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Biomedical subjects

S L Lightman

Publications and source records attributed to S L Lightman.

At least 415 records · Page 23Linked to original sources

Ascending brain-stem noradrenergic pathways modulate the renin response to haemorrhage.

Ventral noradrenergic projections (VNAB) from lateral tegmental (A1, A2) and dorsal noradrenergic projections (DNAB) from the coeruleal (A6) as well as A1 cell groups in the brain-stem of the rat were lesioned by intracerebral injection of 6-hydroxydopamine. A marked increase in plasma renin activity and adrenaline concentrations followed haemorrhage (0.5 ml/100 g body weight) in the sham-operated rats. VNAB-lesioned rats showed a similar response to the sham-operated controls, but in DNAB-lesioned animals the rise of plasma renin was markedly attenuated.

Animals↗

Vasoactive intestinal polypeptide stimulation of prolactin release and renin activity in normal man and patients with hyperprolactinaemia: effects of pretreatment with bromocriptine and dexamethazone.

Vasoactive intestinal polypeptide (VIP) was infused into normal volunteers and patients with hyperprolactinaemia. Heart rate increased from 62 +/- 3 to 75 +/- 3 beats min-1 (P = 0.001) in controls and from 70 +/- 2 to 78 +/- 3 beats min-1 (P = 0.001) in hyperprolactinaemics. Similarly, haematocrit increased from 38 +/- 2 to 44 +/- 1% (P = 0.001) and from 40 +/- 1 to 43 +/- 2% (P = 0.002) and plasma renin activity from 910 +/- 59 to a peak of 3344 +/- 282 pg ml-1 h-1 (P = 0.001) and from 1577 +/- 671 to a peak of 4954 +/- 1364 pg ml-1 h-1 (P = 0.001) in the two groups, respectively. Prolactin concentrations rose in the control group only, from 134 +/- 11 to a peak of 377 +/- 35 mU 1(-1) (P = 0.001), whilst in the hyperprolactinaemics little change occurred from the pre-infusion concentration of 3873 +/- 2179 reaching a peak of 3998 +/- 2347 mU 1(-1) (P greater than 0.07). In separate studies, the normal subjects were pretreated with either bromocriptine or dexamethazone. Dexamethazone did not alter any parameter of the response to VIP. Bromocriptine did not affect the heart rate, haematocrit or renin response to VIP but clearly inhibited the rise in prolactin which remained at unmeasurable concentrations throughout the infusion.

Adenoma↗

Localization and actions of cholecystokinin in the rat pituitary neurointermediate lobe.

Rat pituitary neural lobe contained high concentrations of cholecystokinin-like immunoreactivity (CCK-LI). Section of the pituitary stalk resulted in loss of CCK-LI, and both lactation and replacement of drinking water with 2% saline resulted in marked depletion of CCK-LI. Rats with congenital diabetes insipidus (Brattleboro strain) had a 73% reduction in CCK-LI below the levels of hooded Long-Evans controls, where as levels in the brain were unchanged. Release of CCK-LI, labeled dopamine, and gamma-amino butyric acid in response to potassium depolarization was studied. There was a low fractional release of CCK-LI. Addition of sulfated CCK-8 (CCK-8s) to the medium enhanced the calcium-dependent potassium-stimulated release of dopamine, but basal release was unaffected. gamma-Amino butyric acid release was only poorly calcium dependent and not effected by extracellular CCK-8s. Vasopressin and oxytocin release were stimulated by electrical stimulation of the pituitary stalk, and were unaffected by the addition of CCK-8s to the medium. In vivo, however, the injection of 5 micrograms CCK-8s into the third ventricle resulted in increased plasma vasopressin concentrations.

Animals↗

Plasma volume regulation in patients with progressive autonomic failure during changes in salt intake or posture.

