THE DEVELOPMENT OF ENHANCED ARTERIAL SEROTONERGIC HYPERRESPONSIVENESSIN MINERALOCORTICOID HYPERTENSION

Objective To demonstrate that the receptor in the rat mesenteric arter y mediating contraction in response to 5-hydroxytryptamine switches fr om a 5-hydroxytryptamine-2A to a 5-hydroxytryptamine-2B receptor after 4 weeks of deoxycorticosterone and salt (1.0% NaCl plus 0.2% KCl) the rapy, and, as an extension of these studies, to test the hypothesis th at this switch occurs prior to the development of hypertension. Design Rats were administered deoxycorticosterone-salt therapy or no therapy for 1, 3, 5, 7, or 28 days. Additionally, four groups of rats (sham-n ormal salt, sham-high salt, deoxycorticosterone-normal salt, and deoxy corticosterone-high salt) were administered therapy for 4 weeks (28 da ys) to distinguish between the roles of salt and blood pressure in ser otonergic responsiveness. Methods Superior mesenteric arteries were mo unted in tissue baths for measurement of isometric contractile force; systolic blood pressure was measured by a tail-cuff method. Results Sy stolic blood pressure was first elevated by deoxycorticosterone-salt t herapy relative to that in sham controls on day 5, Contraction in resp onse to phenylephrine was minimally altered after 7 days of deoxycorti costerone-salt therapy. By day 3, the tryptophan metabolite and putati ve 5-hydroxytryptamine-2B receptor agonist kynuramine contracted hyper tensive arteries to a greater maximum (percentage of contraction induc ed by phenylephrine for rats administered deoxycorticosterone-salt the rapy 48.5 +/- 16.0%) than that observed for arteries in sham-treated r ats (9.7 +/- 6.2%); this was also observed for the ergot alkaloid ergo novine (deoxycorticosterone-salt 67.1 +/- 18.5% and sham treatment 14. 5 +/- 9.1%); however, increase in reactivity to 5-hydroxytryptamine be gan on day 5, Ketanserin (a 5-hydroxytryptamine-2A antagonist with a l ow affinity for 5-hydroxytryptamine-2B receptor; 30 nmol/l) competitiv ely inhibited contraction in response to 5-hydroxytryptamine of mesent eric arteries from sham-treated and deoxycorticosterone-salt-treated r ats on days 1, 3, and 5 but had less effect on arteries in deoxycortic osterone-salt-treated rats by day 7, signifying that a change to a non -5-hydroxytryptamine-2A receptor had occurred, Sensitivities to 5-hydr oxytryptamine and to ergonovine of deoxycorticosterone-treated rats fe d a normal or high-salt diet for 28 days tended to increase, as did th ose of sham-treated rats fed a high-salt diet (with normal blood press ure). Contraction in response to phenylephrine was changed in arteries only from animals whose systolic blood pressure had been increased (d eoxycorticosterone-normal salt and deoxycorticosterone-high salt group s). Conclusions These experiments support the hypothesis that the swit ch to ketanserin-insensitive 5-hydroxytryptamine-2 receptors likely oc curs coincident with or just after the initial increase in blood press ure in the deoxycorticosterone-salt-treated rat. (C) 1998 Lippincott-R aven Publishers.