ROLE OF NITRIC-OXIDE IN THE CONTRACTILE RESPONSE TO 5-HYDROXYTRYPTAMINE OF THE BASILAR ARTERY FROM WISTAR-KYOTO AND STROKE-PRONE RATS

1 Isolated basilar arteries from spontaneously hypertensive stroke-pro ne rats (SHRSP) are more sensitive to the contractile effect of 5-hydr oxytryptamine (5-HT) than those from normotensive Wistar Kyoto rats (W KY). This has been attributed to a different proportion of 5-HT recept or subtypes mediating these responses. In the present study we have ex amined if differences in nitric oxide release could also contribute to this difference in sensitivity to 5-HT. 2 At rest, the normalized int ernal diameter was significantly smaller in SHRSP (297.4+/-3.5 mu m, n =88) than in WKY (375.1+/-4.0 mu m, n=62, P<0.01) arteries. The contra ctile response to 100 mM KCI was higher in WKY (3.57+/-0.15 mN mm(-1), n=22) than in SHRSP arteries (2.32+/-0.20 mN mm(-1), n=28, P<0.01). 3 When added on the plateau of contraction to 5-HT (1 mu M), acetylchol ine (ACh, 3 mu M) evoked significant relaxation in all preparations fr om WKY (n=20), but only in 15 out of 26 preparations from SHRSP. The m ean relaxations were 55.4+/-5.2% in WKY and 20.6+/-4.6% in SHRSP (as % of the contractile tone evoked by 5-HT; P<0.01). 4 The NO synthase in hibitor N-omega-nitro-L-arginine (L-NOARG, 0.1 mM) produced a similar increase in tone in both WKY and SHRSP. This tone was equal (in % of t he contractile response to 100 mM KCI) to 70.8+/-4.4% in WKY (n=20) an d 67.6+/-5.9% in SHRSP (n=26) and was reversed by L-arginine (1 mM) an d by 1,4-dihydropyridine calcium channel blockers (10 nM nisoldipine, 10 nM lacidipine, 100 nM nifedipine). The L-NOARG-induced tone was abs ent when the arteries were bathed in phosphate-free Krebs (pH 7.4). 5 EC50 values of 5-HT were about four fold smaller in SHRSP than in WKY arteries (P<0.01). The maximal response to 5-HT (E-max) was higher tha n 100 mM KCI-contraction in SHRSP but not in WKY arteries. Removal of endothelium produced a shift to the left of the 5-HT curve in WKY, but not in SHRSP arteries. 6 When evoked in phosphate-free Krebs, the con tractile responses to 5-HT showed tachyphylaxis, but the responses wer e reproducible by adding the agonist at 30 min intervals. In such cond itions, EC50 values of 5-HT were about two fold smaller in SHRSP than in WKY arteries (P<0.01). In phosphate-free Krebs, the blockade of NO synthase did not change the contractile response to 100 mM KCI; it red uced EC50 and increased E-max of 5-HT in WKY, but not in SHRSP. 7 Thes e results confirm that the sensitivity to 5-HT is higher in basilar ar tery isolated from SHRSP than in those from WKY. They show that endoth elium-dependent vasorelaxation to ACh is impaired in SHRSP. The findin g that removal of endothelium or blockade of NO synthase augmented the contractile response to 5-HT in WKY, but not in SHRSP basilar arterie s indicates that the difference in responsiveness to 5-HT observed bet ween WKY and SHRSP basilar arteries might be, at least in part, relate d to dissimilarities in NO release. Furthermore, the L-NOARG-induced c ontraction sensitive to calcium channel blockers indicates that, in ba silar arteries, NO production might lower L-type calcium channel openi ng and thereby control the tone of the vessels.