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

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DOIResolve DOI: http://doi.org/10.1124/jpet.112.199661
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TypeArticle
Journal titleJournal of Pharmacology and Experimental Therapeutics
ISSN1521-0103
Volume345
Issue3
Pages383392; # of pages: 10
AbstractCatharanthine 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/dtmax), and the slope of the end-systolic pressure-volume relationship (ESPVR) curve. Catharanthine evoked concentrationdependent decreases (Imax .98%) in endothelium-independent tonic responses of aortic rings to phenylephrine (PE) and KCl (IC₅₀ = 28 μM for PE and IC₅₀ = 34 μM for KCl) and of thirdorder branches of the small mesenteric artery (MA) (IC₅₀ = 3 μM for PE and IC₅₀ = 6 μM for KCl). Catharanthine also increased the inner vessel wall diameter (IC₅₀ = 10 μM) and reduced intracellular free Ca²⁺ levels (IC₅₀ = 16 μM) in PE-constricted MAs. Patch-clamp studies demonstrated that catharanthine inhibited voltage-operated L-type Ca²⁺ channel (VOCC) currents in cardiomyocytes and VSMCs (IC₅₀ = 220 μM and IC₅₀ = 8 μM, respectively) of MA. Catharanthine lowers BP, HR, left ventricular systolic blood pressure, and dP/dtmax 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.
PublisherAmerican Society for Pharmacology and Experimental Therapeutics
LanguageEnglish
AffiliationNational Research Council Canada; Aquatic and Crop Resource Development
Peer reviewedYes
NRC number55480
NPARC number21268599
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Record identifier0a12948a-6eff-4695-ba17-71011f1489e8
Record created2013-10-25
Record modified2016-05-09
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