Clinical Trial: Effects of Melatonin to Reduce Nocturnal Hypertension in Patients With Neurogenic Orthostatic Hypotension

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: Identifying the Pathophysiology of Neurogenic Orthostatic Hypotension and the Effects of Melatonin on Reducing Supine Hypertension in Peripherally Intact Versus Denervated

Brief Summary: Neurogenic Orthostatic Hypotension (NOH) is clinically defined as a consistent drop in systolic blood pressure (SBP) ≥30mmHg upon standing from a seated or lying position. However, 50% of NOH patients also have associated supine hypertension. It has been proposed that supine hypertension is the result of intact post-ganglionic sympathetic nerves and therefore due to residual sympathetic tone. Furthermore, research investigating the effects of melatonin shows blood pressure implication of this naturally secreted hormone. Specifically, melatonin has been investigated as a non-traditional anti-hypertensive agent for patients with essential and nocturnal hypertension. Central and peripheral mechanisms have been proposed to help explain how melatonin reduces blood pressures. Therefore, we aim to identify NOH patients as having either intact or denervated post-ganglionic sympathetic nerves, monitor the correlation to supine hypertension and subsequently investigate the effects of melatonin on blood pressure in these patients.

Detailed Summary:

Neurogenic orthostatic hypotension (NOH) is a debilitating condition associated with reduced quality of life, impaired function and is also an independent predictor of mortality(Bendini et al., 2007; Cordeiro et al., 2009; Rose et al., 2006). NOH is clinically defined as a sustained reduction in systolic blood pressure (SBP) ≥30mmHg within 3 minutes of standing or head-up tilt to at least 60 degrees on a tilt table(Freeman et al., 2011). Specifically, neurogenic OH can be differentiated from other causes of orthostatic hypotension, such as hypotension due to endocrine issues, generalized low blood pressure, low blood volume, etc., in that NOH is associated with autonomic dysfunction. Specifically, dysfunction of the reflexive regulation mediated by the sympathetic nervous system(Goldstein and Sharabi, 2009; Low et al., 2008).

Studies have implicated specific dysfunction of the peripheral sympathetic nerves in disorders that have accompanying NOH such as Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF) and Parkinson Disease (PD+NOH)(Imrich et al., 2009; Senard et al., 1993; Sharabi et al., 2006). In clinical NOH populations with known diagnoses such as MSA, PAF and PD+NOH, infusions of yohimbine have been used to detect whether post-ganglionic sympathetic nerves are intact or denervated. Yohimbine is an alpha-adrenoceptor antagonist that, in healthy/intact sympathetic nerves, causes an increase in the release of norepinephrine (NE) from sympathetic nerves via increased sympathetic neuronal outflow. NE is a natural neurotransmitter that is released when the sympathetic nervous system is required to increase its activity. In persons with intact post-ganglionic sympathetic nerves an infusion of yohimbine results in an increase in blood pressure, arterial NE levels, and heart rate levels, with a decrease in forearm blood flow indicative of vasoconstriction. In
Sponsor: Lawson Health Research Institute

Current Primary Outcome:

  • Investigation into the integrity of post-ganglionic sympathetic nerves in idiopathic NOH [ Time Frame: Sympathetic markers will be assessed during and immediately following the test. A comparison between healthy participants and NOH patients will be ongoing throughout recruitment and upon completion of study recruitment ]
    Markers of post-ganglionic sympathetic function will be examined (i.e. sympathetic blood markers, heart rate, blood pressure, sympathetic nerve activity, etc.)
  • Effects of melatonin on supine hypertension in persons with neurogenic orthostatic hypotension [ Time Frame: 4 weeks ]
    Supine systolic blood pressure
  • Effects of melatonin on supine hypertension in patients with neurogenic orthostatic hypotension [ Time Frame: 4 weeks ]
    Change in postural (supine-standing) systolic blood pressure


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Serum markers of sympathetic activation [ Time Frame: Before and during stimulation of sympathetic nervous system ]
  • Carotid artery diameter [ Time Frame: During stimulation of sympathetic nervous system ]
  • Sympathetic nerve activation using microneurography [ Time Frame: During stimulation of sympathetic nervous system ]
  • Orthostatic symptoms based on standard autonomic symptom questionnaires [ Time Frame: 30 minutes before testing ]
  • Sleep quality assessment using Epworth Sleepiness Scale [ Time Frame: Assessed at pre- and post- melatonin treatment; week 1 and week 5 of melatonin intervention timeframe ]
  • Urine and Saliva melatonin levels [ Time Frame: Assessed at pre- and post- melatonin treatment; week 1 and week 5 of melatonin intervention timeframe ]


Original Secondary Outcome: Same as current

Information By: Lawson Health Research Institute

Dates:
Date Received: November 7, 2016
Date Started: January 2017
Date Completion: August 2019
Last Updated: November 14, 2016
Last Verified: October 2016