Noradrenaline attenuates the natriuretic effect of atrial natriuretic factor in man.

1. The effects of noradrenaline (0.025 micrograms kg-1 min-1) and atrial natriuretic factor (0.04 micrograms kg-1 min-1) alone, and in combination, were studied in eight healthy salt replete men. 2. Atrial natriuretic factor increased urinary sodium excretion and flow rate without changing glomerular filtration rate or systemic haemodynamics. 3. Noradrenaline decreased urinary sodium excretion without changing glomerular filtration rate, urinary flow rate or systemic haemodynamics. 4. When atrial natriuretic factor was administered against a background infusion of noradrenaline the natriuretic response to the peptide was significantly attenuated. 5. Further analysis showed that this attenuation was due to the additive antinatriuretic effect of noradrenaline rather than to a specific interaction between atrial natriuretic factor and noradrenaline. 6. The possible significance of this interplay between noradrenaline and atrial natriuretic factor is discussed in the context of experimental evidence for an important role of the sympathetic nervous system in modulating the renal effects of atrial natriuretic factor in animals.     

Venous responsiveness to atrial natriuretic factor in man.

The venorelaxant effect of atrial natriuretic factor in man was studied using the dorsal hand vein technique. Infusion of met-ANF to preconstricted veins at doses up to 240 ng min-1 in 11 healthy male subjects caused only minimal venorelaxation. Atrial natriuretic factor is unlikely to have a significant venorelaxant effect at physiological doses in man.     

Lack of effect of atrial natriuretic factor on the tone induced in rat portal vein by platelet-activating factor

The spontaneous myogenic activity of the isolated rat portal vein was inhibited by atrial natriuretic factor or by sodium nitroprusside. These compounds were not effective on the tone induced by PAF-acether or carbachol. 8-Bromo cyclic GMP and dibutyryl cyclic AMP inhibited myogenic activity and reduced the agonist-induced contractions. Only dibutyryl-cyclic AMP significantly inhibited the PAF-acether-induced contractile responses. These results indicate that the tone induced by PAF-acether can be used to discriminate between drugs which selectively increase cyclic nucleotide levels.     

Effect of atrial natriuretic factor on platelet function in whole blood ex-vivo in man

Summary Atrial natriuretic factor (ANF) binding sites have been shown to be present on human platelet membranes. We investigated the effect of an infusion of ANF 5 pmol·kg^–1.min^–1 on platelet aggregation in whole blood ex-vivo in 8 normal volunteers.Spontaneous platelet aggregation, collagen (0.6–2 g·ml^–1)-induced or ADP (0.5–2.0 M)-induced aggregation was not affected by ANF. Plasma aldosterone was however significantly attenuated by ANF.These results show that a pharmacological dose of ANF does not affect platelet aggregation in man. These results suggest that the high plasma levels of ANF normally achieved in chronic heart failure or acute myocardial infarction are unlikely to contribute to the platelet hyperreactivity, often observed in these conditions.     

Renal response to infusion versus repeated bolus injections of atrial natriuretic factor in man

Summary In 7 healthy humans consuming a 170 mmol sodium diet the effect of the mode of administration of atrial natriuretic factor (human ANF 99–126) on renal function has been investigated, using conventional clearance studies during maximal water diuresis. ANF was administered as four repeated bolus (0.4 μg/kg) injections and, after a 2-day interval, as a one-hour infusion (0.02 μg/kg/min) preceded by a 0.4 μg/kg bolus injection. In the two experiments ANF caused comparable elevations in glomerular filtration rate, free water clearance, and lithium excretion. No change in blood pressure or heart rate was observed in either study, and plasma renin activity and aldosterone fell by a similar extent. As expected, the time course of plasma ANF concentrations was markedly different during the two studies. It is concluded that with those doses of ANF the changes in renal haemodynamics and sodium handling were essentially similar after bolus injections and a constant infusion.     

