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

被引:10
作者
Jadhav, Ashok [1 ]
Liang, Wenbin [4 ,5 ]
Papageorgiou, Peter C. [4 ,5 ,6 ,7 ]
Shoker, Ahmed [2 ]
Kanthan, Selliah C. [3 ]
Balsevich, John [8 ]
Levy, Andrew S. [4 ,5 ]
Heximer, Scott [4 ,5 ]
Backx, Peter H. [4 ,5 ,6 ,7 ]
Gopalakrishnan, Venkat [1 ]
机构
[1] Univ Saskatchewan, Coll Med, Dept Pharmacol, Saskatoon, SK S7N 5E5, Canada
[2] Univ Saskatchewan, Coll Med, Dept Med, Saskatoon, SK S7N 5E5, Canada
[3] Univ Saskatchewan, Coll Med, Dept Surg, Saskatoon, SK S7N 5E5, Canada
[4] Univ Toronto, Heart & Stroke Richard Lewar Ctr Excellence, Dept Physiol, Toronto, ON M5S 3E2, Canada
[5] Univ Toronto, Heart & Stroke Richard Lewar Ctr Excellence, Dept Med, Toronto, ON M5S 3E2, Canada
[6] Univ Toronto, Dept Med, Div Cardiol, Univ Hlth Network, Toronto, ON M5S 3E2, Canada
[7] Univ Toronto, Mt Sinai Hosp, Toronto, ON M5S 3E2, Canada
[8] Natl Res Council Canada, Inst Plant Biotechnol, Saskatoon, SK S7N 0W9, Canada
基金
加拿大健康研究院;
关键词
CA2+ CHANNELS; VINFLUNINE; MODULATION; RESISTANCE; INCREASES; EXTRACT; AORTA;
D O I
10.1124/jpet.112.199661
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 (IC50 = 28 mu M for PE and IC50 = 34 mu M for KCl) and of third-order branches of the small mesenteric artery (MA) (IC50 = 3 mu M for PE and IC50 = 6 mu M for KCl). Catharanthine also increased the inner vessel wall diameter (IC50 = 10 mu M) and reduced intracellular free Ca2+ levels (IC50 = 16 mu M) 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 mu M and IC50 = 8 mu M, 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.
引用
收藏
页码:383 / 392
页数:10
相关论文
共 30 条
[1]  
[Anonymous], 2011, PRESCRIRE INT, V20, P11
[2]  
Ara N, 2009, PAK J PHARM SCI, V22, P267
[3]   Oxidized LDL increases the sensitivity of the contractile apparatus in isolated resistance arteries for Ca2+ via a Rho- and Rho kinase-dependent mechanism [J].
Bolz, SS ;
Galle, J ;
Derwand, R ;
de Wit, C ;
Pohl, U .
CIRCULATION, 2000, 102 (19) :2402-2410
[4]   MESENTERIC ARCADE ARTERIES CONTRIBUTE SUBSTANTIALLY TO VASCULAR-RESISTANCE IN CONSCIOUS RATS [J].
CHRISTENSEN, KL ;
MULVANY, MJ .
JOURNAL OF VASCULAR RESEARCH, 1993, 30 (02) :73-79
[5]   Pharmacological Activity of Novel 2-Hydroxyacetophenone Isatin Derivatives on Cardiac and Vascular Smooth Muscles in Rats [J].
Gabriel, Daniele ;
Pontes, Luana Braga ;
da Silva, Jaqueline Soares ;
Sudo, Roberto Takashi ;
Correa, Marilza Baptista ;
Pinto, Angelo C. ;
Garden, Simon John ;
Zapata-Sudo, Gisele .
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 2011, 57 (01) :20-27
[6]   Anti-vascular effects of vinflunine in the MAC 15A transplantable adenocarcinoma model [J].
Holwell, SE ;
Bill, BT ;
Bibby, MC .
BRITISH JOURNAL OF CANCER, 2001, 84 (02) :290-295
[7]   Antiangiogenic vinflunine affects EB1 localization and microtubule targeting to adhesion sites [J].
Honore, Stephane ;
Pagano, Alessandra ;
Gauthier, Geraldine ;
Bourgarel-Rey, Veronique ;
Verdier-Pinard, Pascal ;
Civiletti, Karine ;
Kruczynski, Anna ;
Braguer, Diane .
MOLECULAR CANCER THERAPEUTICS, 2008, 7 (07) :2080-2089
[8]   Insulin increases endothelin-1-evoked intracellular free calcium responses by increased ETA receptor expression in rat aortic smooth muscle cells [J].
Hopfner, RL ;
Hasnadka, RV ;
Wilson, TW ;
McNeill, JR ;
Gopalakrishnan, V .
DIABETES, 1998, 47 (06) :937-944
[9]  
Inzitari Domenico, 2005, Aging Clin Exp Res, V17, P16
[10]   L-Tryptophan ethyl ester dilates small mesenteric arteries by inhibition of voltage-operated calcium channels in smooth muscle [J].
Jadhav, Ashok ;
Liang, Wenbin ;
Balsevich, John ;
Bastin, Guillaume ;
Kroetsch, Jeff ;
Heximer, Scott ;
Backx, Peter H. ;
Gopalakrishnan, Venkat .
BRITISH JOURNAL OF PHARMACOLOGY, 2012, 166 (01) :232-242