The present study was undertaken to investigate the presence of C-type natriuretic peptide (CNP) immunoreactivity in cultured human vascular endothelial cells and in human plasma. CNP immunoreactivity was present in cultured human aortic endothelial cells by both immunohistochemical staining and by radioimmunoassay. With the utilization of gel permeation chromatography, this immunoreactivity proved to be consistent with the higher molecular weight CNP-53. CNP immunoreactivity was also present in human plasma (n = 22) at low picogram concentrations (6.5 +/- 0.2 pg/ml) by specific radioimmunoassay. This immunoreactivity was consistent with the lower molecular weight CNP-22 by gel permeation chromatography. These findings suggest that the vascular endothelium may be the site of CNP production. The isolation of different molecular forms of CNP in tissue and plasma may be consistent with a storage form of the peptide in endothelial cells CNP-53, while CNP-22 circulates in plasma. In summary, the present study is consistent with CNP being a peptide of endothelial cell origin.

Studies were performed in three groups of anesthetized dogs to compare the structurally related peptides atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP). Group 1 (n = 5) and group 2 (n = 4) received intravenous infusions of CNP or ANP respectively at doses of 10 ng.kg-1.min-1 and 100 ng.kg-1.min-1. Group 3 (n = 5) received CNP intrarenally at doses of 1 ng.kg-1.min-1 and 5 ng.kg-1.min-1. Intravenous infusion of CNP resulted in a greater decrease in blood pressure when compared with ANP. This marked decrease in blood pressure observed with CNP was associated with a significantly smaller increase in guanosine 3',5'-cyclic monophosphate (cGMP). In contrast, neither intravenous nor intrarenal administration of CNP was associated with natriuresis as observed with ANP. The current study also demonstrates the presence of CNP immunoreactivity in canine plasma at low picomolar concentrations. Further characterization by gel permeation chromatography demonstrated that circulating CNP immunoreactivity corresponds to the 22-amino acid form of the peptide. In conclusion, this study demonstrates that CNP circulates in low picomolar concentrations and is potently vasoactive in vivo, suggesting a potential role in the regulation of vascular tone.

Studies were performed in two groups of anesthetized dogs (n = 5 per group) to determine the cardiovascular and renal actions of synthetic C-type natriuretic peptide (CNP). Systemic infusion of CNP (group 1; 10 and 50 ng.kg-1.min-1 iv) resulted in marked cardiovascular hemodynamic effects characterized by a decrease in mean arterial pressure, cardiac output, and atrial pressures in association with a decrease in sodium excretion. Bolus administration of CNP (group 2; 5 micrograms/kg iv) to minimize cardiovascular hemodynamic changes resulted in only a transient decrease in arterial pressure. Sodium excretion decreased despite a return of arterial pressure to baseline. These biological responses were associated with increases in plasma guanosine 3',5'-cyclic monophosphate (cGMP) in both groups but with no change in urinary cGMP. With both systemic infusion or bolus administration of CNP, significant increases in plasma aldosterone were observed in association with increases in distal nephron sodium reabsorption. This study demonstrates that CNP exhibits profound systemic hemodynamic actions and is indirectly, or perhaps directly, antinatriuretic.

Endothelin (ET) is a potent vasoconstrictor peptide of endothelial origin, which at low doses results in renal vasoconstriction and diuresis with variable actions on sodium excretion. The current study conducted in four groups of anesthetized dogs was designed to define the role of the ETA and ETB receptor subtypes in the renal actions of low-dose exogenous ET. Group 1 (n = 4) animals served as time controls. In group 2 (n = 6) a systemic ET-1 (5 ng.kg-1.min-1) infusion mediated renal vasoconstriction, antinatriuresis with increases in proximal fractional reabsorption of sodium, and diuresis with a decrease in urine osmolality. In group 3 (n = 6) intrarenal BQ-123 (4 micrograms.kg-1.min-1), a selective ETA antagonist, abolished the systemic ET-1-mediated changes in renal hemodynamics and unmasked a natriuretic action at the level of the proximal tubule. In contrast, the diuretic response of ET was not altered by BQ-123. In group 4 (n = 6) intrarenal sarafotoxin 6-c, a selective ETB receptor agonist, resulted in a diuretic response without a change in sodium excretion. These studies suggest that the ETA receptor contributes to the renal vasoconstriction, whereas the ETB receptor is largely responsible for the diuretic response during exogenous ET. This study also suggests that at low doses ET is natriuretic in vivo by decreasing proximal tubular reabsorption of sodium independent of ETA or ETB receptor activation.

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