Orexins Depolarize Rostral Ventrolateral Medulla Neurons and Increase Arterial Pressure and Heart Rate in Rats Mainly via Orexin 2 Receptors

Abstract

An injection of orexin A or B into the cisterna magna or the rostral ventrolateral medulla (RVLM), where bulbospinal vasomotor neurons are located, elevated arterial pressure (AP) and heart rate (HR). We examined how orexins affected RVLM neurons to regulate cardiovascular functions by using in vitro recordings of neuronal activity of the RVLM and in vivo measurement of cardiovascular functions in rats. Orexin A and B concentration-dependently depolarized RVLM neurons. At 100 nM, both peptides excited 42% of RVLM neurons. Tetrodotoxin failed to block orexin-induced depolarization. In the presence of N-(2-methyl-6-benzoxazolyl)-NЈ-1, 5-naphthyridin-4-yl urea (SB-334867), an orexin 1 receptor (OX 1 R) antagonist, orexin A depolarized 42% of RVLM neurons with a smaller, but not significantly different, amplitude (4.9 Ϯ 0.8 versus 7.2 Ϯ 1.1 mV). In the presence of (2S)-1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-[(4-pyridinylmethyl)amino]-1-butanone hydrochloride (TCS OX2 29), an orexin 2 receptor (OX 2 R) antagonist, orexin A depolarized 25% of RVLM neurons with a significantly smaller amplitude (1.7 Ϯ 0.5 mV). Coapplication of both antagonists completely eliminated orexin A-induced depolarization. An OX 2 R agonist, [Ala 11 ,D-Leu 15 ]-orexin B, concentration-dependently depolarized RVLM neurons. Regarding neuronal phenotypes, orexins depolarized 88% of adrenergic, 43% of nonadrenergic, and 36 to 41% of rhythmically firing RVLM neurons. Intracisternal TCS OX2 29 (3 and 10 nmol) suppressed intracisternal orexin A-induced increases of AP and HR, whereas intracisternal SB-334867 (3 and 10 nmol) had no effect on the orexin A-induced increase of HR but suppressed the orexin A-induced pressor response at 10 nmol. We concluded that orexins directly excite RVLM neurons, which include bulbospinal vasomotor neurons, and regulate cardiovascular function mainly via the OX 2 R, with a smaller contribution from the OX 1 R.Orexin A and orexin B (also known as hypocretin 1 and hypocretin 2) increase arterial pressure (AP), heart rate (HR), and sympathetic activity in rats and rabbits, when given by an intracerebroventricular (Samson et al., 1999;Shirasaka et al., 1999;Matsumura et al., 2001), intracisternal (Chen et al., 2000, or intrathecal (Antunes et al., 2001) injection. Regarding the sites of action of orexins in regulating cardiovascular and autonomic functions, the hypothalamic paraventricular nucleus was proposed to be one of the critical sites (reviewed in Kannan et al., 2007). In addition, the medullary structures essential for cardiovascular and autonomic regulation may be responsible for orexin-induced cardiovascular alterations. To explore the role of orexins in medullary control of the AP and HR, Chen et al. (2000) found that an intracisternal injection of orexins induced long-lasting pressor and positive chronotropic responses, and microinjection of orexin A into the rostral ventrolateral medulla (RVLM) caused similar responses in rats. The cardiovascular effects of orexins were also ex...

Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice

“…One possibility is that orexin is directly influencing the SNS via activation of the brain stem premotor sympathetic regulatory brain regions within the rostral ventrolateral medulla, similar to that which is reported in SHR. 13,15 Orexin can activate ≈88% of adrenergic neurons within the rostral ventrolateral medulla of rats, 22 and it is these adrenergic bulbospinal neurons within the rostral ventrolateral medulla which are well known to influence sympathetic vasomotor tone. In addition, orexinergic neurons may directly activate the SNS via the sympathetic preganglionic neurons in the spinal cord.…”

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

“…Preclinical studies, mostly in rat, have focused on the cardiovascular effects of exogenously added orexins. In the majority of studies, central administration (intracerebroventricular or intracisternal) of extraphysiological doses of orexin peptides, particularly OX-A, acts to increase blood pressure and heart rate, although differences in experimental paradigms have also found unchanged or decreased cardiovascular parameters with orexin administration (Samson et al, 1999Shirasaka et al, 1999;Chen et al, 2000;White et al, 2006 ]OX-B and TCSOX 2 29 either partially or fully blocked the effects of exogenous orexins, suggesting that both receptor subtypes are involved (White et al, 2006;Samson et al, 2007;Huang et al, 2010). Direct administration to specific brain regions evoked either increases or decreases in blood pressure and heart rate, suggesting that stimulation of different structures may indeed differentially modulate cardiovascular function; however, differences in protocol, dose, and state of anesthesia probably also contribute to the disparate results (Chen et al, 2000;Antunes et al, 2001;Machado et al, 2002;Sato-Suzuki et al, 2002;Smith et al, 2002Smith et al, , 2007de Oliveira et al, 2003;Shahid et al, 2011).…”

“…In fact, the doses used in several of the studies is relatively high compared with the endogenous OX-A levels (0.2-0.4 pmol/ml) in rat CSF , and so the relevance to the role of intrinsic orexins in cardiovascular function is unknown. More relevant to the safety profile of orexin receptor antagonists in the clinic is the finding that central administration of the aforementioned OX 1 or OX 2 SORAs elicited no changes in heart rate or blood pressure when administered alone in preclinical models (Hirota et al, 2003;White et al, 2006;Samson et al, 2007;Huang et al, 2010;Shahid et al, 2011). Furthermore, preclinical studies in rats and dogs showed no effects on heart rate and blood pressure with oral administration of the dual orexin receptor antagonist, almorexant (ACT-078573) Furlong et al, 2009).…”

The Sleep-Modulating Peptide Orexin-B Protects Midbrain Dopamine Neurons from Degeneration, Alone or in Cooperation with Nicotine

“…To our surprise, we failed to detect any significant rise in basal Ca 21 cyt levels when OXB was applied alone to the cultures, at concentrations that were protective for DA neurons. This is rather unexpected as OXB was reported to elicit robust calcium elevations and to cause sustained excitation of various neuronal cell types (Ishibashi et al, 2005;Nakamura et al, 2010), in particular through OX2R (Huang et al, 2010). In addition, the neuroprotective effect of NIC for DA neurons, which was unmasked here by OXB, was reported previously to be gated by Ca 21 cyt (Toulorge et al, 2011).…”