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Role of cGMP signals in
tetramethylpyrazine induced relaxation of the isolated rat aortic strip.
Tsai CC, Lai TY, Huang WC, Liu IM, Liou SS.
School of Post-Baccalaureate Chinese Medicine, China Medical University,
Taichung City, Taiwan 40402, ROC.
In the present study, role of guanosine-3',5'-cyclic monophosphate (cGMP) in the
vasodilatation of tetramethylpyrazine (TMP), one of the active ingredients of
the Chinese herb Chuang-xion, was investigated. We found that the TMP could
decrease the vascular tone of isolated rat aorta precontracted with
phenylephrine (10(-8) M) in a concentration-dependent manner from 10(-5) M to
10(-3) M. Also, the TMP-induced relaxation was reduced by
1H-(1,2,4)-oxadiazol-(4,3-a)-quinoxalin-1-one (ODQ) or methylene blue, the
inhibitor of soluble guanylyl cyclase. Moreover, the vasodilative response to
TMP was enhanced significantly in the presence of sildenafil, a well-known
inhibitor of phosphodiestrase type 5 that is sensitive to cGMP. In addition, TMP
could increase the cGMP level in the isolated aortic rings and TMP-induced
vasodilatation was deleted by cGMP-dependent protein kinases (PKG) blockade.
These results suggest that relaxation of rat aortic strip by TMP is induced in
the cGMP-dependent manner.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15894336&query_hl=1
Is laparoscopic unilateral
sural nerve grafting during radical prostatectomy effective in retaining sexual
potency?
Porpiglia F, Ragni F, Terrone C, Renard J, Musso F, Grande S, Cracco C,
Ghignone G, Scarpa RM.
Division of Urology, Department of Clinical and Biological Sciences, University
of Turin 'San Luigi' Hospital, Turin, Italy.
Associate Editor Michael G. Wyllie Editorial Board Ian Eardley, UK Jean Fourcroy,
USA Sidney Glina, Brazil Julia Heiman, USA Chris McMahon, Australia Bob Millar,
UK Alvaro Morales, Canada Michael Perelman, USA Marcel Waldinger, Netherlands
OBJECTIVES To present a pilot study of laparoscopic unilateral sural nerve
grafting during radical prostatectomy, with the aim of preserving sexual
potency. PATIENTS AND METHODS Because they had localized prostate cancer, 29 men
had a laparoscopic radical prostatectomy with deliberate wide unilateral
neurovascular bundle resection and preservation of the contralateral bundle.
Fifteen men (group A) had an interposition sural nerve graft on the sectioned
bundle, and 14 (group B) had laparoscopic radical prostatectomy with
preservation of the unilateral bundle only. The men were also involved in a
rehabilitation programme, and erectile function was evaluated after surgery, and
at 3, 8, 12 and 18 months, using the five-item version of the International
Index of Erectile Function (IIEF-5) questionnaire. RESULTS The two groups had
similar clinical characteristics (age, prostate-specific antigen level, body
mass index, prostate volume, clinical stage, Gleason score before and after
surgery, postoperative stage). The follow-up was complete for 12 men in group A
and 10 in group B. Group A had significantly higher erectile function scores on
the IIEF-5 at 12 and 18 months than immediately after surgery (P < 0.01),
whereas in group B the improvement was not statistically significant. Overall,
by 18 months after surgery five of 12 men in group A had achieved spontaneous
unassisted erection or erection assisted with sildenafil, while three of 10 in
group B achieved an erection assisted with sildenafil (not significant).
CONCLUSIONS These data suggests that laparoscopic sural nerve grafting during
radical prostatectomy is feasible and safe; nevertheless we cannot conclude that
sural nerve grafting is more effective than preserving the neurovascular bundle
alone in retaining sexual potency. More research is required to validate the
effectiveness of this technique.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15892814&query_hl=1
Phosphorylation of Serine 188 Protects RhoA from
Ubiquitin/Proteasome-Mediated Degradation in Vascular Smooth Muscle
Cells.
