Is augmented central respiratory-sympathetic coupling involved in the generation of hypertension?

Respiratory modulation of autonomic neural activity, with consequent phasic alteration of cardiac and vascular function, has been observed in many species including humans and is considered an index of cardiovascular health. Whilst many factors contribute to this modulation, including for example baroreceptor reflex feedback, it is accepted that a significant component is derived from an interaction within the central nervous system. Functional links between the brainstem circuitry generating the respiratory rhythm and neurons responsible for generate sympathetic and parasympathetic activity to the cardiovascular system have long been hypothesized, although the detailed understanding of these interactions is incomplete. There are several proposed physiological functions for these interactions including the matching of ventilation to cardiac output and tissue blood flow. However, recent observations suggest that altered central respiratory coupling may play a role in the development of hypertension and in the maintenance of elevated levels of sympathetic vasomotor activity in disease. The focus of this review article is to discuss these observations and place them within the context of current understanding of the neural substrates that might be responsible for respiratory-sympathetic coupling.

The potency of different serotonergic agonists in counteracting opioid evoked cardiorespiratory disturbances.

Serotonin receptor (5-HTR) agonists that target 5-HT(4(a))R and 5-HT(1A)R can reverse mu-opioid receptor (mu-OR)-evoked respiratory depression. Here, we have tested whether such rescuing by serotonin agonists also applies to the cardiovascular system. In working heart-brainstem preparations in situ, we have recorded phrenic nerve activity, thoracic sympathetic chain activity (SCA), vascular resistance and heart rate (HR) and in conscious rats, diaphragmatic electromyogram, arterial blood pressure (BP) and HR via radio-telemetry. In addition, the distribution of 5-HT(4(a))R and 5-HT(1A)R in ponto-medullary cardiorespiratory networks was identified using histochemistry. Systemic administration of the mu-OR agonist fentanyl in situ decreased HR, vascular resistance, SCA and phrenic nerve activity. Subsequent application of the 5-HT(1A)R agonist 8-OH-DPAT further enhanced bradycardia, but partially compensated the decrease in vascular resistance, sympathetic activity and restored breathing. By contrast, the 5-HT(4(a))R agonist RS67333 further decreased vascular resistance, HR and sympathetic activity, but partially rescued breathing. In conscious rats, administration of remifentanyl caused severe respiratory depression, a decrease in mean BP accompanied by pronounced bradyarrhythmia. 8-OH-DPAT restored breathing and prevented the bradyarrhythmia; however, BP and HR remained below baseline. In contrast, RS67333 further suppressed cardiovascular functions in vivo and only partially recovered breathing in some cases. The better recovery of mu-OR cardiorespiratory disturbance by 5-HT(1A)R than 5-HT(4(a))R is supported by the finding that 5-HT(1A)R was more densely expressed in key brainstem nuclei for cardiorespiratory control compared with 5-HT(4(a))R. We conclude that during treatment of severe pain, 5-HT(1A)R agonists may provide a useful tool to counteract opioid-mediated cardiorespiratory disturbances.