Oral Administration of L-Tryptophan is Effective to Improve Glucose Metabolism and Hypertension in Stroke-Prone Spontaneously Hypertensive Rats

Ardiansyah*, Hitoshi Shirakawa, Takuya 1, Michio Komai Tetsuya Murayama

1, Koseki

Yoshihito

1, Shiono

Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai-Japan; 1 Faculty of Agriculture, Yamagata University, Tsuruoka-Japan; * Email: ardy@biochem.tohoku.ac.jp
Abstract
Multiple factors related to the metabolic state, such as changes in glucose metabolism and insulin resistance involved in the management of hypertension. We studied the effects of single oral and chronic administration of L-tryptophan (L-Trp) on the regulation of glucose metabolism and hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). Male 9-week-old of SHRSP was administered L-Trp or saline (Control) via a gastric tube. The systolic blood pressure through blood tail vein was measured before and 1, 2, 4, and 6 h after the administration. Hypotensive effect was observed after 1 and 2, and back to the basal condition after 4 and 6 h. Plasma glucose and insulin levels were lower after 4 and 6 h of the administration. Subsequently, the effects of chronic L-Trp administration in SHRSP were studied. SHRSP aged 9-week-old were divided into Control and L-Trp groups that were administered water or L-Trp solution, respectively for 3 weeks. Hypertension was significantly improved in the L-Trp group. We found out that chronic administration of L-Trp showed increased plasma nitric oxide levels in plasma that was corresponded well with the hypotensive effect observed in SHRSP. Plasma glucose and insulin levels were also significantly decreased in the L-Trp group after 2 and 3 week of the administration. In conclusion, single oral and chronic administration of L-Trp has beneficial effect to improve glucose metabolism and hypertension in SHRSP.

Introduction
Driselase-treated fraction of rice branthe filtrate of rice bran treated with plant cell wall-degrading enzymehas a beneficial effect on lowering hypertension and improving lipid profiles. (Ardiansyah et al., 2006, J. Agric. Food Chem., 54, 1914-1920; Ardiansyah et al., 2007, Br. J. Nutr., 97, 67-76) Physiological effect of Tryptophan; 1. Effect on blood pressure lowering activity is not related to the brain serotonin level in normal and SHR rats L-Tryptophan 2. Effect on the liver is related to the gluconeogenic PEPCK enzyme blockage in the experimental acute porphyria

Objectives
This study was designed to know the effects of single oral and chronic administration of L-tryptophan (LTrp) on the regulation of glucose metabolism and hypertension in stroke-prone spontaneously hypertensive rats (SHRSP).

Antihypertensive activity of L-Trp after acute administration

Systolic blood pressure (mmHg) 9 weeks of SHRSP/Izm Oral administration by saline as control 16 h of fasting group1 and L-Trp2 group after 170 160 150 140 130 0
*

L-Trp improves glucose and insulin levels after acute administration

Glucose (mg/dL) Insulin (ng/mL) 130 120 110 100 90 80 4 6
Control L-Trp * *

0.5 0.4 0.3 0.2 0.1 0.0 4 6 time after administration (h)
* *

4 HOMA-R 3 2 1 0
*

Control

L-Trp

Measurement of BP (0, 1, 2, 4, and 6 h) and plasma blood tail vein

1

Control (saline 0.9%) 2 L-Trp in saline (100 mg/kg body weight)

4 6 time after administration (h)

time after administration (h)

Mean + SEM; n= 4 * (p<0.05) ; (p<0.01) vs Control

Experimental methods (chronic administration of L-Trp)

Final body weight (gram) 8 one week acclimation 1.SHRSP had free access to fresh diet (AIN 93M) and drinking water (distilled water). The rats were divided 3 groups; (1) control, (2) L-Trp 200 (200 mg/kg diet), and (3) LTrp 1000 (1000 mg/kg diet). 2.Water intake/food intake measured every day. 3.Systolic blood pressure, body weight, and plasma blood tail vein (plasma lipid, glucose, and insulin) were measured every week. The rats were housed individually in stainless steel cages under a controlled atmosphere (temperature, 23 + 2 oC; humidity 50 + 10 %; 12 h light-dark cycle, 08:00 am-08:00 pm) 1.Sacrificed 2.Blood and organ collecting for further analyses 9 10 11 12 Week 300 250 200 150 100 4 3 2 1 0 Liver Control

Total cholesterol (mg/dL)

Growth parameters
Water intake (ml/day) 30 20 10 0 Control L-Trp 200 L-Trp 1000

Plasma lipid levels after acute administration of L-Trp

80 75 70 65 60 55 50 0 100 90 80 70 60 50 0 1 2 4 6 time after administration (h) 1 2 4 6

L-Trp 200 L-Trp 1000

Relative organ weight (%)

Similar body weight gain and food intake were observed for three groups during experimental period.

Abdominal fat

Epididymal fat

Hypotensive effect of L-Trp administration

Systolic blood pressure (mmHg) 220 200 180

Glucose (mg/dL)

160 150 140 130 120 5 9 10

Control L-Trp 200 L-Trp 1000

Triglyceride (mg/dL)

180 140 100 60 Plasma lipid level (mg/dL)

Total cholesterol (mg/dL)

L-Trp improve glucose and insulin levels after chronic administration

Plasma lipid levels after chronic administration of L-Trp

110 90 70 50

160

140

10 11 Age (weeks) Nitric oxide (M)

12

9 100 80 60 40 20 0

11

12 30 HOMA-R

10 11 age (weeks)

Triglyceride (mg/dL)

12

10 11 age (weeks)
Mean + SEM; n= 5

12

Blood urea nitrogen (mg/dL)

20 16 12 8 4 0 10 week 11 week

4 3 2 1 0 Control L-Trp 200

age (weeks)

Insulin (ng/mL)

4 3 2 1 0 11 week 12 week

* (p<0.05) ; * *

(p<0.01) vs Control

20 10 0 Control L-Trp 200 L-Trp 1000

L-Trp 1000

TG

TC

HDL-C

LDL-C

Conclusion
1. L-Trp had blood pressure lowering activity, and improved glucose metabolism after acute administration. 2. Chronic administration of L-Trp showed increased plasma nitric oxide levels, and this result corresponded well with the hypotensive effect observed in SHRSP. 3. Chronic administration of L-Trp significantly improved plasma glucose, insulin, and HDL-cholesterol levels.

L-Trp is effective and beneficial to improve the metabolic syndrome-related diseases parameters