Exp Clin Endocrinol Diabetes 2000; Vol. 108(3): 214-219
DOI: 10.1055/s-2000-7745
Articles

© Johann Ambrosius Barth

Effect of four cGMP analogues with different mechanisms of action on hormone release by porcine ovarian granulosa cells in vitro

A. V. Sirotkin 1 , A. V. Makarevich 1 , H.-G. Genieser 2 , J. Kotwica 3 , L. Hetényi 1
  • 1 Research Institute of Animal Production, 94992 Nitra, Slovakia
  • 2 BIOLOG Life Science Institute, 28071 Bremen, Germany
  • 3 Institute of Animal Production and Food Research, 10-718 Olsztyn-Kortowo, Poland
Further Information

Publication History

Publication Date:
31 December 2000 (online)

Summary:

The aim of our in-vitro experiments was to examine the role of cGMP-dependent intracellular mechanisms in control of ovarian hormone secretion, as well as to understand, whether cGMP effect on the ovary may be mediated by either protein kinase G (PKG), cGMP-gated ion channels (CGI) or cGMP-specific phosphodiesterases (PDE).

We compared the effects of the cGMP analogues 8-pCPT-cGMP, an activator of PKG 1-alpha, 1-beta and type II and of CGI, but not of PDE; Rp-8-pCPT-cGMPS and Rp-8-Br-cGMPS, inhibitors of PKG, stimulators of CGI with no effect of PDE, and Rp-8-Br-PET-cGMPS, an inhibitor of both, PKG and CGI and stimulator of PDE (all at 0.01, 0.1, 1, 10 or 100 nM), on the release of oxytocin (OT) and progesterone (P) by cultured porcine granulosa cells.

It was observed, that Rp-8-pCPT-cGMPS significantly (p < 0.05) suppressed OT release when given at 1 or 10 nM. Rp-8-Br-cGMPS increased OT output, when given at 1-10 nM too, but decreased it at 100 nM. Rp-8-Br-PET-cGMPS inhibited OT release at 1 nM. No influence of 8-pCPT-cGMP on OT output was found. 8-pCPT-cGMP stimulated P release at 0.1, 10 or 100 nM. All other cGMP analogues studied suppressed P release at all doses used.

The present observations suggest the involvement of cGMP-dependent intracellular mechanisms in control of ovarian steroid and nonapeptide hormone release. The lack of association between patterns of influence of cGMP analogues on CGI and PDE, and the coincidence of the majority of effects of cGMP analogues on P, OT and PKG may indirectly indicate that cGMP action on release of ovarian hormones is mediated mainly by PKG, but not by CGI or PDE.

