Biphasic survival response to amlodipine after myocardial infarction in rats: Association with cardiac vascular remodeling.
In clinical studies, calcium channel blockers have been found to cause adverse cardiovascular reactions after myocardial infarction; however, such effects appear limited to short-acting agents. Thus, our aim was to evaluate the response to a long-acting calcium channel blocker, amlodipine, in terms of both survival and, cardiac and vascular remodeling after infarction. One week after permanent coronary occlusion, rats were randomized to no treatment or daily amlodipine (5 mg/kg) continued for up to 9 months. Amlodipine resulted in improved survival at 200 days (65% versus 26%; p < 0.05), but no difference at 9 months. However, rats with large infarcts died earlier than untreated animals, while those with smaller infarcts died later or survived for nine months. Amlodipine produced no difference in collagen content in non-infarcted tissue or myocyte cross-sectional area versus untreated hearts; however, scar length was increased. In addition, amlodipine was associated with vascular remodeling; muscle:lumen ratio increased in non-infarcted myocardium as did perivascular fibrosis. Vessels within the scar had reduced lumen area because of smooth muscle proliferation. We also examined infarcted hearts subjected to one week of intravenous amlodipine (1 mg/kg) initiated before occlusion and examined three weeks later. In this study, amlodipine exacerbated muscle proliferation in infarct vessels and was associated with less scar collagen. The vascular remodeling associated with amlodipine treatment is considered unfavorable and so the adverse survival for rats with large infarcts was no surprise. However, the prolonged survival associated with smaller infarcts raises the possibility that these vascular changes, under certain circumstances, are beneficial.
Whittaker
P
P
Heart Institute, Good Samaritan Hospital and Department of Medicine, University of Southern California, Los Angeles, CA, USA. pwhittaker@dnamail.com
Zhang
H P
HP
Kloner
R A
RA
D017311:Amlodipine / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005355:Fibrosis; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D002121:Calcium Channel Blockers; D017311:Amlodipine