Molecular mechanisms of nitric oxide modulation of calcium-activated potassium channels in smooth muscle [ 2001 - 2003 ]

Research Grant

Researchers: Dr Richard Lang (Principal investigator) ,  Dr Craig Neylon

Brief description The inappropriate production of nitric oxide (NO) is increasingly being linked to the pathogenesis of numerous disease states such as septic shock, hypoxic-ischaemic brain damage, anti-microbial defense and inflammation. In mammalian visceral smooth muscle organs, the release of NO plays an essential role in the processes that underlie the endothelial-dependent relaxation of vascular smooth muscle, as well as the relaxation of many smooth muscles evoked upon stimulation of intrinsic non-adrenergic non-cholinergic (NANC) inhibitory motor nerves. It is becoming clear that the inappropriate release of NO may also contribute to a number of disorders of visceral organs. In fact, NO donors and NO synthesis blockers are presently being tested in >15 NIH sponsored clinical trials of treatments of such disparate diseases as acute myocardial infarction, endothelial dysfunction during atherosclerosis or coronary heart disease, aspiration syndrome or persistent pulmonary hypertension in infants, and hormone therapy in postmenopausal women. This project represents a unique international collaboration of Drs Lang (Monash Uni.) and Neylon (Baker Inst.) with Dr Reinhart (Duke Uni.)(Neylon et al 1999). We intend to establish the precise site and mechanisms of action of NO on both naturally occurring and artificially reconstructed K channels obtained from intestinal and vascular smooth muscle. These experiments will for the first time establish the molecular site of NO action on the K channels that set the membrane potential and excitability of smooth muscle. This specific knowledge may well lead to a rational development of drugs that specifically restore smooth muscle function in a number of disorders such as slow gastric emptying and slow transit constipation.

Funding Amount $AUD 411,622.54

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant