Relationship Between Obestatin And Blood Pressure And The Effects Of Obestatin On Blood Pressure Regulation

Ghrelin was initially discovered by Kojima et al. in 1999 as an endogenous ligand for the GHSR (growth hormone secretagogue receptor). In recent years, subsequent studies have shown that it has a multiplicity of functions such as stimulate appetite and initiate food intake, modulate energy metabolism, control gastric motility and so on.Ghrelin and its receptor are widely distributed in cardiovascular tissues, which supplies with a base for ghrelin to play a role in the regulations of cardiovascular system's functions. Recently, some studies have also suggested that ghrelin is associated with the regulations of blood pressure. Nayaga et al. found that the intravenous injection of ghrelin could decrease peripheral artery resistance, leading to a drop in blood pressure without an increase in heart rate in healthy volunteers. Makino et al. also found that fasting plasma ghrelin concentration was significantly higher in patients with pregnancy-induced hypertension than normal pregnant women. These results suggest that ghrelin may play an important role in blood pressure regulation.In November,2005, Zhang et al. first reported that they found that preproghrelin could split into two peptides including ghrelin and the other pepetide named obestatin. An interesting finding was that obestatin, though derived from the same peptide precursor as ghrelin, suppressed food intake, inhibited jejunal contraction, decreased body weight gain, and antagonized the actions of ghrelin when both peptides were co-administered. Recently, Anderwald-Stadler et al. found that the fasting plasma obestatin level was negatively correlated with SBP in insulin-resistant humans, suggesting a possible role of obestatin in the regulation of blood pressure.To the best of our knowledge, plasma obestatin profiles in relation to blood pressure and especially the role of obestatin in the blood pressure regulation have not been studied. Therefore, we are intent to investigate the relationship between plasma obestatin levels and blood pressure and the role of obestatin in the blood pressure regulations as follows:Ⅰ:Relationships between plasma obestatin levels and ghrelin levels and blood pressure in spontaneously hypertensive rats (SHR).Ⅱ:Relationships between plasma obestatin levels and ghrelin levels and blood pressure in humans with untreated mild-to-moderate hypertension.Ⅲ:Effects of the intravenous injection of obestatin on blood pressure regulation in SHR. Part I Changes of circulating plasma obestatin levels and its significance in spontaneously hypertensive ratsObjective: To investigate the changes of circulating plasma obestatin and ghrelin levels at fasting and their relationships between them and blood pressure in SHR.Methods: Plasma total ghrelin and obestatin levels at fasting were measured by RIA in fourteen SHR and twelve Wistar-Kyoto rats. Plasma insulin levels were measured by ELISA. The blood pressure, HP and BRS were measured by the continuous record system used for consicious freely rats.Results:Both ghrelin and obestatin levels were significantly higher in SHR group compared with WKY group (649.4±55.3 pg/ml vs 106.3±8.4 pg/ml, P<0.01; 44.6±2.3 pg/ml vs 38.6±1.5 pg/ml, P<0.05 respectively). Moreover, the ratio of ghrelin to obestatin in SHR group was significantly higher compared with WKY group (15.1±1.5 vs 2.8±0.2, P<0.01). HP, BRS, body weight and insulin levels were negatively correlated with ghrelin levels and the ratio of ghrelin to obestatin. SBP, DBP and MAP were positively correlated with ghrelin levels and the ratio of ghrelin to obestatin. BRS was negatively correlated with obestatin levels. The ghrelin levels were also positively correlated with the obestatin levels. In a multiple regression model including body weight, insulin, SBP, DBP, MAP, HP and BRS, body weight and SBP were independent variables of ghrelin level (standardized coefficient=-0.377; P=0.004; standardized coefficient= 0.615; P<0.0005, respectively); and SBP was an independent determinant of the fasting obestatin level (standardized coefficient= 0.460; P=0.018); SBP