Plasma catecholamine, renin activity, and ACTH responses to the serotonin receptor agonist DOI in juvenile spontaneously hypertensive rats

Abstract

Mean arterial blood pressure (MAP), heart rate (HR) and arterial plasma levels of corticotropin (ACTH), renin activity (PRA) and catechols [norepinephrine (NE), epinephrine (EPI), and the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG)] at baseline and in response to the serotonin-1C/2 (5-HT 1C/5-HT 2) agonist 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane (DOI, 1.0 mg/kg i.a) in consious, freely-moving, juvenile (4 week old) spontaneously hypertensive rats (SHR's) and age-matched Wistar-Kyoto (WKY) normotensive control rats were measured simultaneously. Baseline levels of MAP, NE, DHPG, and EPI all were significantly higher in the SHR's. There was a similar trend for PRA, but ACTH did not differ between the two strains. DOI produced marked increases in levels of MAP, ACTH, EPI, and also PRA but did not affect NE or DHPG concentrations. HR decreased only in the WKY group after administration of DOI. The magnitudes of the EPI and ACTH responses did not differ between the rat strains. Responses of MAP and PRA were significantly larger in SHR's. These results suggest that there is a selective hyperresponsiveness of PRA and blood pressure to 5-HT 2 receptor stimulation parallel to a deficient baroreceptor refle in juvenile SHR's. Substantial evidence supports the view that spontaneously hypertensive rats (SHR's) of the Okamoto strain have increased sympathoadrenal activity and reactivity, especially during the development of hypertension (1–7). Plasma levels of norepinephrine (NE), of epinephrine (EPI), and of the intraneuronal NE metabolite, dihydroxyphenylglycol (DHPG), all are increased under resting conditions in conscious, juvenile SHR's (8, 9), and juvenile SHR's have markedly exaggerated increases in plasma levels of these catechols in response to intravenous injection of the α 2-adrenoceptor antagonist, yohimbine (9). Differences in plasma NE levels between SHR's and the control normotensive Wistar-Kyoto (WKY) rats decrease as the animals mature (8, 9). Circulating levels of corticotropin (ACTH), and renin activity do not differ in young SHR and WKY rats (10, 11) but these have not previously been measured with NE, EPI and DHPG under resting conditions and during stimulation in young SHR's. Serotonin (5-HT) and 5-HT agonists can stimulate or inhibit sympathetic nerve activity, increase or decrease blood pressure and heart rate, and constrict or dilate blood vessels depending on the site and route of administration of the neurotransmitter and the type of agonists (12–16). Stimulation of specific serotonin receptors, However, produces more consistent neuroendocrine and hemodynamic effects. Recent studies have shown that stimulation of serotonin-2 (5-HT 2) receptors markedly increases sympathetic nerve discharge and increases plasma levels of EPI and renin activity (PRA) and stimulates release of corticotropin releasing hormone (CRH) and corticotropin (16–25). In addition, agonists at 5-HT 2 receptors constrict isolated blood vessels and increase blood pressure in conscious and in pithed rats (20, 26–29). Conversely, ketanserin, an antagonist at 5-HT 2 and α 1-adrenoceptors, is an effective antihypertensive drug (13). In the present study we measured mean arterial pressure (MAP), heart rate (HR), and plasma levels of EPI, NE, DHPG, PRA, and ACTH at baseline and in response to the administration of the selective 5-HT 1C/5-HT 2 receptor agonist 1-(2, 5-dimethoxy-4-iodophenyl) 2-aminopropane (DOI) in consious juvenile (4 week old) SHR's and their normotensive WKY controls.