Neurovascular Responses to Melatonin in Humans
Open Access
- Author:
- Cook, Jonathan Sutton
- Graduate Program:
- Physiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 28, 2010
- Committee Members:
- Chester A Ray, Dissertation Advisor/Co-Advisor
Chester A Ray, Committee Chair/Co-Chair
Charles H Lang, Committee Member
Urs Andreas Leuenberger, Committee Member
David Nathan Proctor, Committee Member
Stephen R Rannels, Committee Member - Keywords:
- circadian
microneurography
blood pressure - Abstract:
- Melatonin is synthesized and secreted by the pineal gland in a circadian rhythm. As the master circadian regulator in the body, melatonin has many physiological functions depending on its site of action. Pharmacological levels of melatonin have been reported to decrease nerve activity of medial vestibular nuclei in the rat and are associated with attenuated muscle sympathetic nerve activity (MSNA) responses to baroreceptor unloading in humans. Additionally, melatonin has been demonstrated to differentially alter blood flow to assorted vascular beds by MT1 vs. MT2 melatonin receptor activation. Therefore, the overall objective of this dissertation project was to determine the neurovascular changes elicited by exogenous and endogenous plasma melatonin levels at rest and during vestibular stimulation. The purpose of Aim 1 and 2 (Chapter 3) was to determine if melatonin alters the vestibulosympathetic reflex (VSR) and vestibulocollic reflex (VCR) in humans. In Aim 1, MSNA, arterial blood pressure, and heart rate were measured in 12 healthy subjects (28±1 yr; 6 male, 6 female) during head-down rotation (HDR) before and 45 min after ingestion of either melatonin (3 mg) or placebo (sucrose). Subjects returned at least 2 days later at the same time of day to repeat the trial after ingesting the opposite drug. Melatonin increased MSNA during baseline as compared to placebo (11±2 vs. 9±1 bursts/min; p<0.05). However, melatonin significantly attenuated MSNA responses during HDR as compared to placebo (burst frequency: ∆4±1 vs. ∆7±1 bursts/min and total MSNA: ∆51±20 and ∆96±15%, respectively; p<0.02). In Aim 2, vestibular evoked myogenic potentials (VEMP) were measured in 10 healthy subjects (26±1 yr; 4 male and 6 female) before and after ingestion of 3 mg melatonin. Melatonin did not alter the timing of the p13 and n23 peaks (pre-melatonin: 13.2±0.4 and 21.3±0.6 msec vs. post-melatonin: 13.5±0.4 and 21.4±0.7 msec, respectively) or the p13-n23 inter-peak amplitudes (pre-melatonin: 22.5±4.6 a.u. and post-melatonin: 22.7±4.6 a.u.). In summary, melatonin attenuates the VSR does not alter the VCR in humans suggesting melatonin’s effect on the VSR might be mediated by the utricles. The purpose of Aim 3 (Chapter 4) was to determine the effect of melatonin on blood flow to various vascular beds in humans. Renal (Doppler ultrasound), forearm (venous occlusion plethysmography), calf (venous occlusion plethysmography) and cerebral blood flows (transcranial Doppler), arterial blood pressure, and heart rate were measured in 10 healthy subjects (29 ± 1 yr; 5 male, 5 female) while lying on a table for 3 minutes. The protocol began 45 min after the ingestion of either melatonin (3 mg) or placebo (sucrose). Subjects returned at least 2 days later at the same time of day to repeat the trial after ingesting the opposite drug. Melatonin did not alter heart rate and mean arterial pressure. Renal blood flow velocity (RBFV) and renal vascular conductance (RVC) were lower during the melatonin trial as compared to placebo (RBFV: 40 ± 3 vs. 45 ± 2 cm⋅s-1; RVC: 0.47 ± 0.02 vs. 0.54 ± 0.01 cm⋅s-1⋅mmHg-1, respectively). In contrast, forearm blood flow (FBF) and forearm vascular conductance (FVC) were greater with melatonin compared to placebo (FBF: 2.4 ± 0.2 vs. 1.9 ± 0.1 ml⋅100ml-1⋅min-1; FVC: 0.029 ± 0.003 vs. 0.023 ± 0.002 a.u., respectively). Melatonin did not alter calf or cerebral blood flow measurements compared to placebo. In summary, exogenous melatonin differentially alters vascular blood flow in humans. Increases in sympathetic nerve activity are hypothesized to contribute to the observed circadian rhythm of adverse cardiac events. Pharmacological levels of melatonin increase MSNA at rest and attenuate reflexes involved in blood pressure regulation such as the vestibulosympathetic reflex (Aim 1). Melatonin typically increases 8-10 times over daytime concentrations during the late evening hours. The purpose of Aim 4 (Chapter 5) was to determine if MSNA at rest and the VSR follow a circadian rhythm in humans in relation to the endogenous melatonin circadian rhythm. Arterial blood pressure, heart rate, calf blood flow and MSNA were measured in 9 healthy subjects (28±1 yr; 5 male, 4 female) at rest and during head-down rotation. Each subject was tested around noon and 10-12 hr later that evening (day: 11:34±13 min, night: 22:10±5 min). MSNA at rest was significantly lower at night compared to day (8±1 vs. 11±2 bursts/min, respectively; P<0.05). Heart rate and arterial blood pressure were significantly increased at night compared to day (heart rate: 70±4 vs. 66±4 beats/min, arterial blood pressure: 91±2 vs. 87±1 mmHg, respectively). MSNA and cardiovascular responses to head-down rotation were not significantly altered at night compared to day (∆3±1 bursts/min, ∆25±6% for MSNA and calf blood flow, respectively). The data indicate that MSNA at rest is lower during the late evening hours and exhibits a circadian rhythm whereas the vestibulosympathetic reflex is not altered by endogenous changes in melatonin. A circadian rhythm of MSNA in humans may be important for understanding the increase of adverse cardiac events in the morning hours. The current project demonstrated that 3 mg melatonin ingestion attenuates the vestibulosympathetic reflex, increases MSNA at rest and differentially alters vascular blood flow. Additionally, we observed lower MSNA at rest at night compared to daytime. Together, these data demonstrate melatonin’s multiple effects on neurovascular control in humans.