Intact Sympathetic Innervation Research Articles

Mechanism of the ocular hypotensive action of ketanserin.

Ketanserin has been characterized as a relatively selective antagonist for serotonin (5-HT2) receptors. However, recent evidence suggests that ketanserin can also antagonize activity at alpha 1-adrenoceptors. Topically applied ketanserin lowered intraocular pressure (IOP) in rabbits, cats, and monkeys. Ketanserin also suppressed ocular hypertension induced by waterloading and the IOP recovery rate in response to hypertonic saline. In contrast, the ocular hypotensive activity of ketanserin was markedly attenuated in sympathectomized (SX) rabbits. In the cat nictitating membrane, ketanserin produced dose-related inhibition of contractions elicited by neuronal stimulation and by intra-arterial injection of norepinephrine. These data demonstrate that ketanserin: 1) lowers IOP more effectively in eyes with intact sympathetic innervation than in SX eyes, 2) appears to lower IOP by suppressing aqueous inflow, and 3) acts primarily by antagonizing the action of norepinephrine on alpha 1-adrenoceptors.

Cervical ganglionectomy alters the circadian rhythm of intraocular pressure in New Zealand White rabbits.

A circadian rhythm of intraocular pressure in rabbits could provide a useful model for understanding the daily rhythm of intraocular pressure in humans and for studying mechanisms which regulate intraocular pressure. Our results confirm earlier work showing that New Zealand White rabbits housed in an environment with a lighting cycle of 12 hours light and 12 hours dark have a rhythm of intraocular pressure, and that this rhythm persists in constant dark. We show further that the cycle of light and dark is the zeitgeber for entrainment of the rhythm of intraocular pressure, and therefore persistence of this rhythm in constant dark establishes it as a circadian rhythm. Cervical ganglionectomy demonstrated that intact sympathetic innervation to the eye is required for maintenance of the normal circadian rhythm of intraocular pressure in rabbits. Intraocular pressure in sympathectomized eyes is no different from control eyes during the light, but is significantly reduced during the dark.

Whole body and hindlimb cardiovascular responses of the anesthetized dog during CO hypoxia.

To compare with earlier studies of anemic hypoxia obtained by hemodilution, O2 carring capacity was decreased by carbon monoxide (CO) hypoxia. Arterial O2 content was reduced either 50% (moderate CO) or 65% (severe CO). In two groups of anesthetized dogs (moderate and severe CO) hindlimb innervation remained intact while in a third group (moderate CO) the hindlimb was denervated. Measurements were obtained prior to and at 30 and 60 min of CO hypoxia. Cardiac output was elevated at 30 min of CO hypoxia in all groups (p less than 0.01) and in the severe CO group at 60 min (p less than 0.01). Hindlimb blood flow remained unchanged during CO hypoxia in the intact groups. In the denervated group, hindlimb blood flow was greater (p less than 0.05) than that in the intact groups throughout the experiment. A decrease in mean arterial pressure (p less than 0.01) in all groups was associated with a fall in total resistance (p less than 0.01). Hindlimb resistance remained unchanged during moderate CO hypoxia in the intact group but increased (p less than 0.05) in the denervated group. In the severe CO group hindlimb resistance was decreased (p less than 0.05) at 60 min. The results indicate that the increase in cardiac output during CO hypoxia was directed to nonmuscle areas of the body and that intact sympathetic innervation was required to achieve this redistribution.

Release of histamine by sympathetic nerve stimulation in the guinea pig heart and modulation of adrenergic responses. A physiological role for cardiac histamine?

