Neutrons give improved results in selected tumour types.
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Fast Neutrons↗
Biomedical subjects
E Mills
Publications and source records attributed to E Mills.
Methods for the introduction of recombinant DNA into chicken embryos.
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Animals↗
Influence of postnatal maternal stress on blood pressure and heart rate of juvenile and adult rat offspring.
UNLABELLED: Autonomic control of blood pressure (BP) and heart rate (HR) was tested in offspring of rat dams that were unmanipulated (controls) or exposed repeatedly to either (1) Postnatal restraint, (2) Postnatal s.c. injections of alkaline saline, or (3) Prenatal s.c. alkaline saline. Under urethane anesthesia, BP was higher than control in 20-day-old offspring of restrained dams and lower at 80 days. The magnitude of the BP response to autonomic ganglionic blockade (chlorisondamine) changed in parallel; the control HR accelerator response was reversed at 20 days and enhanced at 80 days. Postnatal maternal injections increased BP in 20-day-old offspring and lowered it at 80 days. The BP response to blockade was unchanged; HR acceleration was attenuated at 20 days and increased at 80 days. No influence of Prenatal maternal injections was seen in adult offspring. CONCLUSION: Post--not prenatal maternal stress disrupts BP and HR control in rat offspring; disruption is greater after restraint than injection. There is sympathetic hyperactivity in preweanlings and hypoactivity in adults.
Animals↗
Central serotonergic mechanisms in cardiovascular regulation.
This paper reviews the role of central serotonin-containing neurons in the control of blood pressure. Central serotonin nerves have their cell bodies in the brainstem in a number of discrete collections, from where they ascend to ramify throughout the brain, descend to terminate in the spinal cord, or send shorter projections terminating in medulla, pons, and midbrain. Activation of one important ascending serotonin pathway innervating the preoptic region of the hypothalamus causes an increase in blood pressure. Activation of a bulbospinal serotonin projection descending from the ventrolateral medulla (the B3 cell group) to terminate in the intermediolateral cell column (IML) also evokes a pressor response. This pressor response is independent of that elicited by stimulation of the ventrolateral medulla in the adjacent but separate area containing the C1 adrenaline cell group. The pressor action appears to depend on increased release of serotonin, as detected by microdialysis in the area of the IML, and to be mediated by serotonin receptors of the 5HT1 subclass, probably located on sympathetic preganglionic neurons. It is possible that neuroactive excitatory amino acids, such as glutamate or aspartate, and neuropeptides such as substance P, also play a part in the pressor response evoked by stimulation of the ventrolateral medulla in the area of the lateral B3 serotonin cells. This descending serotonin pathway also appears important in mediating the hypotensive action of the antihypertensive drugs methyldopa and clonidine.
Animals↗
Prenatal nicotine exposure impairs beta-adrenergic function: persistent chronotropic subsensitivity despite recovery from deficits in receptor binding.
Gestational exposure to nicotine has been shown to interfere with biochemical markers of development of central and peripheral noradrenergic activity. The current study examines the development and function of cardiac beta-adrenergic receptors in the offspring of pregnant rats given nicotine infusions of 6 mg/kg/day from gestational days 4 through 20, administered by subcutaneously implanted osmotic minipumps. Prenatal nicotine exposure delayed the development of beta-adrenergic receptor binding capabilities, as assessed with [125I]pindolol in membrane preparations from heart and kidney. The deficits in receptor binding were associated with marked subsensitivity of chronotropic responses to administration of a beta-adrenergic agonist, isoproterenol. Although the effects on receptor binding resolved after weaning, functional deficiencies in responsiveness to isoproterenol or to preganglionic electrical stimulation of sympathetic nerves to the heart persisted into adulthood. These results indicate that prenatal exposure to nicotine produces long-term alterations in adrenergic responsiveness of sympathetic target tissues.
Aging↗
Effect of intrathecal amino acid receptor antagonists on basal blood pressure and pressor responses to brainstem stimulation in normotensive and hypertensive rats.
