Degeneration Contraction Research Articles

“Stone heart” in a neonate

A neonate presented at this institution in September, 1978, with interrupted aortic arch complex, including ventricular septal defect, atrial septal defect, and patent ductus arteriosus. Additional anomalies included bilateral cleft lip and palate, low set ears, and bilateral colobomas. One-stage total correction of the interrupted aortic arch complex was undertaken with standard hypothermic techniques. The repair was completed within a 65 minute period of circulatory arrest at 18 degrees C, perfusion was re-established, and the patient was returned to normothermia. Tetanic contracture of the myocardium, stone heart, was evident at 27 degrees C. Cardiac action did not resume despite several therapeutic maneuvers, and the infant died on the operating table. Extensive calcium flooding was a notable feature on histological sections of the heart, associated with myofibrillar degeneration (contraction bands). This complication has never been reported before in a neonate with congenital heart disease. Deep hypothermia did not prevent ischemic contracture of the myocardium, and this complication must now be added to an already lengthy list of complications of neonatal heart surgery.

Degeneration contraction after local vinblastine treatment of superior cervical ganglia in the rat

The pattern of ‘degeneration contraction’ after unilateral vinblastine (VIN) treatment of cervical superior ganglia (0.1% solution for 15 min) was studied in rats. Control ganglia were saline-treated or soaked with a buffer of pH 4.5, but such treatment did not induce any observable symptoms. After VIN treatment alone, the palpebral aperture was normal until 19–20 hr after the treatment, when the aperture started to diminish. After additional preganglionic denervation the palpebral aperture initially was narrow, but started to widen (degeneration contraction) at about 13 hr after VIN treatment, was maximal at 17–19 hr after operation, and decreased to the previous size at about 27 hr. Bretylium tosylate, 4 mg/kg, s.c., given 11 hr after VIN treatment delayed the onset and maximum of degeneration contraction by about 4 hr, in agreement with previous studies on degeneration contraction after ganglionectomy (Lundberg, 1970). Degeneration of adrenergic nerve terminals after VIN treatment seems to proceed as after ganglionectomy, but with intact impulse conduction. This may be due to the effect of VIN in preventing fast intra-axonal transport of some essential ‘nutrition factor’.

Effects of Colchicine, Vinblastine and Vincristine on Degeneration Transmitter Release after Sympathetic Denervation Studied in the Conscious Rat

AbstractThe effect of the mitosis inhibitors colchicine, vinblastine and vincristine on the time course of the degeneration contraction of the sympathetically innervated periorbital smooth muscle was studied in conscious rats. In conformity with earlier findings with colchicine, single s.c. doses of vinblastine (2–4 mg/kg) or vincristine (1–2 mg/kg) given at the time of axotomy delayed the start of the degeneration contraction, i.e. the leakage of sympathetic transmitter from the degenerating nerve endings. The significance for the delaying effect of the time interval between axotomy and injection of colchicine was studied in some detail. The delaying effect declined gradually with increasing time interval between denervation and injection. Colchicine given later than 4–6 h after axotomy did not delay. In view of this finding and the fact that the mitosis inhibitors used are known to inhibit the intra‐axonal microtubular transport of different nerve constituents it is proposed that the drugs postpone the degeneration transmitter release by slowing down the rate by which an “axotomy information” is transported distally along the neuron. The “axotomy information”, probably linked to some axotomy‐induced change in intra‐axonal structures related to the microtubules, seems to be transported at a rate of about 4 mm per hr. Local treatment of the decentralized superior cervical ganglion with colchicine or vinblastine induced a “degeneration” contraction probably due to a complete inhibition of the flow of some vital matter to the nerve endings.

Bretylium and the supersensitivity to exogenous noradrenaline after sympathetic denervation studied in the conscious rat.

AbstractRats denervated by excision of the superior cervical sympathetic ganglion and given reserpine at the time of operation were used. The width of the palpebral aperture, which reflects the tone of the sympathetically innervated periorbital smooth muscle, was measured in the conscious rats after different i.p. doses of 1‐noradrenaline. The sensitivity of the muscle to exogenous noradrenaline was thus tested during 3 periods of 3 h duration each between 13 and 30 h after denervation. Bretylium, which is known to delay the degeneration contraction of the muscle, i.e. the degeneration transmitter release, postponed the development of denervation supersensitivity. Hence, bretylium seems to preserve temporarily both the amine storage mechanisms and the axonal amine pump in the degenerating adrenergic nerve terminals.

