Exaggerated postnatal surge of orexin and the effects of elimination of excess orexin on blood pressure in spontaneously hypertensive rats in postnatal development

Abstract

AbstractIt has been established that an overactive orexin (OX) system is associated with neurogenic hypertension in spontaneously hypertensive rats (SHRs). However, the chronology and mechanism of such association between orexin system and hypertension is unclear. We hypothesized that an aberrant surge of OX neurons in SHRs precedes the aberrant increase of arterial blood pressure (ABP) during postnatal development, which was primarily contributed by the exaggerated postnatal OX neurogenesis. We found that (1) SHRs experienced a greater surge in the number of orexin neurons than normotensive Wistar-Kyoto (WKY) rats before P16, which led to significantly more OX neurons than age-matched controls by P15-16 (3680±219 vs 2407±182, respectively, P=0.002). (2) Exaggerated OX neurogenesis, marked by bromodeoxyuridine (BrdU), was the primary contributor to excessive OX neurons in SHRs during development. (3) In contrast, SHRs and normotensive control rats have similar mean arterial blood pressure (ABP) at P15, and a significantly higher ABP in SHR than WKY emerges at P20 (74.8 ± 2.5 vs 66.9 ± 4.4 mmHg in wakefulness, respectively, P<0.05), a few days following the surge of OX activity. (4) Selectively eliminating excess (∼30%) orexin neurons, via a targeted neurotoxin, in SHRs between P30 and P40 results in a significantly lowered ABP compared to non-lesioned SHRs at P40. We suggest that the postnatal surge of OX neurons, primarily attributed to the exaggerated postnatal OX neurogenesis, may be necessary for the development of higher ABP in SHRs, and modulation of the overactive OX system may have a preventative effect during the pre-hypertensive period.New FindingsWhat is the central question of this study?Excess orexin neurons have been associated with hypertension in spontaneously hypertensive rats, however, the association and mechanism between developing excess orexin neurons and high blood pressure are unknown.What is the main finding and its importance?Using spontaneously hypertensive rats in anatomical and physiological studies, we provided evidence showing that the excess OX neurons, primarily via exaggerated OX neurogenesis, may be necessary in developing a higher ABP in SHRs during development, and modulation of the overactive orexin system may be beneficial in treating hypertension.