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CLINICAL STUDY

Evidence for functional presynaptic alpha-2 adrenoceptors and their down-regulation in human heart failure

^a Cardiovascular Medicine, Alfred Hospital and Baker Medical Research Institute, Melbourne, Australia

Manuscript received June 20, 2000; revised manuscript received November 29, 2000, accepted December 22, 2000.

Reprint requests and correspondence: Dr. David M. Kaye, Alfred Baker Medical Unit, Baker Medical Research Institute, PO Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, Australia
d.kaye{at}alfred.org.au

OBJECTIVES

The aim of this study was to investigate the role of peripheral presynaptic alpha-2 adrenergic receptors in modulating norepinephrine (NE) release in congestive heart failure (CHF).

BACKGROUND

Activation of the sympathetic nervous system is a hallmark of CHF. Clonidine, an imidazoline and adrenergic agonist with high selectivity for the alpha-2 adrenoceptor, has been shown to reduce generalized sympathetic activity in heart failure after parenteral administration. If it could be shown that peripheral presynaptic alpha-2 adrenoceptors are inhibitory to NE release, then they could be targeted for future therapy, and as a corollary, potentially circumvent unwanted side effects arising from stimulation of alpha-2 adrenoceptors in the brain. Additionally, it could be concluded that these receptors form the basis for an auto-inhibitory feedback to further NE release.

METHODS

Fifteen healthy volunteers and 10 patients with heart failure received intra-arterial clonidine via the brachial artery (0.05 µg and 0.48 µg/100 ml forearm/min). Radio-tracer techniques were employed for studying NE kinetics.

RESULTS

Intra-arterial clonidine caused a dose-dependent decrease in forearm spillover of NE in healthy individuals (low dose, high dose: 26%, 49%: p < 0.05, p < 0.001, respectively). In the patient group, no decrease in forearm spillover was demonstrated after local administration. The difference in response between the two groups was statistically significant (p = 0.004).

CONCLUSIONS

Peripheral sympathoneural alpha-2 adrenoceptors are functionally important in inhibiting NE release in the healthy human. In heart failure, this function is lost. This finding offers further insights into the mechanisms responsible for high circulating levels of NE in patients with heart failure. In addition, it suggests that selective targeting of peripheral presynaptic alpha-2 adrenoceptors will not achieve sympathoinhibition in heart failure.

Abbreviations and Acronyms   ANOVA = analysis of variance   CHF = congestive heart failure   CNS = central nervous system   FBF = forearm blood flow   FSO = forearm spillover   I/A = intra-arterial   IV = intravenous   LVEF = left ventricular ejection fraction   NE = norepinephrine   NS = not significant   PAR = plasma appearance rate   PF = plasma flow

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