The role of PACAP in central cardiorespiratory control

The autonomic nervous system is essential for the tonic and reflex control of the cardiovascular system. Specifically, the rostral ventrolateral medulla (RVLM) is critical in maintaining sympathetic vasomotor tone and mean arterial pressure during rest, and in response to external stimuli. The RVLM may also be implicated in the aeitology of essential/neurogenic hypertension. Presympathetic RVLM neurons directly innervate sympathetic preganglionic neurons (SPN) in the intermediolateral cell column of the thoracic spinal cord, controlling the level of sympathetic outflow to the periphery. RVLM neurons are a heterogenous cell population that contain many metabotropic neurotransmitters, which act to modulate sympathetic outflow and therefore blood pressure. Pituitary adenylate cyclase activating polypeptide (PACAP) is one example of an RVLM neuropeptide. PACAP is an excitatory neuropeptide known to be involved in the central control of blood pressure; PACAP and its receptors are found in the RVLM, SPN and other in important cardiovascular regions within the brain and spinal cord. Intrathecal administration of PACAP causes marked sympathoexcitation, but no change in mean arterial pressure. The aims of this thesis were to further investigate the role of PACAP within the tonic and reflex control of the cardiorespiratory system, at the level of the spinal cord, with a particular interest in determining the mechanistic cause underlying the lack of blood pressure response following intrathecal PACAP. The work presented here finds that 1) intrathecal PACAP causes a prolonged, widespread sympathoexcitation, and does not differentially affect sympathetic outflows, resulting in no net change in blood pressure. 2) That the intrathecal PACAP response is due to neuronal activation at the level of the spinal cord, and not due to activation of higher order brainstem centers through the use of spinal cord transection. 3) That intrathecal PACAP-38 increases metabolic rate and is likely to increase brown adipose tissue thermogenesis. 4) That the PACAP antagonist did not affect mean arterial pressure, heart rate or splanchnic sympathetic nerve activity, suggesting that PACAP is not tonically active in blood pressure control. 5) The vast differences seen in the blood pressure responses to maxadilan (PAC₁ receptor activation) and vasoactive intestinal polypeptide (VPAC₁ and VPAC₂ receptor activation) suggest that the PAC₁ and VPAC receptor subtypes produce opposing blood pressure effects when activated by intrathecal PACAP, producing a cancellation effect that results in no net blood pressure change. 6) Intrathecal PACAP administration increased phrenic nerve amplitude and phrenic nerve frequency, demonstrating a role for PACAP in central respiratory control. 7) That intrathecal PACAP and catestatin alone did not effect the cardiovascular reflex responses, demonstrating that PACAP and catestatin are not involved in the reflex control of blood pressure in this preparation. 8) Finally, pre-treatment with catestatin (90-minute duration; intrathecal injection) before intrathecal PACAP injection causes a significant decrease in mean arterial pressure and phrenic nerve frequency, and enhances sympathetic barosensitivity and chemosensitivity. The data indicates that the responses to intrathecal PACAP are receptor dependant and may be due to differential activation of adrenaline and noradrenaline secreting chromaffin cells. Collectively, the results suggest that PACAP plays an important excitatory role in central cardiorespiratory and metabolic control in the urethane-anaesthetised, vagotomised, paralysed and artificially ventilated rat. The stimulus for the release of PACAP remains unknown, however, PACAP may be involved in another aspect of central cardiovascular control, such as the stress response.