RELEASE OF NITRIC-OXIDE AND PROSTAGLANDIN H-2 TO ACETYLCHOLINE IN SKELETAL-MUSCLE VENULES

The role of endothelium in regulating venular resistance is not well c haracterized. Thus we aimed to elucidate the endothelium-derived facto rs involved in the mediation of responses of rat gracilis muscle venul es to acetylcholine (ACh) and other vasoactive agents. Changes in diam eter of perfusion pressure (7.5 mmHg)- and norepinephrine (10(-6) M)-c onstricted venules (similar to 225 mu m in diam) to cumulative doses o f ACh (10(-9) to 10(-4) M) and sodium nitroprusside (SNP, 10(-9) to 10 (-4) M), before and after endothelium removal or application of variou s inhibitors, were measured. Lower doses of ACh elicited dilations (up to 42.1 +/- 4.7%), whereas higher doses of ACh resulted in smaller di lations or even constrictions. Endothelium removal abolished both ACh- induced dilation and constriction. In the presence of indomethacin (2. 8 x 10(-5) M), a cyclooxygenase blocker, or SQ-29548 (10(-6) M), a thr omboxane Az-prostaglandin Hz (PGH(2)) receptor antagonist, higher dose s of ACh caused further dilation (up to 72.7 +/-: 7%) instead of const riction. Similarly, lower doses of arachidonic acid (10(-9) to 10(-6) M) elicited dilations that were diminished at higher doses. These redu ced responses were, however, reversed to substantial dilation by SQ-29 548. The nitric oxide (NO) synthase blocker, N-omega-nitro-L-arginine (L-NNA, 10(-4) M), significantly reduced the dilation to ACh (from 30. 6 +/- 5.5 to 5.4 +/- 1.4% at 10(-6) M ACh). In contrast, L-NNA did not affect dilation to SNP. Thus ACh elicits the release of both NO and P GH(2) from the venular endothelium.