Nitric oxide and carbon monoxide in the brain pathology of heat stress.
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Animals↗
Biomedical subjects
P Alm
Publications and source records attributed to P Alm.
Size-selectivity of the glomerular barrier to high molecular weight proteins: upper size limitations of shunt pathways.
To evaluate the large pore radius of the glomerular capillary filter, plasma-to-urine fractional clearances of a number of endogenous proteins were assessed in normal and in nephrotic Wistar rats in which proximal tubular reabsorption had been inhibited using lysine. The proteins studied varied in radius from 16.2 A (Beta 2-microglobulin) to 90 A (alpha 2-macroglobulin). The nephrotic syndrome was induced by puromycin aminonucleoside (PAN). A marked restriction of the transport of large proteins across the glomerular capillary wall was found, indicating that there are no non-discriminatory 'shunt pathways' in the glomerular barrier. Rather, there seems to be large pores of radius 110 to 115 A accounting for the clearance of large proteins into the primary urine. This protein excretion pattern was almost the same for control and nephrotic rats, except that in the latter, the number of large pores was increased 170 times. The ratio between the number of large and small pores was calculated to be approximately equal to 7 x 10(-7) in normal rats and to 1.2 x 10(-4) in PAN nephrotic rats, assuming no classic shunt pathways. If classic shunt pathways had still existed, they would normally contribute to no more than approximately equal to 10(-5) of the total glomerular filtration rate. We postulate that very large macromolecules like IgM will not pass the glomerular filter at all under normal conditions, whereas the urine concentration of alpha2-macroglobulin will normally be extremely low.
Animals↗
Nitrergic and cholinergic innervation of the rat lower urinary tract after pelvic ganglionectomy.
The possible coexistence of nitric oxide (NO) and acetylcholine in the rat major pelvic ganglion (MPG) was examined by double immunohistochemistry using antisera raised against NO synthase (NOS) and choline acetyltransferase (ChAT). The smooth muscle responses of the isolated bladder and urethra were recorded after bilateral cryoganglionectomy of the MPG, focusing on the possible development of denervation supersensitivity. In the MPG, NOS immunoreactivity (ir) was seen in a large number of cell bodies, but it was not as abundant as ChAT-ir cell bodies. Double immunolabeling showed that all NOS-ir cell bodies also displayed ChAT-ir. In ganglionectomized bladders, the electrical field stimulation (EFS)-evoked contractile response was markedly reduced. When compared with control bladders, detrusor strips from ganglionectomized rats were more sensitive to carbachol as revealed by a lower negative logarithm of the drug concentration eliciting 50% relaxation (6.5 +/- 0.04 vs. 5.9 +/- 0.07). In the urethra, the NO-mediated relaxant response to EFS was practically abolished by ganglionectomy, whereas no difference was found in sensitivity to 3-morpholinosydnonimine hydrochloride (SIN-1). SIN-1 produced an equal increase in tissue levels of guanosine 3',5'-cyclic monophosphate in urethral preparations from control and ganglionectomized rats. The results suggest that the NOS-ir nerves that mediate inhibition of rat urethral smooth muscle tone originate from the MPG and contain ChAT. No denervation supersensitivity to nitrergic stimulation was observed in the urethra after ganglionectomy.
Acetylcholine↗
The nitric oxide synthase/nitric oxide and heme oxygenase/carbon monoxide pathways in the human ureter.
