Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The putative role of vasoactive intestinal polypeptide (VIP) as the relaxant neurotransmitter in human cavernosal smooth muscle has been studied in isolated tissue preparations. 2. Consistent neurogenic relaxations were evoked by electrical field stimulation (EFS; 2-64 pulses/train, 0.8 ms pulse duration, 10 Hz). VIP (0.1-3 microM) relaxed cavernosal smooth muscle in a dose-dependent fashion. Relaxant responses to both EFS and VIP were reduced in tissue from impotent men. 3. Neurogenic relaxant responses were not diminished in the presence of the VIP-inactivating peptidase, alpha-chymotrypsin (alpha-CT, 2 units ml-1). In contrast VIP-induced relaxations were completely abolished. 4. Inhibition of nitric oxide synthase by NG-nitro-L-arginine (30 microM), and of guanylate cyclase by methylene blue (50 microM) caused highly significant reductions of neurogenic relaxant responses whereas VIP-evoked relaxations were unaffected. 5. It is concluded that VIP-evoked relaxations are not mediated by the NO-guanosine 3':5'-cyclic monophosphate (cyclic GMP) pathway and that VIP release is not essential for neurogenic relaxation of human cavernosal smooth muscle. VIP does not therefore act as the major relaxant neurotransmitter in this tissue.
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PMID:Evidence against vasoactive intestinal polypeptide as the relaxant neurotransmitter in human cavernosal smooth muscle. 809 18

Nitric oxide (NO) released from nonadrenergic-noncholinergic (NANC) nerves seems to be a principal mediator of the relaxation of penile erectile tissue necessary for erection, and drugs acting by release of NO have been shown to produce erection when injected intracorporeally into impotent patients. By producing hyperpolarization, K+ channel openers are effective in relaxing isolated penile erectile tissue from rabbit and man, and can produce tumescence and erection when injected intracorporeally into animals. Nicorandil is classified as a K+ channel opener, but it also acts as a donor of NO. In the present study, the effects of nicorandil on isolated preparations from human corpus cavernosum (CC) and deep cavernous artery (Acc) were compared with those of cromakalim (K+ channel opener) and SIN-1 (NO donor). Nicorandil produced a concentration-dependent relaxation of CC and Acc preparations. The relaxations obtained at the highest nicorandil concentration used (10(-4) M.) were 75 +/- 3% and 66 +/- 4% in CC preparations contracted by noradrenaline and endothelin-1, respectively. The corresponding effects in Acc preparations were 70 +/- 14% and 73 +/- 5%. Glibenclamide (blocking ATP-dependent K+ channels) significantly reduced the nicorandil-induced relaxation in CC, but not in Acc. Methylene blue (believed to block soluble guanylate cyclase) reduced nicorandil's relaxant effect in CC, although statistical significance was not obtained. NG-nitro-L-arginine 10(-4) M. (NO synthase inhibitor) did not significantly influence the effect of nicorandil on precontracted preparations in either tissue. In CC preparations contracted by electrical field stimulation, nicorandil and cromakalim concentration dependently inhibited the responses. This effect was significantly counteracted by glibenclamide. It is concluded that nicorandil is effective in relaxing human CC chiefly by its K+ channel opening action, and to some extent by its ability to release NO. For nicorandil's relaxing effect on Acc, ATP dependent K+ channels seem to be of limited importance. If effective in impotent patients, the drug may represent a new, interesting approach to the treatment of erectile dysfunction.
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PMID:Effects of nicorandil on human isolated corpus cavernosum and cavernous artery. 812 2

The importance of the nitric oxide--guanylate cyclase--cGMP system in modulating corporal smooth muscle tone and penile erection has been amply demonstrated. The goal of these studies was to evaluate the possibility that age- or disease-related alterations in human corporal smooth muscle responsivity to activation of this pathway might play a role in the etiology of erectile dysfunction. Thus, we utilized a previously described heuristic model to assess the kinetic and steady-state characteristics of relaxation of precontracted isolated corporal tissue strips elicited by nitroglycerine (NTG). Studies were conducted on corporal tissue strips excised from 26 patients with organic erectile dysfunction, and 7 patients with documented erections. For the purposes of statistical analysis the impotent patient population was stratified into two age groups (A, < or = 59 years; B, > or = 60 years) and further subdivided into two diagnostic categories, diabetic and nondiabetic patients, respectively. In approximately 75% of precontracted corporal tissue strips derived from impotent patients (contracted to approximately 75% of maximum with phenylephrine), the NTG-induced response was biphasic, consisting of a rapid relaxation response that reached steady state before onset of a more slowly developing regaining of tension, termed the desensitization response. In contrast, a biphasic response was observed much less frequently (approximately 30%) in corporal tissue strips derived from a potent patient population (p < 0.0001). Statistical analysis revealed significant heterogeneity among corporal tissue strips derived from patients with organic erectile dysfunction, with respect to both the kinetic and steady-state characteristics of the NTG-induced relaxation and desensitization responses. In particular, the maximal rate constant for both NTG-induced relaxation (krelmax; p < 0.01) and desensitization (kdes; p < 0.03) responses was significantly greater in corporal tissue strips excised from diabetic than nondiabetic patients. Furthermore, the EC50 for NTG-induced relaxation of precontracted corporal smooth muscle strips from potent patients (approximately 25 nM) was 0.90 log unit less than that for equivalently contracted corporal smooth muscle strips derived from impotent patients (approximately 180 nM; p < 0.03). Such observations suggest that alterations in corporal smooth muscle responsivity to activation of the guanylate cyclase--cGMP pathway, per se, may be a characteristic of organic erectile dysfunction. In the absence of compensatory changes in other vasodilatory mechanisms, this may contribute to incomplete corporal smooth muscle relaxation and the etiology of erectile dysfunction in some patients.
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PMID:Characterization of nitroglycerine-induced relaxation in human corpus cavernosum smooth muscle: implications to erectile physiology and dysfunction. 883 85