Degeneration of sympathetic nerves in vitro and development of smooth muscle supersensitivity to noradrenaline.

1. The sequence of events involved in degeneration of sympathetic nerve terminals has been studied in vitro in the expansor secundariorum muscle of the chicken.2. The muscle underwent a degeneration contraction due to abrupt release of noradrenaline stores from the nerves about 18 hr after isolation. The tension reached its peak within 6 hr at about 44% of the maximum tension developed to added noradrenaline.3. Responses to nerve stimulation were transiently potentiated by 35% on average just before the onset of the degeneration contraction and then failed abruptly.4. Degeneration release of noradrenaline was Ca(2+)-dependent. Development of the degeneration contraction was delayed by temporary withdrawal of Ca(2+) from the medium and was accelerated by a twofold increase in Ca(2+) concentration when applied at a critical period close to the onset.5. Neither continuous nerve stimulation nor alterations in the length of the nerve stump influenced the course of the degeneration contraction in vitro.6. When the muscle was left in situ after denervation, the degeneration contraction occurred between 2 and 3 days later depending on the length of the distal portion of nerve. Cutting the nerve supply 5 cm closer to the muscle in vivo hastened the loss of transmission and the onset of the degeneration contraction by 24-48 hr.7. Supersensitivity to noradrenaline occurred soon after the degeneration contraction but the full development of a sevenfold supersensitivity to noradrenaline, equivalent to that produced by cocaine, took up to 48 hr. No further increase in sensitivity to noradrenaline could be detected in vitro after chronic denervation in vivo for up to 30 days.8. It is concluded that the degeneration contraction and failure of transmission was precipitated by an abrupt increase in the Ca(2+) permeability of the axon causing discharge of transmitter from vesicles. This was probably the result of depletion of essential factors normally transported somatofugally in the axon at 1-2 mm/hr. The supersensitivity to noradrenaline that develops subsequently appears to be due to a loss of the uptake mechanism of the nerve terminals.

Adrenergic re-innervation of smooth muscle of nictitating membrane by preganglionic sympathetic fibres.

1. The preganglionic and post-ganglionic trunks of the cervical sympathetic nerve were joined in an end-to-end anastomosis after excision of the superior cervical ganglion in the cat.2. Seventy-five days after the anastomosis the diameter of the pupil was nearly normal and there was almost complete recovery of the prolapsed palpebra and of the nictitating membrane. The contraction of the nictitating membrane, induced by electrical stimulation, caudally to the point of anastomosis, showed that the smooth muscle of the nictitating membrane had been re-innervated.3. Neither hexamethonium nor nicotine had any marked effect on the contraction of the nictitating membrane. Severing the regenerated nerve trunk produced a degeneration contraction. These results are strong evidence that the denervated membranes were re-innervated by true cholinergic preganglionic fibres.4. Our pharmacological studies indicated that in the re-innervated preparations neuromuscular transmission was adrenergic in the sense that it was blocked by phentolamine and not by atropine. These results were confirmed by the histochemical-fluorescence studies which showed that the endings of the regenerated axons contained high concentrations of catecholamines.5. Electron microscopy showed that the regenerated terminals contained none of the small dense-core vesicles, considered to be typical of adrenergic nerve endings, but contained clear synaptic vesicles and an unusually great number of large granular vesicles.6. Our results suggest that the denervated nictitating membranes were re-innervated by cholinergic presynaptic sympathetic fibres that had been modified so that they could release catecholamines in addition to, or instead of, acetylcholine.

Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behaviour.

AbstractAmphetamine induced vigorous rotational behaviour in rats where the nigrostriatal dopamine (DA) system was unilaterally degenerated by an intracerebral injection of 6‐hydroxydopamine (6‐OH‐DA). The rotational behaviour was analysed in a specially designed “rotometer” and found highly reproducable. The intensity of the rotation was proportional to the extent of degeneration in the DA system. The amphetamine site of action was in all probability presynaptic as amphetamine caused a rotation in the opposite direction as compared to the DA receptor stimulating drug apomorphine. Tyrosine hydroxylase inhibition abolished the amphetamine effect, while reserpine potentiated the effect. Evidence was also obtained that the amphetamine induced release of DA was dependent upon nerve impulses. The rotational behaviour reflected the degree of DA receptor stimulation, but changes in the noradrenaline (NA) transmission seemed to modulate the behaviour. Decreased NA transmission after dopamine‐β‐hydroxylase inhibition increased the rotational behaviour. The unilateral degeneration of the DA system was studied by the changes in posture and movements that occurred during the degeneration. After inhibition of the monoamine oxidase the rats showed a strong rotation beginning on the 23d and ending on the 33d hour after the operation. The rotational behaviour was probably due to degeneration release of DA and equivalent to the degeneration contraction of the nictitating membrane in the peripheral nervous system Amphetamine greatly potentiated the spontaneous degeneration release during this period.