OBJECTIVE: To investigate the nitric oxide synthase (NOS)/nitric oxide (NO) and heme oxygenase (HO)/carbon monoxide (CO) pathways in the human isolated ureter. METHODS: Immunohistochemical studies were performed. NOS activity was measured by monitoring the conversion of [3H]-arginine to [3H]-citrulline. Functional inhibitory effects mediated by NO and CO were assessed, and correlated with cyclic nucleotide levels. RESULTS: The overall innervation of the ureter was moderate, however more prominent in the distal segment. Relative to overall innervation, neuronal NOS-immunoreactive (-IR) nerves were few. In the submucosa, neuronal NOS-IR varicose nerves were found closely together with varicose nerves containing calcitonin gene-related peptide immunoreactivity. In the distal ureter, nerve trunks were demonstrated, expressing immunoreactivity for HO-2. Ca(2+)-dependent NOS activity was 53 +/- 13 pM/mg protein/h. In isolated preparations, NO decreased endothelin-1-induced contraction in a concentration-dependent manner. In strips exposed to NO, there was a 6-fold increase of the cyclic GMP levels in comparison to control preparations (p < 0.001). CO exerted no effect on induced ureteral tone. CONCLUSIONS: Neuronal NOS- and HO-2-IR nerves can be demonstrated in the human ureter, where NO, but probably not CO, may contribute to the regulation of tone. Although the physiological roles for NO and CO remain to be established, the NOS/NO/cyclic GMP pathway may be a target for drugs producing relaxation of the human ureter. The richer innervation of the distal ureter may be of importance for the coordination of ureteral peristalsis and the motility of the ureterovesical junction.
Adolescent↗
Morphological relations between haem oxygenases, NO-synthase and VIP in the canine and feline gastrointestinal tracts.
Carbon monoxide (CO), produced by haem oxygenase (HO), has been suggested as a messenger molecule in the central and peripheral nervous systems. In the present study, we have investigated the occurrence of the two isoforms of HO, HO-2 and HO-1 in the canine and feline gastrointestinal tracts, including the small and large intestine and the gastrointestinal sphincters. An abundance of nerve cell bodies that contained immunoreactivity for HO-2 was found in the submucosal and myenteric plexuses. HO-2 immunoreactivity was frequently co-localized with nitric oxide synthase (NOS) or vasoactive intestinal peptide (VIP) immunoreactivities and was also observed in some nerve fibres, certain non-neuronal cells dispersed among smooth muscle bundles, and in vascular endothelium. The antiserum against HO-1 revealed immunoreactivity in nerve cell bodies in the enteric plexuses, in nerve fibres and in non neuronal cells in the smooth muscle layers. Some of the nerve structures were also NOS- or VIP-immunoreactive. These results demonstrate the presence of HO isoenzymes in nerves and other structures of the canine and feline gastrointestinal tracts and support the view that CO may have a role as a messenger molecule in the enteric nervous system.
Animals↗
Heme oxygenase and NO-synthase in the human prostate--relation to adrenergic, cholinergic and peptide-containing nerves.
In the human prostate, the distribution of heme oxygenase (HO-1 and HO-2)-, nitric oxide synthase (NOS)-, and tyrosine hydroxylase (TH)-immunoreactive (IR), acetylcholine-esterase (AChE)-positive, and some peptidergic nerve structures was investigated. Cell bodies and nerve fibers within coarse nerve trunks expressed HO-1-, HO-2-, NOS-, TH-, and vasoactive intestinal polypeptide (VIP)-immunoreactivities, and were AChE-positive, but, as revealed by confocal microscopy. HO- and NOS-immunoreactivities were found in separate nerves. Along strains of smooth muscle, intraglandular septa, and around acini, HO-1-, NOS-, and VIP-IR nerves, and AChE-positive fibers were observed. Double immunostaining showed that NOS- and VIP-immunoreactivities were generally co-localized in varicose nerve terminals. Some TH-IR terminals had profiles that were similar, but not identical, to those of NOS-, HO-1-, or VIP-IR terminals. NPY-IR nerves were similarly distributed as VIP- and NOS-IR fibers, and were found in rich amounts. Calcitonin gene-related peptide (CGRP)-IR nerves were few compared to other nerve populations studies. NOS- and CGRP-IR terminals had similar profiles, but the immunoreactivities were not co-localized. Nitric oxide and electrical stimulation of nerves relaxed noradrenaline-contracted preparations of prostatic stroma. Inhibition of synthesis of nitric oxide abolished the electrically induced relaxations. VIP had small relaxant effects, whereas carbon monoxide was without effect on noradrenaline-contracted strips. The innervation pattern and the functional effects suggest that the L-arginine/nitric oxide pathway may have a role in the control of human prostatic smooth muscle activity and/or in secretory neurotransmission. A physiological role of carbon monoxide in the prostate remains to be established.
