Contractile effect of the chemotactic factors f-Met-Leu-Phe and C5a on the human isolated umbilical artery. Role of cyclooxygenase products and tissue macrophages.

Abstract

Factors that are chemotactic for phagocytic leukocytes are known to elicit important acute circulatory changes, and the role of circulating leukocytes in these models is controversial. To evaluate the role of the blood vessel wall in the absence of circulating cells, spiral strips of human umbilical artery were exposed in vitro to the chemotactic peptides f-Met-Leu-Phe (1-100 nM) or C5a (2.5-25 nM). Contractile responses were observed for both peptides. Certain agonist analogues and a selective antagonist of the chemotactic action of f-Met-Leu-Phe behaved correspondingly as agonists and antagonist of the contractile effect on umbilical artery. The anaphylatoxin C3a also exerted a contractile effect on the tissue (25 nM and above), but this effect was highly tachyphylactic. Inhibitory drugs were used to examine the contributions of secondary mediators in eliciting the effects of C5a and f-Met-Leu-Phe. The contractile effect of both peptides was massively inhibited either by indomethacin or the thromboxane A2/prostaglandin H2 antagonist SQ 29548. Dazmegrel, a thromboxane A2 synthetase inhibitor, had partial inhibitory effects on contractions induced by either peptide. The contractile effect of C3a was prevented by indomethacin pretreatment. Vascular strips did not release measurable histamine in the bathing fluid after challenge with C5a or f-Met-Leu-Phe. The tissue apparently contains neither histamine nor mast cells. Autoradiography of 125I-labeled C5a or f-Met-Leu-Phe analogue showed specific binding of the peptides to cells dispersed in the vessel wall, but more frequently at the periphery. Cells stained positively for alpha-naphthyl acetate esterase showed a similar distribution. Pure cultures of smooth muscle cells derived from the umbilical artery failed to release prostanoids when exposed to f-Met-Leu-Phe or C5a, whereas fresh strips of this artery released more thromboxane B2 than the baseline in response to these peptides. We conclude that macrophagelike cells, present in the vessel wall, are the likely target cells for the chemotactic peptides. These cells trigger a contractile effect of the smooth muscle by generating cyclooxygenase products.