Renal immunocytochemical distribution and pharmacological properties of the dual angiotensin II/AVP receptor

There is evidence that sympathetic nerve activity leads to endothelium-derived nitric oxide release, which in turn attenuates neurogenic vasoconstriction. Here we tested in vivo (1) whether the magnitude of the vasoconstriction induced by N(G)-nitro-L-arginine methyl ester given systemically is altered when ongoing sympathetic activity is abolished by sectioning the lumbar sympathetic trunk, and (2) whether hindlimb sympathetic vasoconstriction elicited by electrical stimulation of the lumbar sympathetic trunk is enhanced after inhibition of nitric oxide synthesis. Blood flow in the microvascular beds of hairless skin and skeletal muscle of the rat hindlimb was measured with laser Doppler flowmetry. Sectioning the lumbar sympathetic trunk resulted in an increase of blood flow in both tissues, indicating that tonic neurogenic vasoconstriction was abolished. Inhibition of nitric oxide synthesis resulted in vasoconstriction in both vascular beds. This vasoconstriction was more pronounced after abolition of sympathetic activity than with intact sympathetic supply in skin but was smaller in skeletal muscle. The vasoconstriction elicited by graded electrical stimulation of the centrally sectioned lumbar sympathetic trunk with frequencies less than 5 Hz was significantly enhanced after blockade of nitric oxide in skeletal muscle but not in skin microvasculature. These findings suggest that under physiological conditions, sympathetic nerve impulses directly promote the release of nitric oxide in skeletal muscle but not in cutaneous blood vessels. Therefore, basal nitric oxide release is probably in part dependent on sympathetic activity in skeletal muscle, whereas it appears to be mainly due to flow-dependent shear stress in hairless skin microvasculature.     

Nitric oxide modulates vascular permeability in the rat coronary circulation

1. The objective of the present study was to assess whether inhibition of nitric oxide (NO) production could modulate vascular permeability in the coronary circulation in conscious rats. 2. Intravenous injection of NG-nitro-L-arginine methyl ester (L-NAME, 2 mg kg-1) resulted in a slowly developing hypertension and evoked twofold increases in vascular permeability in the left ventricle and right atrium as measured by the extravasation of Evans blue dye. Maintenance of mean arterial blood pressure at the level observed following L-NAME injection by infusion of noradrenaline (620-820 ng kg-1 min-1) did not induce significant protein extravasation in the coronary circulation. 3. L-NAME treatment markedly enhanced (up to 490%) protein extravasation both in the left ventricle and right atrium in response to platelet-activating factor (PAF, 1.9 nmol kg-1, i.v.) and endothelin-1 (1 nmol kg-1, i.v.). Noradrenaline infusion potentiated (up to 69%) endothelin-1-induced protein extravasation. The permeability effect of PAF was only slightly enhanced by noradrenaline. 4. The present findings indicate that inhibition of endogenous NO synthesis leads to an increase in protein extravasation and to potentiation of the permeability effects of PAF and endothelin-1 in the coronary circulation. These results also suggest that NO may be an important regulator of vascular permeability under physiological and pathological conditions.     

Endothelial modulation of neural sympathetic vascular tone in canine skeletal muscle

The effect of nitric oxide synthase (NOS) inhibition and endothelin-A (ETA)-receptor blockade on neural sympathetic control of vascular tone in the gastrocnemius muscle was examined in anesthetized dogs under conditions of constant flow. Muscle perfusion pressure (MPP) was measured before and after NOS inhibition (Nomega-nitro-L-arginine methyl ester; L-NAME) and ETA-receptor blockade [cyclo-(D-Trp-d-Asp-Pro-D-Val-Leu); BQ-123]. Zero and maximum sympathetic nerve activities were achieved by sciatic nerve cold block and stimulation, respectively. In group 1 (n = 6), MPP was measured 1) before nerve cold block, 2) during nerve cold block, and 3) during nerve stimulation. Measurements under these conditions were repeated after L-NAME and then BQ-123. The same protocol was followed in group 2 (n = 6) except that the order of L-NAME and BQ-123 was reversed. MPP and muscle vascular resistance (MVR) increased after L-NAME and then decreased to control values after BQ-123. MVR decreased after BQ-123 alone and, with the addition of L-NAME, increased to a level not different from that observed during the control period. MVR fell during nerve cold block. This response was not affected by administration of L-NAME followed by BQ-123, but it was attenuated by administration of BQ-123 before L-NAME. The constrictor response during sympathetic nerve stimulation was enhanced by L-NAME; no further effect was observed with BQ-123, nor was the response affected when BQ-123 was given first. These findings indicate that endothelin contributes to 1) basal vascular tone in skeletal muscle and 2) the increase in skeletal muscle vascular resistance after NOS inhibition. Finally, nitric oxide "buffers" the degree of constriction in skeletal muscle vasculature during maximal sympathetic stimulation.     