Histamine has been reported to attenuate adrenergic responses in cardiovascular tissues. In guinea pig atria preloaded with [3H]norepinephrine, histamine diminishes the field stimulation-induced efflux of radioactivity; this effect has been attributed to an inhibition of norepinephrine release from nerve endings. To assess the possible physiological relevance of these findings, we have reinvestigated the effects of histamine on cardiac sympathetic responses and on the release of endogenous norepinephrine in the guinea pig heart isolated with its intact sympathetic innervation. Heart rate, left ventricular contractile force, and perfusion pressure all increased with increasing frequencies of sympathetic nerve stimulation (2-8 Hz). Histamine (3 X 10(-8) to 3 X 10(-7) M) caused dose-dependent attenuation of the responses to sympathetic stimulation. The ability of histamine to modulate nerve stimulation-induced norepinephrine overflow into the coronary effluent was dependent on whether the heart had been preloaded with norepinephrine. Whereas histamine did not cause a significant reduction in nerve stimulation-induced norepinephrine overflow in hearts from untreated animals, histamine significantly reduced stimulation-induced norepinephrine overflow in hearts from guinea pigs that had been pretreated with norepinephrine before sacrifice. Histamine also attenuated the increases in left ventricular contractile force, perfusion pressure, and heart rate, which result from the intracardiac administration of norepinephrine (0.16-microgram bolus injection). In this respect, histamine was as effective as it was in inhibiting the responses elicited by nerve stimulation. Thus, in normal animals, the negative modulatory effect of histamine on adrenergic responses can be attributed largely, if not totally, to a postjunctional mechanism. In contrast, a prejunctional action of histamine may contribute significantly to the negative modulation observed in norepinephrine-preloaded hearts. Since we have observed a large increase in the amount of endogenous histamine present in the coronary effluent after sympathetic stimulation (930 pg during the 30 seconds poststimulation vs. 240 pg during 30 seconds prestimulation), as well as a prolongation of nerve stimulation-induced cardiac responses in the presence of the H2 receptor antagonist tiotidine, we postulate that histamine plays a physiological role as a modulator of sympathetic responses in the heart.

Effect of guanethidine sympathectomy on intake and body weight of intact and LHA-lesioned rats

The present study investigated the role of direct sympathetic nervous system innervation of the viscera in the reduced body weight levels maintained by animals bearing lesions of the lateral hypothalamic area (LHA). Adult, male rats with, and without, electrolytic lesions of the (LHA) were treated with guanethidine sulphate (25 mg/kg IP daily for 6 weeks) to produce destruction of the peripheral sympathetic nervous system. LHA-lesioned rats displayed the expected reduced body weight compared to intact rats. Sympathectomy in lesioned rats resulted in an identical pattern of effects to that seen in intact rats. Transitory reductions in intake were effected and weight was significantly depressed by one week of guanethidine treatment. However, weight had recovered to control levels in both intact and lesioned drug-treated groups by the end of the experiment. The reduced body weight level maintained by LHA-lesioned rats was not altered by guanethidine sympathectomy. The major conclusions are (1) the reduced body weights maintained following LHA lesions are not dependent upon an intact sympathetic nervous innervation of visceral organs, and (2) peripheral sympathectomy in intact adult rats has no chronic effects on either body weight or food and water intake.

The importance of an intact sympathetic innervation for the differentiation of the beta-adrenoceptor subtypes in the rat parotid gland.

Acinar cells of the rat parotid gland are in intimate contact with adrenergic nerves, arousing from the ganglion cervicale superior (Bloom et al. 1977). The sympathetic nerves or circulating catecholamines exert their effects by activating α‐adrenoceptors (electrolyte and water secretion) or β‐adrenoceptors (enzyme secretion) (Batzri et al. 1971, Carlsöö et al. 1981). It is now well established that the β‐adrenoceptors can be divided in two subclasses, β1 and β2, present in different proportions depending on the tissue examined (Lands et al. 1967, Carlsson et al. 1972, Barnett et al. 1978, Minneman et al. 1979a). The concentrations of the two subtypes are regulated independently (Minneman et al. 1979b) and their molecular structure seems to be different (Venter et al. 1981). The β1, ‐subtype is dominating in normal rat parotid glands (Carlsöö et al. 1981, Ludford & Talamo 1980). Supersensitivity occuring in salivary glands after interruption of the sympathetic nerve supply in adult animals is usually associated with an increased number of the β‐adrenoceptors (Ludford & Talamo 1980, Stefano & Perec 1981). In the present work we have studied the effect of neonatal sympathetic denervation of the rat parotid gland on the binding of the β‐adrenoceptor radioligand 3H‐dihydroalprenolol (3H‐DHA) and on the β‐adrenoceptor‐induced amylase secretion. The results suggest that the normal dominance of the β1‐adrenoceptors is lost after neonatal sympathetic denervation. Hence, an intact sympathetic nervous system may be of major importance during the development of the β‐adrenoceptor population.

