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)

Mice with a genetic deletion of the atrial natriuretic peptide (ANP) receptor, guanylyl cyclase A (GC-A -/-), have chronic arterial hypertension and cardiac hypertrophy from the first day of life. To characterize the role of the angiotensin II and endothelin systems in the development of this cardiovascular phenotype, the effects of chronic treatment with either the angiotensin type I (AT1) receptor antagonist losartan or the endothelin A receptor antagonist BSF208075 were tested. Losartan almost completely reversed systemic arterial hypertension and left ventricular hypertrophy of GC-A -/- mice. This was accompanied by a marked regression of the left ventricular mRNA expression of cardiac hypertrophy markers such as ANP and brain natriuretic peptide and a significant reduction of left ventricular and pulmonary interstitial collagen accumulation. BSF208075 had no effect on any of these cardiovascular parameters. Intriguingly, GC-A -/- mice also showed a very marked right ventricular hypertrophy, which was not reversed by losartan or BSF208075 treatment. Analyses of components of the renin-angiotensin system (RAS) revealed an inhibition of renal and systemic RAS contrasting with increased local left ventricular angiotensin II levels in GC-A -/- mice. Collectively, the results suggest that RAS plays a more important role than the endothelin system in the pathogenesis of arterial hypertension as well as left ventricular hypertrophy and fibrosis in GC-A gene-disrupted mice.
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PMID:Left but not right cardiac hypertrophy in atrial natriuretic peptide receptor-deficient mice is prevented by angiotensin type 1 receptor antagonist losartan. 1240 81

Pulmonary hypertension (PH) secondary to left heart disease, classified as Group 2, is a widely underestimated target of therapy. Prevention and treatment of initial subclinical stages are not valued as a priority in the management of this chronic disease population, whereas attention is high for PH consequences in patients with advanced heart failure (HF) requiring a left ventricular mechanical assist device or heart transplant candidates. Even so, there is a growing interest toward the evidence of a clinical and prognostic role of PH in the elderly populations and in HF with preserved ejection fraction (HFpEF). Certainly, along with a prevalence definition not yet defined, the search for effective pharmacological approaches that might favorably affect the aging process and the natural history of HFpEF from earlier stages is not an easy task. Pharmacological studies that have tested some traditional pulmonary arterial hypertension approved drugs (i.e., prostanoids and endothelin-1 receptor blockers) primarily in PH and HF with reduced ejection fraction have not been positive, especially because of concomitant side effects, i.e., systemic hypotension, fluid retention and hepatic toxicity. In recent years, interest has moved toward drugs overexpressing the nitric oxide (NO)-cyclic guanosine monophosphate pathway with recent availability of well-tolerated selective pulmonary vasodilators, such as phosphodiesterase type 5 inhibitors and guanylate cyclase stimulators. Single center studies performed with these drugs have shown good tolerability and safety profile providing alternating hemodynamic results mainly because of recruitment of patients at different stages of the pulmonary vascular disease. Nonetheless, the overexpression of NO pathway appears to remain the most solid background for targeting lung microvessel dysfunction and treating RV dysfunction since the earliest stages of the disease.
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PMID:Group 2 PH: Medical Therapy. 2738 9