Development of degeneration contraction and supersensitivity in the cat's nictitating membrane after 6-hydroxydopamine.

After subcutaneous injection of 30 mg/kg of 6-hydroxydopamine into the conscious cat the denervated and the decentralized nictitating membranes contracted immediately. While the response of the denervated membrane is of short duration (1.5 h), the decentralized membrane is half relaxed after 11 h. The duration of the latter contraction is similar to that of the degeneration contraction seen after surgical denervation. It is proposed that the response of the decentralized nictitating membrane to 6-hydroxydopamine corresponds to the degeneration contraction. Treatment of the cats with pargyline prolongs both types of degeneration contractions. However, while beta-TMlO {[2-(2,6-dimethylphenoxy)propyl] trimethylammonium chloride had profound effects on the degeneration contraction seen after surgical denervation, it failed to affect that after 6-hydroxydopamine. Indirectly acting sympathomimetic amines prevented the usual effect of beta-TMlO on the degeneration contraction seen after surgical denervation. It is proposed that the failure of beta-TMlO to affect the response of the decentralized nictitating membrane to 6-hydroxydopamine is due to a similar preventive effect of 6-hydroxydopamine. The development of supersensitivity to (-)-noradrenaline was determined at various time intervals after the injection of 6-hydroxydopamine; pithed cats and isolated nictitating membranes were used. Under both conditions the membranes were in a state of sustained contraction, if the experiment was begun before the response of the decentralized nictitating membrane to 6-hydroxydopamine had worn off. After 6-hydroxydopamine the development of supersensitivity coincided with the falling phase of the degeneration contraction. Very similar results had been obtained earlier during the degeneration contraction after surgical denervation; the temporal relation between degeneration contraction and development of supersensitivity is very similar after surgical and chemical denervation.

Effects of some adrenergic neuron blockers, related quaternary ammonium compounds and guanidine derivatives on degenerating adrenergic nerves in the conscious rat.

AbstractAdrenergic neuron blockers, related quarternary ammonium compounds and guanidine derivatives, and some other drugs have been tested on a degenerating nerve‐effector system in the rat periorbital smooth muscle. The main attention was paid to their influence on the degeneration contraction. The quaternary ammonium compounds structurally related to bretylium and xylocholine, with few exceptions, distinctly delayed the onset of the degeneration contraction. The guanidine derivatives known to be related to bretylium and xylocholine pharmacologically caused almost no delay. The simple compound phenyltrimethylammonium (PTMA) was chosen for further studies. It was found to possess actions on the degenerating system similar to those of bretylium. The PTMA‐induced delay was efficiently reduced by desmethylimipramine, but not at all by anticholinergic drugs.Conclusions: — Guanidine derivatives are much less efficient delayers than related quaternary ammonium compounds. The main structural features essential for delaying activity are found in PTMA. There does not seem to be any correlation between the neuron‐blocking or the sympathomimetic activity and the delaying effect of the drugs. The processes responsible for the onset of the normal degeneration contraction and those effecting the drug‐induced delay do not appear to involve any cholinergic sites.

The degeneration contraction of a sympathetically innervated smooth muscle in the rat after reserpine, inhibition of monoamine oxidase or tyrosine hydroxylase.

AbstractThe degeneration contraction of the periorbital smooth muscle in conscious rats was measured after treatment with each of 3 different monoamine oxidase (MAO) — inhibitors, reserpine or the methylester of α‐methylthyrosine. Pheniprazine (10 mg/kg), nialamide (100 or 200 mg/kg) pargyline (100 or 200 mg/kg) given at the time of denervation and pargyline (100 or 200 mg/kg) given at 10 hrs after denervation significantly increased the size of the degeneration contraction. 200 mg/kg of pargyline tended to delay the onset of the contraction. However, pheniprazine, nialamide or pargyline at 100 mg/kg started it prematurely. An injection of reserpine (1 mg/kg) given at 2–3 hrs before the expected start of the degeneration transmitter release did not induce any excitatory effect and abolished the degeneration contraction. Inhibition of the synthesis of noradrenaline by the methylester of 1‐α‐methyltyrosine (H 22/07) given at the time of denervation or 10–12 hrs later did not influence the size or the time course of the degeneration contraction. It is concluded that: — The degeneration transmitter release is normally influenced by functional MAO. — Since the potent MAO‐inhibitors studied did not consistently delay the start of the degeneration contraction, it does not seem reasonable that bretylium, which earlier has been found both to possess MAO‐inhibiting and delaying effect, induces a delay only by inhibiting intraaxonal MAO. — There is no significant contribution of newly formed noradrenaline to the degeneration contraction.

