The different NO stimulated and ODQ inhibited cNMP patterns

The different NO-stimulated and ODQ-inhibited cNMP patterns in terms of absolute and relative magnitude and time course reported herein suggest distinct functional roles of cGMP, cCMP and cUMP. Therefore, it will be necessary to dissect cellular effects of these cNMPs in numerous cell systems. For this formidable task, the application of membrane-permeant acetoxymethylesters of cNMPs [28] and label-free sensor techniques [29] are feasible approaches. For chemical reasons, the more commonly used butyrate ester approach cannot be applied to cUMP [10], [30]. Noteworthy in this context is the fact that cGMP-independent effects of sGC have been reported before [31], [32], [33], but it is unknown whether cCMP and/or cUMP are involved in these effects. In conclusion, this study unambiguously demonstrated the presence of cCMP and cUMP in intact cultured mammalian cells using HPLC–MS/TOF. sGC generates cCMP and cUMP not only in vitro but also in intact cells. An implication of our data is that Mn2+ is a physiological cofactor for sGC. Our data provide first hints for distinct cellular functions of cGMP, cCMP and cUMP and we have discussed some future directions of research in this exciting new field of signal transduction.
Acknowledgments We thank Mrs. Annette Garbe for expert technical assistance and Dr. Ulrich Förstermann (University of Mainz, Germany) for providing RFL-6 cells. This work was supported by grants of the Deutsche Forschungsgemeinschaft to R.S.
Despite advances in surgical techniques and perioperative management, spasm of arterial grafts is still a clinical problem, and refractory spasm can be lethal . The natriuretic peptides play an important role in cardiovascular homeostasis. The 28-amino Cobicistat atrial natriuretic peptide and 32-amino acid B-type natriuretic peptide are secreted from the heart in response to cardiac stretch and stress. By activating particulate guanylyl cyclase, they exert their pleiotropic actions including natriuresis, vasodilation, suppression of renin, angiotensin II, and aldosterone as well as antihypertrophic, antifibrotic, vascular regenerative, and cytoprotective properties , , . Cardiorenal protective effects of administering exogenous atrial natriuretic peptide (approved in Japan as carperitide) has been reported in various cardiovascular disease states , . Because of these properties, it is expected that carperitide would be beneficial in prophylaxis of graft spasm. However, it has not been reported with regard to the vasorelaxants action of carperitide in the human arterial grafts such as internal thoracic artery (ITA) and gastroepiploic artery (GEA). The present study was designed to examine the inhibitory effects of carperitide on vasoconstriction induced by phenylephrine, prostaglandin F2α, and endothelin-1 in the human ITA and GEA. Patients and Methods
Results
Comment This study has three main findings. First, carperitide produced a concentration-related, endothelium-independent relaxation in ITA and GEA grafts contracted with various vasoconstrictors including KCl, phenylephrine, prostaglandin F2α, and endothelin-1. Second, pretreatment with carperitide significantly attenuated subsequent contractions induced by these vasoconstrictors. Third, carperitide produced more cGMP than nitroglycerin at the same concentration (10−7 M) in ITA and GEA segments contracted with KCl or prostaglandin F2α. The precise mechanism of vascular spasm is still unclear, but it is considered as an extreme form of vasoconstriction and to occur as a result of mechanical or nerve stimulation, endothelial dysfunction, or hypothermia [12], as well as through the action of vasoconstrictor substances (spasmogens) including endothelin-1, prostaglandins, α-adrenoceptor agonists, platelet-derived substances, and the cellular membrane-depolarizing agent potassium, mast cells, and histamine, as well as vasoactive products derived from perivascular adipose tissue. The present study included some of these spasmogens in the experimental protocol and showed that carperitide fully relaxed the arteries precontracted by various vasoconstrictors and also had a potent inhibitory effect on the vasoconstriction mediated by different vasoconstrictors, indicating that the use of carperitide in patients during and after coronary artery bypass graft surgery is favored for the prevention and reversal of graft spasm.