Cardiovascular Actions of Orexin‐A in the Rat Subfornical Organ

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Abstract
Orexin-A is a neuropeptide, primarily produced in the lateral hypothalamic/perifornical hypothalamus. Orexin receptors and immunoreactive neuronal fibres are widely distributed throughout the brain, suggesting integrative neurotransmitter roles in a variety of physiological systems. Intracerebroventricular injections of orexin-A increase blood pressure and stimulate drinking, and the subfornical organ (SFO), a circumventricular structure implicated in autonomic control, is a potential site at which orexin may act to exert these effects. We have therefore used microinjection techniques to examine the effects of orexin-A administered directly into the SFO on blood pressure and heart rate in urethane anaesthetised male Sprague-Dawley rats. Orexin-A microinjection (50 fmol) into the SFO caused site-specific decreases in blood pressure (SFO: mean area under curve (AUC) = -681.7 +/- 46.8 mmHg*s, n = 22 versus non-SFO: 63.68 +/- 54.69 mmHg*s, n = 15, P < 0.001), and heart rate (SFO: mean AUC = -26.7 +/- 2.8 beats, n = 22, versus non-SFO: mean AUC = 1.62 +/- 2.1 beats, n = 15, P < 0.001). Vagotomy did not alter the hypotensive or bradycardic responses elicited by orexin-A microinjection. Prior alpha-adrenoceptor blockade with phenoxybenzamine (1 mg/kg, i.v.) masked the orexin-A induced blood pressure (mean AUC = -122.6 +/- 17.6 mmHg*s, n = 4, P < 0.01 paired t-test) and heart rate (mean AUC = -6.7 +/- 1.7 beats, n = 4, P < 0.05, paired test) response. The orexin-A induced heart rate response was attenuated when beta-adrenoceptors were blocked with propranolol (1 mg/kg, i.v.; mean AUC = 0.6 +/- 2.8 beats, n = 5, P < 0.01 paired t-test). These studies demonstrate that microinjection of orexin-A into the SFO causes site specific decreases in blood pressure and heart rate which is mediated by a reduction in sympathetic tone.