The sensory circumventricular organs of the mammalian brain.

The brain's three sensory circumventricular organs, the subfornical organ, organum vasculosum of the lamina terminalis and the area postrema lack a blood brain barrier and are the only regions in the brain in which neurons are exposed to the chemical environment of the systemic circulation. Therefore they are ideally placed to monitor the changes in osmotic, ionic and hormonal composition of the blood. This book describes their. General structure and relationship to the cerebral ventricles Regional subdivisions Vasculature and barrier properties Neurons, glia and ependymal cells Receptors, neurotransmitters, neuropeptides and enzymes Neuroanatomical connections Functions.

Circulating angiotensin II activates neurones in circumventricular organs of the lamina terminalis that project to the bed nucleus of the stria terminalis.

The aim of this study was to determine, in conscious rats, whether elevated concentrations of circulating angiotensin II activate neurones in both the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) that project to the bed nucleus of the stria terminalis (BNST). The strategy employed was to colocalize retrogradely transported cholera toxin B subunit (CTB) from the BNST, with elevated levels of Fos protein in response to angiotensin II. Circulating angiotensin II concentrations were increased by either intravenous infusion of angiotensin II or subcutaneous injection of isoproterenol. Neurones exhibiting Fos in response to angiotensin II were present in the subfornical organ, predominantly in its central core but with some also seen in its peripheral aspect, the dorsal and lateral margins of the OVLT, the supraoptic nucleus and the parvo- and magnocellular divisions of the paraventricular nucleus. Fos-labelling was not apparent in control rats infused with isotonic saline intravenously or injected with either CTB or CTB conjugated to gold particles (CTB-gold) only. Of the neurones in the subfornical organ that were shown by retrograde labelling to project to BNST, approximately 50% expressed Fos in response to isoproterenol. This stimulus also increased Fos in 33% of neurones in the OVLT that project to BNST. Double-labelled neurones were concentrated in the central core of the subfornical organ and lateral margins of the OVLT in response to increased circulating angiotensin II resulting from isoproterenol treatment. These data support a role for circulating angiotensin II acting either directly or indirectly on neurones in subfornical organ and OVLT that project to the BNST and provide further evidence of functional regionalization within the subfornical organ and the OVLT. The function of these pathways is yet to be determined; however, a role in body fluid homeostasis is possible.

Circulating relaxin acts on subfornical organ neurons to stimulate water drinking in the rat.

Relaxin, a peptide hormone secreted by the corpus luteum during pregnancy, exerts actions on reproductive tissues such as the pubic symphysis, uterus, and cervix. It may also influence body fluid balance by actions on the brain to stimulate thirst and vasopressin secretion. We mapped the sites in the brain that are activated by i.v. infusion of a dipsogenic dose of relaxin (25 microg/h) by immunohistochemically detecting Fos expression. Relaxin administration resulted in increased Fos expression in the subfornical organ (SFO), organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus, and magnocellular neurons in the supraoptic and paraventricular nuclei. Ablation of the SFO abolished relaxin-induced water drinking, but did not prevent increased Fos expression in the OVLT, supraoptic or paraventricular nuclei. Although ablation of the OVLT did not inhibit relaxin-induced drinking, it did cause a large reduction in Fos expression in the supraoptic nucleus and posterior magnocellular subdivision of the paraventricular nucleus. In vitro single-unit recording of electrical activity of neurons in isolated slices of the SFO showed that relaxin (10(-7) M) added to the perfusion medium caused marked and prolonged increase in neuronal activity. Most of these neurons also responded to 10(-7) M angiotensin II. The data indicate that blood-borne relaxin can directly stimulate neurons in the SFO to initiate water drinking. It is likely that circulating relaxin also stimulates neurons in the OVLT that influence vasopressin secretion. These two circumventricular organs that lack a blood-brain barrier may have regulatory influences on fluid balance during pregnancy in rats.

Identification of efferent neural pathways from the lamina terminalis activated by blood-borne relaxin.

The ovarian hormone relaxin, in addition to its role in pregnancy, exerts an action on the brain to influence oxytocin and vasopressin secretion, water drinking, and cardiovascular function. Intravenous (i.v.) infusion of relaxin causes an acute water drinking response, confirming its role as a dipsogenic hormone. The aim of this study was to determine whether neurones in the lamina terminalis, which project to the hypothalamic paraventricular and supraoptic nuclei, are activated by elevated levels of circulating relaxin in conscious rats. Immunocytochemistry combined with retrograde neuronal tracing with cholera toxin B subunit conjugated to cholera toxin B (CTB-gold) was used to identify populations of neurones responding with elevated cells of Fos protein to i.v. relaxin administration and which project to these specific hypothalamic sites. Neurones exhibiting Fos were present in the outer parts of the subfornical organ (SFO), the dorsal part of the organum vasculosum (OVLT), the supraoptic nucleus and the paraventricular nucleus. These did not occur in control rats with i.v. infusions of isotonic saline. Approximately 90% of neurones concentrated in the outer parts of the SFO and in the dorsal OVLT showed both retrogradely transported CTB-gold and Fos in response to i.v. infusion of relaxin. These data support a role for relaxin acting on the brain to regulate body fluid and electrolyte homeostasis by activating neural pathways subserving water drinking, vasopressin and oxytocin secretion.

Involvement of dopamine in control of renal blood flow.

