| 1. |
- Asplund Persson, Anna, 1966-, et al.
(författare)
-
Cross-talk between adenosine and the oxatriazole derivative GEA 3175 in platelets
- 2005
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 517:3, s. 149-157
-
Tidskriftsartikel (refereegranskat)abstract
- We examined the interplay between adenosine and the nitric oxide (NO)-containing oxatriazole derivative GEA 3175 in human platelets. The importance of cyclic guanosine 3′5′-monophosphate (cGMP)-inhibited phosphodiesterases (PDEs) was elucidated by treating the platelets with adenosine combined with either GEA 3175 or the PDE3-inhibitor milrinone. The drug combinations provoked similar cyclic adenosine 3′5′-monophosphate (cAMP) responses. On the contrary, cGMP levels were increased only in GEA 3175-treated platelets. Both drug combinations reduced P-selectin exposure, platelet adhesion and fibrinogen-binding. However, adenosine together with GEA 3175 was more effective in inhibiting platelet aggregation and ATP release. Thrombin-induced rises in cytosolic Ca2+ were suppressed by the two drug combinations. Adenosine administered with GEA 3175 was, however, more effective in reducing Ca2+ influx.In conclusion, the interaction between adenosine and GEA 3175 involves cGMP-mediated inhibition of PDE3. The results also imply that inhibition of Ca2+ influx represent another cGMP-specific mechanism that enhances the effect of adenosine.
|
|
| 2. |
- Asplund Persson, Anna, 1966-, et al.
(författare)
-
Dual actions of dephostatin on the nitric oxide/cGMP-signalling pathway in porcine iliac arteries
- 2005
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 521:1-3, s. 124-132
-
Tidskriftsartikel (refereegranskat)abstract
- We examined the effects of the nitrosoamine dephostatin on the nitric oxide (NO)/cyclic guanosine 3′,5′-monophosphate (cGMP)-signalling in porcine iliac arteries. Dephostatin has been characterised as a tyrosine phosphatase inhibitor, but Western blot analyses showed that dephostatin did not augment tyrosine phosphorylation of arterial proteins. However, dephostatin relaxed pre-contracted arteries, and this effect was antagonised by the soluble guanylyl cyclase inhibitor 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Furthermore, dephostatin increased the cGMP content and the serine phosphorylation of vasodilator-stimulated phosphoprotein. Dephostatin also inhibited the relaxation induced by acetylcholine and the NO-donor S-nitroso-N-acetyl-penicillamine (SNAP). In contrast, dephostatin did not affect the NO-dependent actions of 1,2,3,4-Oxatriazolium, 3-(3-chloro-2-metylphenyl)-5-[[(4methylphenyl)sulfonyl]amino]-hydroxide inner salt (GEA 3175). Measurement of NO revealed that dephostatin accelerated the consumption of NO. In conclusion, dephostatin exerts dual effects on the NO/cGMP-signalling pathway in iliac arteries. The drug actions included scavenging of NO, but also stimulation of cGMP production. These effects were not related to inhibition of tyrosine phosphatases.
|
|
| 3. |
- Asplund Persson, Anna, 1966-
(författare)
-
Pharmacological evaluation of the NO/cGMP signalling system
- 2005
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Platelet activation and inhibition are tightly balanced processes, regulated by various endogenous molecules. In this regard, the endothelium plays a key role in mediating inhibition of platelets by releasing nitric oxide (NO) and cAMP-elevating prostaglandins.The present study put emphasis on drugs that activate directly or modulate the NO/cGMP signalling pathway.The specific aims were i) to compare two different NO-containing compounds; namely the S-nitrosothiol SNAP and the oxatriazole derivative GEA 3175; ii) to evaluate the mechanism of drug action of the nitrosoamine dephostatin; iii) to investigate cross-talk mechanisms between the NO/cGMP and the cAMP signalling pathways. These studies were perfom1ed using human blood platelets and iliac arteries obtained from pigs.The present data revealed that SNAP but not GEA 3175 released detectable amounts of NO. Despite that, both compounds elevated cGMP, inhibited rises in [Ca2+]i and stimulated phosphorylation of vasodilator stimulated phosphoprotein (VASP). Moreover, the results showed that NO/cGMP-induced inhibition of Ca2+ responses, but not NO/cGMP-mediated V ASP phosphorylation, was rapidly desensitised. The results showed that an unstable NO-donor more effectively induced desensitisation.Dephostatin, originally characterised as a protein tyrosine phosphatase (PTP) inhibitor, was found to modulate the NO/cGMP signalling in a complex way. More specifically, dephostatin is an effective NO-scavenger and surprisingly, it also serves as a source of NO and thereby induces cGMPmediated vasorelaxation. In platelets, dephostatin abolished NO/cGMP-mediated inhibition of cytosolic Ca2+, but augmented NO/cGMP-induced VASP phosphorylation.cGMP-induced inhibition of type 3 phosphodiesterases (PDE3) enhanced adenosine-mediated inhibition of platelets. This effect was of main importance for the suppression of several platelet responses. However, inhibition of Ca2+ influx was another cGMP-specific mechanism contributing to a powerful inhibition of the platelets.In conclusion: The present results show that release of NO from drug molecules is not a prerequisite for NO/cGMP-mediated cellular and intracellular responses. On the contrary, drug stability in terms of NO-release appears to be crucial in platelet desensitisation to NO. Therefore it is important to gain more knowledge about the NO/cGMP-signalling pathway regarding future drug design of NO-containing drugs. The findings presented in this thesis suggest that dephostatin can prove to be a very useful tool in this area of research.
