Release of cyclic guanosine monophosphate evaluated as a diagnostic tool in cardiac diseases

Abstract

Concentrations of atrial natriuretic peptide (ANP) are increased in plasma of patients with impaired cardiac and renal function. The second messenger of ANP, cyclic guanosine monophosphate (cGMP), is released into the plasma specifically upon stimulation of cells with ANP. Although nitrates can also activate intracellular cGMP synthesis, we detected no increase in plasma cGMP concentrations after infusions of glycerol trinitrate. Because immunoreactive ANP is highly susceptible to degradation and nonspecific influences in blood samples, determinations of ANP require immediate centrifugation and storage of plasma at -20 degrees C. In contrast, we found that cGMP is stable for five days in vitro in blood samples containing EDTA. In 147 healthy blood donors, the upper cutoff value for plasma cGMP was 6.60 nmol/L, not significantly different (P greater than 0.05) from that for 222 patients with disorders other than cardiovascular and renal. In 69 patients with manifest congestive heart failure (NYHA stages II-IV), 65 had increased cGMP values. Using the above cutoff value for cGMP gave diagnostic sensitivity of 94.2% and specificity of 93.7%. Plasma cGMP may thus provide an alternative for routine clinical measurements of ANP in cardiac diseases in the absence of renal disorders.

In vivo evidence of enhanced guanylyl cyclase activation during the hyperdynamic circulation of acute liver failure

“…The decline in peripheral resistance is unlikely an exclusive result of the activation of the particulate isoform of the GC, as we stated above. This conclusion is supported by the fact that infusion of ANP in human subjects does not induce such a long-lasting increase in cardiac output and severe decline in SVR as reported in our patients with acute liver failure (17)(18)(19). In addition, it seems unlikely that enhanced GC activity may be ascribed to high circulating concentrations of LPS in our patients, as shown in animals (20), because patients with documented hyperkmetic gram-negative sepsis and heartloading conditions, similar to patients with FLF, have significantly higher cGMP levels than do patients with acute hepatocellular failure.…”

“…High ANP levels may also have affected the plasma cGMP concentrations we report. Some support for this : : I is provided by clinical studies in patients with congestive heart failure (17). However, we were unable to demonstrate significant changes in ANP concentrations between the period of acute liver failure and the postoperative period.…”

“…On first consideration, it might seem that these results would support the view that acute liver failure induces cGMP production or occurs together with enhanced cGMP release. In other clinical situations, such findings have been taken as good evidence of increased GC activation (10,17). However, the plasma concentration of cGMP depends on its rates of production and elimination from the circulation, and it is likely that in our patients at least one of these factors is altered.…”

M‐Atrial Natriuretic Peptide and Nitroglycerin in a Canine Model of Experimental Acute Hypertensive Heart Failure: Differential Actions of 2 cGMP Activating Therapeutics

“…16,41,42 These results underscore the physiological compartmentalization of the cGMP linked to either sGC or pGC cGMP signaling with differing cellular actions. [5][6][7][8][9][10]12,13 An additional finding was that M-ANP antagonized aldosterone activation despite continuous Ang II infusion. Most recently in a model of aldosterone-mediated glomerular injury, the GC-A receptor at the level of the glomerulus protected the glomerulus from structural remodeling 43 underscoring an important potential action of M-ANP if given long-term.…”

“…5,6 Furthermore, while both sGC and pGC activation results in the accumulation of cGMP within cells, pGC activation (in contrast to sGC) also results in significant release of cGMP into the extracellular space and circulation. [7][8][9][10][11] Therefore, while both sGC and pGC increase intracellular cGMP, the resulting biological actions are quite different. 4,12,13 Cyclic GMP therapies are currently employed in the treatment of heart failure (HF).…”