Regional Distribution of the Cardiac Output and Renal Responses to Atrial Atriuretic Peptide Infusion in Rabbits With Congestive Heart Failure

Abstract

1. A biventricular, low-output congestive cardiomyopathy was induced in 19 rabbits by administering adriamycin (16 mg/kg). The effects of alpha-rat atrial natriuretic peptide (ANP) infused at 0.1, 0.2 and 0.4 micrograms/kg per min, were then examined in terms of (i) central haemodynamics (ii) regional blood flow (iii) renal function and (iv) plasma norepinephrine and plasma renin. 2. In this dose range, ANP produced progressive and significant falls in stroke volume, cardiac output and mean arterial pressure, owing to a fall in venous return. The heart rate response to this was blunted. 3. Using radiolabelled microspheres, significant falls in the perfusion of cutaneous, gastrointestinal and musculoskeletal tissues were observed, due to reduced vascular conductances in these beds. These changes were accompanied by activation of the sympathetic nervous system as evidenced by a progressive rise in plasma norepinephrine. A significant increase in plasma renin was only observed with the highest infusion of ANP. 4. Renal blood flow was maintained in the face of a falling mean arterial pressure and cardiac output, but diuretic and natriuretic effects were absent. 5. It was concluded that the dominant influence of ANP infusion in this model of heart failure appeared to be a reduction in cardiac preload with detrimental overall haemodynamic consequences.

Evidence for Impaired Endothelium Dependent Vasodilation in Experimental Left Ventricular Dysfunction

“…The adriamycin model of low output heart failure has previously been well validated by a number of independent groups. Langton et al have previously demonstrated neuro-humoral activation in this model of cardiac failure (Langton et al 1989), which was also associated with a reduction in cardiac output of 28% and peripheral vasoconstriction, particularly in splanchnic and musculoskeletal vascular beds. These haemodynamic changes were also confirmed by Wanless et al (1987).…”

“…In this study, the full range of vascular reactivity in the hindlimb vascular bed of conscious, autonomically blocked rabbits with experimental heart failure was investigated. Experimental heart failure was induced by administration of the cardiotoxic agent adriamycin, as validated by a number of previous studies (Arnolda et al 1985;Wanless et al 1987;Langton et al 1989). The resultant dilated cardiomyopathy is characterized…”

“…The proximal end of the intra-aortic infusion catheter was subsequently retrieved under local anaesthesia, flushed with heparinized saline and then refilled with heparin 1000 units/mL, 3 times/ week to maintain patency, Induction and assessment of heart failure Adriamycin (generously supplied by Farmitalia, Melbourne, Vic., Australia) 1 mg/ kg, given intravenously, was administered to nine rabbits (one of which died from sepsis and heart failure), twice weekly for 6 weeks. This protocol has previously been shown to produce a model of chronic low cardiac output (Arnolda et al 1985;Wanless et al 1987;Langton et al 1989), which is associated with neuro-humoral activation. Cardiac function was assessed echocardiographically in control and heart failure rabbits on the day prior to vascular reactivity studies (and at least 3 days after the final adriamycin treatment in the heart failure group).…”

Norepinephrine may be an underlying factor in chemobrain

“…There is evidence that a number of these drugs modulate NE release in the brain and periphery, particularly in animal models. For example, there are data suggesting that vinblastine, vincristine, cyclophosphamide, and doxorubicin can increase release of NE in the brain, 2 peripheral organs, and blood plasma, 3,4 whereas data from other agents suggest decreases in NE release or destruction of noradrenergic sympathetic terminals. 5,6 The possibility that these agents typically increase peripheral NE is reinforced by findings that fatigue and nausea, which frequently accompany chemotherapeutic administration, have been correlated with changes in blood plasma NE.…”