The importance of spinal cord amino acid receptors in the regulation of blood pressure was investigated in normotensive (Wistar Kyoto, WKY), spontaneously hypertensive (SHR), and stroke-prone spontaneously hypertensive (SPR) rats. Also investigated was the possible role of these spinal cord receptors in mediating pressor changes evoked by electrical stimulation of two separate areas of the rostral ventrolateral medulla (RVLM) containing different neuronal populations, either the adrenaline-containing C1 area or the serotonin-containing B3 area. Intrathecal administration of the amino acid receptor antagonist kynurenate (KYN), or the selective N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (2APV), reduced basal blood pressure in anesthetized SHR and SPR in a dose-dependent manner, but were ineffective or elicited only small decreases in WKY. In all three strains, electrical stimulation in RVLM, in either the C1 or B3 area, evoked frequency-dependent pressor responses. Administration of 2APV or KYN was effective in attenuating these pressor responses in all three strains of rats. The effects of stimulation in the RVLM-B3 area were virtually abolished by administration of 2APV followed by the serotonin receptor antagonist methysergide. The results suggest that spinal cord excitatory amino acid receptors are important in blood pressure regulation in rats. Amino acid receptors, perhaps of the NMDA subtype, appeared to mediate pressor responses to stimulation of the RVLM-C1 and RVLM-B3 regions in both normotensive and hypertensive animals. On the other hand, excitatory amino acid receptor antagonists reduced basal blood pressure only in the hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
2-Amino-5-phosphonovalerate↗
Evaluation of selective liver denervation methods.
This study compares four methods of hepatic denervation and defines the rate and physiological significance of reinnervation. Five groups of rats were prepared: 10 underwent orthotopic liver transplantation. In nine rats a 90% aqueous phenol solution was applied circumferentially to the portal vein. Thirteen rats underwent microsurgical denervation; 28 received different doses of 6-hydroxydopamine (6-HODA) administered as a single intraportal injection [50 (n = 10), 75 (n = 6), and 100 mg/kg (n = 6)]. Twelve rats were studied as controls. Rats were killed 1, 4, and 8 wk after surgery to determine liver tissue content of norepinephrine (NE). Changes in mean arterial pressure (MAP) in response to hepatic nerve stimulation, which was supramaximum in intensity and frequency, were measured before rats were killed. NE content in controls ranged from 121 to 204 ng/g and MAP increased by 30-38 mmHg after electrical stimulation. At 1, 4, and 8 wk after treatment the liver NE content was less than 1, 2.3, and 20.2 ng/g in the transplant group; less than 1, 2.7, 4.1 ng/g in the phenol group; and 17.2, less than 1, and 3 ng/g in the surgically denervated group. In the 6-HODA group, values were 18.9, 47, and 61.5 ng/g (50 mg/kg); 5.7, 20.2, and 15 ng/g (75 mg/kg); and 7.7, 2.5, and 17.5 ng/g (100 mg/kg). When the level of NE was undetectable, MAP increase after stimulation was 0-18% that of controls. When NE content was 15-23% of normal, MAP increased 49-62% regardless of the denervation technique.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cerebral venous oxygen content as a measure of brain energy metabolism with increased intracranial pressure and hyperventilation.
In order to test the hypothesis that the cerebral arteriovenous oxygen difference (AVDO2) and venous oxygen content (VO2) could be used to monitor brain energy metabolism in the setting of increased intracranial pressure (ICP). 12 cats were studied with 31P-magnetic resonance spectroscopy. six cats were subjected to intracranial hypertension by cisternal infusion of saline. Energy failure occurred at an average AVDO2 of 8.4 +/- 3.2 vol% (+/- standard deviation) (range 4.7 to 14.7 vol%). The VO2 at the point of metabolic failure averaged 1.45 +/- 0.6 vol% and extended over a narrower range (1.0 to 2.9 vol%). In an additional six cats, ICP was raised to the threshold of metabolic failure and hyperventilation was then instituted (pCO2 10 to 18 torr). Five of the six cats experienced a drop in VO2 with hyperventilation. In two of these animals, hyperventilation resulted in a VO2 of 1.1 vol% or less and in metabolic failure as evidenced by a fall in phosphocreatine. It is concluded that a VO2 of less than 2 vol% is correlated with brain ischemia and that the safety of hyperventilation in the setting of increased ICP can be monitored by the use of VO2.