Blood pressure in patients with progressive autonomic failure falls during salt restriction or orthostasis. We contrasted the regulation of plasma volume in patients with progressive autonomic failure with that of controls to determine whether hypovolemia contributes to this hypotension. When sitting, the plasma volume (measured from distribution of human serum albumin) was normal. During 1 week of low Na+ intake, patients with progressive autonomic failure lost three times as much body weight as controls; however, changes in plasma volume were strictly comparable. Therefore, the extra fluid lost in the patients must have derived primarily from the interstitial space. During alteration in Na+ intake, mean blood pressure values were closely related to plasma volume in the patients (r = 0.80, p less than 0.01) but not in controls. Changes in plasma volume in the head-up tilt position were assessed from the hematocrit values. During tilting, the blood pressure in controls was unchanged, but their plasma volume fell by 10.3% +/- 1.8% (p less than 0.001). In contrast, the mean blood pressure of the patients with progressive autonomic failure fell by 40 +/- 6 mm Hg; yet, their plasma volume was unchanged. Thus, in progressive autonomic failure, plasma volume measured during sitting is normal, but dynamic regulation of plasma volume during salt restriction or orthostasis is abnormal and hypovolemia is offset by partitioning of interstitial fluid into the plasma. Also, because the blood pressure is unusually dependent on volume, this fluid redistribution could be an important defense against severe hypotension in patients lacking cardiovascular reflex control.

Adult↗

Substance P microinjections into the nucleus tractus solitarius elicit a pressor response in capsaicin-treated rats.

The role of Substance P in the nucleus tractus solitarius was investigated by observing the effect of local injections of the peptide on blood pressure, heart rate and vasopressin secretion in both normal and neonatally capsaicin-treated rats. Substance P did not modify and of these parameters in control rats, but elicited a marked pressor response, not associated with changes in heart rate or plasma vasopressin levels, in capsaicin-treated animals. The study demonstrates that neonatal capsaicin treatment modifies the sensitivity of this area of the brainstem to exogenous substance P and provides evidence for a modulatory action of substance P on the cardiovascular system at the site of the nucleus tractus solitarius.

Afferent Pathways↗

Role for lateral tegmental noradrenergic neurons in the vasopressin response to hypertonic saline.

Lesions to the dorsal and ventral noradrenergic pathways were achieved by injecting 6-hydroxydopamine in the periaqueductal midbrain or lateral pons, respectively. Four to 6 weeks after surgery the rats were anaesthetized with pentobarbitone, and hypertonic saline was administered into the peritoneum. Rats with lesions of the ventral noradrenergic pathways showed a significant reduction in the saline-induced rise in plasma vasopressin concentrations, while lesions to the dorsal pathway or control injections were without effect.

Animals↗

Postmenopausal flashes: studies of chronological organisation.

The times of occurrence of climacteric flashes were recorded by three women over a period of one month. The mean intervals between flashes were 130 +/- 5, 142 +/- 6 and 67 +/- 3 min (mean +/- S.E.) for the three women. The flashes did not occur simply randomly in time. Following a flash, a period of suppression of the ability to flash again was apparent. No mathematical model was derived which satisfactorily described the incidence of flashing in all three women. However, models assuming suppression of the ability to flash immediately following a flash gave the best fits to our data. This suggest that there is an inhibitory feedback mechanism mediating partial suppression of flashing for at least 30 min after a flash.

Aged↗

Blood pressure and vasopressin in progressive autonomic failure. Response to postural stimulation, L-dopa and naloxone.

UNLABELLED: We showed previously that patients with progressive autonomic failure with multiple system atrophy (MSA) failed to excrete a water load while they were standing, suggesting abnormal postural regulation of vasopressin release. The rise of plasma arginine vasopressin (AVP) with upright posture is modulated by central dopamine and opioid receptors. Patients with MSA may have depletion of brain dopamine and opioid peptides. We measured the plasma levels of AVP in patients with MSA and control subjects during postural stimulation by head-up tilt and the inhibition of this rise in AVP by L-DOPA (dopamine precursor) and naloxone (opiate antagonist). Since L-DOPA and naxolone can alleviate hypotension, we also studied the effects of these agents on orthostatic hypotension. Plasma AVP concentration of normal subjects rose progressively over 90 min of head-up tilt and this postural rise in AVP was abolished by L-DOPA and naloxone. Patients with MSA had similar levels of AVP while horizontal. However, they showed a severely blunted postural AVP response since their levels rose to only 10 per cent of the rise in the normal subjects despite the additional stimulus to AVP secretion of considerable postural hypotension. They also showed no inhibition of AVP secretion by L-DOPA or naloxone. Naloxone did not alter the blood pressure of either group. Although L-DOPA did not change the blood pressure of normal subjects, it lowered it in patients with MSA both while they were horizontal and tilted. IN CONCLUSION: (1) the postural stimulation of AVP release is blunted in MSA; (2) this postural rise in AVP is not inhibited by a dopamine agonist or opioid antagonist in MSA suggesting loss of dopaminergic and opioid pathways involved in AVP release; (3) endogenous opioids do not contribute to orthostatic hypotension in MSA; (4) patients with MSA are supersensitive to the hypotensive effects of an acute L-DOPA infusion.

