Activation of nitric oxide synthesis in vascular smooth muscle cells and macrophages during development in spontaneously hypertensive rats

We previously showed that the lymphocyte proliferation response was significantly suppressed in spontaneously hypertensive rats (SHR) and that this depressed response was due to excessive production of nitric oxide (NO) in macrophages and vascular smooth muscle cells (VSMC). Whether lymphocyte depression and activation of NO synthesis are related to age and development of hypertension remains unclear. The present study addresses such a correlation by examining the time course of development of hypertension, NO synthesis alteration and lymphocyte depression in SHR. Our results show that 1) SHR spleen cell proliferation responses are depressed at 4, 8, and 12 weeks and 1 year of age, with the lowest response occurring at 4 weeks of age; 2) this depressed response is corrected by either NO synthase inhibitor or removal of macrophages from spleen cells; 3) NO production by SHR spleen macrophages is significantly higher in all age groups; 4) upon stimulation with lipopolysaccharide or cytokines, SHR VSMC produce a significantly greater amount of NO in all age groups; 5) the increase in NO synthesis in VSMC correlates significantly with the rise in blood pressure in SHR. However, statistical correlation analysis suggests that lymphocyte depression and the alteration of NO synthesis in macrophages were not associated with either age or increased blood pressure in SHR. On the contrary, the activation of NO synthesis in VSMC can be statistically correlated with elevated blood pressure throughout the development of hypertension in SHR. Nevertheless, the results also suggest that a general alteration in the NO synthesis system may exist in SHR.