmacol Exp Therap 2000;293:929–938.

    CAS  Google Scholar 

  23. Mammoto T, Kamibayashi T, Hayashi Y, Yamatodani A, Takada K, Yoshiya I. Antiarrhythmic action of rilmenidine on adrenaline-induced arrhythmia via central imidazoline receptors in halothane-anaesthetized dogs. Br J Pharmacol 1996;117:1744–1748.

    PubMed  CAS  Google Scholar 

  24. Hayashi Y, Kamibayashi T, Maze M, et al. Role of imidazoline-preferring receptors in the genesis of epinephrine-induced arrhythmias in halothane-anesthetized dogs. Anesthesiology 1993;78:524–530.

    PubMed  CAS  Google Scholar 

  25. Catelli M, Feldman J, Bousquet P, Tibirica E. Protective effects of centrally acting sympathomodulatory drugs on myocardial ischemia induced by sympathetic overactivity in rabbits. Braz J Med Biol Res 2003;36:85–95.

    Article  PubMed  CAS  Google Scholar 

  26. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 1999;99:2192–2217.

    PubMed  CAS  Google Scholar 

  27. Panfilov V, Morris AD, Donnelly R, Scemama M, Reid JL. The effects of rilmenidine and atenolol on mental stress, dynamic exercise and autonomic function in mild to moderate hypertension. Br J Clin Pharmacol 1995;40:563–569.

    PubMed  CAS  Google Scholar 

  28. Dollery CT, Davies DS, Duchier J, Pannier B, Safar ME. Dose and concentration-effect relations for rilmenidine. Am J Cardiol 1988;61:60D–66D.

    Article  PubMed  CAS  Google Scholar 

  29. Steptoe A, Vogele C. Methodology of mental stress testing in cardiovascular research. Circulation 1991;83(Suppl. II):II14–II24.

    PubMed  CAS  Google Scholar 

  30. Hayashi Y, Maze M. Alpha2 adrenoceptor agonists and anaesthesia. Br J Anaesth 1993;71:108–118.

    PubMed  CAS  Google Scholar 

  31. Fulgencio JP, Rimaniol JM, Catoire P, Bonnet F. Clonidine and postoperative myocardial ischemia. Can J Anaesth 1994;41:550–551.

    Article  PubMed  CAS  Google Scholar 

  32. Dorman BH, Zucker JR, Verrier ED, Gartman DM, Slachman FN. Clonidine improves perioperative myocardial ischemia, reduces anesthetic requirement, and alters hemodynamic parameters in patients undergoing coronary artery bypass surgery. J Cardiothorac Vasc Anesth 1993;7:386–395.

    Article  PubMed  CAS  Google Scholar 

  33. Thomas MG, Quiroz AC, Rice JC, Sander GE, Giles TD. Antianginal effects of clonidine. J Cardiovasc Pharmacol 1986;8:S69–S75.

    PubMed  Google Scholar 

  34. Zochowski RJ, Lada W. Intravenous clonidine treatment in acute myocardial infarction (with comparison to a nitroglycerin-treated and control group). J Cardiovasc Pharmacol 1986;8:S41–S55.

    Article  PubMed  Google Scholar 

  35. Zochowski RJ, Lada W. Intravenous clonidine in acute myocardial infarction in men. Int J Cardiol 1984;6:189–205.

    Article  PubMed  CAS  Google Scholar 

  36. Ceremuzynski L, Zaleska T, Lada W, Zalewski A. Clonidine effect in chronic angina pectoris. Double-blind, crossover trial on 60 patients. Eur J Cardiol 1979;10:415–427.

    PubMed  CAS  Google Scholar 

  37. Giles TD, Thomas MG, Sander GE, Quiroz AC. Central alpha-adrenergic agonists in chronic heart failure and ischemic heart disease. J Cardiovasc Pharmacol 1985;7:S51–S55.

    PubMed  Google Scholar 

  38. Maki T, Naveri H, Leinonen H, Sovijarvi A. Effect of beta-blocking agents with and without intrinsic sympathomimetic activity on work efficiency in healthy men. Clin Physiol 1996;16:543–550.

    Article  PubMed  CAS  Google Scholar 

  39. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002;346:793–801.

    Article  PubMed  Google Scholar 

  40. Laukkanen JA, Kurl S, Salonen R, Rauramaa R, Salonen JT. The predictive value of cardiorespiratory fitness for cardiovascular events in men with various risk profiles: A prospective population-based cohort study. Eur Heart J 2004;25:1428–1437.

    Article  PubMed  Google Scholar 

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Teixeira de Castro, R.R., Tibiriçá, E., de Oliveira, M.A.B. et al. Reduced Hemodynamic Responses to Physical and Mental Stress Under Low-Dose Rilmenidine in Healthy Subjects. Cardiovasc Drugs Ther 20, 129–134 (2006). https://doi.org/10.1007/s10557-006-7653-8

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