B. Bhagat

Effects of chronic administration of nicotine on storage and synthesis of noradrenaline in rat brain

1 Chronic administration of nicotine (0.5 mg/kg, subcutaneously four times a day, 5 days a week, for 6 weeks) did not affect the growth rate and water intake in rats. In these animals food intake was normal for the first 5 weeks, but was significantly increased during the sixth week of treatment. 2 Nicotine administration increased the blood pressure of rats from 120 mm Hg to 151 mm Hg. 3 The concentrations of endogenous noradrenaline, dopamine, 5‐hydroxytryptamine and acetylcholine in the brain remained unaltered. However, chronic treatment with nicotine increased the turnover rate of noradrenaline. Initial accumulation of 3H‐noradrenaline was also significantly increased. 4 It is concluded from these studies that changes in the turnover of cerebral noradrenaline caused by chronic administration rather than changes in the concentration of noradrenaline may be an important factor in nicotine‐induced behavioural changes.

Modification by prostaglandin E2 (PGE2) of the response of guinea-pig isolated vasa deferentia and atria to adrenergic stimuli

1 Prostaglandin E2 (PGE2) exerted positive cardiostimulant effects on isolated guinea‐pig atria. The response was not altered by treatment of the animal with reserpine or by addition of propranolol to the organ bath. These results suggest that the cardiostimulatory actions of PGE2 are not mediated through the release of catecholamines or stimulation of adrenoceptors. 2 On the electrically driven atria, PGE2 consistently exerted a cardiostimulant action which was not appreciably altered by changes in calcium ion in the bathing medium. PGE2 showed no effect on the transport of calcium by the fragments of heart sarcoplasmic reticulum. 3 PGE2 reduced the responses to both noradrenaline and tyramine in the isolated atria. The shifted dose‐response curve was not parallel to the original. 4 PGE2 increased the contractor response of the isolated vas deferens to nerve stimulation or to direct electrical stimulation. 5 PGE2 antagonized the increase caused by noradrenaline in contractor response of isolated vas deferens to direct electrical stimulation, whereas it affected the potentiation by noradrenaline differently when the vas deferens was contracting in response to nerve stimulation. In low concentration it inhibited and in large concentrations, it slightly enhanced the potentiation by catecholamine. 6 It is concluded that PGE2 has actions on multiple sites. It has postjunctional as well as pre‐junctional effects on adrenergic neurones.

Effect of reserpine on the activity of adrenal enzymes involved in the synthesis of adrenaline

1 After administration of reserpine to rats, the tyrosine hydroxylase (TH) and phenylethanolamine‐N‐methyl transferase (PNMT) activity in their adrenal glands was found to be increased under in vitro conditions. 2 The increase in TH activity occurred at 12–18 h after reserpine whereas the PNMT activity increased at 30 hours. Unlike the TH, the increase in PNMT activity did not appear to be neuronally mediated since ganglion blockade by chlorisondamine failed to antagonize the reserpine‐induced increase in PNMT activity. The increase in PNMT activity may be a response to increased utilization of catecholamines. 3 Hypophysectomy resulted in a diminution of the activities of both enzymes; the activity of TH, but not of PNMT, could be partially restored by reserpine. ACTH restored the activities of both enzymes almost to normal. 4 The differential effect of reserpine suggests that the activities of these two enzymes are controlled by different mechanisms.

Noradrenaline and tyramine action on isolated atrial muscle of endotoxin-treated guinea-pigs

1 Isolated left‐atrial strips of guinea‐pigs were driven electrically at a constant rate and log‐concentration curves were determined for the positive inotropic effect of noradrenaline and tyramine. 2 The atrial tissue from endotoxin‐treated animals had a reduced sensitivity to noradrenaline and tyramine. 3 After endotoxin, the sensitizing effect of cocaine on the response to noradrenaline was normal but accumulation of 3H‐noradrenaline in nerve terminals was markedly reduced. 4 Atrial tissue of endotoxin‐treated guinea‐pigs responded normally to stretch.