Adrenergic Fibers↗
Involvement of nitric oxide in the pathophysiology of acute heat stress in the rat. Influence of a new antioxidant compound H-290/51.
The possibility that nitric oxide (NO) is involved in the pathophysiology of brain injury caused by heat stress (HS) was examined using immunohistochemistry of a constitutive isoform of neuronal nitric oxide synthase (c-NOS) in a rat model. In addition, to discover the role of oxidative stress in inducing c-NOS activity in HS, the effect of a new antioxidant H-290/51 on HS-induced expression of c-NOS immunoreactivity was examined. Subjection of conscious young animals to a 4-h HS in a biological oxygen demand (BOD) incubator at 38 degrees C resulted in marked upregulation of c-NOS in the cerebral cortex and hippocampus of stressed rats compared to normal rats kept at room temperature (21 +/- 1 degrees C). The c-NOS immunoreactivity was found in distorted neurons located in the edematous regions not normally showing c-NOS activity. Pretreatment with H-290/51 significantly attenuated the upregulation of c-NOS in animals subjected to HS, and the signs of neuronal distortion and edema were less pronounced. These results suggest that HS has the capacity to induce upregulation of c-NOS, and these effects can be reduced by prior treatment with H-290/51, indicating a possible neuroprotective effect of antioxidants in thermal brain injury.
Animals↗
Localization of nitric oxide synthase and haemoxygenase, and functional effects of nitric oxide and carbon monoxide in the pig and human intravesical ureter.
The distribution of nitric oxide synthase (NOS)-immunoreactive (IR) and haemoxygenase (HO)-IR nerves was investigated in the pig and human intravesical ureter (IVU). NOS activity was measured by monitoring the conversion of [3H]-arginine to [3H]-citrulline. Effects of NO and resulting changes in cyclic nucleotide concentrations were assessed in vitro. The effects of carbon monoxide (CO) on IVU motility was also tested. Immunohistochemistry revealed an abundant overall innervation of the IVU and numerous NOS-IR nerves. Nerve trunks were also found expressing immunoreactivity for HO-1, one of the enzymes synthetising CO. Similar profiles of nerve structures expressing immunoreactivities for NOS and tyrosine-hydroxylase (TH), as well as NOS and vasoactive intestinal peptide (VIP) were demonstrated. In the pig IVU, measurement of NOS activity revealed a moderate calcium-dependent catalytic activity, NO and the NO-donor SIN-1 reduced in a concentration-dependent manner serotonin-induced contractions of pig and human IVU, and the spontaneous contractions of pig IVU. In pig IVU strips precontracted with the thromboxane analogue U-46619, tetrodotoxin-sensitive relaxations were abolished by the NOS inhibitor NG-nitro-L-arginine. CO exerted no significant effect on spontaneous or induced contractions in the pig and human IVU. In precontracted strips of the pig and human IVU exposed to SIN-1 or NO, significant increases of cyclic GMP levels were measured in comparison to control preparations. The results suggest that the L-arginine/NO/cyclic GMP pathway may play a role in the regulation of the valve function in the uretero-vesical junction (UVJ). A role for CO in the UVJ has yet to be established.
Adult↗
Topical application of insulin like growth factor-1 reduces edema and upregulation of neuronal nitric oxide synthase following trauma to the rat spinal cord.
The neuroprotective effects of insulin like growth factor-1 (IGF-1) on spinal cord injury induced edema formation, cell changes and profound upregulation of constitutive isoform of neuronal nitric oxide synthase (cNOS) was examined in a rat model. A focal spinal cord injury produced by making a lesion (about 2 mm deep and 5 mm long) of the right dorsal horn of the T10-11 segment resulted in a marked edema formation, cell injury and upregulation of cNOS following 5 h after trauma. In separate groups application of IGF-1 (0.1 microgram/microliter) topically on the exposed spinal cord (T10-11) starting from 30 min before injury (20 microliter), immediately before injury followed by 30 min, 60 min and thereafter every 1 h after injury until sacrifice resulted in significant attenuation of edema formation and cell changes. Immunohistochemistry showed a less pronounced expression of cNOS in the T9 and T12 segments of the cord in IGF treated rats compared to untreated traumatised controls. These results for the first time show that IGF treatment is neuroprotective and this effects of the IGF appears to be mediated via inhibition of NOS upregulation.
