Alpha adrenoceptors--an overview.

The realisation that transmitter noradrenaline modulated its own release through a pre-junctionally located alpha-adrenoceptor operated control mechanism explained several paradoxical phenomena and raised exciting therapeutic possibilities. Characterisation of the pre- and post-junctional effects of agonists and antagonists led to the conclusion that pre- and post-junctional alpha-adrenoceptors differed in receptor structure and alpha-adrenoceptors were sub-divided into alpha 1- and alpha 2-adrenoceptors. It was subsequently shown that in addition to the differences in receptor structure the biochemical mechanisms of signal transduction were entirely different in the case of each sub-type of adrenoceptor. It has been hypothesised that automodulation of transmitter noradrenaline release occurs between neighbouring varicosities in densely innervated organs and as a consequence ensures that homogeneity in tissue noradrenaline concentration is achieved. In the heart the loss of such automodulation could result in inhomogeneity in transmitter concentration and under certain circumstances favour re-entry phenomena and arrhythmogenesis. There is now a large body of evidence documenting the presence of post-junctional alpha 1-adrenoceptors in the mammalian heart. Recent experimental work strongly supports the concept that enhanced alpha 1-adrenoceptor responsiveness plays a primary pathophysiological role in the genesis of malignant dysrhythmias induced by catecholamines during myocardial ischaemia and reperfusion. Alpha 1-adrenoceptor antagonists have been shown to be effective in restoring sinus rhythm after such arrhythmias have been experimentally induced. It is anticipated that alpha 1-adrenoceptor antagonists possessing potent antiarrhythmic activity and causing minimal changes in heart rate and arterial blood pressure, will become available and be employed to ascertain whether or not the animal results translate to man.