Vasodilator profile of synthetic atrial natriuretic factor

The vasodilator profile of synthetic atrial natriuretic factor (ANF) was characterized using isolated vascular preparations. Nanomolar concentrations of ANF relaxed rabbit aortic rings contracted by serotonin, histamine, methoxamine or angiotensin II. The synthetic peptide was most effective (IC50 = 1.3 X 10(-10) M) in relaxing the tonic, intrinsic contractions of the rabbit facial vein. ANF was poorly active against K+-contracted aortic rings or the phasic contractions of the rat portal vein. A similar vasodilator profile was obtained for sodium nitroprusside but not papaverine, hydralazine, adenosine or nifedipine. This first demonstration of the vascular activity of synthetic ANF depicts this substance as a nonselective vasodilator of agonist-induced contractions. The observed similarities in the vasodilator activity of ANF and sodium nitroprusside suggest a common mechanism of action.     

Atrial natriuretic factor and endothelin interactions in control of vascular tone

Endothelin-1 (ET-1) is reported to be the most powerful constrictor of blood vessels known. Atrial natriuretic factor is a potent relaxor of contracted vessels. This study examined the potential interaction between these vasoactive peptides on rabbit aortic rings. ET-1 contracted the rings in a dose-dependent manner with an EC50 (-log M) of 9.78 +/- 0.16. Atriopeptin III (APIII) completely relaxed ET-1 (10(-9) M)-contracted rings with an EC50 of 9.63 +/- 0.07 and methoxamine contracted rings with an EC50 of 9.18 +/- 0.09. Pretreatment of aortic rings with APIII (up to 3 x 10(-6) M) did not alter the normal ET-1 dose-response curve with respect to potency but did diminish the maximal contraction achieved. An interesting additional finding was that the temporal nature of ET-1-induced contraction is remarkably dose-variable. In conclusion, the potent contractile effects of ET-1 on vascular smooth muscle can be effectively reversed but not prevented by APIII.     

Hemodynamic actions of a synthetic atrial natriuretic factor

The recently discovered atrial natriuretic factor (ANF), as well as synthetic ANF, has been demonstrated to produce diuresis and vasodilation. However, the vascular actions appear to be selective. In view of this apparent relative specificity, the hemodynamic actions of synthetic ANF (atriopeptin II, 23 amino acid rat sequence) were examined in intact animals and in vascular beds as well as in isolated cardiac preparations. Administration of 1-100 micrograms/kg of ANF i.v. into conscious spontaneously hypertensive rats (SHRs) resulted in a dose-related fall in blood pressure. Heart rate decreased at the lowest dose. Cardiac output was depressed. Infusion of 1 microgram/kg/min also reduced blood pressure and decreased cardiac output slightly (approximately 15%). Intraarterial (i.a.) administration or i.v. injection of ANF into the blood supply of a kidney of anesthetized SHRs augmented renal blood flow and reduced renal vascular resistance. In contrast, i.a. administration into the hindquarters failed to increase blood flow or decrease resistance of this bed significantly. The specific dopamine1 (DA1)-receptor agonist SKF 82526 was examined for comparative purposes and was found to augment both renal and hindquarter blood flow following i.a. administration. The renal vasodilator actions of SKF 82526 but not ANF were antagonized by the specific DA1-receptor blocker SCH 23390 (hindquarter effects were not evaluated). ANF did not affect the force of contraction or rate of beating of isolated guinea pig atria or isolated hearts and therefore does not appear to possess direct inotropic or chronotropic properties. In conclusion, ANF lowered blood pressure in conscious SHRs; the lowering of pressure was accompanied by a slight fall in cardiac output, but there was no reflex tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vascular responses to local atrial natriuretic peptide infusion in man.

1. The effect on skin and muscle blood flow of arterial infusion of atrial natriuretic peptide (ANP) directly into the forearm circulation, and on venous tone of direct infusion into a dorsal hand vein, was studied in normal subjects. 2. ANP produced a dose-dependent increase in both skin and muscle blood flow, but at equivalent doses, produced no dilatation of noradrenaline-preconstricted dorsal hand veins. These findings indicate that ANP acting locally, is an arterioselective dilator in the upper limb circulation in normal man. 3. Measurements of ANP in venous plasma during arterial infusion suggest marked clearance of ANP across the forearm vascular bed. Such peripheral clearance may, at least in part, account for the short plasma half-life of this peptide. 4. The lowest dose of ANP infused was calculated to produce plasma levels similar to those found in patients with heart failure. The findings with this dose suggest that, in heart failure, circulating levels of ANP may be within a range capable of influencing peripheral vascular resistance directly.     

