PHARMACOLOGICAL NATURE OF TP RECEPTOR-MEDIATED CONTRACTION IN HUMAN INTRAPULMONARY ARTERY

The present experiments were undertaken to elucidate the pharmacologic al nature of thromboxane A(2)/prostaglandin H-2 receptor (TP)-mediated contraction in human intrapulmonary arteries. epithio-11,12-methano-t hromboxane A(2) (STA(2)) and (15S)-hydroxy-9 alpha, 11 alpha-(epoxymet hano) prosta-5Z, 13E-dienoic acid (U46619) (TXA(2) agonists) caused co ntractions in a concentration-dependent manner with EC(50) values of 1 .4 x 10(-9) M and 3.1 x 10(-9) M, respectively. S-1452 and ONO-3708 (T P receptor antagonists) concentration-dependently attenuated the STA(2 ) (10(-8) M)-induced contraction with IC50 values of 5.8 x 10(-9) M an d 4.2 x 10(-8) M, respectively. U-73122 (3 x 10(-6) M) and 2-nitro-4-c alboxyphenyl-N,N-diphenylcarbamate (3 x 10(-5) M) (phospholipase C inh ibitors) significantly attenuated the STA(2)-induced contraction. Ca+-induced contraction in the presence of STA(2) (10(-8) M) in Ca++-free medium was attenuated by nifedipine (10(-6) M) by 40 %. The remaining nifedipine-resistant Ca++-induced contraction was not attenuated by n itroglycerin (10(-5) M), but forskolin (10(-5) M) (adenylate cyclase s timulant) significantly decreased it by 75 %. The results clearly indi cate that in human intrapulmonary artery, there are TP receptors coupl ed with phospholipase C activation and that TP receptor-mediated Ca++- mobilization is in part nifedipine- and nitroglycerin-resistant, but f orskolin-sensitive.