Introduction. Nitric oxide-cyclic guanosine monophosphate (NO-cGMP)-mediated relaxation of cavernosal smooth muscle during erection is accompanied by a decrease in intracellular calcium concentrations ([Ca2+]i). However, it is not known whether and how an increase in [Ca2+]i is responsible for (i) initiating smooth muscle contraction/detumescence following relaxation; and (ii) maintaining the penis in a flaccid state under nonstimulating conditions.
Aim. To elucidate (i) the mechanism(s) of [Ca2+]i homeostasis regulation in human cavernosal smooth muscle cells (HCSMC); and (ii) how NO-cGMP interacts with such [Ca2+]i homeostasis.
Methods. We evaluated the expression and function of both T-type and L-type Ca2+ channels in HCSMC by employing selective probes/inhibitors using various cellular and molecular techniques (e.g., reverse transcriptase and real-time polymerase chain reaction, cell proliferation assay, fura-2 Ca2+ fluorescence spectroscopy, enzyme-linked immuno-absorbent assay (ELISA)).
Main Outcome Measure. We have demonstrated for the first time significant interactions of NO-cGMP with the T-type (α1G) Ca2+ channel in HCSMC.
Results. Our results suggest that in addition to NO-induced rapid and transient decrease in [Ca2+]i that results in smooth muscle relaxation, NO-cGMP also enhanced mRNA expression of the T-type (α1G) Ca2+ channel resulting in delayed elevation of [Ca2+]i. This could be abolished by a selective T-channel blocker, NNC 55-0396. Another unique finding of this study is that dose-dependent HCSMC proliferation in vitro by NO is associated with the activation of the T-type (α1G) Ca2+ channel that regulates [Ca2+]i homeostasis in these cells.
Conclusions. Human cavernosal cells express T-type (α1G) Ca2+ channels that are involved in maintaining [Ca2+]i homeostasis and regulation of NO-cGMP-induced smooth muscle relaxation–contraction responsible for penile erection, flaccidity, and tonicity. Targeting these Ca2+ channels may (i) associate various comorbidities with the onset of erectile dysfunction; (ii) provide a biochemical basis for differences between therapeutic profiles of various phosphodiesterase type 5 inhibitors, especially in nonresponders to current therapy; and (iii) provide biochemical basis in understanding mechanism(s) of drug tolerance. Zeng X, Keyser B, Li M, and Sikka SC. T-type (α1G) low voltage-activated calcium channel interactions with nitric oxide-cyclic guanosine monophosphate pathway and regulation of calcium homeostasis in human cavernosal cells. J Sex Med 2005;2:620–633.