Permanent ligation of the left descending artery resulted in significant mortality (65%) over the three days of observation, particularly during the first 24 h (45%). Pretreatment with BAY X1005 was life saving during the first 24 h after ligation (no mortality) and significantly reduced overall mortality at 72 h (25%) (Figure 1).
Challenge of PMNL recirculating in spontaneously beating, perfused rabbit heart caused a marked and progressive increase in CPP that appeared to depend largely on the formation of cys-LT, as shown by the protection afforded by pretreatment with the 5-lipoxygenase inhibitor BAY X1005. These data are in agreement with previously published findings and provide further support for a role of cys-LT, locally formed through cooperation between PMNL and endothelial cells, in the control of coronary tone.
Pretreatment of rabbits with the specific 5-lipoxygenase inhibitor BAY X1005 in vivo also afforded significant protection against mortality induced by permanent ligation of the left descending coronary artery, suggesting a potential pathophysiological role of LTs in the development of cardiac damage following permanent ischemia resulting from ligation.
Figure 1 Cardioprotective effect of BAY X1005in the rabbit (n=20) after permanent coronary artery ligation. Mortality is reported as the number of animals surviving at a given time. *P<0.01, **P<0.0001 or 0.001?? versus control (coronary artery ligated) group
Taken together, our results suggest that 5-lipoxygenase metabolites, possibly synthesized through the transcellular synthetic pathway involving PMNL-endothelial cell cooperation, may play a significant role in alteration of coronary flow and cardiac contractility. In agreement with this hypothesis, cys-LT appears to be released during episodes of myocardial ischemia, as indicated by increased urinary LTE4 excretion.
Given the biochemical mechanism proposed for cys-LT biosynthesis, the pharmacological control of 5-lipoxygenase may be of potential interest in pathological conditions where leukocytes adhesion is increased, such as in the presence of oxidized LDL.