Animals↗
Development of the sympathetic nervous system response to endotoxicosis in the rat: importance of non-baroreflex mechanisms in pre-weanlings and adults.
The sympathetic nervous system response to endotoxicosis was studied in the rat at ages before (11-12 days) and after (19-20 days) maturation of the baroreflex and in adults by recording preganglionic impulses during i.v. infusions of endotoxin (S. enteriditis). At all ages, the discharge rate increased before there was any decrease in arterial blood pressure. The magnitude of the increase (65%) was the same in 11-12 days-old and adult rats while 19-20 days-old rats were hyperactive (278% increase). Subsequently, in the hypotensive phase of the endotoxicosis (diastolic pressure decrease 50-60%) there was an additional increase in discharge in the 19-20 days- old rats (43% and in adults (70%) but not in 11-12 days-old rats. The hypotensive discharge rate of the 11-12 days-old rat reached only 20% of the maximum; it reached 80% in the hyperactive 19-20 days-old rat and 65% in adults. At all ages, the elevated hypotensive discharge rate persisted after steady state blood pressure was raised by infusing dextran. The discharge rate was diminished transiently during pressor responses to accelerated infusion or bolus injections of dextran. The conclusions are: (i) endotoxic stimulation of sympathetic outflow is initiated by a non-baroreflex mechanism in adult as well as in pre-weaning rats; (ii) there is added stimulation during hypotension after the baroreflex is mature, but (iii) the non-baroreflex stimulation continues to excite the preganglionic neurons and obtunds baroreflex feedback inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Vectors, promoters, and expression of genes in chick embryos.
Transgenic chickens were produced by injecting the Day-1 egg with 10(5) infectious particles of a replication-competent virus based on the Schmidt-Ruppin A strain of Rous sarcoma virus. The chickens were resistant to transforming subgroup A virus containing the src gene but not the corresponding subgroup B virus. Transgenic chickens producing bovine growth hormone (bGH) were generated using a modified virus containing the Bryan high titre polymerase gene. The virus was constructed with the bGH gene and the mouse metallothionein promoter in the reverse orientation relative to the viral structural genes. Two male chickens produced serum concentrations of approximately 100 ng bGH/ml; the birds were larger than controls and matured more rapidly. Transgenic mice required for the analysis of skeletal muscle-specific expression in vivo were produced using 5'-flanking regions of the chicken alpha-skeletal actin promoter linked to a luciferase reporter gene to determine the region essential for tissue-specific expression. The defined promoter sequences are to be used in experiments designed to direct expression of growth-promoting genes in skeletal muscle of chickens.
Animals↗
Non-neurogenic stimulation of adrenomedullary secretion during endotoxicosis in the one day old rat.
In both newborn and twenty day old rats, bacterial (S. enteritidis) endotoxin caused a marked decrease in adrenal epinephrine and norepinephrine. Catecholamine release was prevented by ganglionic blockade in 20 day old, but not 1 day old animals, indicating that the release in the neonatal rat is "non-neurogenic." The amount released was physiologically significant: equivalent to 20 micrograms/kg by i.v. administration. Two possible mechanism known to promote non-neurogenic secretion are hypoxia or histamine release, both of which can occur during endotoxicosis.
Adrenal Medulla↗
Central serotonergic mechanisms in hypertension.
Serotonin-containing neurons in the central nervous system are grouped into a number of discrete and distinctive collections with cell bodies in the brainstem and projections passing to many regions of the brain and spinal cord. Evidence is presented that activation of one projection of serotonin-containing neurons from the midbrain to the hypothalamus elevates arterial pressure. Evidence is also presented that activation of a projection descending from the lateral B3 serotonin cell group to the spinal cord elicits a pressor response that is accompanied by increased release of serotonin in the spinal cord and is independent of the C1 adrenaline-containing neurons that lie close by. In contradistinction, experiments are described demonstrating that activation of the midline group of B3 serotonin cells in the raphe nucleus causes a fall in arterial pressure, consistent with the view that different groups of serotonin neurons in the brain and spinal cord participate in the control of blood pressure in diverse ways and can have different effects on blood pressure. Finally, experiments are described showing that the hypotensive action of methyldopa is mediated in part through central serotonin nerves.