and body weight were significantly independent determinants of the ghrelin to obestatin ratio (standardized coefficient= 0.567; P=0.01; standardized coefficient=-0.332; P=0.037, respectively). None of these parameters showed any significant correlations with ghrelin, obestatin, and the ratio of ghrelin to obestatin in SHR group or WKY group when considered alone.Conclusions:Circulating plasma ghrelin and obestatin levels were significantly higher in SHR group compared with WKY group suggesting that obestatin might play a role in the regulations of blood pressure. Part II Changes of ciculating plasma obestatin levels and its significance in humans with hypertensionObjective: To investigate the changes of circulating plasma obestatin and ghrelin levels and the relationships between them and blood pressure in humans with untreated mild-to-moderate hypertension.Methods: Plasma total ghrelin and obestatin levels at fasting were measured by RIA in fourteen humans with untreated mild-to-moderate hypertension and fourteen humans with normal blood pressure. Plasma insulin levels at fasting were measured by ELISA. Body mass index and waist-hip ratio were calculated.Results:Plasma ghrelin levels at fasting were significantly higher in hypertension group compared with control group (236.3±12.3 pg/ml vs 381.4±25.6 pg/ml, P<0.01).The plasma concentration of obestatin was 276.2±15.1 pg/ml and 325.4±25.8 pg/ml in hypertension group and control group, respectively, but the difference between the two groups was not significant (P>0.05). The ratio of ghrelin to obestatin in hypertension group was significantly lower compared with control group (0.89±0.06 vs 1.2±0.06, P<0.01). SBP, DBP, BMI, TG, glucose, and insulin were all negatively correlated with ghrelin. Both glucose and insulin were negatively correlated with obestatin. What's more, the ratios of ghrelin to obestatin were negatively correlated with SBP and DBP. In a multiple regression model analysis both SBP and TG were independent predictors of ratio of ghrelin to obestatin (standardized coefficient=-0.385; P=0.033; standardized coefficient=-0.430; P=0.018, respectively), whereas other parameters did not show any significant correlations with the ratio of ghrelin to obestatin.Conclusions:Circulating plasma ghrelin levels were significantly lower in humans with untreated mild-to-moderate hypertension compared with control group and the difference between the obestatin levels of the two groups was not significant. Obestatin might play a minor role in the blood pressure regulation compared with ghrelin. PartⅢEffects of the intravenous injection of obestatin on blood pressure in spontaneously hypertensive ratsObjective: To investigate the effects of the intravenous injection of obestatin and ghrelin on blood pressure, heart period and BRS in SHR.Methods: Changes of blood pressure, heart period and BRS were measured by continuous record system used for consicious freely rats after the intravenous injection of obestatin and ghrelin.Results:Bolus intravenous injection of different dosages of obestatin (10μg/kg,50μg/kg,100μg/kg) showed no significant effects on mean blood pressure (10μg/kg: 113.8±2.0 mmHg vs 114.4±1.6 mmHg; 50μg/kg:110±2.4 mmHg vs 109±3.2 mmHg; 100μg/kg:115.9±1.5 mmHg vs 115.8±2.4 mmHg; all P>0.05), heart period (10μg/kg: 184.7±3.9 ms vs 185.5±4.1 ms; 50μg/kg:185.9±4.1 ms vs 193.4±4.5 ms; 100μg/kg: 137.7±4.5 ms vs 143.9±5.6 ms; all P>0.05), or baroreflex sensitivity (10μg/kg: 0.414±0.03 ms/mmHg vs 0.442±0.02 ms/mmHg; 50μg/kg:0.453±0.04 ms/mmHg vs 0.439±0.01 ms/mmHg; 100μg/kg:0.398±0.02 ms/mmHg vs 0.401±0.01 ms/mmHg; all P>0.05). However, intravenous injection of ghrelin (10μg/kg) could decrease mean arterial pressure (115.9±1.5 mmHg vs 108.6±3.6 mmHg, P<0.01) and increase heart period (132.4±2.8 ms vs 152.6±7.4 ms, P<0.05), but did not change baroreflex sensitivity (0.35±0.008 ms/mmHg vs 0.36±0.009 ms/mmHg, P>0.05) in SHR.Conclusions: Intravenous injection of obestatin showed no significant effects on mean arterial pressure, heart period or baroreflex sensitivity in SHR. Obestatin might play a minor role in the blood pressure regulation in rats compared with ghrelin.