FORMATION OF SULFIDOPEPTIDE-LEUKOTRIENES BY CELL-CELL INTERACTION CAUSES CORONARY VASOCONSTRICTION IN ISOLATED, CELL-PERFUSED HEART OF RABBIT

1 We have studied the transcellular biosynthesis of bioactive leukotri enes (LTs), generated upon blood cell-vascular wall interactions and t heir functional consequences, in the spontaneously beating, cell-perfu sed, heart of the rabbit. Rabbit isolated hearts were perfused under r ecirculating conditions (50 ml) with 5 x 10(6) cells of unpurified (bu ffy coat) or purified human neutrophils (PMNL), and challenged with 0. 5 muM A23187 for 30 min. Coronary perfusion pressure (CPP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP) and left ventri cular pressure (LVP) were monitored continuously. Leukotriene formatio n was measured by specific enzyme-immunoassay and confirmed by reverse d phase h.p.l.c. and u.v. spectral analysis. 2 Basal CPP values averag ed 44 +/- 1.4 mmHg; A23187 triggered a marked increase in CPP both in the presence of buffy coat cells (+ 100% above basal) and PMNL (+ 270% above basal); the latter change in CPP was accompanied by a rise in L VEDP (+ 138% above basal). 3 The increase in CPP was preceded by a sta tistically significant rise in iLTC4-D4 concentration in the circulati ng buffer. Pretreatment with two structurally unrelated LTD4 receptor antagonists, LY171883 and SKF104353 (10 muM), fully prevented the incr ease in CPP and LVEDP. A similar protection was also observed when the rabbit heart was perfused with PMNL that had been pretreated with MK8 86 (1 muM), a potent inhibitor of leukotriene biosynthesis. 4 The incr eased coronary tone was accompanied by a marked release of lactate deh ydrogenase (LDH), a marker of ischaemic damage; pretreatment of the he art with the LTD4 receptor antagonists as well as of the PMNL with MK8 86 resulted in a complete suppression of LDH activity release. 5 Posit ive identification of LTC4-D4 in the perfusates was obtained and a sig nificant correlation observed between the CPP values and iLTC4-D4 conc entrations. 6 This study suggests that challenge of PMNL present withi n the coronary vasculature, causes a LTD4-dependent coronary vasoconst riction, favoured by an efficient uptake of PMNL-derived LTA4 by endot helial cells. The activation of the 5-lipoxygenase pathway in the cont ext of tight interactions between blood cells and coronary vasculature , is suggested to have an important outcome in the alterations of coro nary flow and cardiac contractility.