Synergism between low-dose nicorandil and neuropeptides on adenosine-induced vasodepression in rats

The involvement of endogenous nitric oxide (NO) in the control of gastric acid secretion induced by some secretagogues was studied in the mouse isolated whole stomach. The gastric acid secretion induced by McNeil A-343 [4-[[[(3-chlorophenyl)amino]carbonyl]oxy]-N,N,N-trimethyl-2-butyn- 1-aminium chloride], a muscarinic M1 receptor agonist, pentagastrin or electrical vagus nerve stimulation was markedly inhibited by pretreatment with the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA). This inhibitory effect of L-NNA was reversed by L-arginine, but not by D-arginine. Histamine-induced gastric acid secretion was not influenced by treatment with L-NNA. Famotidine completely inhibited the gastric acid secretion induced by McNeil A-343, pentagastrin or electrical vagus nerve stimulation, showing that these stimulations induced gastric acid secretion mainly through histamine release from histamine-containing cells in the gastric mucosa. Moreover, the pentagastrin- and bethanechol-induced histamine release from gastric mucosal cells was significantly inhibited by L-NNA. The NO donor, sodium nitroprusside, at a concentration not affecting histamine-induced gastric acid secretion, increased the acid secretory response, and this response was inhibited by famotidine. These results suggest that endogenous NO is involved in the gastric acid secretion via histamine release from histamine-containing cells.     

Neurogenic nitric oxide mediates relaxation of canine corpus cavernosum

PURPOSE: The aim of the present study is to analyze mechanisms underlying neurogenic relaxation of the corpus cavernosum which are believed to participate in penile erection. MATERIALS AND METHODS: Mechanical responses to nerve stimulation by electrical pulses and nicotine were measured in strips of canine corpus cavernosum precontracted with phenylephrine. Cyclic guanosine monophosphate (GMP) contents in the strips were also measured by radioimmunoassay. Immunohistochemistry for nitric oxide synthase (NOS) and vasoactive intestinal polypeptide (VIP) was performed. RESULTS: Transmural electrical stimulation and nicotine produced relaxations in the isolated canine corpus. The neurogenic relaxation was abolished by N omega-nitro-L-arginine, a NOS inhibitor, and the inhibition was reversed by L-arginine. Relaxations induced by nerve stimulation and exogenous nitric oxide (NO) were depressed by oxyhemoglobin and methylene blue. Vasoactive intestinal polypeptide (VIP)-induced relaxations were not influenced by these inhibitors. In the controls strips and those made unresponsive to VIP by its repeated application, the responses to nerve stimulation did not differ. The content of cyclic GMP in the tissue increased in response to nicotine, the effect being abolished by the NO synthase inhibitor. Immunohistochemical study demonstrated neurons containing NOS and VIP. CONCLUSIONS: It appears that the relaxation induced by nerve stimulation is mediated solely by NO liberated from the nerve that activates soluble guanylate cyclase and increases the production of cyclic GMP in smooth muscle, whereas VIP does not play a role in the regulation of muscle tone under the experimental conditions used.     

