Endothelin is a recently discovered vasoconstrictor peptide that is synthesized in certain vascular endothelial cells. We have identified the cardiovascular, renal, and hormonal responses that can be elicited in conscious dogs by intravenous administration of endothelin at rates of 10 and 30 ng.kg-1.min-1 for 60 min (0.24 and 0.72 nmol.kg-1/1-h infusion). Each dose of endothelin increased total peripheral resistance, arterial pressure, and left atrial pressure and decreased heart rate and cardiac output. Hematocrit increased by 4.8% (NS) and 22.9% (P less than 0.01) in response to the lower and higher infusion rates, respectively. Urinary sodium excretion, urine osmolality, and osmolar clearance decreased and free water clearance increased. The lower dose of endothelin decreased plasma norepinephrine and increased plasma atriopeptin. The higher dose increased plasma levels of vasopressin, renin, aldosterone, norepinephrine, epinephrine, and atriopeptin. The higher infusion rate of the peptide caused one or more brief vomiting episodes in four of five dogs. Although it is not yet known whether endothelin is a circulating hormone, it is clear that this peptide is capable of causing profound cardiovascular, renal, and endocrine alterations in conscious dogs. The possible relevance of these observations to physiological processes and to pathological conditions such as hypertension remains to be established.

Summary. Gas6 (encoded by growth arrest-specific gene 6) is a vitamin-K dependent protein highly homologous to coagulation protein S that is secreted from platelet a-granules and has recently been demonstrated to participate in platelet thrombus formation. The current study evaluated the contribution of each of the three known Gas6 receptors (Axl, Sky and Mer) in human and mouse platelet function. Flow cytometry analyses confirmed that all three receptors are present on both human and mouse platelets. Pre-incubation of human platelets with either an anti-Gas6 antibody or blocking antibodies to Sky or Mer inhibited platelet aggregation and degranulation responses to both ADP and the PAR-1 activating peptide, SFLLRN, by more than 80%. In contrast, a stimulatory anti-Axl antibody increased activation responses to these agonists, suggesting a potentiating role for Gas6 in platelet activation. Moreover, in a mouse model of thrombosis, administration of Gas6 or Sky blocking antibodies resulted in a decrease in thrombus weight similar to clopidogrel but, unlike clopidogrel, produced no increase in template bleeding. Thus, Gas6 enhances platelet degranulation and aggregation responses through its known receptors, promoting platelet activation and mediating thrombus formation such that its inhibition prevents thrombosis without increasing bleeding.

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The effects of atrial distension on plasma atrial natriuretic factor and renal salt and water excretion were studied in normal dogs and in cardiac-denervated dogs. In five conscious normal dogs, elevation of left atrial pressure (7.8 Torr) consistently increased plasma concentrations of radioimmunoassayable atrial natriuretic factor (riANF), urine flow, and sodium excretion. Elevation of right atrial pressure (3.5 Torr) in the same five dogs also consistently increased riANF, but sodium excretion and urine flow did not increase. In four conscious cardiac-denervated dogs, elevation of left atrial pressure (9.2 Torr) consistently increased riANF, but urine flow and sodium excretion did not increase. Because atrial distension increased plasma riANF in each of the three types of experiments, but urine flow and sodium excretion increased in only one type, we conclude that atrial natriuretic peptides are not responsible for the diuretic and natriuretic responses elicited by left atrial distension. It is conceivable, of course, that atrial peptides released during atrial distension may act synergistically with other changes evoked by atrial distension and thereby contribute to the natriuresis elicited by left atrial stretch. However, the increase in plasma riANF during atrial distension appears to be incapable of independently increasing salt and water excretion in the conscious dog.