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Objective: The renal response to exogenous atrial natriuretic factor (ANF) is blunted in chronic heart failure. The aim of the present studies was to investigate whether renal ANF receptor regulation in chronic heart failure is a time related event. Methods: Glomerular ANF receptors were analysed in radioligand binding experiments at 0, 1, 2, 6, 12, 24, and 48 h, as well as at 1, 2, 4, and 8 weeks after the induction of an aortocaval shunt. Results: Rats with aortocaval shunts had lower packed cell volume and body weight and higher relative heart weight than sham operated controls. Plasma ANF C and N terminal levels were increased in shunt rats as early as 5 min after establishment of the shunt. Right and left atrial ANF concentrations were decreased and ventricular ANF concentration was increased in shunt rats at 6 and 12 h respectively. Competitive inhibition of 125I-ANF binding showed that at 6 h the density (Bmax) of glomerular ANF receptors was significantly lower than in the controls [518(SEM 10) ν 759(12) fmol·mg−1 protein] without differences in their affinity (Kd). The low Bmax in shunt animals persisted at 12, 24, and 48 h, even at 1 week [Bmax: 400(29) and 713(28) fmol·mg−1 protein; Kd: 80(2) and 70(4) pM, for AC rats and controls, respectively]. Bmax values were not significantly different at 2, 4, and 8 weeks. In 24 h animals, C-ANF displaced 65% of total binding, with both total and C ANF binding sites being 38% lower in shunt animals. Conclusion: Downregulation of glomerular ANF receptors is a transient event during the development of high output heart failure in the rat. Thus the blunted renal response to ANF during chronic heart failure is not likely to be due to a decrease in renal ANF receptor density or affinity.

Objective: Low output heart failure induces abnormalities of endothelium dependent vasodilatation, but the mechanisms responsible for this remain unclear. As blood flow can alter endothelial cell function, in particular nitric oxide (NO) release, the activity of endothelium derived relaxing factor (EDRF) was investigated in a rat model of high output heart failure. Methods: The thoracic aorta upstream of an aorto-caval fistula in rats was submitted to hormonal changes (similar to those in heart failure) and to high blood flow (opposite to that found in low output heart failure). Functional and biochemical arterial properties were studied in aorto-caval fistula rats and in sham operated rats three months after operation. The vascular responses were studied by exposing aortic segments from fistula and sham operated rats to increasing concentrations of agonists. Aortic cyclic guanosine monophosphate (cGMP) concentration was assessed as an index of NO synthase activity. The effect of NO synthase blockade on functional and biochemical arterial properties was also studied. Results: Plasma atrial natriuretic factor (ANF) was increased in fistula rats compared to sham operated rats. The concentrations of acetylcholine or the calcium ionophore A23187 required to produce 10% and 50% maximum relaxation (EC, and EC50) were similar in the two groups. Relaxation in response to low concentrations of Sin-1 (an NO donor) was shifted rightwards in fistula rats and EC10 was greater than in the controls. The aortic cGMP concentration was higher in aorto-caval fistula rats than in sham operated rats (p=0.008). The differences between aorto-caval fistula rats and sham operated rats were probably the result of increased basal EDRF-NO release in the former, since NO synthase blockade abolished the differences in both aortic cGMP and the dose-response curve to Sin-1. Conclusions: The arterial wall upstream of a chronic aorto-caval fistula has increased cGMP content and hyposensitivity to Sin-1, which may be due to enhanced basal EDRF-NO release. These changes, strikingly different from those found in the low output heart failure, suggest that haemodynamic rather than neuroendocrine factors play a determinant role in the altered vasodilator response in heart failure. Cardiovascular Research 1993; 27 :1651-1656

Objective: The aims were (1) to characterise plasma and tissue atrial natriuretic factor (ANF) levels, haemodynamic variables, and renal function at different stages of moderate chronic high output heart failure in the rat; and (2) to assess the contribution of the atria and ventricles to plasma ANF levels. Methods: Plasma and tissue ANF levels, haemodynamics, and renal function were evaluated at 1, 2, 4, 8, and 16 weeks after the development of aorto-caval shunts. Sham operated animals served as controls at identical time points. Male Sprague-Dawley rats weighing 225-275 g were used in all experiments. Results: Mean arterial blood pressure was lower and right atrial pressure was higer in the aorto-caval shunt groups than in sham operated controls at all time periods. Left ventricular end diastolic pressure was increased significantly in aorto-caval shunt rats at 1, 2, and 4 weeks when compared with their control counterparts. Plasma COOH terminal and NH2 terminal ANF concentrations were increased significantly in aorto-caval shunt animals. Plasma ANF was positively correlated with right atrial pressure and left ventricular end diastolic pressure in aorto-caval shunt rats but not in sham operated controls. Aorto-caval shunt animals also developed marked cardiac hypertrophy with decreased atrial ANF concentration, but not content, and increased ventricular ANF concentration and content. Despite high plasma ANF concentrations, aorto-caval shunt rats had a lower packed cell volume at all observed periods and reduced urinary sodium excretion and urinary volume at 1 and 2 weeks, with trends to a reduction at 4, 8, and 16 weeks. Body weight was higher in aorto-caval shunt animals at 16 weeks than in sham operated controls. Conclusions: (1) Chronically increased cardiac filling pressure stimulated not only ANF release but also ANF synthesis in each cardiac chamber, which in turn contributed to raised plasma ANF concentrations in aorto-caval shunt rats; (2) an attenuated renal response to endogenous ANF and sodium and water retention were apparent in A-C shunt rats. Activation of neurohormonal vasoconstrictor systems and gradually decreased plasma ANF concentrations may contribute to sodium and water retention at different stages of this experimental model of heart failure. Cardiovascular Research 1993; 27 :464-470

