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E Mills

Publications and source records attributed to E Mills.

At least 55 records · Page 3Linked to original sources
PubMed1988

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↗
PubMed1988

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↗
PubMed1988

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↗
PubMed1987

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↗
PubMed1987

Do pressor neurons in the ventrolateral medulla release amines and neuropeptides?

Activation of neurons arising in the rostral ventrolateral medulla evokes a pressor response in the rat and the rabbit. This region of the medulla gives rise to bulbospinal neurons containing many different neurotransmitters, including amines such as adrenaline, noradrenaline and serotonin, and neuropeptides such as substance P and neuropeptide Y. Colocalization of amines and neuropeptides has been described in some neurons descending from the rostral ventrolateral medulla. In this paper we discuss the evidence that bulbospinal serotonin-containing neurons (B3) and adrenaline-containing neurons (C1) arising from this part of the medulla exert pressor effects by distinct central pathways and conclude that they do. We also consider the possibility that the pressor effects of activating these two groups of neurons are associated with release of neuropeptides and highlight evidence that substance P is released into the spinal cord by activation of descending serotonin-containing neurons, while neuropeptide Y may be released by activation of bulbospinal adrenaline-containing neurons.

Animals↗
PubMed1986

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↗
PubMed1986

Development of adrenergic and nonadrenergic pressor mechanisms in rats sympathectomized from birth.

Rats were sympathectomized by administering guanethidine from birth through 50 days of age. Experiments were performed in vivo under anesthesia at 18, 25, 40, 60, 70 and 100 days of age to determine if sympathectomy (SNX) attenuated development of vascular noradrenergic contraction and the mechanisms that support mean arterial blood pressure (MAP) after SNX. The maximum and ED50 of the pressor response to the alpha-1 noradrenergic agonist methoxamine was used to test contractility. MAP support mechanisms were assessed indirectly by measuring hypotensive responses to sequential interventions: adrenalectomy, chlorisondamine (ganglionic blockade), phentolamine (alpha-1 and alpha-2 noradrenergic blockade), angiotensin II antagonist, arginine vasopressin antagonist and hydralazine (direct acting vasodilator). Guanethidine abolished the pressor response to tyramine-evoked norepinephrine release, decreased plasma norepinephrine 70% without change in epinephrine and decreased methoxamine ED50. Maxima of methoxamine pressor responses were comparable in sympathectomized rats and controls at all ages. Resting MAP was 7 to 20% lower in sympathectomized rats, but MAP after eliminating autonomic nerve influences was 27 to 36% higher. SNX abolished hypotensive responses to chlorisondamine and decreased responses to phentolamine. In contrast, there were increased responses to angiotensin II antagonist (70-240%), arginine vasopressin antagonist (250%) and hydralazine (50-300%). SNX did not change MAP measured after maximum dilation with hydralazine. We conclude that in rats sympathectomized from birth vascular noradrenergic contraction and intrinsic resistance develop normally, blood pressure is independent of circulating catecholamines from the adrenal or other sources although the vasculature is supersensitive and blood pressure support depends on an enhanced pressor influence of nonadrenergic vasoactive substances including angiotensin II and arginine vasopressin.

Angiotensin II↗
PubMed1983

Abnormal development of blood pressure and growth in rats exposed to perinatal injection stress.

Subcutaneous injections of alkaline saline were made perinatally in Sprague-Dawley rats according to two schedules. In a pre-/postnatal group, dams were treated from 19th gestational day to 9th day postpartum and pups from day 0-9. In a postnatal group, pups alone were injected from day 0-6. At 19-23, 50-56 and 82-86 days of age, injected rats and uninjected controls were anesthetized and arterial blood pressure measured. Rats from the pre-/postnatal group had higher blood pressures (58%) and body weights at 19-23 days and lower blood pressure (35%) and body weight at 82-86 days of age. Blood pressure and body weight were comparable to control at all ages in the postnatal injection group. It is concluded that as a result of the maternal stress produced by the injections there was a generalized disturbance of growth processes resulting in hypotension and decreased body weight in adulthood.

Aging↗
PubMed1983

Degenerative and regenerative changes in central projections of glossopharyngeal and vagal sensory neurons after peripheral axotomy in cats: a structural basis for central reorganization of arterial chemoreflex pathways.

Hypoxic hyperventilation in cats is a reflex normally initiated by afferent impulses originating in the carotid body and conducted to the brain stem by the carotid sinus nerves. The reflex response is abolished acutely after section of carotid sinus nerves and excision of the carotid bodies; but, chronically, there is a chemoreflex restoration which is mediated by the aortic body via the aortic depressor nerves. The restoration is associated temporally with changes in efficacy of ventilatory reflexes elicited by electrically stimulating carotid sinus and aortic depressor nerves, and these changes are postulated to reflect a central reorganization of the reflex pathways. In the present study, histological and ultrastructural techniques were used to investigate the neuroanatomical basis of the reorganization. The brain stem of the cat was examined using the Fink-Heimer silver stain to determine if degenerating axons were present following section of the carotid sinus nerve peripheral to its sensory ganglion. Degeneration was found 4-15 days postoperatively and the distribution of the axons corresponded with that reported for central projections of carotid sinus nerves labeled by transganglionic transport of horseradish peroxidase. The fine structure of nerve terminals in nucleus tractus solitarius was then examined with electron microscopy after cutting the vagus and glossopharyngeal nerves unilaterally peripheral to the sensory ganglia. Structural changes consistent with nerve terminal degeneration were observed 4-91 days postoperatively, and presumptive axonal sprouts were seen at 56-91 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗
PubMed1983

Functional development of the cervical sympathetic pathway in the neonatal rat.

Maturation of the cervical sympathetic innervation of the levator palpebrae smooth muscle was studied physiologically in vivo in the rat. Tonic pre- and postganglionic nerve activity and responses to centrally acting stimuli, asphyxia and hypoglycemia, were recorded. Development of functional capacity of the sympathetic nerve terminal-smooth muscle complex was assessed by measuring contractions evoked by directly acting noradrenergic agonists, endogenous nerve terminal norepinephrine released by tyramine, and electrical stimulation of preganglionic axons. Tonic preganglionic activity and responses to asphyxia and hypoglycemia were fully developed by the second postnatal day. Ganglionic neurotransmission, however, is not established until the end of the first postnatal week so that sympathetic outflow from the central nervous system (CNS) does not affect the nerve terminal-smooth muscle complex before this time. Functional capacity of the complex develops in a stepwise fashion with intervening plateau periods. There is an initial rapid increase before onset of ganglionic neurotransmission, and development to the mature level is attenuated only modestly by decentralization of the ganglion on the first postnatal day. It is concluded that conduction of impulses to the postganglionic neuron is not essential to initiate maturation of this nerve terminal-smooth muscle complex, that a significant degree of maturation occurs before ganglionic transmission is established, and that maturation to the adult level is usually largely independent of neural connections between the CNS and the postganglionic neuron.

Age Factors↗
PubMed1983

Paradoxical elevation of sympathetic activity during catecholamine infusion in rats.

Chronic infusion of norepinephrine (NE) or epinephrine in rats by an Alzet osmotic minipump (0.1 mg/kg/hr s.c.) caused a 40 mm Hg increase in systolic blood pressure with no change in heart rate. The administration of chlorisondamine or bretylium, drugs which inhibit sympathetic neuronal function by blocking ganglia and by inhibiting release of neuronal NE, respectively, decreased systolic blood pressure to the same level in NE-infused and vehicle-infused rats whereas heart rate increased only in NE-infused animals. Infusion of NE or epinephrine resulted in a marked elevation in the plasma level of the infused amine and a smaller elevation of its counterpart. Chlorisondamine caused a 30 to 70% reduction in plasma levels of NE and epinephrine during the infusion of these catecholamines. Acute infusion of NE at a rate which caused a slow pressor response was accompanied by an elevation of impulse frequency in the preganglionic cervical sympathetic nerve. In contrast, a faster rate of NE infusion which produced a more rapid pressor response was accompanied by the classical decrease in impulse frequency. These studies demonstrate that the maintenance of elevated blood pressure during catecholamine infusion in rats is dependent upon a paradoxical increase in the activity of the sympathetic nervous system.

Animals↗
PubMed1982

Abnormal functional development of sympathetic nerve terminal-smooth muscle complex in neonatal spontaneously hypertensive rats.

In neonatal and young adult SH and WK rats, maturation of a functional unit consisting of sympathetic nerve terminals and smooth muscle (levator palpebrae) was assessed in vivo by measuring the contractile response to tyramine, an agent which releases endogenous norepinephrine from sympathetic nerve terminals. Responses in SH are comparable to WK at 5-6 days postnatally, smaller from the 8th through 19th day and larger in young adults (41-46 days old). Results indicate that functional maturation of the nerve terminal-smooth muscle complex is retarded in SH relative to WK during the 2nd and 3rd postnatal weeks. It is suggested that retardation in the neonatal SH rat is an expression of a genetic defect in the growth of the complex and that the enhanced response in young adult SH is a consequence of the neonatal abnormality.

Age Factors↗
PubMed1982

Development of sympathetic ganglionic neurotransmission in the neonatal rat. Pre- and postganglionic nerve response to asphyxia and 2-deoxyglucose.

To determine the time course of development of neurotransmission in the sympathetic ganglion of the rat, pre- and postganglionic activity was recorded from the cervical sympathetic trunk in anesthetized neonatal and mature preparations. Tonic activity and responses to two stimuli, cellular hypoglycemia induced by 2-deoxyglucose and asphyxia, which are known to evoke CNS-mediated sympathetic activation in mature rats were measured. In 2-11-day-old neonates, tonic preganglionic activity recorded from the cervical sympathetic nerve and responses to hypoglycemia and asphyxia were comparable to or greater than that in mature rats. In 17-19-day-old neonates these variables were elevated to twice the adult value. In contrast, tonic postganglionic activity recorded from the internal carotid nerve was barely detectable through 5 days of age and there was no response to hypoglycemia. During asphyxia, maximum postganglionic impulse frequency and total number of impulses discharged were 10-20% of the mature value through the 5th postnatal day and the duration of the postganglionic response was only 25% of the preganglionic response. Tonic postganglionic activity and response to stimuli were equivalent to those in mature rats by the 10th postnatal day. The compound action potential evoked in the postganglionic axons by direct electrical stimulation was comparable in 4-5 and 10-13 day-old rats. In the concluded that functional ganglionic neurotransmission is established in the neonatal rat between the 5th and 10th postnatal day. The relation between biochemical changes associated with maturation of the postganglionic neuron, ganglionic synaptogenisis and neurotransmission is discussed. It is concluded that synaptogenisis and onset of neurotransmission are causally associated with development of CNS regulation of postganglionic activity and end organ response rather than with maturation of the postganglionic neuron and that cholinergic excitation of the postganglionic neuron adequate to evoke action potentials is not essential to initiate maturation of the neuron.

Animals↗