Pharmacological studies of human erectile tissue: characteristics of spontaneous contractions and alterations in α‐adrenoceptor responsiveness with age and disease in isolated tissues

Abstract

1 The pathophysiology of impotence related to vascular smooth muscle dysfunction in the male corpus cavernosum was studied on human isolated erectile tissue (HET). Studies were conducted on 140 sections of HET obtained from 38 male patients undergoing surgery for implantation of penile prostheses to correct underlying erectile dysfunction. 2 Spontaneous myotonic oscillations were characteristic of greater than 90% of all HET preparations at 37°C. These spontaneous oscillations were markedly attenuated by indomethacin, BW755C, nifedipine, removal of extracellular Ca²⁺, or lower temperatures (≤ 32°C), but were not sensitive to inhibition by atropine, phentolamine or tetrodotoxin. Our data suggest that the oscillations may, at least in part, result from the generation and/or release of a stable cyclo-oxygenase product and a consequent increase in transmembrane Ca²⁺ influx. 3 The phenylephrine-induced contractions in HET may be reliably assayed up to 24 h after surgical removal, without significant alterations in the EC₅₀, maximum response (E_max) or slope index of the steady-state concentration-response curve to phenylephrine. 4 The competitive and surmountable nature of the antagonism of phenylephrine-induced contractions by prazosin and yohimbine allowed calculation of antagonist dissociation constants. The calculated pK_b values for prazosin and yohimbine, respectively, were 9.47 ± 0.49 and 5.54 ± 0.22. The rank order of agonist potency in HET was: noradrenaline = phenylephrine ≫ clonidine. These data indicate the presence of a population of membrane receptors that are predominantly of the α₁-adrenoceptor subtype. 5 The entire patient population was stratified on a decennial basis into five age groups, and each age group was subsequently subdivided into diabetic and nondiabetic diagnostic categories. With respect to the steady-state phenylephrine concentration-response curves, a Winer two-factor analysis of variance revealed a significant effect of age on the calculated pEC₅₀ value, as well as a significant age-diagnosis interaction. A post hoc statistical analysis for unpaired samples yielded significant differences between pEC₅₀ values for diabetic and nondiabetic patients in age groups 41–50 and 61–70 years. In addition, a Winer two-factor analysis of variance also detected a significant effect of age on the calculated E_max value. 6 In conclusion, our studies demonstrate that spontaneous contractions in HET are likely to be mediated by the generation and release of a stable cyclo-oxygenase product. Furthermore, the results of both agonist and antagonist studies are consistent with the presence of a homogeneous α₁-adrenoceptor population. Lastly, the responsiveness of isolated HET to phenylephrine was shown to be altered by both age and disease.