Thromboxane A(2) modulates cyclic AMP relaxation and production in human internal mammary artery

Two forms of thromboxane A(2) (TP) receptors, TPalpha and TPbeta receptors, have recently been cloned. These receptors regulate adenylate cyclase activity in two opposite ways: TPalpha receptors activate, whereas TPbeta receptors inhibit adenylate cyclase and cAMP generation. The aim of this study was to examine the effects of the thromboxane A(2) analogue, U46619 (9,11-dideoxy-9alpha,11 alpha-methanoepoxy-prostaglandin F(2alpha)), on forskolin-induced relaxation and cAMP accumulation in human internal mammary artery (IMA) and saphenous vein (SV). In organ baths, IMA rings precontracted with U46619 (3.10(-9) and 3.10(-8) M) were less sensitive to forskolin than rings precontracted with methoxamine (3. 10(-6) M). In contrast, the sensitivity to forskolin was similar in SV rings contracted with the same concentrations of these agonists. U46619 reduced significantly the ten-fold increase in cAMP induced by forskolin in IMA but not in SV rings. Sensitivity and maximal relaxation in response to sodium nitroprusside were not altered in either IMA or SV. In summary, stimulation of TP receptors with the thromboxane A(2) analogue, U46619, inhibited the cAMP pathway of relaxation through the inhibition of cAMP synthesis in human IMA but not in SV. It is suggested that thromboxane A(2) may play a role in the control of muscle tone in IMA both by its potent contractile effect and by its inhibitory effect on the cAMP pathway of relaxation.