Blunted Fenfluramine-Evoked Prolactin Secretion in Hypertensive Rats

Abstract

Abstract-Plasma prolactin (PRL) levels after acute administration of fenfluramine (FEN) have been used as a probe of brain serotonin activity. FEN-evoked increases in PRL levels inversely correlate with arterial blood pressure (ABP) in humans (Muldoon et al. Hypertension. 1998;32:972-975), thereby suggesting that brain serotonin activity may be reduced in hypertension. The present study sought to determine whether the relation between FEN-evoked PRL levels and ABP was present in two rat models of hypertension. Experiments were performed in awake male rats that were instrumented with femoral arterial and venous catheters 2 days before experiments. FEN (3.0 mg/kg IV) significantly increased plasma PRL levels in both spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY); however, FEN-evoked PRL levels were significantly lower in SHR compared with WKY, though baseline levels were similar between strains. Similar results were obtained in rats with chronic hypertension produced by figure-8 renal wrap plus contralateral nephrectomy. In contrast, the increase in PRL levels evoked by the serotonin receptor agonist m-CPP or the dopamine receptor antagonist eticlopride did not differ between SHR and WKY, indicating that PRL secretion is not generally blunted in chronic hypertensive rats. Furthermore, FEN-evoked PRL levels were not attenuated in rats made acutely hypertensive by an infusion of the ␣-adrenergic agonist phenylephrine. Thus, the present findings are consistent with the human data and suggest that chronic hypertension is associated with a presynaptic alteration in brain serotonin function. Key Words: brain Ⅲ blood pressure Ⅲ central nervous system Ⅲ hypertension, chronic Ⅲ hypertension, experimental B rain serotonin participates in the regulation of sympathetic outflow and arterial blood pressure (ABP). 1,2 Pharmacological stimulation of serotonin receptors produces complex changes in cardiovascular parameters, including increases and decreases in ABP. [3][4][5][6] Moreover, activation of neuronal populations that contain serotonin has been reported to produce increases or decreases in ABP and sympathetic nerve activity. 1,7 On the other hand, changes in ABP have been reported to alter serotonin neurotransmission in several brain nuclei. 1,8 -10 Studies in hypertensive rats have indicated that chronic hypertension may be associated with changes in serotonin function. 1,[11][12][13][14][15] However, the role of brain serotonin systems in the pathophysiology of chronic hypertension is poorly understood.The increases in plasma prolactin (PRL) and cortisol levels after acute administration of fenfluramine (FEN) have been used as indices of brain serotonin function. 16,17 As FEN increases serotonin release and decreases its reuptake by neurons, FEN increases serotonin-mediated neurotransmission, thereby increasing the secretion of PRL and cortisol. Differences in PRL and cortisol responses to FEN are thought to reflect differences in ongoing serotonin activity. In a study of 270 healthy human subjects,...

Role of the serotoninergic system in the sodium appetite control

“…In this study, it was evidenced that prolactin liberation induced by fenfluramine was correlated inversely with the blood pressure, in white Caucasian individuals suggesting a role of the central 5-HTergic system in the pathogeny of hypertension. The same authors demonstrated a lower prolactin secretory response in SHR rats injected with fenfluramine (Stocker et al 2003).…”

“…It is tempting to compare our experimental model, at least partially, with the functional condition of the spontaneously hypertensive rats (SHR). SHR rats develop an intense sodium appetite associated with increased angiotensinergic sensitivity in forebrain loci related with the cardiocirculatory and hydroelectrolytic homeostasis (Stocker et al 2003). It is noteworthy that these alterations have been concomitant with a defi cit in the 5-HT turnover in forebrain sites.…”

Serotonin Receptor 2A (HTR2A) Gene Polymorphisms Are Associated with Blood Pressure, Central Adiposity, and the Metabolic Syndrome

“…Within the brain serotonergic responsivity in the hypothalamic-pituitary axis, as assessed by standard fenfluramine challenge, has been found to covary inversely with resting blood pressure in humans 1 and is attenuated in spontaneously hypertensive rats, relative to normotensive controls. 27 In this regard, the brainstem nuclei involved in BP regulation receive projections from serotonergic neurons, and the central application of serotonin and serotonergic drugs have well-documented acute effects on sympathetic nervous activity, vasopressin release and arterial BP. 7,8 The vasoconstrictve and BPelevating effects of serotonin, both peripherally and centrally, appear to be mediated by 5-HT 2A receptors, whereas 5-HT 1A receptor activation results in sympathoinhibition and vasodilation.…”

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Lower Central Serotonergic Responsivity Is Associated With Preclinical Carotid Artery Atherosclerosis

“…42 Central 5-HT also regulates sleep, and various sleep disturbances may predispose to atherosclerosis. 43,44 Neuroanatomic and neuropharmacologic studies indicate that CNS 5HT modulates sympathetic and parasympathetic outflow affecting heart rate and blood pressure, 45,46 as well as glucose and energy homeostasis. 47,48 Therefore, the influence of CNS serotonergic circuits on autonomic activity could affect atherosclerosis via several internal mechanisms.…”