Previous studies have shown that the renal nerve supply in the dog contains a population of dopaminergic vasodilator neurons. In order to obtain more information on the possible physiological functions of these neurons, we examined two situations in which there is existing evidence for active intrarenal vasodilation--the reflex response to coronary artery occlusion and the autoregulatory response to reduced renal perfusion pressure. We were unable to confirm published reports that coronary artery occlusion evokes renal vasodilation. However, our results support the view that dopaminergic nerves participate in maintenance of renal blood flow and glomerular filtration at perfusion pressures around the lower limit of autoregulation.

Effects on renal sympathetic axons in dog of acute 6-hydroxydopamine treatment in combination with selective neuronal uptake inhibitors.

1. In anaesthetized dogs, we have investigated the effect on renal responses to sympathetic nerve stimulation of acute treatment with the catecholaminergic neurotoxin 6-hydroxydopamine (2 mg kg-1 i.v.), administered alone or after blockade of neuronal catecholamine uptake pathways for noradrenaline (NA) or dopamine with desmethylimipramine or benztropine, respectively. 2. Under control conditions, renal nerve stimulation caused renal vasoconstriction, reduced glomerular filtration and sodium and water excretion and caused net efflux of NA and dopamine into the renal venous plasma. Two h after administration of 6-hydroxydopamine alone, there was abolition of both functional responses and catecholamine efflux during nerve stimulation. 3. In animals pretreated with desmethylimipramine (1 mg kg-1), 6-hydroxydopamine had no significant effect on functional responses to renal nerve stimulation and nerve-evoked efflux of NA was only moderately reduced. Efflux of dopamine was still markedly reduced by 6-hydroxydopamine, but more variably than occurred without desmethylimipramine treatment. 4. In animals pretreated with benztropine (0.2 mg kg-1), nerve-evoked efflux of dopamine, but not that of NA, was protected against reduction by 6-hydroxydopamine. A higher dose of benztropine (1 mg kg-1) protected efflux of both NA and dopamine against 6-hydroxydopamine. 5. We conclude that acute treatment with a low dose of 6-hydroxydopamine is an effective method of inactivating peripheral sympathetic nerves. The differential effects of desmethylimipramine and benztropine in preserving nerve-evoked efflux of NA and dopamine after 6-hydroxydopamine support the view that these catecholamines originate predominantly from different intrarenal axons. However, neither uptake blocker appears to be completely specific in its actions.

A functional role for renal dopaminergic nerves in the dog.

1. Efferent renal nerve stimulation at 5 Hz causes secretion of both dopamine (DA) and noradrenaline (NA) into renal venous plasma. DA comprises about 8% of the total catecholamine overflow; by contrast, DA efflux into femoral venous plasma following stimulation of the lumbar sympathetic nerves is 1% or less of total catecholamine. 2. Intact, but not denervated, kidneys of volume-loaded dogs also secrete both dopamine (DA) and noradrenaline (NA) into renal venous blood at rest, but the DA:NA ratio is considerably higher than that evoked by nerve stimulation. 3. Acute animal treatment with 6-hydroxydopamine (6-OHDA) abolishes stimulus-evoked catecholamine overflow and the usual fall in glomerular filtration and sodium and water excretion that accompanies renal nerve activation. 4. When 6-OHDA is administered in the presence of a selective inhibitor of UptakeDA (GBR 12909), stimulus-evoked DA overflow is selectively protected against the effect of 6-OHDA. Under these circumstances, nerve stimulation increases glomerular filtration and excretion of water, but not of sodium. These effects are abolished by DA1 receptor blockade. 5. These data indicate that DA is released from intrarenal dopaminergic nerve terminals in vivo, both in response to direct nerve stimulation and tonically under conditions of volume expansion. The main effects of dopaminergic nerve activation are juxtaglomerular vasodilatation and inhibition of distal tubular water reabsorption.

31P NMR spectroscopy of hypertrophied rat heart: effect of graded global ischemia.

To investigate the cause for the greater susceptibility of hypertrophied hearts to ischemic injury, we determined the interrelations of total work output, contractile function and energy metabolism in isolated, perfused normal and hypertrophied rat hearts subjected to graded global ischemia. Cardiac hypertrophy was induced by giving rats seven daily injections of either triiodothyronine (0.2 mg/kg) or isoproterenol (5 mg/kg). All hearts were perfused at an aortic pressure of 100 mmHg in the isovolumic mode in an NMR spectrometer (7.05 Tesla). Heart rate, developed pressure, and coronary flow were monitored simultaneously with changes in pH, creatine phosphate, ATP and inorganic phosphate. During pre-ischemic perfusion, the total work output (rate-pressure product) of hyperthyroid hearts was 28% higher than that of control hearts, whereas hearts from isoproterenol-treated animals showed no difference. However, when related to unit muscle mass, work was normal in hyperthyroid hearts and 26% lower after isoproterenol. Contractile function per unit myocardium (developed pressure/g wet weight) was lower in the hypertrophied hearts. ATP content was the same in all groups. Creatine phosphate decreased 41% after triiodothyronine and 25% after isoproterenol. Inorganic phosphate levels and intracellular pH were similar in control and isoproterenol-treated rat hearts, but were higher in the hyperthyroid rat hearts. The phosphorylation potential and the free energy change of ATP hydrolysis were lowered by hypertrophy, the levels correlating with the depressed contractile function. At each ischemic flow rate, both work and contractile function per unit myocardium were the same for all hearts, but the relations between flow and phosphorylation potential were different for each type of heart. Thus, at low flow rates, hypertrophied hearts perform the same amount of work and have the same contractile function as control hearts, but with abnormal changes in energy metabolism, indicating that the relations of energy status to coronary flow, total work output and contractile function are altered during the process of hypertrophy.