Effects of 6-hydroxydopamine on the canine sinus node.

The acute effects of 6-hydroxydopamine (6-OH-DA) injected directly into the sinus node artery were studied in 57 dogs. The positive chronotropic effect of 6-OH-DA was intermediate between that of norepinephrine and that of tyramine, when these substances were compared on the basis of their ED 50. The increase in heart rate produced by 6-OH-DA was inhibited by prior intranodal injection of propranolol and desmethylimipramine. At high doses, injection of 6-OH-DA was often associated with arrhythmias such as periodic slowing of the sinus rate, atrial premature beats, atrial fibrillation, and ventricular extrasystoles. In the 72 hours following injection of 1.5 mg 6-OH-DA, the norepinephrine content of the sinus node region decreased progressively. In agreement with the norepinephrine depletion, response to intranodally injected tyramine was significantly diminished. The number of fluorescent adrenergic nerve fibers was also reduced. Impaired norepinephrine uptake and enhanced release were also demonstrated by using tritiated norepinephrine. After 6-OH-DA treatment, response to right stellate stimulation was diminished, and the response to vagal stimulation was not altered. It was concluded that the local perfusion of the sinus node with 6-OH-DA produces a marked norepinephrine depletion of the perfused region compatible with a localized degeneration of the sympathetic nerve terminals. KEY WORDS adrenergic nerve terminals cardiac arrhythmias right stellate ganglion stimulation tyramine histofluorescence uptake and release of norepinephrine • Studies on the autonomic innervation of the heart indicate that this organ is richly innervated but that innervation of the sino-atrial and atrioventricular nodes is denser than that of other cardiac regions (1, 2). The role of the adrenergic system in the control of the heart rate and contractility has been studied by various procedures such as surgical de-nervation, immunosympathectomy, or use of substances interfering with norepinephrine synthesis, storage mechanisms, or the action on receptors. Each of these techniques has some disadvantages in producing incomplete sympathetic denervation, requiring high technical skill, or affecting functions unrelated to the sympathetic system. Recent studies (3-5) have shown that 6-OH-DA produces a specific degeneration of adrenergic nerve terminals, without affecting surrounding Schwann cells, smooth muscle cells, and cholinergic nerve terminals. This compound constitutes a new means for producing sympathectomy and thus provides a more specific approach to evaluate the role of the sympathetic nervous system. The possibility of producing a local adrenergic denervation of the sinus node was studied by injecting 6-OH-DA into the sinus node artery. The effects of 6-OH-DA on heart rate, metabolism of …