Endothelial dysfunction in the San Juan hypertensive rat: Possible role of the nitric oxide synthase

Endothelial dysfunction is recognized as a critical event in the etiology of cardiovascular diseases, but its possible role during aging in arterial hypertension remains poorly defined. We evaluated the response of aortic rings precontracted with 0.1 mu M norepinephrine (NE) to acetylcholine (ACh) in the San Juan hypertensive rats (SJH-Rs) (F-19, F-20) and Munich Wistar rats (MW). SJH-Rs is a model of inbred salt-sensitive hypertension, whereas similarly treated inbred MW rats are their normotensive counterpart. These experiments were performed with adult (6-7 months) and aged (11-13 months) rats to assess the effects of age and hypertension on endothelium-dependent relaxation. We generated dose-response curves by adding cumulative doses of ACh from 1.0 nM to 10.0 mu M. In addition, we evaluated the Ca2+ -dependent nitric oxide synthase (NOS) activity by increasing cell calcium with the ionophore A23187. The results indicate that hypertension induces a displacement to the right of the dose-response curve to ACh in both adults and aged SJH-Rs; IC50 for adult rats was 0.72 +/- 0.3 mu M for SJH-Rs and 0.059 +/- 0.03 mu M for MW (p < 0.05). Aged animals showed similar results: IC50 of 0.78 +/- 0.03 mu M for SJH-Rs and of 0.043 +/- 0.01 mu M in age-matched MW rats (p < 0.025). However, no difference was observed between hypertensive (SJH-Rs) adult and aged an animals. Similarly, no difference was observed between adult and aged MW control animals, The displacement of the dose-response curve to ACh in SJH-Rs appears to be associated with a reduced activation of NOS since in precontracted aortas from aged animals 1 mu M A23187 induced a relaxation of 51.2 +/- 12% in MW as compared with 34.4 +/- 7% in SJH-Rs (n = 5, p < 0.05). These results indicate that endothelial dysfunction exists in SJH-Rs. The data suggest that an alteration of the endothelial NOS may be the cause of this abnormality. Finally, the magnitude of the endothelial dysfunction is not age dependent within the range evaluated.