Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm
Impairment of the nitric oxide/soluble guanylate cyclase (NO)/sGC) signalling cascade is associated with many forms of cardiovascular disease, resulting not only in compromised vasodilatation but also loss of anti-aggregatory homeostasis. Myocardial ischaemia, heart failure, and atrial fibrillation...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-05-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/11/9273 |
| _version_ | 1797597464105058304 |
|---|---|
| author | Armin Muminovic Yuliy Y. Chirkov John D. Horowitz |
| author_facet | Armin Muminovic Yuliy Y. Chirkov John D. Horowitz |
| author_sort | Armin Muminovic |
| collection | DOAJ |
| description | Impairment of the nitric oxide/soluble guanylate cyclase (NO)/sGC) signalling cascade is associated with many forms of cardiovascular disease, resulting not only in compromised vasodilatation but also loss of anti-aggregatory homeostasis. Myocardial ischaemia, heart failure, and atrial fibrillation are associated with moderate impairment of NO/sGC signalling, and we have recently demonstrated that coronary artery spasm (CAS) is engendered by severe impairment of platelet NO/sGC activity resulting in combined platelet and vascular endothelial damage. We therefore sought to determine whether sGC stimulators or activators might normalise NO/sGC homeostasis in platelets. ADP-induced platelet aggregation and its inhibition by the NO donor sodium nitroprusside (SNP), the sGC stimulator riociguat (RIO), and the sCG activator cinaciguat (CINA) alone or in addition to SNP were quantitated. Three groups of individuals were compared: normal subjects (<i>n</i> = 9), patients (Group 1) with myocardial ischaemia, heart failure and/or atrial fibrillation (<i>n</i> = 30), and patients (Group 2) in the chronic stage of CAS (<i>n</i> = 16). As expected, responses to SNP were impaired (<i>p</i> = 0.02) in patients versus normal subjects, with Group 2 patients most severely affected (<i>p</i> = 0.005). RIO alone exerted no anti-aggregatory effects but potentiated responses to SNP to a similar extent irrespective of baseline SNP response. CINA exerted only intrinsic anti-aggregatory effects, but the extent of these varied directly (r = 0.54; <i>p</i> = 0.0009) with individual responses to SNP. Thus, both RIO and CINA tend to normalise anti-aggregatory function in patients in whom NO/sGC signalling is impaired. The anti-aggregatory effects of RIO consist entirely of potentiation of NO, which is not selective of platelet NO resistance. However, the intrinsic anti-aggregatory effects of CINA are most marked in individuals with initially normal NO/sGC signalling, and thus their magnitude is at variance with extent of physiological impairment. These data suggest that RIO and other sGC stimulators should be evaluated for clinical utility in both prophylaxis and treatment of CAS. |
| first_indexed | 2024-03-11T03:05:29Z |
| format | Article |
| id | doaj.art-392322b12e254db7891c61b31af9d34e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T03:05:29Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-392322b12e254db7891c61b31af9d34e2023-11-18T07:56:47ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012411927310.3390/ijms24119273Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery SpasmArmin Muminovic0Yuliy Y. Chirkov1John D. Horowitz2Basil Hetzel Institute for Translational Research, University of Adelaide, 37a Woodville Road, Adelaide, SA 5011, AustraliaBasil Hetzel Institute for Translational Research, University of Adelaide, 37a Woodville Road, Adelaide, SA 5011, AustraliaBasil Hetzel Institute for Translational Research, University of Adelaide, 37a Woodville Road, Adelaide, SA 5011, AustraliaImpairment of the nitric oxide/soluble guanylate cyclase (NO)/sGC) signalling cascade is associated with many forms of cardiovascular disease, resulting not only in compromised vasodilatation but also loss of anti-aggregatory homeostasis. Myocardial ischaemia, heart failure, and atrial fibrillation are associated with moderate impairment of NO/sGC signalling, and we have recently demonstrated that coronary artery spasm (CAS) is engendered by severe impairment of platelet NO/sGC activity resulting in combined platelet and vascular endothelial damage. We therefore sought to determine whether sGC stimulators or activators might normalise NO/sGC homeostasis in platelets. ADP-induced platelet aggregation and its inhibition by the NO donor sodium nitroprusside (SNP), the sGC stimulator riociguat (RIO), and the sCG activator cinaciguat (CINA) alone or in addition to SNP were quantitated. Three groups of individuals were compared: normal subjects (<i>n</i> = 9), patients (Group 1) with myocardial ischaemia, heart failure and/or atrial fibrillation (<i>n</i> = 30), and patients (Group 2) in the chronic stage of CAS (<i>n</i> = 16). As expected, responses to SNP were impaired (<i>p</i> = 0.02) in patients versus normal subjects, with Group 2 patients most severely affected (<i>p</i> = 0.005). RIO alone exerted no anti-aggregatory effects but potentiated responses to SNP to a similar extent irrespective of baseline SNP response. CINA exerted only intrinsic anti-aggregatory effects, but the extent of these varied directly (r = 0.54; <i>p</i> = 0.0009) with individual responses to SNP. Thus, both RIO and CINA tend to normalise anti-aggregatory function in patients in whom NO/sGC signalling is impaired. The anti-aggregatory effects of RIO consist entirely of potentiation of NO, which is not selective of platelet NO resistance. However, the intrinsic anti-aggregatory effects of CINA are most marked in individuals with initially normal NO/sGC signalling, and thus their magnitude is at variance with extent of physiological impairment. These data suggest that RIO and other sGC stimulators should be evaluated for clinical utility in both prophylaxis and treatment of CAS.https://www.mdpi.com/1422-0067/24/11/9273nitric oxidesoluble guanylate cyclaseriociguatcinaciguatplatelet aggregationcoronary artery spasm |
| spellingShingle | Armin Muminovic Yuliy Y. Chirkov John D. Horowitz Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm International Journal of Molecular Sciences nitric oxide soluble guanylate cyclase riociguat cinaciguat platelet aggregation coronary artery spasm |
| title | Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm |
| title_full | Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm |
| title_fullStr | Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm |
| title_full_unstemmed | Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm |
| title_short | Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm |
| title_sort | effects of soluble guanylate cyclase stimulators and activators on anti aggregatory signalling in patients with coronary artery spasm |
| topic | nitric oxide soluble guanylate cyclase riociguat cinaciguat platelet aggregation coronary artery spasm |
| url | https://www.mdpi.com/1422-0067/24/11/9273 |
| work_keys_str_mv | AT arminmuminovic effectsofsolubleguanylatecyclasestimulatorsandactivatorsonantiaggregatorysignallinginpatientswithcoronaryarteryspasm AT yuliyychirkov effectsofsolubleguanylatecyclasestimulatorsandactivatorsonantiaggregatorysignallinginpatientswithcoronaryarteryspasm AT johndhorowitz effectsofsolubleguanylatecyclasestimulatorsandactivatorsonantiaggregatorysignallinginpatientswithcoronaryarteryspasm |