RESPONSES OF CAROTID-ARTERY IN MICE DEFICIENT IN EXPRESSION OF THE GENE FOR ENDOTHELIAL NO SYNTHASE

We examined the hypotheses that responses to acetylcholine are impaire d and responses to NO are enhanced in carotid artery from mice made de ficient in endothelial nitric oxide synthase (eNOS) by gene targeting (eNOS-deficient mice). We also tested the hypothesis that deletion of one copy of the eNOS gene is sufficient to alter vascular responses. V essels were studied in vitro from heterozygous (+/-) and homozygous (- /-) eNOS-deficient mice as well as wild-type [eNOS(+/+)] littermates. After precontraction with prostaglandin F-2 alpha, acetylcholine produ ced marked relaxation of carotid arteries in eNOS(+/+) mice, with impa ired vasorelaxation in eNOS(+/-) mice. For example, 1 mu M acetylcholi ne relaxed carotid arteries by 55 +/- 5% (mean +/- SE in eNOS(+/-) mic e (n = 13) compared with 83 +/- 3% in eNOS(+/+) mice (n = 14, P < 0.00 1 vs, +/-). In contrast, acetylcholine caused no relaxation in carotid arteries from eNOS(-/-) mice (P < 0.001 vs. +/+ and +/-). Relaxation of the carotid artery in response to nitroprusside [a nitric oxide (NO ) donor] was enhanced (P < 0.001) in eNOS-deficient mice. For example, in response to 10 nM nitroprusside, the carotid artery relaxed by 18 +/- 2% in eNOS(+/+) mice (n = 14), 33 +/- 2% in eNOS(+/-) mice (n = 13 ), and 47 +/- 4% in eNOS(-/-) mice (n = 5). Thus relaxation of the car otid artery is impaired with acetylcholine and enhanced with the NO do nor nitroprusside in eNOS-deficient mice. Enhanced responses to NO may represent a compensatory response expressed in the absence of eNOS. T he findings that. vascular responses to acetylcholine and NO are alter ed in eNOS(+/-) mice compared with those observed in eNOS(+/+) mice su ggest ''gene-dosing'' effect.