ENDOTHELIN-1 AS A PUTATIVE MODULATOR OF ERECTILE DYSFUNCTION .1. CHARACTERISTICS OF CONTRACTION OF ISOLATED CORPORAL TISSUE STRIPS

Normal erectile physiology is heavily dependent on a delicate balance between the effects of endogenous vasoconstricting and vasorelaxing ho rmones on the tone of the corporal smooth muscle. Recent studies indic ate that endothelin-1 (ET-1) is present and physiologically active in the human corpora. The primary goal of the present investigation was t o further define the role of ET-1 in corporal physiology and to ascert ain whether it might play a role in augmenting corporal tone in vivo, as reported in other vascular tissues. Thus, we conducted pharmacologi cal studies of ET-1-induced steady-state contractions in isolated huma n corporal smooth muscle strips to determine if there were any detecta ble age- or diabetes-related alterations in ET-1-induced contractions. For statistical analysis, the patient population was divided into 2 a ge groups, A (less than or equal to 59 years of age; = 11 patients) an d B (greater than or equal to 60 years of age; n = 7 patients), and fu rther subdivided into 2 diagnostic categories, diabetic (n = 7 patient s) and nondiabetic (n = 11 patients). Construction of cumulative conce ntration response curves (CRCs) for ET-1-induced contractions revealed characteristically slow onset and long-lasting responses. Endothelin- 1 CRC data were computer fit to the logistic equation to derive E(max) (calculated maximal response), pEC(50) (negative logarithm of the con centration that elicits one-half of the calculated maximal response) a nd slope factor (n) values. Two-factor analysis of variance revealed n o detectable age- or diabetes-related alterations, nor any age-diabete s interaction in any of the logistic parameters. Furthermore, logistic analysis of ET-1 CRC data on 14 isolated corporal tissue strips deriv ed from 3 potent patients with documented spontaneous erections reveal ed no differences in ET-1 contractility from that observed for patient s with organic erectile dysfunction. Importantly, despite an apparent absence of age- or diabetes-related alterations in ET-1-induced steady -state contractions, preliminary studies demonstrated that coadministr ation of the alpha(1)-adrenergic agonist phenylephrine and ET-1 produc e much greater contractile responses than those observed in the presen ce of phenylephrine (PE) alone. Moreover, the magnitude of the augment ation was precisely that predicted by a model for simple additivity of agonist effects. Such observations suggest that the physiological rel evance of ET-1 to corporal physiology may be related to its ability to augment the contractile responses of other vasomodulators present in the human corpora, in particular, perhaps modulating the contractile r esponses to sympathetic activity.