Rolli-Derkinderen M, Sauzeau V, Boyer L, Lemichez E,
Baron C, Henrion D, Loirand G, Pacaud P.
INSERM U-533, Faculte des
Sciences, Nantes, INSERM U-627, Faculte de Medecine, Nice and CNRS UMR 6188,
Faculte de Medecine, Angers, France.
cAMP and cyclic GMP-dependent
kinases phosphorylate the small G protein RhoA on Ser188. We have previously
demonstrated that phosphorylation of Ser188 inhibits RhoA-dependent functions
and positively regulates RhoA expression, and that the nitric oxide
(NO)/cGMP-dependent protein kinase (PKG) pathway plays an essential role, both
in vitro and in vivo, in the regulation of RhoA protein expression and functions
in vascular smooth muscle cells. Here we analyze the consequences of Ser188
phosphorylation on RhoA protein degradation. By expressing Ser188 phosphomimetic
wild-type (WT-RhoA-S188E) and active RhoA proteins (Q63L-RhoA-S188E), we show
that phosphorylation of Ser188 of RhoA protects RhoA, particularly its active
form, from ubiquitin-mediated proteasomal degradation. Coimmunoprecipitation
experiments indicate that the resistance of the phosphorylated active form of
RhoA to proteasome-mediated degradation is due to its cytoplasmic sequestration
through enhanced RhoGDI interaction. In rat aortic smooth muscle cells,
stimulation of PKG and inhibition of proteasome by lactacystin induce
nonadditive increases in RhoA protein expression. In addition, stimulation of
PKG leads to the accumulation of GTP-bound RhoA in the cytoplasm. In vivo
stimulation of the NO/PKG signaling by treating rats with sildenafil increased
RhoA level and RhoA phosphorylation, and enhanced its association to RhoGDI in
the pulmonary artery, whereas opposite effects are induced by chronic inhibition
of NO synthesis in N-omega -nitro-L-arginine-treated rats. Our results thus
suggest that Ser188 phosphorylation-mediated protection against degradation is a
physiological process regulating the level of endogenous RhoA and define a novel
function for RhoGDI, as an inhibitor of Rho protein degradation.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15890975&query_hl=1
Acute and chronic effects of sildenafil in patients with
pulmonary arterial hypertension.
Preston IR, Klinger JR, Houtches J, Nelson D, Farber HW, Hill NS.
Department of Pulmonary, Critical Care and Sleep, Tufts-New England Medical
Center, 750 Washington Street, Box #257, Boston, MA 0211, USA.
Sildenafil and inhaled nitric oxide (iNO) relax smooth muscle by inhibiting the
degradation and stimulating the production of cyclic guanosine monophosphate,
respectively. We compared the acute pulmonary vasodilator effects of sildenafil,
iNO, and epoprostenol and asked whether the combination of iNO with sildenafil
had additive pulmonary vasodilator effects. We assessed the effects of extended
use of sildenafil in a small cohort of patients. Twenty patients with pulmonary
arterial hypertension underwent an acute vasodilator trial with sildenafil (all
patients), iNO and iNO plus sildenafil (11), and epoprostenol (19). We also
provided sildenafil to patients who were ineligible for, or had clinical
deterioration on epoprostenol, treprostinil, or bosentan. Mean+/-se pulmonary
artery pressure dropped by 13+/-3%, 19+/-4%, 14+/-3%, and 26+/-4% with
epoprostenol, iNO, sildenafil, and iNO+sildenafil, respectively. Cardiac index
increased with epoprostenol and sildenafil. A correlation was found between the
effects of iNO and epoprostenol. Nine out of ten patients who were started on
long-term sildenafil treatment alone or in combination with other vasodilators
had symptomatic improvement. Three died of right heart failure. In conclusion,
sildenafil is a potent acute pulmonary vasodilator, an effect that is
potentiated by combination with iNO. Long-term therapy of pulmonary hypertension
with sildenafil alone or in combination with other agents appears to be safe and
well tolerated.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15890512&query_hl=1
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