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 ischemic-reperfused myocardium, myocardial cells are jeopardized not only by reoxygenation-induced hypercontracture but also by the development of a transsarcolemmal osmotic gradient. Here the question of whether osmotic fragility of cardiomyocytes can be reduced by interventions during reoxygenation was addressed. Isolated ventricular cardiomyocytes (from adult rats), exposed to 120 min of hypoxia and subsequent reoxygenation, were used as model. With reoxygenation, medium osmolarity was reduced from 270 to 80 mosM. Loss of sarcolemmal integrity was characterized by enzyme loss from cells (creatine kinase and lactate dehydrogenase). Cardiomyocytes reoxygenated after 120 min of hypoxia hypercontracted, but enhanced enzyme loss was observed only at 80 mosM. The nitric oxide (NO) donors 3-morpholinosydnonimine (10 mM), sodium nitroprusside (10 mM), S-nitroso-N-acetyl-DL-penicillamine (100 microM), and the antilipid peroxidant diphenylphenylenediamine (DPPD, 2.5 microM) reduced enzyme loss with hyposmolar reoxygenation. Agents activating guanosine 3',5'-cyclic monophosphate (cGMP)-dependent pathways [atrial natriuretic peptide (1 microM), urodilatin (1 microM), and 8-bromo-cGMP (10 mM)], the contractile inhibitor 2,3-butanedione monoxime (10 mM), and the SIN-1 metabolite SIN-1C (10 mM) did not protect cardiomyocytes against osmotic fragility. The results show that increased osmotic fragility of isolated adult rat cardiomyocytes can be prevented at the time of reoxygenation by NO donors and DPPD in a cGMP-independent way.
We measured concentrations of guanosine 3',5'-monophosphate (cGMP) in plasma and urine of healthy subjects and patients with congestive heart failure, renal impairment, neoplastic disease, and hepatic cirrhosis. There was no correlation between cGMP concentrations in urine and in plasma. In all patients except those with renal impairment, urinary cGMP concentrations were significantly higher than in healthy persons. Only patients with heart failure or renal impairment showed significantly increased plasma cGMP concentrations. In contrast, cGMP in urine does not relate to the clinically assessed severity of heart failure (New York Heart Association functional classes). Determination of cGMP in plasma results in higher sensitivity and specificity for diagnosing heart failure than measurement of cGMP in urine.
Measurement of plasma cGMP concentrations 30 minutes after ergometric exercise testing allows better discrimination between healthy subjects and patients with symptomless left ventricular dysfunction or mild heart failure (NYHA class I) than measurement of such concentrations before exercise.
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