5-HT2B-receptor antagonist LY-272015 is antihypertensive in DOCA-salt-hypertensive rats

We previously demonstrated a change in the receptors mediating 5-hydroxytry ptamine (5-HT)-induced contraction in arteries of deoxycorticosterone aceta te (DOCA)-salt-hypertensive rats. Specifically, contraction to 5-HT is medi ated primarily by 5-HT2A receptors in arteries from normotensive sham rats and by both 5-HT2A and 5-HT2B receptors in arteries from hypertensive rats. We hypothesized that the 5-HT2B receptor may play a role in maintaining th e high blood pressure of DOCA-salt-hypertensive rats, and herein we provide data connecting in vitro and in vivo findings. The endothelium-denuded iso lated superior mesenteric artery of DOCA-salt rats displayed a marked incre ase in maximum contraction to the newly available 5-HT2B-receptor agonist: BW-723C86 compared with that of arteries from sham rats, confirming that th e 5-HT2B receptor plays a greater role in 5-HT-induced contraction in arter ies from DOCA-salt rats. In chronically instrumented rats, the 5-HT2B-recep tor antagonist LY-272015 (0.3, 1.0, and 3.0 mg/kg iv at 30-min intervals) w as given cumulatively 1 time/wk during 4 wk of continued DOCA-salt treatmen t. LY-272015 did not; reduce blood pressure of the sham-treated rats at any time or dose. However, LY-272015 (1.0 and 3.0 mg/kg) significantly reduced mean blood pressure in a subgroup of week 3 (-20 mmHg) and week 4 DOCA-sal t (-40 mmHg) rats that had extremely high blood pressure (mean arterial blo od pressure similar to 200 mmHg). Blockade of 5-HT2B receptors by in vivo a dministration of LY-272015 (3.0 mg/kg) was verified by observing reduced 5- HT-induced contraction in rat stomach fundus, the tissue from which the 5-H T2B receptor was originally cloned. These data support the novel hypothesis that 5-HT2B-receptor expression is induced during the development of DOCA- salt hypertension and contributes to the maintenance of severe blood pressu re elevations.