STUDY OBJECTIVE - The aim of the study was to develop a new procedure to produce abdominal aortocaval shunts in the rat without vascular microsurgery. PROCEDURE - The inferior vena cava and abdominal aorta were exposed by laparotomy. The aorta was punctured caudal to the left renal artery with an 18 gauge disposable needle which was advanced into the vessel, perforating the adjacent wall between aorta and vena cava and penetrating the latter. A bulldog vascular clamp was placed across the aorta cephalic to the puncture, the needle was withdrawn, and the aortic puncture point was sealed with a drop of cyanoacrylate glue. The clamp was removed 30 s later. Patency of the shunt was verified visually by swelling of the vena cava and admixture of arterial and venous blood. No local haemorrhages were seen. The laporatomy was then closed. The procedure takes less than 10 min. RESULTS - Of 11 rats which received this procedure, only one died within 24 h. All the other animals were killed 4 weeks after operation. Nine of these 10 animals had developed cardiac hypertrophy of about the same magnitude. There were no changes in sham operated controls. CONCLUSIONS - This is a reproducible, simple and rapid method of developing high output heart failure and cardiac hypertrophy in the rat which could be useful in many laboratories.

Objective: The aim of this study was to develop a new shunting procedure for producing heart failure in the rat incorporating microvascular techniques and avoiding an abdominal operation. Method: We performed an end-to-side anastomosis between the femoral vein and the femoral artery just proximal to their trifurcation into the saphenous, epigastric, and distal femoral vessels. Results: Of the 15 rats which underwent this procedure, six died within 48 h. The nine surviving animals were sacrificed and examined six weeks following surgery. All nine had developed cardiac hypertrophy and cardiac failure. Conclusion: This model provides a relatively simple and reproducible means of creating high output heart failure and cardiac hypertrophy in the rat without necessitating abdominal surgery.

Objective: Atrial natriuretic factor (ANF) release and the renal response to moderate volume expansion have been shown to be conserved in rats with a mild to moderate degree of high output heart failure (aortocaval shunt). The aim of this study was to investigate whether these variables are also conserved in animals with moderate to severe heart failure induced by an aortocaval shunt. The effect of angiotensin converting enzyme (ACE) inhibition by captopril on these responses was also investigated. Methods: An aortocaval shunt was developed in Sprague-Dawley rats weighing 180-200 g; sham operated rats served as controls. Three weeks after surgery, three experimental groups were established: aortocaval shunt and sham operated controls, and aortocaval shunt rats treated with captopril during the last week before the experiments were started. Four weeks after surgery, haemodynamic variables, ANF release, diuresis, and natriuresis were evaluated following a moderate volume expansion. Results: Mean arterial blood pressure was lower in shunt animals and still lower in the ACE inhibited group than in the sham operated controls. Central venous pressure and left ventricular end diastolic pressure (LVEDP) were significantly higher in untreated shunt rats than in their controls. ACE inhibition returned the raised central venous pressure, but not LVEDP, to control values. Shunt rats had lower baseline urinary sodium excretion (UNaV), urinary volume, and packed cell volume than their sham operated controls. ACE inhibition reversed baseline urinary volume to control values. Baseline COOH terminal and HN2 terminal ANF were greatly increased in both treated and untreated shunt rats. Volume expansion was performed three times in conscious animals at 15 min intervals with human plasma protein fraction. Its effect on LVEDP was similar in all three groups, but the increase in central venous pressure was much higher in untreated shunt animals. UNaV, urinary volume, and the release of COOH terminal and NH2 terminal ANF in response to volume expansion were blunted in both treated and untreated shunt rats when compared with their sham operated counterparts. Both absolute and relative heart weights were significantly lower in captopril treated shunt animals than in the untreated shunt group, the latter presenting very significant cardiac hypertrophy. Conclusions: Aortocaval shunt animals with moderate to severe heart failure show a blunted ANF release and renal response to volume expansion, which, despite significant haemodynamic improvement, are not restored by ACE inhibition. Cardiovascular Research 1994; 28 :1533-1539