Abstract
Cellular levels of cyclic GMP (cGMP) are tightly controlled by synthetic and degradative mechanisms. Pharmacological manipulation of these processes (e.g. soluble guanylate cyclase stimulators and phosphodiesterase 5 inhibitors) augments cGMP-dependent signalling and is beneficial in treating cardiovascular disease (eg. pulmonary hypertension). An additional mechanism potentially important in the inactivation of cGMP is cellular extrusion, driven by a family of multidrug resistance proteins (MRPs). Herein, we investigated if MRPs modulate vascular reactivity, smooth muscle cell proliferation, and systemic hemodynamics. The functional reactivity of murine aortic rings and proliferation of human pulmonary artery smooth muscle cells (PASMC) were determined in the absence and presence of the MRP inhibitor MK571. Hemodynamic changes in vivo in response to MK571 were analysed acutely by bolus dosing and chronically by radiotelemetry. MK571 (1nM-50µM) caused a concentration-dependent relaxation of mouse aortic r...
Highlights
Cellular levels of cyclic GMP are tightly controlled by synthetic and degradative mechanisms
We investigated if inhibition of multidrug resistance proteins (MRPs) modulates vascular reactivity, smooth muscle cell proliferation, and systemic hemodynamics
MK571 (0.001-10mg/kg; i.v.) elicited an acute, dosedependent hypotensive activity and when delivered via the drinking water caused a more sustained drop in mean arterial pressure (~5 mmHg). These data suggest that extrusion by MRPs contributes to the dynamic equilibrium regulating intracellular levels of cyclic GMP (cGMP), and may represent a further target amenable to drug intervention for the treatment of cardiovascular disease
Summary
Investigation of the role of multidrug resistance proteins (MRPs) in vascular homeostasis. Robert M H Allen*, Aniruthan Renukanthan, Kristen J Bubb, Inmaculada C Villar, Amie J Moyes, Reshma S Baliga, Adrian J Hobbs. From 7th International Conference on cGMP Generators, Effectors and Therapeutic Implications Trier, Germany. From 7th International Conference on cGMP Generators, Effectors and Therapeutic Implications Trier, Germany. 19-21 June 2015
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