ORIGINAL ARTICLE Cardiovascular Effects of Eugenol, a Phenolic Compound Present in Many Plant Essential Oils, in Normotensive Rats Saad Lahlou, PhD,* Leylliane Fátima Leal Interaminense,* Pedro Jorge Caldas Magalhães, PhD,† José Henrique Leal-Cardoso, PhD,‡ and Gloria Pinto Duarte, PhD* Abstract: Cardiovascular effects of intravenous (i.v.) treatment with eugenol (Eug), a natural pungent present in many plant essential oils, were investigated in normotensive rats. In either anesthetized or conscious rats, i.v. bolus injections of Eug (1 to 10 mg/kg) elicited immediate and dose-dependent hypotension and bradycardia. Magni- tude of Eug-induced hypotension was similar in both groups. Pre- treatment of anesthetized rats with bilateral vagotomy almost abol- ished the bradycardic responses to Eug without affecting the hypotension. Likewise, i.v. pretreatment of conscious rats with meth- ylatropine (1 mg/kg) or hexamethonium (30 mg/kg) significantly re- duced the Eug-induced bradycardia without affecting the hypoten- sion. However, i.v. pretreatment with the nitric oxide synthase inhibitor, N G -nitro-L-arginine methyl (L-NAME, 20 mg/kg), af- fected neither the hypotension nor the bradycardia elicited by Eug. In rat mesenteric bed preparations precontracted with potassium (60 mM), Eug (0.1–2 mM) induced a reversible and concentration- dependent vasodilator effect, which remained unaffected by atropine (1 μM). These results show that i.v. treatment of rats with Eug induces dose-dependent hypotension and bradycardia, which occurred inde- pendently. The bradycardia appears dependent upon the presence of an intact and functional parasympathetic nerve drive to the heart while the hypotension is due to an active vascular relaxation rather than withdrawal of sympathetic tone. Released nitric oxide from vas- cular endothelial cells seems to be not involved in the mediation of Eug-induced hypotension. Key Words: autonomic nervous system, cardiovascular effects, eu- genol, nitric oxide, mesenteric vascular bed, rat (J Cardiovasc Pharmacol™ 2004;43:250–257) E ugenol (Eug), a natural pungent and the major constituent of oil of clove, is used as food flavor and fragrance agent, and is commonly used in dentistry for the sedation of tooth- ache, pulpitis, and dental hyperalgesia. 1 Several biologic ac- tions of Eug have previously been reported. For instance, this compound induces central nervous system effects in mammals such as hypothermia, decrease in spontaneous motor activity, anticonvulsant, and general anesthetic effects. 2 Eugenol is a potent depressant of peripheral nervous activity 3,4 and of ex- citation-contraction coupling in skeletal muscle. 1 This com- pound has also been documented to induce myorelaxant and antispasmodic effects 5 and vasorelaxant effects on either rat 6 or rabbit 7 thoracic aorta as well as on rat mesenteric vascular bed. 8 Eugenol was suggested to act, at least, as a Ca 2+ channel antagonist either through voltage-dependent or through recep- tor-operated Ca 2+ channels to induce its vasodilatory effects in the rat isolated aorta 6,7 but not in the small resistance vessels. 8 It was also reported that methyl-eugenol, an analogue of Eug, also possesses myorelaxant and antispasmodic effects in labo- ratory animals. 9 Eugenol is also an important chemical constituent of the essential oils of many aromatic plants, such as Eugenia caryo- phyllus (Spr.) Merril et Harr, Dicipelium cariophyllatum Nees, Pimenta dioica (L) Merril, Croton zehntneri Pax et Hoffm, var. eugenoliferum, and Ocimum gratissimum L. 10–13 Croton zehntneri, and O. gratissimum have a rich essential oil content and are used in folk medicine of northeastern Brazil as sto- machics, carminatives, and intestinal antispasmodics. 14 Previ- ous studies from our laboratory showed that the essential oils of C. zehntneri and C. nepetaefolius (EOCN), which are rich in Eug analogues as well as in methyl-eugenol, possess myore- laxant and antispasmodic effects in laboratory animals. 9,15,16 It was also shown that intravenous (i.v.) treatment with EOCN induces dose-dependent decreases in mean aortic pressure (MAP) and heart rate (HR) in either anesthetized or conscious, normotensive rats. 17 Both in vivo and in vitro data suggested that the hypotensive response to EOCN 18 results from its va- sodilatory action directly upon vascular smooth muscle rather than withdrawal of sympathetic tone. However, very few pa- pers in the international literature have systematically studied the cardiovascular effects of Eug in rats. Received August 27, 2003; accepted September 24, 2003. From the *Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife, Brazil; †Department of Physiology and Pharma- cology, Federal University of Ceará, Fortaleza, Brazil; and ‡Department of Physiological Sciences, State University of Ceará, Fortaleza, Brazil. Supported by the Universidade Federal of Pernambuco (UFPE), the Conselho Nacional de Pesquisa (CNPq), and the Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP). Reprints: Dr. Saad Lahlou, Department of Physiology and Pharmacology, Center of Biological Sciences, Federal University of Pernambuco, 50670- 901, Recife, Pernambuco, PE, Brazil. E-mail: lahlou@ufpe.br Copyright © 2004 by Lippincott Williams & Wilkins 250 J Cardiovasc Pharmacol  • Volume 43, Number 2, February 2004