Role of endothelin receptor subtypes in the in vivo regulation of renal function.

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.

Biological actions of brain natriuretic peptide in thoracic inferior vena caval constriction.

Brain natriuretic peptide (BNP) shares structural and functional similarities to atrial natriuretic peptide (ANP). Although BNP and ANP interact with the same biologically active guanylate cyclase-coupled receptor, recent reports conflict with regard to the biological actions of exogenous BNP in sodium-retaining and edematous states. We studied the biological actions of BNP in normal dogs (n = 5) and sodium-avid dogs with chronic thoracic inferior vena caval constriction (TIVCC) (n = 6). In normal dogs BNP increased glomerular filtration rate, renal blood flow, and urinary sodium excretion and decreased proximal and distal fractional reabsorption of sodium with activation of urinary guanosine 3',5'-cyclic monophosphate (cGMP). These renal actions occurred in association with marked hypotensive actions and activation of systemic cGMP. In TIVCC, a state characterized by chronic reductions of cardiac output, avid sodium retention, edema, and activation of the renin-angiotensin-aldosterone system (RAAS), the renal actions of BNP were absent in association with marked attenuation of the urinary cGMP response. In contrast, an enhanced hypotensive response with preserved activation of systemic cGMP was observed. In neither normal dogs nor TIVCC dogs did BNP inhibit the RAAS. These studies report that BNP is a potent vasoactive and natriuretic peptide with potent proximal and distal tubular actions in normal dogs. These studies also demonstrate that in TIVCC, a model of low cardiac output and congestive failure that results in marked sodium retention with edema in which there is activation of the RAAS, the renal actions of BNP are attenuated while the vasoactive actions are enhanced.

Biological role for the endothelin-A receptor in aortic cross-clamping.

The current study was undertaken to define a biological role for the endothelin-A receptor in a clinically relevant model of altered systemic and renal function produced by suprarenal aortic cross-clamping. This model is associated with profound systemic and renal vasoconstriction, acute renal failure, and a significant increase in circulating endothelin. Studies were performed in three groups of anesthetized mongrel dogs. Group 1 (n = 5) underwent aortic cross-clamping for 1 hour; group 2 (n = 5) underwent aortic cross-clamping for 1 hour in the presence of BQ-123, a specific antagonist of the endothelin-A receptor; group 3 (n = 4) received BQ-123 alone. The marked systemic and renal vasoconstriction associated with aortic cross-clamping in group 1 was markedly attenuated in group 2 in the presence of BQ-123. Unlike the vasoconstrictor response, BQ-123 did not attenuate the decrease in glomerular filtration rate associated with this model. Under unstimulated conditions in group 3, BQ-123 had no actions on systemic or renal hemodynamics. In conclusion, the current study demonstrates that the systemic and renal vasoconstriction associated with aortic cross-clamping are in part mediated through the interaction of endothelin and the endothelin-A receptor. This study demonstrates the functional importance of increased endogenous endothelin in the regulation of vascular tone in this pathophysiological state.

C-type natriuretic peptide: a selective cardiovascular peptide.

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.

Presence of C-type natriuretic peptide in cultured human endothelial cells and plasma.

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.

C-type natriuretic peptide immunoreactivity in human breast vascular endothelial cells.

The present study was undertaken to determine the presence of CNP immunoreactivity in human breast tissue (n = 9). Immunohistochemical staining of breast tissue revealed the presence of CNP immunoreactivity localized to vascular endothelial cells. This study demonstrates for the first time that CNP immunoreactivity is present in humans. Based upon the knows biological actions of CNP, these findings suggest that CNP may function as part of an endothelium-derived vasoregulatory system.

Endothelin in a model of acute ischemic renal dysfunction: modulating action of atrial natriuretic factor.

This study was undertaken to investigate circulating endothelin (ET) and associated renal hemodynamics in the acute ischemic renal dysfunction associated with suprarenal aortic cross-clamping (ACC) in the presence and absence of prostaglandin inhibition in the anesthetized dog. Second, the modulating action of exogenous atrial natriuretic factor (ANF) was also investigated. In Group I (ACC; N = 6), ACC was performed in the absence of prostaglandin inhibition. No change in mean arterial pressure, GFR, RBF, renal vascular resistance, or ET was noted 2 h after reperfusion when compared with baseline values. In the presence of prostaglandin inhibition with indomethacin (10 mg/kg iv) (Group II, ACC + INDO; N = 10), an increase in plasma ET was first noted to be elevated above baseline ET in Group I as well as during and 2 h after ACC in association with a reduction in GFR, marked renal vasoconstriction, and a sustained increase in arterial pressure. To evaluate the role of the kidney in this increase in ET, another group (Group III, ACC + INDO + NEPH; N = 6) was investigated in the presence of prostaglandin inhibition, and bilateral renal artery clamping was performed 30 min before ACC and maintained throughout the protocol to simulate nephrectomy. In this group, plasma ET concentrations did not increase during ACC. Because ANF may antagonize the renal actions of ET in vivo and may suppress ET release in vitro, the action of ANF upon GFR and plasma ET was evaluated in Group IV (ACC + INDO + ANF; N = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular and renal actions of C-type natriuretic peptide.

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.