Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Raising the frequency and intensity of stimulation to one of two sets of parallel fibre synaptic inputs to cerebellar Purkinje cells results in a localised calcium influx and a long-term depression (LTD) of parallel fibre-Purkinje cell responses. Although the calcium influx remains spatially constrained, depression spreads heterosynaptically to distant sites. Inhibition of the synthetic enzyme for cGMP, guanylate cyclase, did not significantly affect the overall level of calcium-dependent synaptic depression observed at the site of raised stimulation (test site), but it entirely prevented synaptic depression at the distant (control) site. Inhibition of protein kinase G produced identical results. In contrast, protein kinase A inhibition had no effect. Selective inhibition of either metabotropic glutamate receptors (mGluRs), protein kinase C (PKC) or tyrosine protein kinase (PTK) blocked depression at both sites equally effectively. These data reveal that two, inter-dependent cellular pathways capable of inducing cerebellar LTD exist. The levels of PF stimulation required to induce heterosynaptic depression were similar to those used routinely in more widely accepted models of LTD. The data predict that cerebellar long-term depression will not be input specific at the single cell level under those conditions of PF-activation that give rise to NO/cGMP production.
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PMID:Receptors, second messengers and protein kinases required for heterosynaptic cerebellar long-term depression. 1107 81

Pulmonary arterial hypertension is a progressive and debilitating disorder with an associated high morbidity and mortality rate. Significant advances in our understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary hypertension have occurred over the past several decades. This has allowed the development of new therapeutic options in this disease. Today, our selection of therapeutic modalities is broader, including calcium channel blockers, prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, and soluble guanylate cyclase stimulators, but the disease remains fatal. This underscores the need for a continued search for novel therapies. Several potential pharmacologic agents for the treatment of pulmonary arterial hypertension are under clinical development and some promising results with these treatments have been reported. These agents include rho-kinase inhibitors, long-acting nonprostanoid prostacyclin receptor agonists, tyrosine protein kinase inhibitors, endothelial nitric oxide synthase couplers, synthetically produced vasoactive intestinal peptide, antagonists of the 5-HT2 receptors, and others. This article will review several of these promising new therapies and will discuss the current evidence regarding their potential benefit in pulmonary arterial hypertension.
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PMID:Existing drugs and agents under investigation for pulmonary arterial hypertension. 2509 1

Pulmonary arterial hypertension (PAH) is a vascular disorder associated with high morbidity and mortality rate and is characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, ultimately resulting in right ventricular failure and death. Over the past few decades, significant advances in the understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary arterial hypertension have occured. This has led to the development of disease specific treatment including prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, and soluble guanylate cyclase stimulators. These therapies significantly improve exercise capacity, quality of life, pulmonary hemodynamics, but none of the current treatments are actually curative and long-term prognosis remains poor. Thus, there is a clear need to develop new therapies. Several potential pharmacologic agents for the treatment of pulmonary arterial hypertension are under clinical development and some promising results with these treatments have been reported. These agents include tyrosine protein kinase inhibitors, rho-kinase inhibitors, synthetically produced vasoactive intestinal peptide, antagonists of the 5-HT2 receptors, and others. This article will review several of these promising new therapies and will discuss the current evidence regarding their potential benefit in pulmonary arterial hypertension.
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PMID:Pulmonary arterial hypertension specific therapy: The old and the new. 3241 72