Cardiovascular effects induced by N-(4'-dihydro)-piperoylthiomorpholine in normotensive rats.
OBJECTIVE
We have tested the cardiovascular effects of N-(4'-dihydro)-piperoylthiomorpholine (LASSBio 365) on rats using an in-vivo and in-vitro approach.


METHODS
LASSBio 365 (0.025, 0.05, 0.1, 0.25, 0.5 or 1 mg/kg, randomly injected) was administered to conscious unrestrained rats and the mean arterial pressure and heart rate were measured. The effects of LASSBio 365 (3 x 10⁻⁶-3 x 10⁻⁴ m) on rat isolated aortic rings with and without endothelium were investigated. Key findings  LASSBio 365 induced a dose-dependent decrease in mean arterial pressure and heart rate (ED50 = 158 ± 53 µg/kg). The effects evoked by LASSBio 365 (0.5 mg/kg) were inhibited by pretreatment with atropine. In anaesthetized rats, electrocardiogram recordings revealed second/third degree sinoatrial and atrioventricular blockade induced by the compound, which were completely inhibited after cardiac muscarinic blockade or cervical bilateral vagotomy. In rat isolated aortic rings, LASSBio 365 (3 x 10⁻⁶-3 x 10⁻⁴ m) was capable of antagonizing the contractile effects induced by phenylephrine (1 µm) or KCl (80 mm) (IC50 = 107 ± 6; 92 ± 6 µm, respectively). This effect was not inhibited after removal of the vascular endothelium (IC50 = 84 ± 4; 92 ± 10 µm, respectively). LASSBio 365 (10⁻⁶-10⁻⁴ m) antagonized CaCl₂-induced contractions in a concentration-dependent manner. Furthermore, LASSBio 365 (98 µm) inhibited contractions produced by noradrenaline (1 µm), but not those induced by caffeine (20 mm).


CONCLUSIONS
These results suggested that LASSBio 365 produced negative chronotropism and reduced peripheral resistance that were probably due to the stimulation of cardiac muscarinic pathways. Peripheral vasodilation was probably linked to voltage-dependent Ca²+-channel blockade and/or specific inhibition of Ca²+ release from noradrenaline-sensitive intracellular stores.
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro-RJ, Brazil. joaoxjr@yahoo.com.br
João Xavier
JX
Araújo
Eurica Adélia Nogueira
EA
Ribeiro
Carlos Alberto Manssour
CA
Fraga
Lídia Moreira
LM
Lima
Eliezer Jesus
EJ
Barreiro
Isac Almeida
IA
de Medeiros
D000818:Animals; D001011:Aorta / Q000187:drug effects*; D052117:Benzodioxoles / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002319:Cardiovascular System / Q000187:drug effects*; D004562:Electrocardiography / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D010656:Phenylephrine / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
D052117:Benzodioxoles; D009025:Morpholines; C555808:N-(4'-dihydro)piperoylthiomorpholine; D014665:Vasodilator Agents; D010656:Phenylephrine; D009638:Norepinephrine