Aged↗

The effect of selective and non-selective beta-adrenoceptor blockade, and of naloxone infusion, on the hormonal mechanisms of recovery from insulin-induced hypoglycaemia in man.

The rise in plasma adenosine-3',5'-monophosphate occurring in response to insulin induced hypoglycaemia in normal human subjects, was abolished by non-selective beta-adrenoceptor blockade but unaffected by selective beta 1-adrenoceptor blockade. This implies that the rise is secondary to beta 2-adrenoceptor stimulation. The abolition of this rise by non-selective beta-adrenoceptor blockade had no pronounced effect on the recovery from hypoglycaemia. Endogenous opiate receptor blockade with naloxone had no significant effect on the recovery from insulin induced hypoglycaemia, or the hormonal mechanisms involved.

Adrenergic beta-Antagonists↗

Localization of [3H]spiperone binding sites in the intermediate lobe of the rat pituitary gland.

[3H]Spiperone binding sites in all three lobes of the rat pituitary gland were studied using an in vitro autoradiographic technique. [3H]Spiperone binding was present throughout the pituitary gland but there was a much higher density of autoradiographic silver grains over the cells of the intermediate lobe than elsewhere. The density of spiperone binding sites in pars intermedia was comparable to that in sections of the rat corpus striatum. [3H]Spiperone binding was displaced by the specific dopamine agonist ADTN.

Animals↗

Effects of opiates and osmotic stimuli on rat neurohypophyseal metabolic activity monitored with [3H]-2-deoxyglucose.

The metabolic activity of the neural lobe of the rat pituitary gland was measured by autoradiographic estimation of the rate of accumulation of 1-[3H]-2-deoxy-D-glucose ( [3H]-2DG). Replacement of drinking water by 2% saline for 5 days resulted in a 300% increase in [3H]-2DG accumulation in the neural lobe. Morphine (8 mg/kg s.c.) increased [3H]-2DG uptake by 213%, and this effect was antagonized by naloxone. Morphine-tolerant rats also showed an increased uptake of [3H]-2DG, and morphine actually reduced the neural lobe activity in these animals. Rats with monosodium glutamate induced lesions of the circumventricular organs no longer showed any increase in neural lobe activity after morphine. Homozygous Brattleboro rats on an ad libitum water intake showed greater neural lobe activity than normal controls, and replacement of drinking water with 2% saline for 24 h resulted in a massive increase in [3H]-2DG uptake. In none of these studies was any alteration detected in the metabolic activity of the supraoptic or paraventricular nuclei.

Animals↗

Dopamine and [D-ALA2, D-Leu5]enkephalin inhibit the electrically stimulated neurohypophyseal release of vasopressin in vitro: evidence for calcium-dependent opiate action.

The effects of both dopamine and enkephalin agonists were assessed on electrically stimulated vasopressin secretion from the isolated neural lobe. Both dopamine (10(-6) M) and the dopamine agonist ADTN (2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene; 10(-6) M) significantly reduced the stimulated release of vasopressin. This reduction in vasopressin secretion was prevented by the dopamine antagonist sulpiride (10(-6) M). [D-Ala2, D-Leu5]Enkephalin (DADLE) also inhibited vasopressin release and its effect was additive to that of ADTN. The effect of DADLE was prevented by the opiate antagonist naloxone and was also sensitive to the calcium content of the medium. Low calcium concentrations markedly increased the inhibitory effect of DADLE, while high concentrations abolished its effect. These findings provide evidence of a direct inhibitory action of both dopamine and enkephalins at the level of the neural lobe and suggest that the effect of enkephalins may be intimately related to calcium-sensitive neurosecretory events.

Animals↗

Is cutaneous flushing prostaglandin mediated?

Intravenous administration of nicotinic acid (25 mg), resulted in a readily reproducible facial flush. The development of this flush was inhibited by two prostaglandin synthetase inhibitors, indomethacin and benorylate, but was not affected by the administration of the opiate receptor antagonist naloxone. Indomethacin, the agent with the greater anti-prostaglandin activity, was markedly more effective than benorylate in inhibiting the nicotinic-acid-induced rise in facial temperature. These findings will be useful in the in vivo assessment of the activity of prostaglandin inhibitors.

Adolescent↗