References

  • 1 Brunswick-Spickenheier B, Mukhopadhyay A K. Stimulation of nitric oxide-cyclic guanosine monophosphate pathway in bovine ovarian theca cells by tumor necrosis factor alpha. Is this pathway implicated in the TNF alpha-induced inhibition of luteinizing hormone-stimulated prorenin production?.  Biol Reprod. 57 700-706 1997; 
  • 2 Butt E, Nolte C, Schulz S, Beltman J, Beavo J, Jastorff B, Walter U. Analysis of the functional role of cGMP-dependent protein kinase in intact human platelets using a specific activator 8-pCPT-cGMP.  Biochem Pharmacol. 43 2591-2600 1992; 
  • 3 Butt E, Poehler D, Genieser H-G, Higgins J P, Bucher B. Inhibition of cyclic cGMP-dependent protein kinase-mediated effects by (Rp)-8-bromo-PET-cyclic GMPS.  Brit J Pharmacol. 116 3110-3116 1995; 
  • 4 Chun S Y, Eisenhauer K M, Minami S, Billig H, Perlas E, Hsueh A J. Hormonal regulation of apoptosis in early antral follicles: follicle-stimulating hormone as a major survival factor.  Endocrinology. 137 1447-1456 1996; 
  • 5 Danisova A, Scsukova S, Matulova L, Orlicky J, Kolena J. Role of calcium in luteinization stimulator-enhanced progesterone production of porcone granulosa cells.  Physiol Res. 44 185-192 1995; 
  • 6 Houslay M D, Milligan G. Tailoring cAMP signalling responses through isoform multiplicity.  Trends Biochem Sci. 22 217-224 1997; 
  • 7 Hsueh A J, Eisenhauer K, Chun S Y, Hsu S Y, Billig H. Gonadal cell apoptosis.  Recent Progr Horm Res. 51 433-455 1996; 
  • 8 Kaipia A, Hsueh A JW. Regulation of ovarian follicle atresia.  Annu Rev Physiol. 59 349-363 1997; 
  • 9 Kotwica J, Skarzynski D. Influence of oxytocin removal from the corpus luteum on secretory function and duration of the estrous cycle in cattle.  J Reprod Fertil. 97 411-417 1993; 
  • 10 Kramer R H, Tibbs G R. Antagonists of cyclic nucleotide-gated channels and molecular mapping of their site of action.  J Neurosci. 16 1285-1293 1996; 
  • 11 LaPolt P S, Hong L S. Inhibitory effects of superoxide dismutase and cyclic guanosine 3′5′-monophosphate on estrogen production by cultured rat granulosa cells.  Endocrinology. 136 5533-5539 1995; 
  • 12 Lincoln T M, Kamalavilas P, Boerth N J, MacMillan-Crow L A, Cornwell T L. cGMP signaling through cAMP- and cGMP-dependent protein kinases.  Adv Pharmacol. 34 305-322 1995; 
  • 13 Martinez S P, Franchi A M, Viggiano J M, Herrero M B, Gimeno M. Effect of prostaglandin F2-alpha (PGF) on oviductal nitric oxide synthase (NOS) activity: possible role of endogenous NO on PGF-induced contractions in rat oviduct.  Prostagland & Other Lipid Mediat. 56 155-166 1998; 
  • 14 Masuda M, Kubota T, Karnada S, Aso T. Nitric oxide inhibits steroidogenesis in cultured porcine granulosa cells.  Molec Human Reprod. 3 285-292 1997; 
  • 15 McGee E, Spears A, Minami S, Hsu S Y, Chun S Y, Billig H, Hsueh A J. Preantral ovarian follicles in serum-free culture: suppression of apoptosis after activation of the cyclic guanosine 3′5′-monophosphate pathway and stimulation of growth and differentiation by follicle-stimulating hormone.  Endocrinology. 138 2417-2424 1997; 
  • 16 Nitray J, Sirotkin A V, Rafay J. Effect of FSH, LH, LH-RH and arginine-vasotocin on the production of steroids, nonapeptide hormones and cGMP by rabbit granulosa cells isolated at different stages of reproductive cycle.  Endocr Regulat. 26 95-99 1992; 
  • 17 Pandey K N, Osteen K G, Inagami T. Specific receptor-mediated stimulation of progesterone secretion and cGMP accumulation by rat atrial natriuretic factor in cultured human granulosa-lutein (G-L) cells.  Endocrinology. 121 1195-1197 1987; 
  • 18 Perry M J, Higgs G A. Chemotherapeutic potential of phosphodiesterase inhibitors.  Curr Opinion Chem Biol. 2 472-481 1998; 