|
|
| 4. |
- Persson Asplund, Robert, et al.
(författare)
-
Experiences of internet-delivered and work-focused cognitive behavioral therapy for stress : A qualitative study
- 2019
-
Ingår i: Internet Interventions. - : Elsevier BV. - 2214-7829. ; 18
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Stress is one of the major challenges of modern society, causing significant costs and personal problems. In the recent decade a growing body of research has provided support for the efficacy of internet interventions for stress. However, few studies have focused on how participants experience internet interventions for stress.Method: The current study was a qualitative follow-up study of an internet-delivered and work-focused cognitive behavioral treatment for stress. The aim was to capture participants' experiences of the treatment and their views on effects on health and well-being. Participants were selected from a controlled study (n = 27), using a criterion-based sampling approach selecting those participants who had completed all treatment modules. Nine semi-structured interviews were held, and the material was analyzed using Thematic Analysis.Results: The results indicated that most of the participants experienced positive effects on their mental health and well-being in both life and at work. All participants emphasized the importance of having access to therapist support. In line with previous research, participants found the intervention to be extensive and demanding and expressed the need for extended treatment time and therapist support.Conclusions: Considering the limitations of the present study, future research could examine the feasibility of reducing the length of each session, extending deadlines and increasing therapist support. This could improve treatment efficacy and further enhance utilization in the target population.
|
|
| 5. |
- Støen, R., et al.
(författare)
-
Relative significance of the nitric oxide (NO)/cGMP pathway and K+ channel activation in endothelium-dependent vasodilation in the femoral artery of developing piglets
- 2001
-
Ingår i: Acta Physiologica Scandinavica. - 0001-6772 .- 1365-201X. ; 171:1, s. 29-35
-
Tidskriftsartikel (refereegranskat)abstract
- Mechanisms mediating endothelium-dependent vasodilation were investigated in femoral artery rings from <2-day-old (newborn) and 2-week-old piglets. Based on previous results we hypothesized an age difference in the relative contribution of nitric oxide(NO)-cyclic 3′,5′-guanosine monophosphate (cGMP) and K+ channel-activation to acetylcholine (ACh)-induced vasodilation. Changes in vascular tone were studied in organ baths in the absence or presence of NO synthase(NOS) inhibition or K+ channel blockade and the intra-arterial accumulation of cGMP in response to ACh was measured with radioimmunoassay (RIA). In control experiments, relaxant responses to ACh were equal in the two age groups. In the presence of the NOS-inhibitors N G-monomethyl-L-arginine acetate (L-NMMA; 100 μM) or NG-nitro-L-arginine (L-NOARG; 1–100 μM), however, relaxation was significantly more reduced in femoral artery rings from 2-week-old than from newborn, with lower pD2 values in the older age group. Inhibition of large (BKCa) conductance calcium-sensitive K+ channels with tetraethylammonium chloride (TEA; 1 mM), gave a significant rightward shift in the concentration-response curves to ACh which was of the same magnitude in both age groups. The ACh-induced vasodilation was abolished in both age groups by high K+ (20 mM) in combination with L-NOARG (100 μM). The relative increase in cGMP levels after addition of ACh (10 nM) was significantly larger in rings from newborn compared with 2-week-old piglets (12- vs. four-fold). In summary, sensitivity to NOS inhibition increased with age while the effect of K+ channel blockade with TEA was the same in femoral artery rings from newborn to 2-week-old piglets. Lower sensitivity to NOS inhibition and a larger increase in cGMP in response to ACh could indicate a higher efficacy of the NO/cGMP pathway in this vessel in the newborn piglet.
|
|