Sympathetic nerves exert a chronic influence on the intact vasculature that is age related.

The hypothesis of this study is that the chronic presence of intact sympathetic innervation influences the structure, and thereby function, of the rabbit ear vascular bed, and that this influence may be age related. Therefore we examined the effect of chronic sympathetic denervation on vascular resistance of the rabbit ear nine to ten weeks after unilateral superior cervical ganglionectomy. Two age groups were studied: growing juvenile rabbits denervated at 4 weeks of age and adult rabbits denervated at 16 weeks. We assessed the flow-pressure (resistance) curves of the chronically denervated and contralateral innervated isolated rabbit ears during maximum dilation. The flow-pressure curve was significantly shifted downward in the denervated compared to the contralateral innervated ears of juvenile rabbits operated on at 4 weeks (p less than 0.001) but was not different in adult rabbits operated on at 16 weeks. These results support the concept that the sympathetic nerves chronically influence blood vessel properties in growing animals, apart from their acute effect on vasomotor tone.

Increased activity of carotid sinus baroreceptors by sympathetic stimulation and norepinephrine.

Effects of electrical stimulation of sympathetic nerves to the carotid sinus on the discharge of single active baroreceptor fibers of the rabbit were examined in situ and in functionally isolated carotid sinus preparations with an intact sympathetic innervation under controlled conditions of pressure and temperature. Among 30 single units, 18 units responded to sympathetic stimulation of increasing discharge frequency. The excitatory effect of sympathetic stimulation on baroreceptor activity was not abolished by phentolamine (1 mg/kg iv or 10(-6) g/ml in perfusate). In isolated carotid sinus preparations perfused with Krebs-Henseleit solution, various pressure steps were applied to the sinus, and effects of norepinephrine (NE; 10(-9) and 10(-6) g/ml) on activity of nine single baroreceptor units were examined. In the presence of 10(-9) g/ml NE, discharge frequency of all units significantly increased at a given pressure step when compared with the control, whereas NE at a high concentration (10(-6) g/ml) did not produce significant changes in the discharge frequency. It is concluded that NE released by sympathetic nerve endings most likely acts directly on the baroreceptor nerve endings and sensitizes them.

Effects of selective inhibition of type A and type B monoamine oxidase on intraocular pressure in the cat and the rabbit.

Ocular tension of conscious cats and rabbits was measured after topical application of clorgyline, a selective inhibitor of type A monoamine oxidase, or deprenyl, a selective inhibitor of line (1,4 and 12%) showed a dose-related reduction of intraocular pressure, with maximal lowerings amounting to 6 to 7 mm Hg. Pretreatment of eyes with clorgyline, 1%, markedly potentiated the pressure lowering response to epinephrine, 0.1%, applied topically. Sympathetic denervation almost completely abolished the effect of clorgyline. In contrast, deprenyl (2 to 8%) did not lower intraocular pressure after topical application to cat or rabbit eyes. beta-Phenylethylamine (2 to 16%) a specific substrate for the B form of monoamine oxidase, likewise did not lower ocular tension when given either alone or after pretreatment with deprenyl. These findings suggest that the intraocular pressure lowering effect of monoamine oxidase inhibitors is due primarily to inhibition of the A form of the enzyme and is dependent on intact sympathetic innervation.

Causes of erectile dysfunction

Normal male erection depends upon a combination of factors including normal cortico-sensory perception, intact spinal pathways, normal parasympathetic and sympathetic peripheral nerve innervation, normal blood supply, both arterial and venous to the penis and normal corpora cavernosa. It is obvious, therefore, that disturbances in any of the above components might result in loss of erectile function. It is useful for the clinician to try to identify the cause of erectile function in a particular patient. While these basic anatomic pathways are the prerequisite for normal male sexual function, they in turn depend upon specific hormonal and biochemical support for their integrity.

