Direct effects of colchicine on myocardial function - Studies in hypertrophied and failing spontaneously hypertensive rats

The aging spontaneously hypertensive rat (SHR) is a model in which the tran sition from chronic stable left ventricular hypertrophy to overt heart fail ure can be observed. Although the mechanisms for impaired function in hyper trophied and failing cardiac muscle from the SHR have been studied, none ac counts fully for the myocardial contractile abnormalities. The cardiac cyto skeleton has been implicated as a possible cause for myocardial dysfunction . If an increase in microtubules contributes to dysfunction, then myocardia l microtubule disruption by colchicine should promote an improvement in car diac performance. We studied the active and passive properties of isolated left ventricular papillary muscles from 18- to 24-month-old SHR with eviden ce of heart failure (SHR-F, n=6), age-matched SHR without heart failure (SH R-NF, n=6), and age-matched normotensive Wistar-Kyoto rats (WKY, n=5). Mech anical parameters were analyzed before and up to 90 minutes after the addit ion of colchicine (10(-5), 10(-4), and 10(-3) mol/L). In the baseline state , active tension (AT) developed by papillary muscles from the WKY group was greater than for SHR-NF and SHR-F groups (WKY 5.69+/-1.47 g/mm(2) [mean+/- SD], SHR-NF 3.41+/-1.05, SHR-F 2.87+/-0.26; SHR-NF and SHR-F P<0.05 versus WKY rats). The passive stiffness was greater in SHR-F than in the WKY and S HR-NF groups (central segment exponential stiffness constant, K-cs: SHR-F 7 0+/-25, SHR-NF 44+/-17, WKY 41+/-13 [mean+/-SD]; SHR-F P<0.05 versus; SHR-N F and WKY rats). AT did not improve after 10, 20, and 30 minutes of exposur e to colchicine (10(-5), 10(-4), and 10(-3) mol/L) in any group. In the SHR -F group, AT and passive stiffness did not change after 30 to 90 minutes of colchicine exposure (10(-4) mol/L). In summary, the data in this study fai l to demonstrate improvement of intrinsic muscle function in SHR with heart failure after colchicine. Thus, in the SHR there is no evidence that colch icine-induced cardiac microtubular depolymerization affects the active or p assive properties of hypertrophied or failing left ventricular myocardium.