Herein we describe the use of intracavernous methylene blue (MB), a guanylate cyclase inhibitor, or internal pudendal artery embolization for the treatment of priapism. Eleven patients with priapism were treated from 1993-1996. Etiologies of priapism included PGE1/papaverine (3), trazodone (2), and sickle cell disease (1), in the other five cases the causes the cause was unknown. The average duration of priapism was 27 h for all patients (6-72 h). Five patients who failed intracavernous MB or an alpha-adrenergic agonist, underwent unilateral or bilateral pudendal artery embolization. The average duration of priapism for patients undergoing embolization was 43 h. Sixty-seven percent of the patients treated with MB responded with immediate detumescence. One-hundred percent of patients with priapism secondary to intracavernous injection therapy or trazodone responded. Of the five patients who underwent embolization, 40% achieved immediate pain relief and subsequent detumescence. The three non-responders exhibited a partial detumescence over 47-72 h. After follow-up of one year embolization available for only two patients revealed that one regained potency while the other remained impotent. These results confirmed that MB is effective for pharmacologically-induced priapism. Embolization is a less invasive option for refractory priapism, although results are less than satisfactory in men with priapism of several days duration.
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PMID:Alternative approaches to the management of priapism. 954 85

For erection to take place, the penile arteries and sinusoids have to dilate, thereby increasing the blood flow into the penis. There is increasing evidence that release of l-arginine derived nitric oxide (NO) from nonadrenergic-noncholinergic (NANC) nerves and from the sinusoidal endothelium is a major event in penile smooth muscle relaxation and promotes the endogenous formation of cyclic guanosine monophosphate (cGMP). Nitrovasodilators can be attributed to the activation of soluble guanylate cyclase, resulting in an increase in intracellular level of cyclic guanosine monophosphate, but prolonged exposure to high levels of nitroglycerine and other organic nitroesters induces tolerance against the cardiovascular effect. In this study, the aim was to determine the effect of diabetes on the corporal smooth muscle relaxant effect of ISDN and the effect of diabetes on the process of tolerance to the drug. For this purpose, alloxan-induced diabetic rabbits were used to form diabetes group. The responses of the corpus cavernous strips obtained from control and alloxan-induced diabetic rabbit were studied in organ chamber. In conclusion, prolonged in vitro exposure of corpus cavernosum strips obtained from control and diabetic groups to high concentrations of ISDN caused significant desensitization to the relaxant effect the drug. So, prolonged exposure of corporal tissue to the agents like nitroglycerine, used for treatment of impotence, may render ineffective the therapy in diabetic erectile impotence. However, intolerance to nitric oxide provides a rationale for the concept of using nitro oxide agents (like SNP) in the treatment of diabetic erectile dysfunction.
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PMID:Does diabetes mellitus affect the progress of tolerance to isosorbide dinitrate (ISDN) in corporal tissue? 1073 70

Nitric oxide (NO) as a mediator in smooth muscle cells causes rapid and robust increases in cGMP levels. The cGMP-dependent protein kinase I has emerged as an important signal transduction mediator for smooth muscle relaxation. The purpose of this study was to examine the existence and distribution of two key enzymes of the NO/cGMP pathway, the cGMP-dependent kinase I (cGK I) and the soluble guanylate cyclase (sGC) in human cavernosal tissue. The expression of the enzymes were examined in corpus cavernosum specimens of 23 patients. Eleven potent patients suffered from penile deviations and were treated via Nesbit's surgical method. Nine long-term impotent patients underwent implantation of flexible hydraulic prothesis. Three potent patients underwent trans-sexual operations. Expression of the sGC and cGK I were examined immunohistochemically using specific antibodies. In all specimens of cavernosal tissue a distinct immunoreactivity was observed in different parts and structures. We found a high expression of sGC and cGK I in smooth muscle cells of vessels and in the fibromuscular stroma. The endothelium of the cavernosal sinus, of the cavernosal arteries, and the cavernosal nerve fibers showed an immunoreactivity against sGC. The distribution analysis of cGK I revealed a predominately vesicular localization in smooth muscle cells. The examination of the endothelium showed no clear immunoreactivity against cGK I. There was no distinct difference in immunoreactivity and cellular distribution between potent and impotent patients.
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PMID:Soluble guanylate cyclase and cGMP-dependent protein kinase I expression in the human corpus cavernosum. 1104 9