  • 19 Sirotkin A V, Nitray J. Steroid hormones regulate cAMP and cGMP production by porcine granulosa cells in vitro.  J Steroid Biochem Molec Biol. 46 573-577 1993; 
  • 20 Sirotkin A V. A direct influence of melatonin on steroid, nonapeptide hormones and cyclic nucleotide secretion by granulosa cells isolated from porcine ovaries.  J Pineal Res. 17 112-117 1994; 
  • 21 Sirotkin A V, Nitray J. Growth hormone and prolactin affect oxytocin, vasopressin, progesterone and cyclic nucleotide secretion by bovine granulosa cells in vitro.  J Endocrinol. 143 417-422 1994; 
  • 22 Sirotkin A V, Nitray J, Kolena J, Bulla J. Cooperation between LH-RH and LH in the direct action on the ovary: LH-RH stimulation of LH/hCG receptors, basal and LH-induced cAMP and cGMP release by porcine granulosa cells in vitro.  Cell Signalling. 6 135-140 1994; 
  • 23 Sirotkin A V, Mlyncek J, Laurincik J, Bulla J, Hetenyi L. The ability of steroid hormones to control cAMP and cGMP production by human granulosa cells in culture.  Cell Signalling. 7 61-65 1995; 
  • 24 Sirotkin A V. Inter-relationships between nonapeptide hormones and cyclic nucleotides within cultured porcine granulosa cells.  J Endocrinol. 150 343-348 1996; 
  • 25 Sirotkin A, Schaeffer H-J, Mlyncek M, Missik J, Bulla J. Oxytocin affect the release of steroids, insulin-like growth factor-I, prostaglandin F2 and cyclic nucleotides by human granulosa cells in vitro.  Human Reprod. 11 152-155 1996; 
  • 26 Sirotkin A V, Makarevich A V, Kotwica J, Marnet P-G, Kwon H B, Hetenyi L. Isolated porcine ovarian follicles as a model for the study of hormone and growth factor action on ovarian secretory activity.  J Endocrinol. 159 313-321 1998; 
  • 27 Tabraue C, Penate R D, Gallardo G, Hernandez I, Quintana J, Blanco F L, Reyes J G, Fangjul L F, Degalarreta G MR. Induction of guanosine triphosphate-cyclohydrolase by follicle-stimulating hormone enhances interleukin-1 beta-stimulated nitric oxide synthase activity in granulosa cells.  Endocrinology. 138 162-168 1997; 
  • 28 Thomas M K, Francis S H, Beebe S J, Gettys T W, Corbin J D. Partial mapping of cyclic nucleotide sites and studies of regulatory mechanisms of phosphodiesterases using cyclic nucleotide analogues.  Adv Second Messenger and Phosphoprotein Res. 25 45-53 1992; 
  • 29 Van Voorhis B J, Dunn M S, Snyder G D, Weiner C P. Nitric oxide: an autocrine regulator of human granulosa-luteal cell steroidogenesis.  Endocrinology. 135 1799-1806 1994; 
  • 30 Wathes D C. Oxytocin and vasopressin in the gonads.  Oxford Rev Reprod Biol. 11 226-283 1989; 
  • 31 Wei J-Y, Cohen E D, Yan Y-Y, Genieser H-G, Barnstable C J. Identification of competitive antagonists of the rod photoreceptor cGMP-gated cation channel: PET-substituted cGMP analogues as probes of the cGMP-binding site.  Biochemistry. 35 16815-16823 1996; 
  • 32 Wei J-Y, Cohen E D, Genieser H-G, Barnstable C J. Substituted cGMP analogs can act as selective agonists of the rod photoreceptor cGMP-gated cation channel.  J Molec Neurosci. 10 53-64 1998; 
  • 33 Wyne K L, Schreiber J R, Larsen A L, Getz G S. Regulation of apolipoprotein E biosynthesis by cAMP and phorbol ester in rat ovarian granulosa cells.  J Biol Chem. 264 981-989 1989; 
  • 34 Yallampali Ch, Byam-Smith M, Nelson S O, Garfield R E. Steroid hormones modulate the production of nitric oxide and cGMP in the rat uterus.  Endocrinology. 134 1971-1974 1994; 

1 + - stimulation, - - inhibition, ± - biphasic effect, 0 - no effect

Dr. Alexander V. Sirotkin

Head, Lab. Endocrinology

Research Institute of Animal Production

Hlohovská 2

SK-94992 Nitra

Slovak Republic

Phone: +4 21-87-54 63 35

Fax: +4 21-87-54 63 61

Email: sirotkin@vuzv.sk