Administration, Topical↗
Acute heat stress induces edema and nitric oxide synthase upregulation and down-regulates mRNA levels of the NMDAR1, NMDAR2A and NMDAR2B subunits in the rat hippocampus.
The influence of heat stress on constitutive isoform of neuronal nitric oxide synthase (cNOS) and NMDA receptor gene expression in hippocampus was examined in a rat model. Subjection of animals to 4 h heat stress at 38 degrees C resulted in a marked upregulation of cNOS in the hippocampus accompanied with a marked general expansion and edematous cell changes. On the other hand NMDA receptor messenger RNA encoding NMDAR1, NMDAR2A and NMDAR2B subunits showed a marked downregulation in the hippocampus of heat stressed rats compared to the controls. Our results show that upregulation of cNOS is instrumental in heat stress associated edema and cell injury. Furthermore, an increased production of NO as evident with upregulation of cNOS appears to be a key factor in the downregulation of NMDA receptor gene expression in heat stress.
Acute Disease↗
Nitric oxide synthase and vasopressin in rat circumventricular organs. An immunohistochemical study.
The distribution of immunoreactivity to neuronal nitric oxide synthase (nNOS) and vasopressin (AVP) was studied in the circumventricular organs of the female rat. The occurrence of NOS immunoreactivity showed correspondence to nicotinamide dinucleotide phosphate diaphorase reactivity, a previously used but less specific marker for neuronal NOS. nNOS immunolabeling was detected in the two most rostrally located circumventricular organs - the organum vasculosum of the lamina terminalis and the subfornical organ. In the latter, AVP immunoreactivity was observed in some cell bodies, which also were nNOS-immunoreactive. In the median eminence and the neurohypophysis there were large amounts of nNOS- and AVP-immunoreactive nerve fibers, which often displayed similarities in distribution and morphology. Within the pineal gland, only very few nNOS-immunoreactive varicose terminals were observed, which ran along blood vessels. nNOS immunoreactivity was also seen in the epithelium of the choroid plexus, whereas no nNOS immunoreactivity could be found in the subcommissural organ or in the area postrema. The present demonstration of nNOS and AVP immunoreactivity in the subfornical organ, median eminence, and neurohypophysis, and the occurrence of nNOS immunoreactivity also in the choroid plexus and organum vasculosum of the lamina terminalis, provides a morphological background for a functional role for nitric oxide in water homeostatic mechanisms, both as executed through the hypothalamohypophyseal system and via the production of cerebrospinal fluid.
Animals↗
Morphological and functional evidence against a sensory and sympathetic origin of nitric oxide synthase-containing nerves in the rat lower urinary tract.
To establish which type of nerves (parasympathetic, sympathetic or sensory) produce nitric oxide in the rat lower urinary tract, chemical denervation of primary afferents and sympathetic nerves was carried out by systemic treatment with capsaicin and 6-hydroxydopamine, respectively, followed by identification of neuronal nitric oxide synthase immunoreactivity. Functional in vitro studies were also performed to examine whether the synthesis and release of nitric oxide was affected following treatment with the respective neurotoxins. Nerve fibres immunoreactive for substance P and calcitonin gene-related peptide were found in control tissue, but could not be detected following capsaicin treatment. In comparison, nitric oxide synthase-immunoreactive fibres appeared to be unaffected by capsaicin treatment. Administration of 6-hydroxydopamine resulted in a complete disappearance of tyrosine hydroxylase-immunoreactive nerves, whereas nitric oxide synthase-containing nerve fibres did not appear to be affected by the treatment. In ultrastructural studies, nitric oxide synthase immunoreactivity, as studied by colloidal gold particles, was found in the axoplasm and not in association with intraneuronal structures or synaptic vesicles. Gold particles representing substance P immunoreactivity were seen as clusters associated with large granular vesicles. In consecutive sections of nerve fibres, substance P and nitric oxide synthase were not found in the same axon profile. In functional studies on urethral tissue, application of capsaicin (1 microM) produced a long-lasting relaxation. The nitric oxide synthase inhibitor NG-nitro-L-arginine (0.1 mM) had no effect on this response. Systemic treatment with capsaicin or 6-hydroxydopamine had no effect on nerve-evoked, nitric oxide-mediated relaxations. The data suggest that nitric oxide synthase-containing nerves in the rat lower urinary tract do not belong to nerve populations sensitive to either the sympathetic neurotoxin, 6-hydroxydopamine, or the sensory neurotoxin, capsaicin.
