Article date: August 1995
By: Leonor Sterin‐Borda, Agustina Vila Echagüe, Claudia Perez Leiros, Ana Genaro, Enri Borda, in Volume 115, Issue 8, pages 1525-1531
In this paper we have determined the different signalling pathways involved in muscarinic acetylcholine receptor (AChR)‐dependent inhibition of contractility in rat isolated atria.
Carbachol stimulation of M2 muscarinic AChRs exerts a negative inotropic response, activation of phosphoinositide turnover, stimulation of nitric oxide synthase and increased production of cyclic GMP.
Inhibitors of phospholipase C, protein kinase C, calcium/calmodulin, nitric oxide synthase and guanylate cyclase, shifted the dose‐response curve of carbachol on contractility to the right. These inhibitors also attenuated the muscarinic receptor‐dependent increase in cyclic GMP and activation of nitric oxide synthase. In addition, sodium nitroprusside, isosorbide, or 8‐bromo cyclic GMP, induced a negative inotropic effect, increased cyclic GMP and activated nitric oxide synthase.
These results suggest that carbachol activation of M2 AChRs, exerts a negative inotropic effect associated with increased production of nitric oxide and cyclic GMP. The mechanism appears to occur secondarily to stimulation of phosphoinositides turnover via phospholipase C activation. This in turn, triggers cascade reactions involving calcium/calmodulin and protein kinase C, leading to activation of nitric oxide synthase and soluble guanylate cyclase.
In this paper we have determined the different signalling pathways involved in muscarinic acetylcholine receptor (AChR)‐dependent inhibition of contractility in rat isolated atria.
Carbachol stimulation of M2 muscarinic AChRs exerts a negative inotropic response, activation of phosphoinositide turnover, stimulation of nitric oxide synthase and increased production of cyclic GMP.
Inhibitors of phospholipase C, protein kinase C, calcium/calmodulin, nitric oxide synthase and guanylate cyclase, shifted the dose‐response curve of carbachol on contractility to the right. These inhibitors also attenuated the muscarinic receptor‐dependent increase in cyclic GMP and activation of nitric oxide synthase. In addition, sodium nitroprusside, isosorbide, or 8‐bromo cyclic GMP, induced a negative inotropic effect, increased cyclic GMP and activated nitric oxide synthase.
These results suggest that carbachol activation of M2 AChRs, exerts a negative inotropic effect associated with increased production of nitric oxide and cyclic GMP. The mechanism appears to occur secondarily to stimulation of phosphoinositides turnover via phospholipase C activation. This in turn, triggers cascade reactions involving calcium/calmodulin and protein kinase C, leading to activation of nitric oxide synthase and soluble guanylate cyclase.
DOI: 10.1111/j.1476-5381.1995.tb16646.x
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