title: R(+)-pulegone impairs Ca²+ homeostasis and causes negative inotropism in mammalian myocardium.
abstract: The present study aimed to investigate the inotropic effects of R(+)-pulegone, a monoterpene found in plant species belonging to the genus Mentha, on the mammalian heart. In electrically stimulated guinea pig atria, R(+)-pulegone reduced the contractile force (~83%) and decreased the contraction time measured at 50% of the maximum force amplitude (CT(50)) from 45.8 ± 6.2 ms to 36.9 ± 6.2 ms, suggesting that R(+)-pulegone may have an effect on Ca(2+) homeostasis. Nifedipine (40 μM), taken as a positive control, showed a very similar profile. To explore the hypothesis that R(+)-pulegone is somehow affecting Ca(2+) handling, we determined concentration-response curves for both CaCl(2) and BAY K8644. R(+)-pulegone shifted these curves rightward. Using isolated mouse ventricular cardiomyocytes, we measured whole-cell L-type Ca(2+) current and observed an I(Ca,L) peak reduction of 13.7 ± 2.5% and 40.2 ± 2.9% after a 3-min perfusion with 0.11 and 1.1mM of R(+)-pulegone, respectively. In addition, the intracellular Ca(2+) transient was decreased (72.9%) by 3.2mM R(+)-pulegone, with no significant changes in [Ca(2+)](i) transient decay kinetics. Moreover, R(+)-pulegone at 1.1mM prolonged the action potential duration at 10, 50, and 90% of repolarisation. The lengthening of the action potential duration may be attributed to the substantial blockade of the outward K(+) currents caused by 1.1mM of R(+)-pulegone (90.5% at 60 mV). These findings suggest that R(+)-pulegone exerts its negative inotropic effect on mammalian heart mainly by decreasing the L-type Ca(2+) current and the global intracellular Ca(2+) transient.
authors: Laboratório de Biofísica do Coração, Departamento de Fisiologia, Universidade Federal de Sergipe, Aracaju, SE, Brazil.
authors: Sandra Valeria Santos
authors: SV
authors: de Cerqueira
authors: Antonio Nei Santana
authors: AN
authors: Gondim
authors: Danilo
authors: D
authors: Roman-Campos
authors: Jader Santos
authors: JS
authors: Cruz
authors: Amilton Gustavo da Silva
authors: AG
authors: Passos
authors: Sandra
authors: S
authors: Lauton-Santos
authors: Aline
authors: A
authors: Lara
authors: Silvia
authors: S
authors: Guatimosim
authors: Eduardo Antonio
authors: EA
authors: Conde-Garcia
authors: Evaleide Diniz
authors: ED
authors: de Oliveira
authors: Carla Maria Lins
authors: CM
authors: de Vasconcelos
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D000081005:Cyclohexane Monoterpenes; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D039821:Monoterpenes / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D000081005:Cyclohexane Monoterpenes; D039821:Monoterpenes; C039648:pulegone; D011188:Potassium; D002118:Calcium