Effect of T-kinin on microvascular permeability and its modulation by peptidases in rat airways

T-kinin (Ile-Ser-bradykinin), the product of T-kininogen, has been found in rat plasma during systemic inflammation, but the effect of this kinin on airway inflammatory response is unknown. We examined the effect of T-kinin on vascular permeability in airways of anesthetized rats in vivo by using photometric measurement of the extravasated Evans blue. Intravenous injection of T-kinin (0.1-10 mumol/kg) increased dye extravasation in a dose-dependent manner, with 134% for trachea and 117% for bronchi by 1 mumol/kg. Pretreatment with bradykinin B2-receptor antagonist Hoe-140 (100 nmol/kg), but not the B1-receptor antagonist des-Arg9-Leu8-bradykinin (5 mg/kg), abolished plasma extravasation evoked by T-kinin (1 mumol/kg). NK1 tachykinin-receptor antagonist CP-99994 (4 mg/kg) did not affect T-kinin-induced vascular leakage. Pretreatment with captopril (2.5 mg/kg), angiotensin-converting enzyme inhibitor, potentiated T-kinin (100 nmol/kg)-induced plasma extravasation, whereas phosphoramidon (2.5 mg/kg), a neutral endopeptidase inhibitor, had no effect. We conclude that T-kinin produces airway vascular extravasation via stimulation of B2 receptors. The effect is modulated by endogenous angiotensin-converting enzyme and is not mediated via activation of sensory nerve.     

Release of somatostatin and its role in the mediation of the anti-inflammatory effect induced by antidromic stimulation of sensory fibres of rat sciatic nerve

1. The effect of antidromic stimulation of the sensory fibres of the sciatic nerve on inflammatory plasma extravasation in various tissues and on cutaneous vasodilatation elicited in distant parts of the body was investigated in rats pretreated with guanethidine (8 mg kg(-1), i.p.) and pipecuronium (200 microg kg(-1), i.v.). 2. Antidromic sciatic nerve stimulation with C-fibre strength (20 V, 0.5 ms) at 5 Hz for 5 min elicited neurogenic inflammation in the innervated area and inhibited by 50.3 +/- 4.67% the development of a subsequent plasma extravasation in response to similar stimulation of the contralateral sciatic nerve. Stimulation at 0.5 Hz for 1 h also evoked local plasma extravasation and inhibited the carrageenin-induced (1%, 100 microl s.c.) cutaneous inflammation by 38.5 +/- 10.0% in the contralateral paw. Excitation at 0.1 Hz for 4 h elicited no local plasma extravasation in the stimulated hindleg but still reduced the carrageenin-induced oedema by 52.1 +/- 9.7% in the paw on the contralateral side. 3. Plasma extravasation in the knee joint in response to carrageenin (2%, 200 microl intra-articular injection) was diminished by 46.1 +/- 12.69% and 40.9 +/- 4.93% when the sciatic nerve was stimulated in the contralateral leg at 0.5 Hz for 1 h or 0.1 Hz for 4 h, respectively. 4. Stimulation of the peripheral stump of the left vagal nerve (20 V, 1 ms, 8 Hz, 10 min) elicited plasma extravasation in the trachea, oesophagus and mediastinal connective tissue in rats pretreated with atropine (2 mg kg(-1), i.v.), guanethidine (8 mg kg(-1), i.p.) and pipecuronium (200 microg kg(-1), i.v.). These responses were inhibited by 37.8 +/- 5.1%, 49.7 +/- 9.9% and 37.6 +/- 4.2%, respectively by antidromic sciatic nerve excitation (5 Hz, 5 min) applied 5 min earlier. 5. Pretreatment with polyclonal somatostatin antiserum (0.5 ml/rat, i.v.) or the selective somatostatin depleting agent cysteamine (280 mg kg(-1), s.c.) prevented the anti-inflammatory effect of sciatic nerve stimulation (5 Hz, 5 min) on a subsequent neurogenic plasma extravasation of the contralateral paw skin. The inhibitory effect of antidromic sciatic nerve excitation on plasma extravasation in response to vagal nerve stimulation was also prevented by somatostatin antiserum pretreatment. 6. Cutaneous blood flow assessment by laser Doppler flowmetry indicated that antidromic vasodilatation induced by sciatic nerve stimulation was not inhibited by excitation of the sciatic nerve of the contralateral leg (1 Hz, 30 min) or by somatostatin (10 microg/rat, i.v.) injection. 7. Plasma levels of somatostatin increased more than 4 fold after stimulation of both sciatic nerves (5 Hz, 5 min) but the stimulus-evoked increase was not observed in cysteamine (280 mg kg(-1), s.c.) pretreated rats. 8. These results suggest that somatostatin released from the activated sensory nerve terminals mediates the systemic anti-inflammatory effect evoked by stimulating the peripheral stump of the sciatic nerve.     

