Role of Prostaglandins on Niacin-Induced Flushing

Exploring the Role of Prostaglandin D2 and the DP1 Receptor on Nicotinic Acid Induced Flushing

This study will focus on investigating the nicotinic acid stimulated release of prostaglandin D2 in normal controls. In subsequent studies, the investigators would like to further explore this pathway in people with type 2 diabetes. Enhanced blood flow (or flushing) may be compromised or exaggerated in type 2 diabetes particularly in those with impairment of autonomic function measured as the respiratory heart rate variability (HRV) of different frequencies reflecting the balance between the sympathetic and parasympathetic nervous systems. The investigators hypothesize that the vasodilatory effects induced by nicotinic acid will be different in glabrous and hairy skin and that autonomic imbalance may alter the response.

The investigators propose that nicotinic acid (NA) stimulates release of prostaglandin D2 (PGD2). To fully understand this mechanism, the investigators will examine the systemic release of PGD2 and skin blood flow using laser Doppler (LDF) on the upper and lower limbs of healthy control subjects. The investigators will quantify and establish the effects of oral nicotinic acid (Niaspan®) given alone and in combination with aspirin on:

1. skin blood flow using laser Doppler (LDF) of glabrous and hairy skin of the forearm of healthy subjects
2. the severity and intensity of flushing using a visual analog scale, FAST tool, and whether aspirin is able to block the flushing response
3. the impact on sympathetic/parasympathetic balance using the various frequencies of heart rate variability (HRV) which reflect the contribution of the different divisions of the autonomic nervous system (ANS)
4. circulating levels of PGD2 and other neuropeptides to determine other mediators of the flushing response. This will allow us to conclude whether this pathway is intact and explore other non-DP1 vasodilatory mechanisms.
5. Langerhans cell density in epidermis and microvasculature using immunohistochemistry of Langerin (measured as CD1a) in 3 mm skin biopsies of volar and hairy surfaces of the forearm and hairy surface of the lateral aspect of proximal lower limb. To date, there is very little known about the density or distribution of Langerhans cells. The PGD2 receptor DP1 will be examined for its content in the epidermis using immunohistochemistry or RTPCR.

Inclusion Criteria:

Healthy controls ages 30-80

Exclusion Criteria:

1. Presence of type 1 diabetes or type 2 diabetes

2. Presence of clinically significant neuropathy, (Dyck stage >2b) defined by abnormal neurologic testing (neurologic physical exam, nerve conduction, autonomic and quantitative sensory tests)

3. History of major macrovascular events such as myocardial infarction or stroke within the past 3 months

4. Participation in another clinical trial concurrently or within 30 days prior to entry into this study.

5. Uncontrolled or untreated hypothyroidism as evidenced by TSH concentrations >4.8 uU/ml

6. Other serious medical conditions which, in the opinion of the investigator, would compromise the subject's participation in the study, including sensitivity to aspirin

7. Abnormalities of liver function defined as any liver enzymes (AST, ALT, SGPT, SGOT) greater than 3 times the upper limit of normal

8. History of NYHA Class IV congestive heart failure.

9. Allergy to Niaspan or aspirin

10. Use of drugs known to affect prostaglandin metabolism such as angiotensin converting enzyme inhibitors (ACE) inhibitors and angiotensin receptor blockers (ARBs) will be allowed with stable use for 3 months.

11. Pregnancy or breastfeeding

12. History of peptic ulcer disease

13. Current history of smoking

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