title: Catharanthine dilates small mesenteric arteries and decreases heart rate and cardiac contractility by inhibition of voltage-operated calcium channels on vascular smooth muscle cells and cardiomyocytes.
abstract: Catharanthine is a constituent of anticancer vinca alkaloids. Its cardiovascular effects have not been investigated. This study compares the in vivo hemodynamic as well as in vitro effects of catharanthine on isolated blood vessels, vascular smooth muscle cells (VSMCs), and cardiomyocytes. Intravenous administration of catharanthine (0.5-20 mg/kg) to anesthetized rats induced rapid, dose-dependent decreases in blood pressure (BP), heart rate (HR), left ventricular blood pressure, cardiac contractility (dP/dt(max)), and the slope of the end-systolic pressure-volume relationship (ESPVR) curve. Catharanthine evoked concentration-dependent decreases (I(max) >98%) in endothelium-independent tonic responses of aortic rings to phenylephrine (PE) and KCl (IC(50) = 28 µM for PE and IC(50) = 34 µM for KCl) and of third-order branches of the small mesenteric artery (MA) (IC(50) = 3 µM for PE and IC(50) = 6 µM for KCl). Catharanthine also increased the inner vessel wall diameter (IC(50) = 10 µM) and reduced intracellular free Ca(2+) levels (IC(50) = 16 µM) in PE-constricted MAs. Patch-clamp studies demonstrated that catharanthine inhibited voltage-operated L-type Ca(2+) channel (VOCC) currents in cardiomyocytes and VSMCs (IC(50) = 220 µM and IC(50) = 8 µM, respectively) of MA. Catharanthine lowers BP, HR, left ventricular systolic blood pressure, and dP/dt(max) and ESPVR likely via inhibition of VOCCs in both VSMCs and cardiomyocytes. Since smaller vessels such as the third-order branches of MAs are more sensitive to VOCC blockade than conduit vessels (aorta), the primary site of action of catharanthine for lowering mean arterial pressure appears to be the resistance vasculature, whereas blockade of cardiac VOCCs may contribute to the reduction in HR and cardiac contractility seen with this agent.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Ashok
authors.initials: A
authors.lastname: Jadhav
authors.forename: Wenbin
authors.initials: W
authors.lastname: Liang
authors.forename: Peter C
authors.initials: PC
authors.lastname: Papageorgiou
authors.forename: Ahmed
authors.initials: A
authors.lastname: Shoker
authors.forename: Selliah C
authors.initials: SC
authors.lastname: Kanthan
authors.forename: John
authors.initials: J
authors.lastname: Balsevich
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Levy
authors.forename: Scott
authors.initials: S
authors.lastname: Heximer
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.forename: Venkat
authors.initials: V
authors.lastname: Gopalakrishnan
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001464:Barium / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D002469:Cell Separation; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014748:Vinca Alkaloids / Q000494:pharmacology*
chemical_list: D020746:Calcium Channels, L-Type; D014662:Vasoconstrictor Agents; D014748:Vinca Alkaloids; D010656:Phenylephrine; D001464:Barium; C017836:catharanthine