R-(-)-alpha-methyl-histamine has nitric oxide-mediated vasodilator activity in the mesenteric vascular bed of the cat

Responses to the histamine H3 receptor agonist R-(-)-alpha-methyl-histamine were investigated in the mesenteric vascular bed of the cat under constant-flow conditions. Injections of R-(-)-alpha-methyl-histamine and histamine caused dose-related decreases in mesenteric perfusion pressure with R-(-)-alpha-methyl-histamine being 1000-fold less potent than histamine when doses were compared on a nmol basis to take molecular weight into account. Responses to R-(-)-alpha-methyl-histamine were not altered by histamine H1 or H2 receptor antagonists at a time when responses to histamine were significantly reduced. The histamine H3 receptor antagonist thioperamide reduced responses to R-(-)-alpha-methyl-histamine but was without effect on responses to histamine [6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoro-methylphenyl)heptaneca rdoxamide dimaleate] (HTMT), or dimaprit. These data suggest the presence of histamine H1, H2 and H3 receptors mediating vasodilation in the mesenteric vascular bed. Responses to R-(-)-alpha-methyl-histamine and histamine were reduced by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) but were not altered by the cyclooxygenase inhibitor meclofenamate, the alpha-adrenoceptor blocker phentolamine, or adrenergic nerve terminal depleting agent reserpine. The present data suggest that histamine H3 receptors mediating vasodilation are present in the mesenteric vascular bed and that responses are mediated by the release of nitric oxide but not vasodilator prostaglandins or an effect on the adrenergic nervous system. These results indicate that vasodilator responses to histamine involve the activation of histamine H1 and H2 receptors and the release of nitric oxide in the mesenteric vascular bed of the cat.     

Localization of dopamine receptor subtypes in corpus striatum and nucleus accumbens septi of rat brain: comparison of D1-, D2-, and D4-like receptors

The purpose of this study was to determine whether bradykinin mediates ovalbumin-induced increase in macromolecular efflux from the nasal mucosa of ovalbumin-sensitized hamsters in vivo and, if so, whether the L-arginine/nitric oxide biosynthetic pathway transduces, in part, this response. We found that suffusion of ovalbumin onto the in situ nasal mucosa of ovalbumin-sensitized hamsters, but not of controls, elicited a significant time- and concentration-dependent increase in clearance of fluorescein isothiocyanate-labeled dextran (mol mass, 70 kDa; P < 0.05). HOE-140, but not des-Arg9,[Leu8]-bradykinin, and NG-L-arginine methyl ester (L-NAME), but not NG-D-arginine methyl ester, significantly attenuated ovalbumin-induced responses. L-Arginine, but not D-arginine, abolished the effects of L-NAME. L-NAME also significantly attenuated bradykinin-, but not adenosine-induced increase in macromolecular efflux from the in situ nasal mucosa. Overall, these data suggest that ovalbumin increases macromolecular efflux from the in situ nasal mucosa of ovalbumin-sensitized hamsters, in part, by producing bradykinin with subsequent activation of the L-arginine/ nitric oxide biosynthetic pathway.     

Nitroglycerin does not alter pulmonary vascular permeability in isolated rabbit lungs

Nitroglycerin (NTG) produces vasodilation by releasing nitric oxide (NO) at the cellular level. Other studies have suggested that NO may directly alter vascular permeability and may alter the development of tissue injury. We therefore examined the effects of NTG on vascular permeability in the buffer-perfused rabbit lung under normal conditions and during lung injury. Vascular permeability was assessed by measurement of the capillary filtration coefficient (Kf,c). In normal lungs, NTG did not alter Kf,c or the rate of weight gain. Oxidant lung injury was produced by the addition of purine and xanthine oxidase and resulted in increased Kf,c and increased weight gain. However, NTG did not alter these effects of oxidant lung injury. We conclude that NTG does not alter pulmonary vascular permeability in either normal or oxidant-injured lungs.     