THE INFLUENCE OF HORMONAL AND NEURONAL FACTORS ON RAT HEART ADRENOCEPTORS

1 The influence of hormonal and neuronal factors on adrenoceptors mediating increased cardiac force and rate of contraction were studied in rat isolated atria. The pharmacological properties of these receptors were deduced from the relative potencies of agonists and from the effects of selective alpha- and beta-adrenoceptor antagonists. The numbers and affinities of alpha- and beta-adrenoceptors were also determined by radioligand binding to ventricular membrane fragments.2 Hypophysectomy reduced the inotropic potency of isoprenaline and increased the potency of phenylephrine and methoxamine in left atria. The effect of phenylephrine was inhibited by propranolol less effectively and by phentolamine or phenoxybenzamine more effectively in hypophysectomized than in control rats. The difference in block was smaller at low than at high antagonist concentrations. Similar but smaller changes were observed for chronotropic responses of right atria.3 The decreased beta- and increased alpha-receptor response after hypophysectomy was similar to that observed earlier in thyroidectomized rats (Kunos, 1977). These changes developed slowly after hypophysectomy (>2 weeks), they were both reversed within 2 days of thyroxine treatment (0.2 mg/kg daily), but were not affected by cortisone treatment (50 mg/kg every 12 h for 4 days).4 Treatment of hypophysectomized rats for 2 days with thyroxine increased the density of [(3)H]-dihydroalprenolol ([(3)H]-DHA) binding sites from 27.5 +/- 2.7 to 45.5 +/- 5.7 fmol/mg protein and decreased the density of [(3)H]-WB-4101 binding sites from 38.7 +/- 3.1 to 18.7 +/- 2.5 fmol/mg protein. The affinity of either type of binding site for agonists or antagonist was not significantly altered by thyroxine treatment and the sum total of alpha(1)- and beta-receptors remained the same.5 Sympathetic denervation of thyroidectomized rats by 6-hydroxydopamine increased the inotropic potency of isoprenaline and noradrenaline and the blocking effect of propranolol, and decreased the potency of phenylephrine and the blocking effect of phenoxybenzamine to or beyond values observed in euthyroid controls. The density of [(3)H]-DHA binding sites was higher and that of [(3)H]-WB-4101 binding sites was lower in the denervated than in the innervated hypothyroid myocardium. Depletion of endogenous noradrenaline stores by reserpine did not significantly alter the adrenoceptor response pattern of the hypothyroid preparations and did not influence the density or affinity of [(3)H]-DHA and [(3)H]-WB-4101 binding sites.6 These results indicate that thyrotropin or steroids do not contribute to the reciprocal changes in the sensitivity of cardiac alpha(1)- and beta-adrenoceptors in altered thyroid states. These thyroid hormone-dependent changes are probably due to a parallel, reciprocal change in the numbers but not the affinities of alpha(1)- and beta-adrenoceptors. Reciprocal regulation of cardiac alpha(1)- and beta-adrenoceptors by thyroid hormones requires intact sympathetic innervation but not the presence of normal stores of the neurotransmitter.

Skin Wrinkling on Immersion of Hands

Skin wrinkling of the fingers following immersion in warm water depends on intact sympathetic innervation. It is abolished by lesions affecting both central and peripheral sympathetic pathways. It affords a simple and reliable clinical test of sympathetic function.

Phenoxybenzamine in Neurogenic Bladder Dysfunction After Spinal Cord Injury. I. Voiding Dysfunction

Phenoxybenzamine is a welcomed adjunct in the pharmacologic management of patients with neurogenic bladder dysfunction resulting from spinal cord trauma. Side effects are infrequent. Bladder balance was predictably and effectively achieved and maintained in patients with 1) lower motor neuron lesions, 2) upper motor neuron lesions and coexisting autonomic dysreflexia and 3) intact sympathetic innervation and upper motor neuron bladders. The response was unpredictable in patients with upper motor neuron lesions without coexisting dysreflexia.

