Research Letter

Journal of Human Hypertension (2006) 20, 537–539. doi:10.1038/sj.jhh.1002034; published online 20 April 2006

Nitric oxide and cell adhesion molecules in essential hypertension: a case control study

K Srivastava1, R Narang2, S Das1 and N Das1

  1. 1Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
  2. 2Department of Cardiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India

Correspondence: N Das, E-mails: nibhriti@hotmail.com, nibhriti@rediffmail.com

To elucidate the significance of nitric oxide (NO), E-selectin and sVCAM-1 in essential hypertension, we determined the levels of these molecules in healthy volunteers and patients with essential hypertension, evaluated their correlations and association with the disease. This case–control study, the first of its kind from India, revealed significant association of low levels of NO and high levels of E-selectin and sVCAM-1 with the disease and negative correlations of NO with the cell adhesion molecules and diastolic blood pressure. An impairment of the normal homeostasis of these molecules is envisaged to play a significant role in the pathophysiology and hence, the risk of essential hypertension.

A total of 65 patients (age 49.45plusminus7.4 years, 43 male, 22 female, systolic blood pressure=145.5plusminus14.05 mm Hg, diastolic blood pressure=93.6plusminus8.09 mm Hg) diagnosed for essential hypertension at the Department of Cardiology, All India Institute of Medical Sciences (AIIMS), New Delhi, India and 53 normal healthy volunteers (age 47.13plusminus4.56 years, 36 male, 17 female, systolic blood pressure=120plusminus3.47 mm Hg, diastolic blood pressure=80.49plusminus2.53 mm Hg, and no history of cardiovascular disorders) were recruited for the study. Individuals who smoked heavily were grouped under smokers. Out of 53 controls, 10 were smokers. Out of 65 patients, 25 were smokers. Volunteers with history of recent medication, drugs and alcohol abuse, major infection, secondary forms of hypertension, diabetes mellitus, renal failure and women on oral contraceptives were excluded from the study. Approval of the ethical committee of AIIMS, New Delhi was obtained, and its guidelines were followed.

The plasma NO levels were determined in terms of nitrite by the standard procedure using Griess reaction.1 Levels of soluble E-selectin and soluble VCAM-1 in serum and plasma samples, respectively, were monitored using enzyme-linked immunosorbent assay kits (R&D Systems, Abington, UK). Differences between the means of the groups were analysed by Student's t-test and Mann–Whitney test as appropriate. Correlations between different parameters were determined by Spearman's rho-test. Odds ratios were determined by multivariate analysis of different parameters after adjusting for age, sex, smoking habits, systolic and diastolic blood pressure. The median value in controls for different parameters was taken as cutoff to determine the odds ratio.

Table 1 represents the data. Despite wide range, the mean value of nitrite was significantly lower (P<0.001) in patients than the controls. The percent decline of nitrite (57%, data not shown in the table) in our patients was comparable to the earlier reports.1, 2 Node et al.1 in his study on a Japanese population reported endothelial dysfunction and 43% decline in the levels of plasma nitrite in patients with hypertension as compared to controls. Whether the decrease in plasma nitrite level was the cause or the effect of impairment of endothelial function was not clear. We found a highly significant inverse-correlation between the levels of nitrite and the diastolic blood pressure in the patients. This affirms the role of NO as an important regulator of blood pressure.3, 4 On multivariate logistic analysis (after adjusting for age, sex, smoking status, systolic and diastolic blood pressures), NO (>3 muM in plasma) emerged as an important protective factor against essential hypertension (odds ratio 0.22 (0.1–0.51) at 95% CI, P<0.01). It is widely believed that smoking leads to both oxidative inactivation of endothelial derived NO and direct oxidative damage of endothelial cells.5 Several studies on the patients with hypertension suggested a negative role of smoking on the levels of NO.6, 7, 8 Our study showed that among the smokers, the mean values of nitrite declined by 39% in controls and by 52% in patients as compared to the nonsmoker controls. This narrowed down the difference in the levels of nitrite between the patients and controls. The difference however, was nonsignificant, may be because of the small sample size. The levels of E-selectin in patients (both smokers and nonsmokers) were significantly higher than the controls. The multivariate logistic analysis suggested that individuals with E-selectin levels higher than 44 ng/ml had a five times higher odds to develop hypertension (odds ratio 5.2 (2.21–12.24) at 95% CI, P<0.01). Beumi et al.9 suggested that the alterations in the serum concentrations of E-selectin in hypertensive patients may be a sign of simple endothelial activation to vessels caused by blood pressure increase. Blann et al.10 found a positive correlation between the levels of E-selectin and diastolic blood pressure in essential hypertension and suggested that raised levels of E-selectin in hypertension indicate endothelial activation rather than endothelial cell injury. Our data did not show any correlation between the levels of E-selectin and blood pressure. Smoking, per se, had no significant effect on the levels of E-selectin as the mean values of E-selectin were comparable between the smoker and nonsmoker controls and the patients in these two groups. Highly marked significant increase (P<0.001) in the levels of sVCAM-1 was observed in the serum samples of patients in comparison with controls. The multivariate logistic analysis suggested that individuals with sVCAM-1 levels higher than 338 ng/ml had a 19 times higher odds to develop hypertension (odds ratio 19.67 (5.51–70.23) at 95% CI, P<0.01). Beumi et al.9 reported a borderline increase in the levels of sVCAM-1 in the patients with essential hypertension and suggested that high arterial blood pressure because of increased vascular distending and transmural pressure might increase the production of sVCAM-1 probably through endothelial activation. However, Beumi et al.9 did not find any correlation between the levels of sVCAM-1 and systolic and diastolic blood pressure. Similarly, we did not find any correlation between the systolic/diastolic blood pressure and sVCAM-1 levels. The reports on the effect of cigarette smoking on the levels of sVCAM-1 are very rare. Mazzone et al.6 reported a significant increase in the levels of sVCAM-1 in smoking hypertensives and suggested smoking as a cause for endothelial dysfunction. We found no significant influence of smoking on the levels of sVCAM-1. There is growing evidence that endothelium-derived NO and cell adhesion molecules, both, play crucial role in the regulation of blood pressure.11 NO had been shown to downregulate the expression of cell adhesion molecules, however, in humans, only few studies pertain to the relationship between NO, E-selectin and sVCAM-1. Most of these studies are in CAD patients.12. In the present study, significant negative correlations were observed between the levels of nitrite and that of E-selectin and sVCAM-1. On the whole, our data suggest an impairment of the normal homeostasis of NO and cell adhesion molecules (E-selectin and sVCAM-1) in essential hypertension. This impairment may contribute to the pathophysiology and risk of the disease. Data on smoking versus nonsmoking in relation to different parameters, especially, nitrite levels need to be confirmed by a larger sample study. The study is the first of its kind from India.


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