Clinical presentations and results of therapy of 63 acromegalic patients Chang Gung Memorial Hospital

The role of nitric oxide in inflammatory responses to substance P and other mediators of inflammation was examined in rat skin microvasculature in a blister base raised on the hind footpad. Superfusion of substance P (1 microM) over the blister base caused an increase in plasma extravasation and a vasodilator response which was not maintained. N(G)-Nitro-L-arginine (100 microM), an inhibitor of nitric oxide biosynthesis, attenuated vasodilatation and plasma extravasation due to substance P. The inactive isomer N(G)-nitro-D-arginine was without effect. Neurokinin A (1 microM), 5-hydroxytryptamine (1 microM), ATP (50 microM) and vasoactive intestinal polypeptide (1 microM) elicited vasodilation, which for vasoactive intestinal polypeptide was maintained even after washout. 5-Hydroxytryptamine and neurokinin A, but not ATP or vasoactive intestinal polypeptide, significantly increased plasma extravasation. Vasodilatation to neurokinin A, 5-hydroxytryptamine and ATP, and the increase in plasma extravasation due to neurokinin A and 5-hydroxytryptamine were unaffected by N(G)-nitro-L-arginine (100 microM), whereas vasodilation due to vasoactive intestinal polypeptide was significantly attenuated. These findings suggest that in rat skin microvasculature in vivo, nitric oxide is involved in vasodilator responses due to substance P and vasoactive intestinal polypeptide, and plasma extravasation due to substance P, but does not contribute significantly to vasodilatation induced by neurokinin A, 5-hydroxytryptamine or ATP, or the plasma extravasation induced by neurokinin A or 5-hydroxytryptamine.     

Role of endothelin receptors, calcium and nitric oxide in the potentiation by endothelin-1 of the sympathetic contraction of rabbit ear artery during cooling

1. To examine further the potentiation by endothelin-1 on the vascular response to sympathetic stimulation, we studied the isometric response of isolated segments, 2 mm long, from the rabbit central ear artery to electrical field stimulation (1-8 Hz), under different conditions, at 37 degrees C and during cooling (30 degrees C). 2. Electrical stimulation produced frequency-dependent contraction, which was reduced (about 63% for 8 Hz) during cooling. At 30 degrees C, but not at 37 degrees C, endothelin-1 (1, 3 and 10 nM) potentiated the contraction to electrical stimulation in a dose-dependent way (from 43 +/- 7% to 190 +/- 25% for 8 Hz). 3. This potentiation by endothelin-1 was reduced by the antagonist for endothelin ETA receptors BQ-123 (10 microM) but not by the antagonist for endothelin ETB receptors BQ-788 (10 microM). The agonist for endothelin ETB receptors IRL-1620 (0.1 microM) did not modify the contraction to electrical stimulation. 4. The blocker of L-type Ca2+ channels verapamil (10 microM l-1) reduced (about 72% for 8 Hz) and the unspecific blocker of Ca(2+)-channels NiCl2 (1 mM) practically abolished (about 98%), the potentiating effects of endothelin-1 found at 30 degrees C. 5. Inhibition of nitric oxide synthesis with NG-nitro-L-arginine (L-NOARG, 0.1 mM) increased the contraction to electrical stimulation at 30 degrees C more than at 37 degrees C (for 8 Hz, this increment was 297 +/- 118% at 30 degrees C, and 66 +/- 15% at 37 degrees C). Endothelium removal increased the contraction to electrical stimulation at 30 degrees C (about 91% for 8 Hz) but not at 37 degrees C. Both L-NOARG and endothelium removal abolished the potentiating effects of endothelin-1 on the response to electrical stimulation found at 30 degrees C. 6. These results in the rabbit ear artery suggest that during cooling, endothelin-1 potentiates the contraction to sympathetic stimulation, which could be mediated at least in part by increasing Ca2+ entry after activation of endothelin ETA receptors. This potentiating effect of endothelin-1 may require the presence of an inhibitory tone due to endothelial nitric oxide.     

Analysis and counter measure prevention and treatment of osteoporosis with traditional Chinese medicine]

The present study was devised to determine the effects of amphetamine on the sympathetic function of human nasal mucosa. A tissue bath method was employed on the vitro preparations of nasal turbinate mucosa from adult patients with nasal allergies or hypertrophic rhinitis. The effects of amphetamine on the contractile response of isolated human nasal mucosal blood vessels were investigated following electrical field stimulation and methoxamine. The results showed that amphetamine inhibited field stimulation and antagonized the effects on mucosal contraction induced by methoxamine. Likewise, the drug increased mucosal basal tension but had local drug toxicity when a 10(-4) M solution was used. Amphetamine could potentiate mucosal contraction induced by norepinephrine or epinephrine. The study indicated that amphetamine may increase sympathetic function by potentiating the effect of norepinephrine and that high concentration of amphetamine may actually antagonize alpha-adrenoceptors.     