Demonstration of alpha-adrenergic coronary control in different layers of canine myocardium by regional myocardial sympathectomy

The direct effects of sympathetic coronary innervation in conscious dogs were analyzed by comparison of myocardial blood flow in a sympathectomized section of the left ventricle with blood flow in another section of the same ventricle with intact sympathetic innervation. Regional myocardial sympathectomy was accomplished by a protocol of intracoronary application of 6-hydroxydopamine (6-OHDA). Regional adrenergic nerve function was checked by studies on accumulation, retention and stimulus-induced release of labelled norepinephrine together with studies on regional ventricular contractility during stellate ganglion stimulation. These tests demonstrated complete sympathectomy in the 6-OHDA-treated section and an unimpaired adrenergic nerve function in the untreated control section. In these dogs at rest, myocardial blood flow (MBF) was 66±14 ml/min·100 g in the left ventricular control section and 108±16 ml/min·100 g in the 6-OHDA-treated section. Transmural distribution of MBF was similar in these two sections: subendocardial MBF/subepicardial MBF was 1.28±0.17 in the control section and 1.36±0.12 in the 6-OHDA-treated section. Application of 1.0 mg/kg propranolol i.v. did not modify MBF and its distribution in either section. Following 1.0 mg/kg phentolamine i.v., MBF in the control section approached that in the 6-OHDA-treated sympathectomized section. These results demonstrate that a substantial α-adrenergic constrictive coronary tone is operative in the ventricular control section in these conscious dogs at rest, which is of similar magnitude in different layers of the left ventricular wall.

Control of amylase secretion in the rat parotid gland during feeding

The object was to determine the relative importance of the sympathetic and parasympathetic innervation of the rat parotid gland in (a) the secretion of amylase during natural feeding (b) the synthesis of amylase during fasting and (c) the production of saliva. Under Avertin anaesthesia, the preganglionic cervical sympathetic or auriculo-temporal nerve was sectioned on the right. Glands on the left acted as controls. Amylase was determined in gland homogenates prepared in aqueous Triton X-100. Sympathectomy markedly prevented the amylase depletion seen in control glands after 1–1 1 2 hr feeding in previously fasted animals, but did not impair resynthesis during fasting. Parasympathectomy also restricted amylase release during feeding, but to a smaller extent. This finding was attributed to the large reduction in salivary secretion rate. Sympathectomy did not reduce flow-rates in response to gustatory stimulation in conscious rats. A technique was developed which allowed saliva to be collected during feeding. Although Sympathectomy reduced the amylase concentration in saliva, the secretion of amylase under these conditions seemed less dependent upon an intact sympathetic innervation than in the gland analyses. The most probable explanation for this is that in rats with cannulated ducts the pattern of eating might be different from normal because of a drying of the mouth and discomfort when chewing and also that the duration of feeding was short.

Cardiovascular effects of prazosin in normotensive and genetically hypertensive rats.

1. The cardiovascular effects of prazosin, a new antihypertensive drug, were studied in normotensive and genetically hypertensive rats. 2. Prazosin, infused intra-arterially, lowered vascular resistance in the blood-perfused rat hind limb. This effect was dependent on the presence of intact sympathetic innervation to the limb; no direct vasodilatation was demonstrated. In this preparation prazosin infusion reduced vasoconstrictor responses to noradrenaline. 3. In the saline-perfused rat mesenteric artery preparation prazosin reduced responses to noradrenaline and sympathetic nerve stimulation but not those to serotonin and vasopressin. Prazosin was more potent than phentolamine, on a molar basis, in reducing the vasoconstrictor effects of noradrenaline. 4. A comparison of the effects of prazosin injected intravenously and into a lateral cerebral ventricle failed to show any central action of the drug on blood pressure. Experiments using the donor blood-perfused, vascularly isolated rat hind limb preparation confirmed that the sympatholytic effect of prazosin occurred within the limb itself.

The skin in magnesium-deficient rats.

The cutaneous vasodilatation occuring in the early stages of dietary deficiency of magnesium has been investigated in rats. While the time of onset of erythema varies in proportion to the weight of the animal, the duration is not related to weight. In severe states of vasodilatation, the skin is thickened and infiltrated with mononuclear cells, apparently derived from the blood. Intact sympathetic and sensory innervation are not necessary for the development of vasodilatation in the skin. Neither can the genesis of the erythema be attributed to degranulation of mast cells. From consideration of this and other investigations, it is concluded that the cutaneous abnormalities of magnesium-deficient rats cannot be due directly to hypomagnesaemia.

