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 (TPH2-/-), specifically deficient in CNS 5-HT, and wild-type (TPH2+/+) controls at 2-3, 5-8, and 12-13 mo of age. Compared with TPH2+/+, mean arterial pressure of 5-8- and 12-13-mo-old (middle-aged) male TPH2-/- rats was significantly elevated (∼10 mmHg) in QW and rapid eye movement (REM) sleep. Middle-aged male TPH2-/- rats also had more frequent extreme hypertensive events during prolonged episodes of REM sleep. Female TPH2-/- had normal ABP. The low- and very-low-frequency components of systolic ABP variability were significantly higher in middle-aged male, but not female, TPH2-/- rats compared with in TPH2+/+ rats, suggesting elevated sympathetic vascular tone in male TPH2-/- rats. However, the hypertension of male TPH2-/- rats was not ameliorated by ganglionic blockade. Hearts and lungs of middle-aged male TPH2-/- 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.NEW & NOTEWORTHY 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.