RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 383
OP 392
DO 10.1124/jpet.112.199661
VO 345
IS 3
A1 Jadhav, Ashok
A1 Liang, Wenbin
A1 Papageorgiou, Peter C.
A1 Shoker, Ahmed
A1 Kanthan, Selliah C.
A1 Balsevich, John
A1 Levy, Andrew S.
A1 Heximer, Scott
A1 Backx, Peter H.
A1 Gopalakrishnan, Venkat
YR 2013
UL http://jpet.aspetjournals.org/content/345/3/383.abstract
AB 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/dtmax), and the slope of the end-systolic pressure-volume relationship (ESPVR) curve. Catharanthine evoked concentration-dependent 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 third-order 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.