Effects of mibefradil, a T- and L-type calcium channel blocker, on cardiac remodeling in the UM-X7.1 cardiomyopathic hamster.
Abnormalities of T-type calcium channel function reported to occur in the transition phase to heart failure in the hamster cardiomyopathy may contribute to progression of the disease. We tested the hypothesis that chronic exposure to mibefradil, a selective T-type calcium channel blocker, improves the deleterious cardiac remodeling observed in this condition. In the present study, 40 normal (N) and 40 UM-X7.1 cardiomyopathic hamsters (CMH), aged 180 days, were treated daily by gavage for 21 days with mibefradil (30 mg/Kg). Eight to 10 animals from each group were sacrificed at the end of the treatment period while the remainder were followed for an additional 30 days without treatment (washout period). Hearts were harvested, fixed with 10%-buffered paraformaldehyde and then cut in half down the middle. Several slices were dehydrated, embedded in paraffin and stained with Masson Trichrome. Wall thickness and dilatation index of the left ventricle were estimated by planimetry. Myocardial capillary density was also computed. The greater heart weight/body weight ratio seen in untreated CMH (7.7 +/- 0.4 vs 5.5 +/- 0.2 in N, p < 0.05) was improved with mibefradil. The dilatation index averaged 0.504 +/- 0.04 in N was increased in untreated CMH (0.566 +/- 0.03) and ameliorated in mibefradil-treated CMH. The 1-month washout period led to further deterioration of the dilatation index in untreated and mibefradil-treated CMH. Capillary density averaged 10,000 +/- 781 per mm2 in hearts from untreated N hamsters and 8,830 +/- 795 per mm2 in untreated CMH (p = NS). Chronic exposure to mibefradil resulted in a significant reduction of capillary density in both N and CMH hearts. Following the 1-month washout period, the change in myocardial capillary density associated with mibefradil was no longer detectable. In conclusion, chronic exposure to mibefradil, a T- and L-type calcium channel blocker, exerts opposite effects during the transition phase to heart failure in CMH, improving the deleterious left ventricular remodeling in UM-X7.1 hamsters and reducting myocardial capillary density independently of the disease process.
Villame
J
J
Département de pharmacologie, Faculté de médecine, Université de Montréal, QC, Canada.
Massicotte
J
J
Jasmin
G
G
Dumont
L
L
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D002196:Capillaries / Q000473:pathology; D009202:Cardiomyopathies / Q000473:pathology*; D006224:Cricetinae; D006333:Heart Failure / Q000188:drug therapy / Q000473:pathology; D008647:Mesocricetus; D020748:Mibefradil / Q000494:pharmacology*; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D020748:Mibefradil