Abstract

The effects of peptidoleukotrienes (LTs) on electrically driven guinea pig left atria (GPLA) were investigated. LTD4 produced a positive inotropic response; however, rapid desensitization required the construction of noncumulative dose-response curves to naive tissues. The maximal inotropic response to LTD4 was 24 +/- 3% of isoproterenol and the EC50 = 267 +/- 77 nM. The functional response was corroborated by the demonstration of specific and rapid [3H]LTD4 binding to GPLA membranes with low affinity (Kd = 212 +/- 80.2 nM), in a saturable (Bmax = 20 +/- 1.1 pmol/mg protein) manner. In tissues pretreated with acivicin, which inhibits conversion of LTC4 to LTD4, the response to LTC4, but not LTD4, was abolished. Selectivity towards LTD4 was demonstrated by the inability of propranolol, prazosin, atropine, pyrilamine, capsaicin or indomethacin (all tested at 1 microM) to alter the functional response to LTD4. Similarly, none of the tested compounds (100 microMs) was inhibitory in the binding assay. Structurally diverse LTD4 antagonists SKF102922 (pKb = 6.42) and ICI 198.615 (pKb = 8.74) were able to inhibit the functional response as well as [3H]LTD4 binding to GPLA membranes. The calcium channel antagonist, verapamil, inhibited the functional response but did not alter [3H]LTD4 binding. These data support the existence of specific LTD4 receptors in GPLA which evoke a modest, rapidly desensitized, increase in the force of myocardial contraction.