Oxygen-mediated pulmonary vasodilation and plasma levels of endothelin-1, atrial natriuretic peptide and cyclic GMP in patients with left-to-right shunt and pulmonary hypertension

Cyclic GMP (cGMP) dependent vasodilating agents (natriuretic peptides, nitric oxide) inhibit secretion of endothelin-1 (ET-1) in cultured endothelial cells. However, in circulatory conditions associated with acute hypotension, a marked increase in plasma ET-1 has repeatedly been observed. Therefore, after administration of cGMP-dependent agents in hypotensive dose, the net effect of these opposing influences on ET-1 release may shed light on the mechanisms determining circulating levels of this peptide. We have studied the effect of a hypotensive dose of atrial natriuretic peptide (n = 16), 8-Br-cGMP (n = 5), and papaverin (n = 7) on plasma ET-1 in anesthetized dogs. All agents produced marked increases in the peptide level at the end of infusion (178, 280, and 240% of the last preinfusion level, respectively) and a mean arterial blood pressure (MAP) decrease of 19, 18, and 42 mmHg (1 mmHg = 133.3 Pa), respectively. In all three protocols, plasma ET-1 continued to rise when the hypotensive agent was discontinued and remained elevated for 2–3 h postinfusion, even though MAP was normalized. There was a close positive correlation between the maximal increment in plasma ET-1 and the maximal decrease in MAP (r = 0.67, p < 0.001). These results show that acute hypotension due to directly acting vasodilators is a potent stimulus for systemic release of ET-1, even when due to agents known to inhibit ET-1 production in cultured endothelial cells. The discrepancy between the previous in vitro data and the present in vivo data can be explained either by non-endothelial origin of circulating ET-1, at least during acute hypotension, or by substantial differences in the production of ET-1 in the intact organism as opposed to endothelial cells in culture.Key words: endothelin secretion, big endothelin, atrial natriuretic peptide, cyclic GMP, papaverin.

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Renal and Hormonal Effects of Chronic Inhibition of Neutral Endopeptidase (EC 3.4.24.11) in Normal Man

Clinical Science ◽

10.1042/cs0850019 ◽

1993 ◽

Vol 85 (1) ◽

pp. 19-26 ◽

Cited By ~ 18

Author(s):

Janice E. O'Connell ◽

Alan G. Jardine ◽

David L. Davies ◽

James McQueen ◽

John M. C. Connell

Keyword(s):

Angiotensin Ii ◽

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Active Treatment ◽

Cyclic Gmp ◽

Plasma Levels ◽

Neutral Endopeptidase ◽

Active Therapy ◽

Days Of Therapy ◽

Atrial Natriuretic

1. Acute pharmacological inhibition of the enzyme neutral endopeptidase (EC 3.4.24.11), which cleaves the cardiac hormone atrial natriuretic peptide, raises endogenous levels of the hormone. Short-term administration of inhibitors causes natriuresis and diuresis in normal and hypertensive subjects; we report here the effects of an orally active neutral endopeptidase inhibitor (candoxatril, 200 mg) given twice daily for 10 days to normal salt-replete male subjects (n = 12) in a placebo-controlled cross-over study. 2. Candoxatril administration caused a transient natriuresis on day 1 of treatment, but this was not sustained, and cumulative sodium excretion at the end of the study was not altered by active therapy [1720 ± 40 versus 1734 ± 57 (placebo) mmol; means ± SEM]; exchangeable body sodium content was similarly unchanged. However, urinary cyclic GMP excretion was elevated throughout the active treatment phase when compared with placebo. 3. Although a change in plasma levels of atrial natriuretic peptide could not be demonstrated, platelet atrial natriuretic peptide binding sites were reduced by active treatment [23 ± 3 versus 39 ± 4 (placebo) fmol/109; P <0.001]. 4. Basal blood pressure and heart rate were not affected by candoxatril treatment. After 10 days of therapy subjects were given incremental infusions of angiotensin II (2, 4 and 8 ng min−1 kg−1) followed by phenylephrine. Although active therapy had not altered basal plasma concentrations of active renin and angiotensin II, levels of angiotensin II during infusion of the octapeptide were higher during the active phase. The diastolic pressor response to angiotensin II was increased during candoxatril treatment, although this is likely to reflect the higher plasma levels of angiotensin II during infusion of the octapeptide. In contrast, the systolic and diastolic pressor responses to phenylephrine were reduced by active treatment. 5. In conclusion, chronic candoxatril administration increases urinary cyclic GMP excretion without causing sustained natriuresis; evidence of atrial natriuretic peptide receptor down regulation was seen. There were no sustained hormonal or haemodynamic changes during therapy. The increased levels of angiotensin II during its infusion in the presence of candoxatril may reflect the role of neutral endopeptidase in clearing angiotensin II from the circulation.

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