Influence of urocortin and corticotropin releasing factor on venous tone in conscious rats

The corticotropin releasing factor (CRF) family includes CRF and urocortin. The effects of urocortin and CRF (0.3, 1, 3 and 10 nmol/kg, i.v.) relative to those of vehicle (0.9% NaCl) on mean arterial pressure and mean circulatory filling pressure (index of venous tone) were examined in conscious, unrestrained rats that were either intact (unblocked) or ganglion-blocked by treatment with mecamylamine (10 mg/kg, i.v.) followed by noradrenaline (4 microg/kg/min, i.v.) to increase vasomotor tone. Both urocortin and CRF dose-dependently decreased mean arterial pressure in intact rats and ganglion-blocked rats. The depressor action of urocortin was greater than that of CRF at all doses. In intact rats, neither compound reduced mean circulatory filling pressure. In ganglion-blocked rats, urocortin and the highest dose of CRF decreased mean circulatory filling pressure. In conclusion, both urocortin and CRF are vasodepressor agents with venodilator action.     

Hyperresponsiveness to atrial natriuretic factor in adult Brattleboro rats

Renal and hemodynamic effects of an intravenous infusion of atrial natriuretic factor (ANF) (8 micrograms/h) were studied in homozygous Brattleboro rats, which lack endogenous vasopressin. Heterozygous rats were used as controls. ANF-induced increases in sodium, chloride and volume excretion were higher, whereas changes in potassium excretion were lower in homozygous, as compared to heterozygous rats. The initial decrease in arterial blood pressure after ANF infusion was greater in the homozygous group, whereas there were no differential effects on heart rate. Inulin clearance, as well as clearance and fractional excretion of lithium were not significantly different between groups. The results indicate that Brattleboro rats show an exaggerated diuretic as well as saluretic response to ANF. They suggest that these effects are localized in the distal nephron and may be due to the known anatomical abnormalities in juxtamedullary nephrons of Brattleboro rats.     

Effects of atrial natriuretic factor on noradrenergic neurotransmission in vivo in the rat mesentery

The effects of synthetic atrial natriuretic factor (ANF) on noradrenergic neurotransmission were assessed in the in situ blood-perfused rat mesentery. Synthetic ANF was infused (.003-1 micrograms/min) directly into the mesenteric artery, and vascular responses to periarterial (i.e., sympathetic) nerve stimulation (PNS) and exogenous norepinephrine (NE) were elicited. Synthetic ANF did not significantly alter vascular responses to PNS and only slightly suppressed responses to exogenous NE at blood levels greater than 10 ng/ml. In contrast, under similar conditions, low doses of adenosine attenuated vascular responses to PNS without reducing responses to exogenous NE, and high doses of adenosine nearly abolished responses to both PNS and exogenous NE. We conclude that synthetic ANF exerts very little influence on noradrenergic neurotransmission in the rat mesenteric vascular bed.     

Human pharmacokinetics of an analogue of atrial natriuretic factor

Summary The pharmacokinetics of ANP-270, a 26 amino acid analogue of alpha human natriuretic factor (-hANF) with a prolonged effect on isolated arterial preparations has been studied in 40 healthy males, in a doubleblind placebo controlled investigation. Placebo or ANP-270 0.3, 1.5 or 3.0 g/kg were given by intravenous bolus injection, each to groups of 10 subjects. Blood samples were assayed for ANP-270 by a specific sandwich ELISA.The disappearance of ANP-270 from plasma followed a two-compartment decay, with mean distribution and elimination half-lives of 2.6 min (n = 30) and 10.6 min (n=20), respectively. These estimates were similar to those obtained by other investigators for -hANF. Their brevity explains the lack of a prolonged effect of ANP-270 in vivo compared to -hANF.