Effect of stimulation of carotid body chemoreceptors upon ganglioglomerular nerve activity and on chemoreceptor discharges in contralateral sinus nerve

The mammalian carotid bodies receive sympathetic innervation from the superior cervical ganglion. The purposes of the present study were: (10 to investigate whether sympathetic innervation influences the carotid body response to hypoxia, and, if so, (2) to determine the involvement fo adrenoceptors in these influence. Chemo-sensory activity was recorded from clearly identifiable action potentials form the carotid sinus nerve in 20 anaesthetized, paralyzed and artificially ventilated cats. Chemoreceptor responses to sustained isocapnic hypoxia (30 min, duration) were compared before and after carotid body sympathectomy (n = 8 cats). In response to low PCO2, chemoreceptor discharge increased during the first 10 min, and plateaued for the rest of the hypoxic challenge. After sympathectomy, chemoreceptor response in the initial 10 min was the same; whereas, the magnitude of the response in remaining 20 min was significantly greater than controls (P < 0.01). Systemic administration of SKF-86466, an α2-adrenoceptor antagonist augmented the hypoxic response by 805 n = 6 cats. Ini presence of α2-antagoonist, sympathectomy had no further effect on the hypoxic response, but the magnitude of potentiation was less than with intact sympathetic innervation (34% vs 80%; P < 0.01; n = 6 cats. From these results,it is concluded that (1) sympathetic innervation exerts an inhibitory influence on chemoreceptor response to sustained hypopxia, and (2) this inhibitory influence is mediated at least in part by α2-adrenoceptors. The inhibitory effects of sympathetic innervations could be of importance in the efferent regulation of the carotid body activity during sustained hypoxia.

Persistence of cerebral blood flow autoregulation following chronic bilateral cervical sympathectomy in the monkey.

AbstractThe cerebral blood flow was measured in 11 monkeys after step changes in arterial blood pres sure in the pressure range 30–140 mmHg. In one group of 5 animals a bilateral excision of the superior cervical ganglia was performed about 2 weeks prior to the experiment. These animals, as well as those with an intact sympathetic innervation of the cerebral vessels, demonstrated an almost constant rCBF at pressures above 50–60 mmHg, 2.e. both groups showed autoregulation. It is concluded that cervical sympathectomy does not abolish autoregulation of the cerebral blood flow.

Pineal and gonadal function in the rat following cervical sympathectomy.

The activity of the melatonin-forming enzyme, hydroxyindole-O-methyltransferase (HIOMT), is high in the pineals of rats kept in constant darkness and low in the glands of animals kept in constant light. The sympathetic innervation of the pineal is necessary to maintain this response to light. Following removal of the superior cervical ganglion (ganglionectomy) or section of the preganglionic fibers to the ganglion (decentralization), the pineal HIOMT response to light is lost. In addition, HIOMT levels after decentralization are significantly less than after ganglionectomy and these, in turn, are significantly less than constant-light, control levels. The decreases in pineal HIOMT content produced by ganglionectomy and decentralization are evident within 1 week and become maximal by 2 to 3 weeks after operation. Thereafter, they remain stable for at least 120 days. These data indicate that an intact sympathetic innervation to the pineal is necessary, not only for an HIOMT response to light, but, also, to maintain normal enzyme activity in the gland. The observation of a substantial decrease in HIOMT activity in the squirrel monkey pineal following decentralization suggests that this may be a more general phenomenon in mammals. Despite the effect on pineal HIOMT, denervation of the pineal does not alter the normal estrous cycle of the female rat kept in diurnal light, nor does it affect the alterations in estrous activity produced by prolonged exposure to constant light or blinding. These findings are in accord with the view that light-mediated alterations in pineal function are not essential in the rat to either the maintenance of normal estrous cycles or to estrous responses to conditions of continuous illumination.