Regional sympathetic nerve activity in human congestive heart failure

The analysis of plasma kinetics of the sympathetic neuro transmitter noradrenaline has been used to determine the rate at which noradrenaline "spills over" to plasma for the body as a whole and for individual organs. The elevated plasma noradrenaline concentration of patients with congestive heart failure was due to both increased spillover of noradrenaline to plasma (indicating increased overall sympathetic stimulation) and reduced plasma noradrenaline clearance. The sympathetic nervous response to heart failure was not an "all-or-nothing" phenomenon: the rotes of noradrenaline spillover from the heart end kidney were markedly increased, but those from the lungs end hepa to-roesen teric region were normal. The effects of marked cardiorenal sympathetic stimulation in heart failure have not been studied. Cardiac sympathetic stimulation may provide inotropic support for the failing heart, but may also be associated with disease progression, arrhythmias and sudden death. Renal sympathetic stimulation may contribute to vasoconstriction end to salt and water retention, directly or through renin and angiotensin release.

While the plasma noradrenaline concentration, end plasma noradrenaline clearance, were related to the severity of heart failure as measured by the left ventricular ejection fraction, noradrenaline spillover to plasma was not predictable from univariate analysis of haemodynamic and clinical data. Discriminant function analysis of the variables arterial blood pressure, pulmonary artery wedge pressure and the serum sodium concentration did separate patients with normal noradrenaline spillover from those in which the rate of spillover was increased. Together these variables include contributions from plasma volume, tissue perfusion end ventricular performance.to vasoconstriction end to salt and water retention, directly or through renin and angiotensin release.

I next, tested the hypothesis that, because sympathetic stimulation at rest in patients with heart failure is considerable, there is diminished reserve for response to physiological stimuli. Overall and regional noradrenaline spillover were measured at rest and during steady-state supine bicycle exercise in patients and in normal subjects. The increased plasma noradrenaline concentration during exercise was due to increased spillover, rather then reduced plasma clearance, in both groups. There were similar increases in cardiac and renal noradrenaline spillover during exercise in both groups. This study refuted the concept of impaired sympathetic reserve in patients with heart failure. The sympathetic response to exercise in normal subjects included a marked selective increase in cardiac stimulation, so that the heart contributed 10% of total noradrenaline spillover to plasma during exercise but only 3% at rest.

The necessity for regional venous catheterisation in these studies has permitted a more rigorous analysis of blood flow to internal organs than has been usual in clinical studies. It has also been possible to consider possible relationships between regional sympathetic activity end vasoconstriction in patients with heart failure. Coronary sinus blood flow was normal in patients with heart failure. Hepatic blood flow was normal in this population, but renal blood flow was reduced for the whole group, end comprised a smaller proportion of cardiac output in patients with more severe heart failure. There was no association between renal vascular resistance end renal noradrenaline spillover.

A second theme of this thesis has been the involvement of the sympathetic nervous system in the clinical actions of the inotropic drug milrinone. In isolated guinea pig atria, milrinone was found to have similar potencies fo inotropic and chronotropic effects to several other phosphodiesterase inhibitors.

Milrinone potentiated the effects of isoprenaline, but in the presence of milrinone isoprenaline induced arrhythmias at concentrations which previously were not arrhythmogenic. The ED_so of milrinone for its inotropic effect was similar to that reported for phosphodiesterase inhibition, and there was no selectivity for inotropic effects over chronotropic effects at therapeutic concentrations.

The importance of sympathetic stimulation in the clinical effects of milrinone was tested in normal subjects end in patients with congestive heart failure. In normal subjects, autonomic receptor blockade markedly reduced the tachycardia and abolished the increase in cardiac output produced by milrinone, but had no effect on its vasodilator action. In patients with congestive heart failure, milrinone did not Increase cardiac or total noradrenaline spillover, but still increased heart rate end reduced pulmonary artery wedge pressure. The clinical haemodynamic effects of milrinone most likely result from a combination of direct vasodilatation of resistance end capacitance vessels, and amplification of the high resting level of sympathetic stimulation in patients with heart failure.

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