Bretylium and the degeneration contraction of the sympathetically innervated periorbital smooth muscle in the rat.

AbstractThe ability of bretylium to delay the start of the degeneration contraction of the sympathetically innervated periorbital muscle has been studied in conscious rats. The sympathomimetic and neuron blocking action of bretylium at the doses most frequently used were also tested. A low dose, 0.5 mg/kg, that induced no measurable neuron block still delayed. The delay caused by local injection into the muscle exceeded the duiation of the neuron block. These findings indicate that the bretylium‐induced delay is not caused by neuron block and that the delaying action mainly is exerted on the terminal parts of the neurons. Bretylium given repeatedly postponed the onset of the degeneration contraction at least 6 to 10 hrs. Later the processes responsible for the degeneration contraction appeared to develope despite the treatment. Within 4 hrs preceding or just including the start of the degeneration contraction the time of injection was very critical for the effect of bretylium on the time course of the contraction. An injection of bretylium during an ongoing degeneration contraction interrupted the contraction and displaced the latter part for several hrs. Before the interruption the drug seemed to enhance the transmitter release. It appeared that early during the degeneration contraction there are nerve endings at different stages of degeneration on which bretylium acts differently.

Interactions between inhibitors of the axonal amine pump and bretylium in the degeneration release of sympathetic transmitter.

AbstractLundberg, D. Interactions between inhibitors of the axonal amine pump and bretylium in the degeneration release of sympathetic transmitter. Acta physiol. scand. 1970. 78. 503–521.The time course of the degeneration contraction of periorbital smooth muscles has been studied in conscious rats given different inhibitors of the axonal mine pump either alone or in combination with bretylium. Desmethylimipramine (DMI) or cocaine at 20 mg/kg did not influence the time of onset of the degeneration contraction while Lu 3–010 (10 mglkg) caused a somewhat premature start. Lu 3–010, DMI or protriptyline at 10 mg/kg but not trimipramine or cocaine at 20 mglkg antagonized bretylium. They reduced and prevented (DMI) the bretylium‐induced delay. DMI reduced the delay by a non‐competitive mechanism. The antagonism to bretylium does not seem to be explainable by simple interference with the axonal amine pump. Indirect evidence suggests that the duration of the delay induced by bretylium is related to the rate of disappearance of bretylium from critical sites in the nerve endings. –DMI and Lu 3–010 seem to have somewhat different actions on the degenerating adrenergic nerve terminals.

Skin temperature of the rabbit ear during degeneration of its sympathetic nerve supply.

The skin temperature of the ears was recorded in conscious rabbits. A marked decrease in temperature, lasting for some hours, appeared 20–26 hours after extirpation of the superior cervical ganglion. This phenomenon is compared with the degeneration secretion of saliva and the degeneration contraction of the nictitating membrane, and attributed to leakage of transmitter from the degenerating vasoconstrictor fibres in amounts sufficient to contract the blood vessels.

Adrenergic neuron blockers and transmitter release after sympathetic denervation studied in the conscious rat.

Abstract13 to 15 hrs after excision of the superior cervical ganglion the postdenervation ptosis in the rat is reversed for about 12 hrs due to release of transmitter from degenerating nerve terminals. This degeneration contraction has been studied in unanesthetized rats. A special apparatus with an image splitting eyepiece was constructed for the measurement of the palpebral aperture at a distance. The time course of the degeneration contraction was found to correlate well with that of postdenervation transmitter depletion earlier found by other workers using biochemical and histochemical methods. Earlier findings that postdenervation depletion is delayed by bretylium were fully confirmed. It was also found that the neuron‐blockers beta‐TM 10 (10–50 mg/kg), bethanidine (10–50 mg/kg) and BW 392C60 (10–75 mg/kg) caused much less delay than bretylium at 1 to 50 mg/kg. The delayed degeneration contraction has a normal appearance and magnitude. There is no correlation between the neurone blocking action of the drugs and their “delaying effect”.