Acetylcholinesterase↗
Nitric oxide synthase immunoreactive nerves in rat and ferret salivary glands, and effects of denervation.
Nitric oxide has been implicated in mechanisms mediating nerve-evoked vasodilatory and secretory responses in salivary glands. In the present study, the occurrence and distribution of nitric oxide synthase (NOS)-immunoreactive nerves in ferret and rat salivary glands were investigated using immunocytochemistry with rabbit and sheep NOS antisera, and using NADPH-diaphorase enzyme histochemistry. In the parotid, submandibular and sublingual glands of the rat and the ferret, NOS-immunoreactive varicose terminals encircled acini and arteries of various sizes. In the ferret, collecting ducts were also supplied with NOS-immunoreactive fibres. In the rat, only the granular ducts of the submandibular gland were supplied with such fibres. The NOS-immunoreactive innervation of acinar cells was more abundant in the rat than in the ferret, whereas the opposite was true for the innervation of blood vessels. No NOS immunoreactivity was observed in the vascular endothelium. In both species, NOS-positive ganglionic cell bodies were found in the hilar regions of the submandibular and sublingual glands, whereas none could be detected in the parotid glands. NADPH-diaphorase reactivity had the same neuronal distribution as NOS immunoreactivity and, in addition, NADPH-diaphorase reactivity was expressed in ductal epithelium. Neither sympathetic denervation (by removal of the superior cervical ganglion) nor treatment with the sensory neurotoxin capsaicin reduced the NOS-immunoreactive innervation of the parotid gland. However, parasympathetic denervation (by cutting the auriculo-temporal nerve) caused an almost total disappearance of the NOS-immunoreactive innervation. The present findings provide a morphological background to the suggested role of nitric oxide in parasympathetic secretory and vascular responses of salivary glands.
Animals↗
Cardiovascular regulation by endogenous nitric oxide is essential for survival after acute haemorrhage.
Our previous studies have indicated that endogenous nitric oxide serves as a physiologically important inhibitor of vascular tone during acute haemorrhage. This vasodilator action attenuates the concomitant reflex adrenergic constriction and thereby prevents critical reduction of tissue blood flow. The present study aimed to evaluate the overall importance of this nitric oxide regulation for survival after acute haemorrhage. This was done by comparative observations of survival time and circulatory, metabolic and histopathological changes after an acute standardized lethal blood loss (45%) in cats exposed to nitric oxide synthase (NOS) inhibition and in matched control animals with intact nitric oxide regulation. NOS inhibition was instituted by intravenously administered N omega-nitro-L-arginine methyl ester. The survival time averaged 2 h 49 min in the NOS-blocked animals and 10 h 14 min in the control animals (P < 0.001). NOS inhibition thus reduced the posthaemorrhagic survival time to < 30% of that in the control cats. Haemorrhage in the NOS-blocked animals led to rapidly developing arterial hypotension, increased anaerobic metabolism, metabolic lactacidosis, hyperkalaemia, and morphological tissue damage especially in heart and liver, in spite of maintained arterial normoxia, which signifies tissue hypoxia caused by seriously impaired nutritional blood supply. At the time of death of the NOS-blocked cats, the control animals still exhibited a virtually normal circulatory/metabolic state. A much later, and more slowly developing circulatory/metabolic deterioration was observed in the control animals. These differences between the two groups of animals indicate that nitric oxide release, by its vasodilator action, to a significant extent helps to maintain an adequate nutritional blood supply to the tissues in acute haemorrhage.
