DIFFERENT MECHANISMS OF ENDOTHELIAL DYSFUNCTION WITH AGING AND HYPERTENSION IN RAT AORTA

We analyzed the effects and mechanisms of aging in aortic endothelium and vascular smooth muscle of 12-week-old (adult) and 72-week-old (senescent) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Aortas were suspended in organ chambers filled with physiological salt solution (95% O-2/5% CO2; 37 degrees C), and isometric tension was measured. In WKY, endothelium-dependent relaxations to acetylcholine were diminished with aging (P<.05); in SHR, they were reduced compared with WKY (P<.05) but unchanged with aging. The thromboxane/endoperoxide receptor antagonist SQ 30741 increased relaxations only in adult SHR. Relaxations to sodium nitroprusside were slightly enhanced with age in WKY and SHR (P<.05). Endothelium-dependent contractions to acetylcholine were unmasked by N-G-nitro-L-arginine methyl ester (P<.05) and prevented by SQ 30741 or endothelium removal. In WKY, contractions increased with age. In adult SHR, marked endothelium-dependent contractions occurred (P<.05 versus WKY), which diminished with age (P=NS versus senescent WKY). The thromboxane analogue U46619 elicited similar contractions in adult and senescent WKY and adult SHR, whereas responses in senescent SHR were weaker (P<.05). In WKY and SHR, contractions to norepinephrine were similar and unaltered by aging. In WKY, contractions to endothelin-1 remained unaffected by aging. Adult SHR exhibited contractions to endothelin-1 comparable to those in WKY, whereas senescent SHR contracted less (P<.05). Bosentan, a combined endothelin-A/endothelin-B receptor antagonist, inhibited endothelin-1 markedly, especially in SHR (P<.05). Thus, aging causes different alterations in endothelium and smooth muscle in WKY and SHR aorta. In adult SHR, endothelium-dependent relaxations are reduced because of formation of prostaglandin H-2, whereas in senescent SHR and senescent WKY, impaired formation or increased inactivation of nitric oxide must be involved. Contractions to endothelin but not to norepinephrine are reduced with aging only in SHR.