Chronic colchicine administration attenuates cardiac hypertrophy in spontaneously hypertensive rats.
To determine whether the long-term inhibition of microtubule integrity in vivo by colchicine could attenuate the development of cardiac hypertrophy, we studied five groups of rats: Wistar-Kyoto rats receiving saline for 4 weeks (WKYsaline); WKY receiving colchicine, which depolymerizes microtubules (WKYcolchicine); spontaneously hypertensive rats receiving saline (SHRsaline); SHRs receiving colchicine (SHRcolchicine); and SHRs receiving lumicolchicine, an inactive stereoisomer of colchicine (SHRlumicolchicine). Seven-week-old animals were administered drugs or control substances via alternate day intraperitoneal injection for a period of 4 weeks. Dosage was gradually increased from 0.6 to 1.0 mg/kg to avoid drug toxicity. Depolymerization of myocardial microtubules by the in vivo administration of colchicine into the rats was confirmed by both Western blot analysis and immunofluorescence of tubulin protein in the hearts. Body weight (BW) was lower, while systolic blood pressure was significantly elevated in SHRs vs the WKY rats. No significant difference was found in either of these parameters between the control or treatment groups of each strain. Left ventricular (LV) weight-to-BW ratio was elevated and showed significant increases in the SHRs as compared to WKY animals, indicative of cardiac hypertrophy. When the SHRs were treated with colchicine but not vehicle or lumicolchicine, LV/BW was similar to the WKY. Changes of myocyte cross-sectional area determined using LV mid-free wall specimens were concordant with the LV/BW data. No significant changes were found in collagen volume fraction between groups. Thus the inhibition of microtubule polymerization abolished the progression of cardiac myocyte hypertrophy in SHRs independently of blood pressure.
Tsutsui
H
H
Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, Fukuoka, 812-8582, Japan. prehiro@cardiol.med.kyushu-u.ac.jp
Ishibashi
Y
Y
Takahashi
M
M
Namba
T
T
Tagawa
H
H
Imanaka-Yoshida
K
K
Takeshita
A
A
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced* / Q000473:pathology*; D048429:Cell Size / Q000187:drug effects; D003078:Colchicine / Q000008:administration & dosage*; D003094:Collagen / Q000187:drug effects; D004594:Electrophysiology; D008297:Male; D008870:Microtubules / Q000187:drug effects* / Q000473:pathology; D009200:Myocardial Contraction / Q000502:physiology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013045:Species Specificity; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
D014404:Tubulin; D003094:Collagen; D003078:Colchicine