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.

The effects of alpha-human atrial natriuretic peptide (alpha-hANP) on cardiovascular and renal function in conscious dogs were evaluated in two experimental protocols. In one protocol, alpha-hANP was infused intravenously at increasing rates of 50, 100, and 200 ng.min-1.kg-1 (stepup infusion) during successive 20-min periods. The greatest responses occurred during the final 20-min period of the stepup infusion when the plasma concentration of immunoreactive atrial natriuretic peptide (irANP) was increased by 44-fold over preinfusion values; pressures in the aorta and both atria were decreased at this time, whereas glomerular filtration rate, urine flow, and sodium excretion were increased. In a second protocol, alpha-hANP was infused for 1 h at constant rates of either 12.5, 25, or 50 ng.min-1.kg-1; these constant infusions increased plasma irANP by 3-, 7-, and 12-fold, respectively. Each infusion rate decreased left and right atrial pressures and increased urine flow and sodium excretion. The two lowest infusion rates elevated plasma irANP to levels that would be expected to occur only during unusual physiological, or perhaps pathophysiological, conditions. The two highest infusion rates decreased plasma renin activity. Nevertheless, the accompanying maximal increases in sodium excretion were modest (41-72%). These data imply that small changes in circulating atrial peptides that presumably occur under normal physiological conditions would not have a dominant effect on the regulation of sodium excretion; the peptides may, however, play a modulatory role on sodium excretion under these conditions. It remains to be determined whether the ability of atrial peptides to lower cardiac filling pressures is of physiological significance.

The hypothesis that the weak natriuretic effect elicited by modest amounts of atrial peptide is mediated via the inhibition of renin and aldosterone was evaluated in the conscious dog. The formation of angiotensin II (ANG II) and the effects of aldosterone (Aldo) were blocked acutely by enalaprilat and canrenoate, respectively. Infusion of alpha-human atrial natriuretic peptide (alpha-hANP) for 2 h at 25 ng.kg-1.min-1 increased plasma atrial peptide concentration 7- to 10-fold. In control experiments, i.e., experiments without ANG II-Aldo blockade, infusion of atrial peptide doubled urine volume (UV) from 0.21 +/- 0.01 to 0.43 +/- 0.09 ml/min and sodium excretion (UNaV) from 18 +/- 5 to 37 +/- 7 mueq/min; mean arterial blood pressure (AP) and atrial pressures decreased, whereas total peripheral resistance increased. The induction of ANG II-Aldo blockade elevated UNaV and UV 10- and 6-fold, respectively, and decreased AP. The subsequent 2-h infusion of atrial peptide elicited a further increase in UNaV (from 195 +/- 28 to 334 +/- 60 mueq/min); the hemodynamic changes were similar to those seen in the absence of ANG II-Aldo blockade, except that AP did not decrease significantly during the administration of atrial peptide. The data demonstrate that pharmacological inhibition of the effects of converting enzyme and Aldo does not impede the natriuretic response elicited by a 7- to 10-fold increase in circulating atrial peptide; in fact, the magnitude of the natriuresis is markedly enhanced during this blockade.

In the conscious dog, left atrial distension elicits a composite response that modulates both cardiovascular and renal function. The response to atrial distension may be mediated by the combined effects of neural reflexes and the release of atriopeptin. To assess the relative contributions of atrial reflex mechanisms and circulating atriopeptin to the renal response elicited by atrial distension, alpha-human atrial natriuretic peptide (alpha-hANP) was infused into conscious dogs at 50 ng.kg-1.min-1 for 60 min. Then the infusion was stopped abruptly, and left atrial pressure was increased 8 mmHg by inflating a balloon positioned above the mitral valve. Plasma atriopeptin decreased during the 40-min period of atrial distension, but urine flow and sodium excretion increased during this time. In another series of experiments, volume expansion was substituted for atrial distension. Saline (24 ml/kg) was infused intravenously for 5 min immediately after the 60-min period of alpha-hANP infusion. Urine flow and sodium excretion increased after administration of saline even though plasma atriopeptin decreased substantially during the same time period. These results provide evidence that circulating levels of atriopeptin do not play a dominant role in influencing sodium excretion either during atrial distension or in response to saline infusion.

To elucidate the cardiovascular effects of alpha-human calcitonin gene-related peptide (CGRP), we infused CGRP intravenously at increasing rates of 3, 10, and 30 pmol.kg-1.min-1 during successive 15-min intervals into intact dogs, cardiac-denervated (CD) dogs, and cardiac-denervated dogs pretreated with beta-blockers. In intact dogs, the initial infusion rate of CGRP at 3 pmol.kg-1.min-1 did not produce significant hemodynamic changes, but the two higher infusion rates produced dose-dependent decreases in total peripheral resistance, mean arterial pressure, and left and right atrial pressures and produced dose-dependent increases in heart rate (HR) and cardiac output (CO). In addition, stroke volume decreased and pulmonary vascular resistance increased at the highest infusion rate. In CD dogs, CGRP produced qualitatively similar responses, although the increase in HR was markedly attenuated. The increase in CO was also attenuated, but the difference did not reach statistical significance. In CD dogs pretreated with beta-blockers, CGRP did not increase HR and the increase in CO was further attenuated. In a separate experiment, the lowest dose of CGRP (3 pmol.kg-1.min-1) was infused intravenously for 60 min in intact dogs; significant cardiovascular responses, qualitatively similar to those produced by higher rates of infusion, occurred. We conclude that CGRP is an extremely potent vasodilator and that the increase in HR is mediated primarily by autonomic reflexes.