Sex- and age-based differences in the effect of central serotonin on arterial blood pressure regulation.

Medullary serotonin (5-hydroxytryptamine; 5-HT) neurons project to multiple autonomic nuclei in the central nervous system (CNS). Infant rats lacking 5-HT have low arterial blood pressure (ABP) in quiet sleep, but the role of 5-HT in ABP regulation across vigilance states in adults has not been studied. We hypothesized that in adults, CNS 5-HT deficiency leads to hypotension mainly in quiet wakefulness (QW) and non-rapid eye movement (NREM) sleep, when 5-HT neurons are active. We tested male and female tryptophan hydroxylase 2 knockout rats , specifically deficient in CNS 5-HT, and wild-type () controls at 2-3, 5-8, and 12-13 mo of age. Compared with , mean arterial pressure of 5-8- and 12-13-mo-old (middle-aged) male rats was significantly elevated (∼10 mmHg) in QW and rapid eye movement (REM) sleep. Middle-aged male rats also had more frequent extreme hypertensive events during prolonged episodes of REM sleep. Female had normal ABP. The low- and very-low-frequency components of systolic ABP variability were significantly higher in middle-aged male, but not female, rats compared with in +/+ rats, suggesting elevated sympathetic vascular tone in male -/- rats. However, the hypertension of male rats was not ameliorated by ganglionic blockade. Hearts and lungs of middle-aged male rats were significantly heavier than those of TPH2+/+ rats. We show that a loss of CNS 5-HT leads to high ABP only in middle-aged males during wakefulness and REM sleep, possibly due to increased vascular tone. It should be investigated whether elevated ventricular afterload associated with CNS 5-HT deficiency initiates cardiac remodeling or alters pulmonary hemodynamics. The role of serotonin in arterial blood pressure (ABP) regulation across states of vigilance is unknown. We hypothesized that adult rats devoid of CNS serotonin (TPH2-/-) have low ABP in wakefulness and NREM sleep, when serotonin neurons are active. However, TPH2-/- rats experience higher ABP than TPH2+/+ rats in wakefulness and REM only, a phenotype present only in older males and not females. CNS serotonin may be critical for preventing high ABP in males with aging.