Acute Disease↗
The role of lipopolysaccharide and Shiga-like toxin in a mouse model of Escherichia coli O157:H7 infection.
The role of lipopolysaccharide (LPS) and Shiga-like toxin (SLT) in the pathogenesis of hemolytic uremic syndrome (HUS) was studied in a mouse model. Mice inoculated intragastrically with Escherichia coli O157:H7 developed gastrointestinal, neurologic, and systemic symptoms, necrotic foci in the colon, glomerular and tubular histopathology, and fragmented erythrocytes. LPS-responder (C3H/HeN) mice developed a combination of neurologic and systemic symptoms, whereas LPS-nonresponder (C3H/HeJ) mice had a biphasic course of disease, first developing systemic symptoms and later severe neurologic symptoms. Mice inoculated with SLT-II-positive strains developed severe neurotoxic symptoms and a higher frequency of systemic symptoms and glomerular pathology compared with SLT-II-negative strains. Anti-SLT-II antibodies protected against these symptoms and pathology. These results demonstrate that this model could be used to study aspects of human HUS and that both LPS and SLT are important for disease development.
Animals↗
Occurrence and putative hormone regulatory function of a constitutive heme oxygenase in rat pancreatic islets.
Recent observations suggest that carbon monoxide (CO) may serve as a neuroendocrine modulator in hypothalamus. Here we provide evidence, for the first time, that the islets of Langerhans contain the constitutive isoform of the CO-producing enzyme heme oxygenase (HO-2), the activity of which was found to modulate islet hormone release. Most insulin and glucagon cells in the rat endocrine pancreas expressed strong immunoreactivity for HO-2. In the exocrine parenchyma, scattered HO-2-positive ganglionic cell bodies were occasionally observed. Furthermore, Western blot analysis revealed the presence of HO-2 in isolated islets but not in acinar cells. Islet homogenates displayed a comparatively high HO-2 enzymatic activity measured as CO formation (approximately 600 pmol CO.min-1.mg islet protein-1). This HO-2 enzymatic activity was greatly suppressed by zincprotoporphyrin-IX (ZnPP-IX), a recognized inhibitor of HO activity. Neither ZnPP-IX nor the HO activator, hemin, influenced basal insulin release from isolated rat islets at low (1 mM) glucose. However, glucagon release at 1 mM glucose was increased by hemin and inhibited by ZnPP-IX. The hemin-induced increase in glucagon secretion was abolished by ZnPP-IX. Furthermore, a series of experiments at high glucose (16.7 mM) revealed that hemin induced a dose-dependent potentiation of glucose-stimulated insulin release. Moreover, glucose-induced insulin release was dose-dependently suppressed by ZnPP-IX but unaffected by protoporphyrin-IX, a compound known not to influence HO-2 activity in other tissues. Similarly, glucagon release at high glucose was dose-dependently increased by hemin and suppressed by ZnPP-IX. Finally, the hemin-induced increase in islet hormone release at high glucose was totally abolished by ZnPP-IX. The data strongly suggest that CO production positively modulates both glucagon and insulin secretion. We propose that CO may serve as a novel messenger molecule within the islets of Langerhans.
Animals↗
Role of PACAP in the female reproductive organs.
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Adolescent↗
PACAP occurs in sensory nerve fibers and participates in ocular inflammation in the rabbit.
PACAP is a sensory neuropeptide; it occurs together with CGRP in a population of C fibers in the rabbit eye. PACAP is likely to be involved in the inflammatory response in as much as PACAP-induced responses mimic the symptoms of inflammation and because the concentration of PACAP-LI in the aqueous humor increased greatly in response to noxious stimuli. The observation that capsaicin releases both PACAP and CGRP from the iris and ciliary body supports the view that PACAP is present in C fibers in the rabbit eye.
Animals↗