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.


METHODS
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.
Watts
S W
SW
Department of Pharmacology and Toxicology, Michigan State University, E. Lansing 48824-1317, USA. wattss@pilot.msu.edu
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D003900:Desoxycorticosterone; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D010120:Oxytocics / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D012965:Sodium Chloride / Q000008:administration & dosage; D014661:Vasoconstriction / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D010120:Oxytocics; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D010656:Phenylephrine; D003900:Desoxycorticosterone; D012965:Sodium Chloride