5,7-Dihydroxytryptamine↗
Pressor mechanisms linked obligatorily to spontaneous hypertension in the rat.
To identify genetic factors linked obligatorily to hypertension in the rat, pithed spontaneously hypertensive rats (SHR) were compared with genetically similar (Wistar-Kyoto rats; WKY) and different (Sprague-Dawley) normotensive strains. The only variables that distinguished SHR from both WKY and Sprague-Dawley rats were a greater maximum pressor response to electrical stimulation of sympathetic outflow and decreased sensitivity to submaximal doses of the alpha 1-adrenergic agonist methoxamine (i.e., higher ED50). SHR had in common with Sprague-Dawley rats basal blood pressure after pithing plus adrenalectomy and the maximum pressor response to methoxamine; both these values were higher than those in WKY. All strains demonstrated equal sensitivity of the vasoconstrictor response to endogenous norepinephrine released by electrical simulation at submaximal frequency, even though sensitivity to the alpha 1-adrenergic receptor agonist was lower in SHR. The alpha 2-adrenergic receptor antagonist rauwolscine attenuated the pressor response to electrical stimulation in SHR and WKY but increased it in Sprague-Dawley rats. The alpha 1-adrenergic receptor antagonist prazosin attenuated the response more in SHR and WKY than in Sprague-Dawley rats. We conclude that 1) sympathetic hyperactivity is linked obligatorily to hypertension in SHR; 2) increased basal blood pressure and noradrenergic vasoconstrictor response are present in SHR, but they are not obligatorily linked to hypertension; 3) feedback inhibition of norepinephrine release is comparable in SHR or WKY and poorly developed compared with that in Sprague-Dawley rats; 4) decreased sensitivity of the pressor response to stimulation of vascular alpha 1-adrenergic receptors in SHR compensates partially for increased sympathetic activity or hyperinnervation, or both.
Animals↗
Development of prejunctional alpha 2 adrenergic receptor mediated feedback control of the pressor response to sympathetic nerve stimulation in hypertensive and normotensive rats.
Development of prejunctional alpha 2 adrenergic receptor inhibition of pressor responses to sympathetic nerve stimulation in the spontaneously hypertensive Wistar-Kyoto rat was compared with genetically similar (Wistar-Kyoto) and different (Sprague-Dawley) normotensive rats. The sympathetic outflow was stimulated at frequencies of 1 to 20 Hz in pithed rats at 10,14,20 and 60 days of age. The antagonist, rauwolscine was given to block alpha 2 mediated feedback inhibition of noradrenaline release and the incidence of enhanced pressor responses determined. In Sprague-Dawley but not in spontaneously hypertensive or Wistar-Kyoto rats the changes in the incidence of enhanced responses parallel development of indices of sympathetic activity in other studies of the rat. Thus at 10 days of age (when activity is low), the incidence of rauwolscine-enhanced responses was 45%; at 14 days, (coinciding with onset of baroreflex control), incidence fell to 14%; in the 3rd postnatal week (when there is sympathetic hyperactivity), incidence increased to greater than 90%; finally, incidence, like activity declined in adults. In Wistar-Kyoto rats, the incidence of enhanced responses was like the other strains at 10 days but then decreased during development. In spontaneously hypertensive rats, enhanced responses were also less evident during week 3 and greatly diminished in adults. We conclude that in the spontaneously hypertensive and normotensive variants of Wistar-Kyoto strain rats the limit of alpha 2 adrenergic receptor feedback control of noradrenaline release is reached prematurely and is attenuated relative to the level of neuronal activity. In keeping with this hypothesis, the basal rate of noradrenaline utilization (measured in kidney) was higher at 20 days in Wistar-Kyoto than in Sprague-Dawley, but Sprague-Dawley showed greater enhancement of noradrenaline level and utilization after rauwolscine. Thus, the limitation to feedback control may be in development of prejunctional alpha 2 adrenergic receptors and/or their coupling to transmitter synthesis and release. Attenuated prejunctional alpha 2 adrenergic receptor inhibition is not linked obligatorily to development of hypertension in the spontaneously hypertensive Wistar-Kyoto rat.