MODULATION OF ADRENAL MEDULLARY ENZYMES BY STRESS

Publisher Summary Catecholamines (CA) in sympathetic nerves and in the adrenal medulla are stored in dense core vesicles from which they are continuously being released. Four enzymes are involved in the biosynthesis of epinephrine from tyrosine: tyrosine hydroxylase (TH), dopa decarboxylase, dopamine β-oxidase (DBO), and phenylethanolamine-N-methyl transferase (PNMT). 1-Tyrosine, the natural precursor, is present in the circulation. It enters the adrenergic neuron and is hydroxylated to form 1-dopa by TH; 1-dopa is decarboxylated by dopa-decarboxylase to form dopamine. Dopamine is taken up into the storage particles, where it is converted to norepinephrine (NE) by an enzyme DBO. For this uptake, adenosine triphosphate (ATP) and magnesium are essentially required. This requirement for ATP and magnesium disappears when the enzyme is made soluble. In the adrenal medullary cells, NE migrates from the chromaffin granules to the cytoplasm and is N-methylated by PNMT to form epinephrine. Epinephrine is also stored in the granules. Norepinephrine and other catechols have been shown to inhibit the TH, a rate limiting enzyme in the biosynthesis of CA.

Mechanism of the antihypertensive effect of propranolol

Abstract Propranolol is indicated in the management of essential hypertension. Among the factors that may be involved in propranolol-induced lowering of blood pressure are: (1) suppression of cardiac output, (2) inhibition of renin release, (3) diminution of tonic sympathetic outflow from the vasomotor center in the brain, (4) restoration of defective vascular relaxation and, (5) inhibition of presynaptic β-receptors. But all these factors do not explain sufficiently how beta-blockade lowers blood pressure. In our laboratory, prolonged treatment of spontaneously hypertensive rats with propranolol causes a reduction in adrenal tyrosine hydroxylase activity. The resultant reduced synthesis of catecholamines may lead to a decrease in the amout of amine available for release. This would result in decreased smooth muscle tone and could explain the hypotensive effect of the drug in the hypertensive patient.

Effect of chronic administration of nicotine on the concentrations of adrenal enzymes involved in the synthesis and metabolism of adrenaline

Chronic administration of nicotine caused an increase in tyrosine hydroxylase and catecholamine concentrations in rat adrenals, but failed to affect adrenal monoamine oxidase, catechol-O-methyl transferase or phenylethanol-amine N-methyl transferase activities.

Catecholamine depletion as a factor in the induction of adrenal tyrosine hydroxylase

Abstract 1. 1. The activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in the biosynthesis of catecholamines, was measured in homogenates of rat adrenal gland following various drugs to determine whether depletion of catecholamines may also be a factor in induction of TH. 2. 2. In contrast to reserpine, treatment of rats with guanethidine for 1 day or 4 days failed to elevate adrenal TH activity, suggesting that hypotension (and the subsequent increase in nerve activity) is not sufficient stimulus for induction of adrenal TH. 3. 3. Reserpine depletes the adrenal catecholamine, whereas guanethidine does not do so. It seems that depletion of catecholamine by reserpine may also be a factor which can lead to an increase in adrenal activity. 4. 4. Support for the suggestion is derived from the observation that interference with reserpine-induced depletion of catecholamine by pargyline, reduced the increase in adrenal TH activity by reserpine. 5. 5. Phentolamine which does not deplete catecholamine failed to cause induction of TH. 6. 6. It is concluded that depletion of catecholamines may also be a factor regulating adrenergic TH activity.

Antitumor Activity of Antiserum Nerve Growth Factor (anti-NGF)

Summary and Conclusion Pretreatment of newborn mice with antiserum to nerve growth factor or daily three injections of nicotine to mice delayed the formation of tumors induced by benzo[α]pyrene and reduced the occurrence. While anti-NGF reduced significantly the rate of growth of the tumor developed, nicotine treatment increased it.

MECHANISM OF ANTIHYPERTENSIVE EFFECT OF PROPRANOLOL

Treatment of spontaneously hypertensive rats (SHR) with 1-propranolol (P) caused reduction in adrenal tyrosine hydroxylase (TH) and systolic blood pressure (B.P.) and antagonized reserpine induction of adrenal TH. Plasma dopamine B-hydroxylase (DBH) levels fell prior to the fall in B.P. Decreased sympathetic nerve activity and reduced synthesis of NE would diminish vascular tone and lead to a fall in B. P. This may explain the anti-hypertensive effect of P.