Muscarinic Agonist Properties Involved in the Hypotensive and Vasorelaxant Responses of Rotundifolone in Rats

Abstract

The acute cardiovascular effects of rotundifolone (ROT), the major constituent (63.5 %) of the essential oil of Mentha x villosa (OEMV), were tested in rats by using a combined (in vivo and in vitro) approach. ROT (1, 5, 10, 20 and 30 mg kg^-1 i. v.) induced a significant and dose-dependent hypotension and bradycardia in non-anaesthetized normotensive rats. The hypotensive effect was significantly attenuated by pre-treatment of the rats with atropine (2 mg kg^-1 i. v.) or L-NAME (20 mg kg^-1 i. v.). Furthermore, the bradycardic effect was abolished by atropine. In isolated rat atrial preparations, ROT (10, 100, 300 and 500 μg ml^-1) produced concentration-related negative inotropic and chronotropic effects. In isolated intact aortic rings, increasing concentractions of ROT (0.3, 1, 10, 100, 300 and 500 μg ml^-1) were able to antagonize the contractile effect of phenylephrine (1 μM) (IC₅₀ = 184 ± 6 μg ml^-1). The smooth muscle-relaxant activity of ROT was inhibited by either removal of vascular endothelium, atropine (1 μM), L-NAME (100 and 300 μM) or indomethacin (10 μM) (IC₅₀ values = 235 ± 7, 247 ± 8, 387 ± 21, 723 ± 75 and 573 ± 38 μg ml^-1, respectively). These results suggest that rotundifolone markedly lowers arterial pressure and heart rate in non-anaesthetized animals. The hypotensive action of rotundifolone can be a consequence of a decrease in heart rate and peripheral vascular resistance, probably due to a non-selective muscarinic receptor stimulation.

Key words

Rotundifolone - hypotension - muscarinic receptor - aortic rings - nitric oxide - vasodilation

References

• 1 Almeida R N, Hiruma C A, Barbosa-Filho J M. Analgesic effect of rotundifolone in rodents.  Fitoterapia. 1996;  67 334-8
• 2 Alencastro F MMR, Scatone Z, Prisco J T, Laboriau L FG. Contribuição para uma bibliografia do gênero Mentha L. Campinas, Assoc. Bras. Pesq. Plantas Arom. Óleos Essenciais 1965: 354
• 3 Sousa P JC, Magalhães P JC, Oliveira V S, Lima C C, Leal-Cardoso J H. Effects of piperitenone oxide on the intestinal muscle of the guinea pig.  Braz J Med Res. 1997;  30 787-91
• 4 Nasa Y, Ichiara K, Yoshida R, Abiko Y. Positive inotropic and negative chronotopic effects of (-)-cis-diltiazem in rat isolated atria.  Br J Pharmacol. 1992;  105 696-702
• 5 Altura B M, Altura B T. Differential effects of substrate depletion on drug-induced contractions of rabbit aorta.  Am J Physiol. 1970;  219 1698-705
• 6 Smith T L, Hutchins P M. Anesthetic effects on hemodynamics of spontaneously hypertensive and Wistar-Kyoto rats.  Am J Physiol. 1980;  238 539-44
• 7 Fluckiger J P, Sonnay M, Boillat N, Atkinson J. Attenuation of the baroreceptor reflex by general anesthetic agent in the normotensive rat.  Eur J Pharmacol. 1985;  109 105-9
• 8 Higgins C B, Vatner S F, Braunwald E. Parasympathetic control of the heart.  Pharmacol. 1973;  25 119-54
• 9 Dhein S, Koppen C JV, Brodde O E. Muscarinic receptors in the mammalian heart.  Pharmacol Research. 2001;  44 161-82
• 10 Stengel W P, Gomeza J, Wess J, Cohen L M. M₂ and M₄ receptor knockout mice: muscarinic receptor function in cardiac and smooth muscle in vitro .  J Pharmacol Exper Ther. 2000;  292 877-85
• 11 Difrancesco D. Pacemaker mechanisms in cardiac tissue.  Annu Rev Physiol. 1993;  55 455-72
• 12 Lahlou S, Carneiro-Leão L FR, Leal-Cardoso H J, Toscano F C. Cardiovascular effects of the essential oil of Mentha x villosa and main constituent, piperitenone oxide, in normotensive anaesthesised rats: role of the autonomic nervous system.  Planta Med. 2001;  67 638-43
• 13 Thoren P. Role of cardiac vagal C-fibers in cardiovascular control.  Rev Physiol Biochem Pharmacol. 1979;  86 1-94
• 14 Brunning T A, Hendriks M GC, Chang P C, Kuypers E AP, Van Zwieten P A. In vivo characterization of vasodilating muscarinic receptors in humans.  Circ Res. 1994;  74 912-9
• 15 Moncada S, Palmer R MJ, Higgs E A. Nitric oxide: Physiology, pathophysiology and pharmacology.  Pharmacol Rev. 1991;  43 109-42
• 16 Furchgott R F. Role of the endothelium in responses of vascular smooth muscles.  Circ Res. 1983;  53 557-73
• 17 Vanhoutte P M, Boulanger C M, Mombouli J V. Endothelium-derived relaxing factors and converting enzyme inhibition.  Am J Cardiol. 1995;  76 3-12
• 18 Eglen R M, Hegde S S, Watson N. Muscarinic receptor subtypes and smooth muscle function.  Pharmacol Rev. 1996;  48 531-65
• 19 Sawada Y, Sakamaki T, Nakamura T, Sato K, Ono Z, Murata K. Release of nitric oxide in response to acetylcholine is unaltered in spontaneously hypertensive rats.  J Hypertens. 1994;  12 745-50
• 20 Moncada S, Higgs E A. The L-arginine-nitric oxide pathway.  N Engl J Med. 1993;  29 2002-12
• 21 Meade E A, Smith W L, Dewitt D L. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs.  J Biol Chem. 1993;  268 6610-4