Vivienne S. Stopper

Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway.

Relaxation of the smooth muscle cells in the cavernosal arterioles and sinuses results in increased blood flow into the penis, raising corpus cavernosum pressure to culminate in penile erection. Nitric oxide, released from non-adrenergic/non-cholinergic nerves, is considered the principle stimulator of cavernosal smooth muscle relaxation, however, the inhibition of vasoconstrictors (that is, norepinephrine and endothelin-1, refs. 5–9) cannot be ignored as a potential regulator of penile erection. The calcium-sensitizing ρ-A/Rho-kinase pathway may play a synergistic role in cavernosal vasoconstriction to maintain penile flaccidity. Rho-kinase is known to inhibit myosin light chain phosphatase, and to directly phosphorylate myosin light-chain (in solution), altogether resulting in a net increase in activated myosin and the promotion of cellular contraction. Although Rho-kinase protein and mRNA have been detected in cavernosal tissue, the role of Rho-kinase in the regulation of cavernosal tone is unknown. Using pharmacologic antagonism (Y-27632, ref. 13, 18), we examined the role of Rho-kinase in cavernosal tone, based on the hypothesis that antagonism of Rho-kinase results in increased corpus cavernosum pressure, initiating the erectile response independently of nitric oxide. Our finding, that Rho-kinase antagonism stimulates rat penile erection independently of nitric oxide, introduces a potential alternate avenue for the treatment of erectile dysfunction.

Androgenic maintenance of the erectile response in the rat.

Ongoing studies in this laboratory have used the castrated rat, with and without testosterone replacement, to investigate how androgens maintain the erectile response. The high intracavernosal pressures during erection depend on both an increase in the rate at which blood flows into the sinuses of the corpus cavernosum and a decrease in the rate at which blood flows out (veno-occlusion). Accordingly, our studies investigated androgenic regulation of the arterioles that regulate inflow and of the intracavernosal muscle that regulates the veno-occlusive mechanism controlling outflow. The results of these studies show that castration causes a decline in the rate of inflow and that androgen replacement reverses this decline. The decline in inflow in the castrated rats is also reversed by the administration of a nitric oxide donor drug, suggesting that the androgen may regulate inflow by increasing the synthesis of nitric oxide. Testosterone also appears to regulate outflow by controlling the sensitivity of the erectile mechanisms to norepinephrine, considered to be the principle vaso-constrictor neurotransmitter in the erectile response. Taken together, the results of these studies suggest that androgens control the erectile response by altering the synthesis and action of the neurotransmitters that normally alter the state of contraction and relaxation of smooth muscle in the erectile tissue.

The intraovarian progesterone modulation of follicle development in the rabbit ovary

Intraovarian progesterone levels were manipulated by surgically adjusting the number of corpora lutea (CL) present in rabbit ovaries and this model was used to study the local effect of luteal progesterone on growth of follicles. The results show that when a single CL or several CL were present, follicle growth was inhibited. However, when all CL on one ovary were removed, increased numbers of follicles grew even when a single CL was present in the contralateral ovary. These findings show that progesterone inhibits follicle growth and that at least part of its action is local, i.e., exerted within the ovary. Additionally, ovarian blood vessels and periovarian lymph ducts were cannulated, and samples were collected and analyzed for steroid and protein content. The results show that when CL were present, ovarian vein progesterone levels were elevated 10-30-fold over levels in ovaries without CL; this high concentration points to the blood vascular system as the principal carrier of the steroid within the ovary. Analysis of lymph showed that protein content was consistently high and that the progesterone concentration was not significantly altered with the presence of CL; these two findings show that ovarian capillaries are extremely permeable to proteins, but the unexpectedly low concentrations of progesterone in lymph may signal an intraovarian countercurrent mechanism by which it is returned to the blood.