THE 5‐HT₂ RECEPTOR ANTAGONIST SARPOGRELATE REDUCES URINARY AND PLASMA LEVELS OF THROMBOXANE A₂ AND URINARY ALBUMIN EXCRETION IN NON‐INSULIN‐DEPENDENT DIABETES MELLITUS PATIENTS^†

Abstract

1. Therapeutic effects of a 5-HT2 receptor antagonist sarpogrelate on microalbuminuria and thromboxane (TX)A2 biosynthesis were examined in non-insulin-dependent diabetes mellitus (NIDDM) patients. 2. In protocol I, the ankle-brachial pressure index (API; an indicator of peripheral blood flow) and urinary albumin excretion (UalbV; an indicator of renal function) were determined in 42 NIDDM patients who had been treated with 300 mg/day sarpogrelate for 8 weeks. In an analysis of the results, the NIDDM patients were divided into four groups based on the severity of either vasculopathy or nephropathy as follows: group A, API < 0.9, UalbV > or = 100 mg/day; group B, API < 0.9, UalbV < 100 mg/day; group CAPI > or = 0.9, UalbV > or = 100 mg/day; and group D, API > or = 0.9, UalbV < 100 mg/day. 3. In protocol II, 10 NIDDM patients with UalbV values > 100 mg/day were divided into two groups to further confirm the effect of sarpogrelate on albuminuria: group E, the sarpogrelate treatment group (n = 5); and group F, the no treatment group (n = 5). 4. In protocol I, the incidence of a cold sensation in the lower extremities was reduced from 45.2 to 21.4% following sarpogrelate treatment. In patients with UalbV > or = 100 mg/day (groups A and C), UalbV was significantly decreased independent of API, while it did not change in patients with UalbV < 100 mg/day (groups B and D). Plasma TXB2 levels were significantly decreased following sarpogrelate treatment, whereas plasma 6-keto-prostaglandin F1 alpha levels were not. 5. In protocol II, in the sarpogrelate treatment group (group E), albuminuria was significantly improved and both plasma levels TXB2 and urinary TXB2 excretion were significantly decreased. In contrast, in the untreated group (group F), neither plasma levels TXB2 nor urinary TXB2 excretion was changed. 6. In conclusion, microalbuminuria was improved by treatment with the 5-HT2 receptor antagonist sarpogrelate independent of latent vasculopathy. Blockade of 5-HT2 receptors is suggested to be beneficial for the treatment of nephropathy in NIDDM patients. It is possible that the inhibition of TXA2 biosynthesis is involved in the therapeutic effect of 5-HT2 receptor antagonists.

Diabetes‐induced changes in the 5‐hydroxytryptamine inhibitory receptors involved in the pressor effect elicited by sympathetic stimulation in the pithed rat

“…Also, the enterochromaffin cell 5‐HT content is altered in diabetes, some studies found an increased level of serotonin in small intestine of STZ‐diabetic rats (Martin et al ., 1995; Takahara et al ., 2001), but other showed decreased (Cicin‐Sain & Jernej, 1996) or normal levels of serotonin (Richter et al ., 1986) in the small intestine of alloxan‐ and STZ‐induced diabetic rats. Recently, a clinical study carried out in noninsulin‐dependent diabetes mellitus patients has suggested the potential benefits of the 5‐HT 2 receptor antagonist sarpogrelate in the treatment of diabetic nephropathy (Ogawa et al ., 1999; Doggrell, 2004). In addition, Sandrini et al .…”

Sarpogrelate diminishes changes in energy stores and ultrastructure of the ischemic-reperfused rat heart

“…Sarpogrelate inhibits vascular smooth muscle cell migration (Tamura et al 1997) and proliferation (Sharma et al 1999) and prevents serotonin-induced coronary spasm in animals (Miyata et al 2000). Because of its antiplatelet effects, sarpogrelate is being used in patients for the treatment of peripheral vascular occlusive disease (Takada et al 1997;Ogawa et al 1999). Furthermore, this drug reduces plasma serotonin concentration in patients with thromboangitis obliterans (Buerger's disease) (Rydzewski et al 1996) and improves the exercise capacity of patients with effort angina, by augmenting collateral circulation (Tanaka et al 1998).…”

The prevention of contrast induced nephropathy by sarpogrelate in patients with chronic kidney disease: a study protocol for a prospective randomized controlled clinical trial

“…A pilot study demonstrated that sarpogrelate improved the symptoms and signs of diabetic nephropathy and neuropathy in three of eight patients with Type 2 diabetes and mild nephropathy [25]. Sarpogrelate also reduced the urinary and plasma levels of thromboxane A 2 and this may be associated with the reduced albumin excretion [26]. Another study demonstrated that sarpogrelate reduced albuminuria in diabetic patients with early-stage diabetic nephropathy within 3 months [27].…”