The development of enhanced arterial serotonergic hyperresponsiveness in mineralocorticoid hypertension.

Objective: To demonstrate that the receptor in the rat mesenteric artery mediating contraction in response to 5-hydroxytryptamine switches from a 5-hydroxytryptamine-2A to a 5-hydroxytryptamine-2B receptor after 4 weeks of deoxycorticosterone and salt (1.0% NaCl plus 0.2% KCl) therapy, and, as an extension of these studies, to test the hypothesis that 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-normal salt, sham-high salt, deoxycorticosterone-normal salt, and deoxycorticosterone-high salt) were administered therapy for 4 weeks (28 days) to distinguish between the roles of salt and blood pressure in serotonergic responsiveness.
Methods: Superior mesenteric arteries were mounted in tissue baths for measurement of isometric contractile force; systolic blood pressure was measured by a tail-cuff method.
Results: Systolic blood pressure was first elevated by deoxycorticosterone-salt therapy relative to that in sham controls on day 5. Contraction in response to phenylephrine was minimally altered after 7 days of deoxycorticosterone-salt therapy. By day 3, the tryptophan metabolite and putative 5-hydroxytryptamine-2B receptor agonist kynuramine contracted hypertensive arteries to a greater maximum (percentage of contraction induced by phenylephrine for rats administered deoxycorticosterone-salt therapy 48.5 +/- 16.0%) than that observed for arteries in sham-treated rats (9.7 +/- 6.2%); this was also observed for the ergot alkaloid ergonovine (deoxycorticosterone-salt 67.1 +/- 18.5% and sham treatment 14.5 +/- 9.1%); however, increase in reactivity to 5-hydroxytryptamine began on day 5. Ketanserin (a 5-hydroxytryptamine-2A antagonist with a low affinity for 5-hydroxytryptamine-2B receptor; 30 nmol/l) competitively inhibited contraction in response to 5-hydroxytryptamine of mesenteric arteries from sham-treated and deoxycorticosterone-salt-treated rats on days 1, 3, and 5 but had less effect on arteries in deoxycorticosterone-salt-treated rats by day 7, signifying that a change to a non-5-hydroxytryptamine-2A receptor had occurred. Sensitivities to 5-hydroxytryptamine and to ergonovine of deoxycorticosterone-treated rats fed a normal or high-salt diet for 28 days tended to increase, as did those of sham-treated rats fed a high-salt diet (with normal blood pressure). Contraction in response to phenylephrine was changed in arteries only from animals whose systolic blood pressure had been increased (deoxycorticosterone-normal salt and deoxycorticosterone-high salt groups).
Conclusions: These experiments support the hypothesis that the switch to ketanserin-insensitive 5-hydroxytryptamine-2 receptors likely occurs coincident with or just after the initial increase in blood pressure in the deoxycorticosterone-salt-treated rat.