ABSTRACT
The field of natriuretic peptides (NPs) as an endocrine hormone has been developing since 1979. There are three peptides in humans: atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which bind to the guanylyl cyclase-A (GC-A) receptor (also called natriuretic peptide receptor-A (NPR-A)), and C-type natriuretic peptide (CNP), which binds to the GC-B receptor (also called the NPR-B) and then synthesizes intracellular cGMP. GC-A receptor stimulation has natriuretic, vasodilatory, cardiorenal protective and anti-renin-angiotensin-aldosterone system actions, and GC-B receptor stimulation can suppress myocardial fibrosis and can activate bone growth before epiphyseal plate closure. These physiological effects are useful as therapeutics for some disease states, such as heart failure, hypertension, and dwarfism. To optimize the therapeutics for each disease state, we must consider drug metabolism, delivery systems, and target receptor(s). We review the cardiac NP system; new designer NPs, such as modified/combined NPs and modified peptides that can bind to not only NP receptors but receptors for other systems; and oral drugs that enhance endogenous NP activity. Finally, we discuss prospective drug discoveries and the development of novel NP therapeutics.
Subject(s)
Aortic Aneurysm/diagnosis , Aortic Dissection/diagnosis , Hematoma/diagnosis , Pulmonary Artery , Aortic Dissection/complications , Aortic Dissection/diagnostic imaging , Aortic Aneurysm/complications , Aortic Aneurysm/diagnostic imaging , Back Pain/etiology , Diagnosis, Differential , Hematoma/complications , Hematoma/diagnostic imaging , Humans , Male , Middle Aged , Tomography, X-Ray ComputedABSTRACT
The mechanism for noradrenaline (NA)-induced increases in intracellular Ca(2+) concentration ([Ca(2+)](i)) and physiological significance of Na(+) influx through receptor-operated channels (ROCs) and store-operated channels (SOCs) were studied in Chinese hamster ovary (CHO) cells stably expressing human alpha(1A)-adrenoceptor (alpha(1A)-AR). [Ca(2+)](i) was measured using the Ca(2+) indicator fura-2. NA (1 microM) elicited transient and subsequent sustained [Ca(2+)](i) increases, which were inhibited by YM-254890 (G(alphaq/11) inhibitor), U-73122 (phospholipase C (PLC) inhibitor), and bisindolylmaleimide I (protein kinase C (PKC) inhibitor), suggesting their dependence on G(alphaq/11)/PLC/PKC. Both phases were suppressed by extracellular Ca(2+) removal, SK&F 96365 (inhibitor of SOC and nonselective cation channel type-2 (NSCC-2)), LOE 908 (inhibitor of NSCC-1 and NSCC-2), and La(3+) (inhibitor of transient receptor potential canonical (TRPC) channel). Reduction of extracellular Na(+) and pretreatment with KB-R7943, a Na(+)/Ca(2+) exchanger (NCX) inhibitor, inhibited both phases of [Ca(2+)](i) increases. These results suggest that 1) stimulation of alpha(1A)-AR with NA elicits the transient and sustained increases in [Ca(2+)](i) mediated through NSCC-2 that belongs to a TRPC family; 2) Na(+) influx through these channels drives NCX in the reverse mode, causing Ca(2+) influx in exchange for Na(+) efflux; and 3) the G(alphaq/11)/PLC/PKC-dependent pathway plays an important role in the increases in [Ca(2+)](i).
