ERECTILE DYSFUNCTION IN AGING - UP-REGULATION OF ENDOTHELIAL NITRIC-OXIDE SYNTHASE

Objectives. To evaluate whether alterations in nitric oxide (NO) synth esis or activity contribute to age-related erectile dysfunction and to elucidate the mechanisms causing these alterations using the rabbit a s our model of aging. Methods. We compared the ability of the rabbit c avernosal smooth muscle to relax in the organ bath in response to acet ylcholine (Ach, endothelium-dependent vasodilator), sodium nitroprussi de (SNP, an NO donor), and A23187 (a calcium ionophore) in young (6 mo nth old) and aged (2.5 to 3.5 year old) rabbits. In addition, the immu nohistochemical expression of endothelial nitric oxide synthase (eNOS) in both young and aged rabbit cavernosal tissue was examined. Endothe lial integrity was examined immunohistochemically with JC70. Results. Ach-mediated relaxation of penile corporal tissue was significantly at tenuated from a maximum of 68.39 +/- 6.27 (0.1 mM Ach, n = 4) in young rabbits to 39.02 +/- 4.88 (0.1 mM Ach, n = 6) in aged rabbits (P < 0. 04). No statistically significant difference (P > 0.05) was noted betw een cavernosal relaxation to sodium nitroprusside between young rabbit s (97.8%, 0.1 mM SNP, n = 5) and aged rabbits (76.1%, 0.1 mM SNP, n = 5). This suggested that the defect in the Ach-NO pathway was at the le vel of NO synthesis, not activity. Immunohistochemical staining for eN OS demonstrated upregulation in both the vascular endothelium and corp oral smooth muscle of aged rabbit tissue compared with young rabbit: c avernosal tissue (n = 5). Anatomic endothelial integrity was demonstra ted in the young and aged rabbits by the presence of JC70. This sugges ted that the defect in the Ach-NO synthetic pathway was not at the lev el of eNOS and was not due to anatomic endothelial cell disruption. Fi nally, Ach-mediated cavernosal smooth muscle relaxation in the young r abbit was not significantly augmented (P > 0.05) in the presence of th e calcium ionophore A23187 (10 mu M). A23187, however, significantly a ugmented (P < 0.04) Ach-mediated relaxation in the aged rabbit from a maximum of 33.93 +/- 6.58 to 41.55 +/- 6.58 (10 mu M Ach, n = 5). This suggested that a potential defect in the Ach-NO synthetic pathway was at the level of intracellular calcium flux and possibly at the level of the calcium-eNOS interaction. Conclusions. Endothelium-dependent re laxation is attenuated in the aging rabbit; eNOS is upregulated in the aging rabbit; and no difference is noted in response to direct NO don ation between the young and aged rabbit. The endothelium is anatomical ly intact in both the young and aging rabbit. The calcium ionophore A2 3187 augmented the attenuated vasorelaxation in the aging rabbit caver nosum (although not to the levels seen in the young rabbit cavernosum) and had no effect on the young rabbit cavernosum. These data suggest that erectile dysfunction in the aging rabbit cavernosum appears to be related to endothelial dysfunction and is characterized by eNOS upreg ulation and aberrant intracellular calcium fluxes. (C) 1998, Elsevier Science Inc. All rights reserved.