Animals↗
Reinnervation of Müller's smooth muscle by atypical sympathetic pathways following neonatal ganglionectomy in the rat: structural and functional investigations of enhanced neuroplasticity.
Müller's extraocular smooth muscle is reinnervated by sympathetic nerves following denervation by ipsilateral superior cervical ganglionectomy in neonates but not in older animals. Experiments were performed to determine: (1) the source and extent of reinnervation, (2) the role of impulse activity in sympathetic outgrowth and (3) the effects of reinnervation on smooth muscle maturation. Müller's muscles were evaluated structurally (muscle volume, catecholamine histochemistry, retrograde labeling of sympathetic neurons) and functionally (contractile responses to electrical stimulation of postganglionic innervation and adrenoceptor agonist) in control preparations and in muscles following neonatal ipsilateral superior ganglionectomy, ipsilateral decentralization, ipsilateral superior ganglionectomy combined with contralateral decentralization of chemical (guanethidine) sympathectomy. Fluorescent tracer injections of muscles in adult control rats labeled cells in the ipsilateral superior (98%) and middle cervical ganglia. Acute ipsilateral superior ganglionectomy produced complete degeneration of sympathetic innervation of Müller's muscle in neonatal and adult rats. In preparations denervated neonatally and maintained chronically, muscles were reinnervated by neurons in both the contralateral superior and ipsilateral middle cervical ganglia. The total number of neurons reinnervating the muscle was one half that of controls. Sectional density of innervation was 45% of control. Electrical stimulation of postganglionic axons in the contralateral pathway produced muscle contractions with a prolonged time course. Reinnervation alleviated, in part, deficits in muscle volume and contraction which occurred following sustained denervation by chemical sympathectomy. Decentralization decreased ipsilateral muscle volume but did not affect numbers of neurons projecting to or nerve density within the muscle. Stimulation frequencies required to produce a 50% maximum contraction were reduced in these preparations. Decentralization of the contralateral ganglion did not impede sprouting into the denervated muscle, as nerve density and number of labeled cells were comparable to muscles reinnervated by contralateral ganglia with intact preganglionic innervation. However, maximum contraction to electrical stimulation was reduced. Comparisons with ipsilaterally decentralized muscles revealed that increased stimulation frequencies were required for 50% maximum contraction.(ABSTRACT TRUNCATED AT 400 WORDS)
Adrenergic Fibers↗
Mechanisms of adrenergic control of blood pressure in developing rats.
The rat is a species in which the sympathetic nervous system (SNS) is highly immature at birth. Blood pressure was measured directly in anesthetized preparations starting on the first postnatal day (days 1, 5, 9, 20, 40, 55, and 85), and pharmacological tests were used to evaluate the functional development of the vasomotor nerves (maximum pressor response to tyramine), the sensitivity of the vasculature to direct stimulation of alpha 1-adrenoceptors (maximum and 50% effective dose of methoxamine pressor response), and relative magnitude of the SNS contribution to resting blood pressure (hypotensive response to ganglionic blockade divided by resting blood pressure). The SNS contribution was not significant on postnatal day 1, but the relative magnitude was comparable to the adult by the end of the first postnatal week. During week 1 the vasomotor nerves were functionally immature (tyramine response was 48% of mature value on day 5), and the vasculature was supersensitive to alpha 1-adrenoceptor stimulation (154% of mature value). Conversely, in postnatal weeks 2 and 3, when the developing SNS is known to be hyperactive, the vasculature was subsensitive to noradrenergic stimulation (60-70% of adult). The net effect was to attenuate the SNS contribution to resting blood pressure during this period (55% of adult value). We conclude that there is an inverse relation between the level of tonic SNS activity and vascular sensitivity to noradrenergic stimulation in the developing rat. Supersensitivity may be critical for cardiovascular adjustments to asphyxia perinatally when the vasomotor nerves are functionally immature; subsensitivity may act homeostatically to prevent hypertension during the developmental period when SNS is hyperactive.
Animals↗
Physiological and ultrastructural observations on regenerated carotid sinus nerves after removal of the carotid bodies in cats.
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Action Potentials↗
Time course for development of vagal inhibition of the heart in neonatal rats.
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Aging↗