Multiple nitric oxide sources in neurogenic plasma extravasation in rat hindpaw skin

The contribution of nitric oxide (NO) to capsaicin-evoked plasma extravasation was studied in rat hindpaw skin. Two inhibitors of NO synthase were used: 7-nitroindazole, with a selectivity for nerve-derived NO, and the L-arginine derivative, N(omega)-nitro-L-arginine (L-NOARG), which is a non-selective inhibitor. Plasma extravasation was induced by intraplantar injection of 5 microg/50 microl capsaicin and measured by the Evans blue leakage technique. Both acute and chronic administration of 7-nitroindazole significantly reduced capsaicin-evoked plasma extravasation in rat hind-paw skin, whereas L-NOARG enhanced it. This enhancement was abolished non-stereospecifically by either L- or D-arginine. Our results suggest that NO production from different sources yields a complex action in maintaining the endothelial integrity in neurogenic plasma extravasation.     

In vitro expression of inducible nitric oxide synthase in the nasal mucosa of guinea pigs after incubation with lipopolysaccharides or cytokines

In order to demonstrate the involvement of nitric oxide synthases (NOS)--in particular the inducible isoform (iNOS)--in inflammatory processes within the nasal airways, we used organ-bath incubation to study isolated inferior turbinates and mucosa of the maxillary sinus of guinea pigs. The pattern of the expression in various substructures of the nasal mucosa was of special interest. Mucosa was incubated for 6 h with lipopolysaccharides (LPS) produced by E. coli, interleukin II (IL-2) or tumor necrosis factor-alpha (TNF-alpha). Saline was used as the control solution. Following incubation the specimens were fixed in buffered 4% formaldehyde solution over a period of 4 h. Tissues were next exposed to nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase-reaction and immunostained with specific antibodies to iNOS. Results then showed a clearly increased or initiated expression of iNOS in epithelium, glands, leucocytes and blood vessels of treated tissues in comparison to the control specimens. The inflammatory mediator LPS and the cytokines Il-2 or TNF-alpha alone were found to be capable of increasing the expression of iNOS, although the effects of LPS clearly exceeded those of the cytokines. This finding implicates iNOS-generated nitric oxide as a key factor for causing nasal swelling, secretion and obstruction during nasal infections and allergic episodes.     

Peroxynitrite: a mediator of increased microvascular permeability?

1. Increased expression of inducible nitric oxide synthase (iNOS) and subsequent elevation of nitric oxide (NO) levels at inflammatory sites have led to the suggestion that peroxynitrite (the reaction product of superoxide and NO) is involved in pro-inflammatory processes. The present study has investigated the ability of peroxynitrite to induce oedema formation in the rat cutaneous microvasculature. 2. Peroxynitrite was synthesized from hydrogen peroxide and acidified nitrite. Spectrophotometry was used to measure the concentration and breakdown of peroxynitrite. It was also used to determine maximum amounts of hydrogen peroxide and sodium nitrite remaining after synthesis. 3. Oedema formation in response to intradermally (i.d.) injected peroxynitrite, hydrogen peroxide and sodium nitrite was measured by the extravascular accumulation of i.v. [125I]-albumin in the anaesthetized rat. 4. Peroxynitrite (40, 100 and 200 nmol/site) acted in a dose-dependent manner to cause a mean (+/- SEM) increase in plasma extravasation of 24 +/- 2, 55 +/- 5 and 69 +/- 6 microL, respectively (n = 4), with resulting inflammatory oedema. Peroxynitrite induced significantly larger plasma extravasation than equivalent vehicle controls at doses of 100 (P > 0.05) and 200 nmol (P > 0.001). This increased extravasation appears to be a direct microvascular response to peroxynitrite administration and not due to either a raised pH, necessary to stabilize the peroxynitrite, or contaminating concentrations of hydrogen peroxide or sodium nitrite from which peroxynitrite is formed. 5. These results suggest that peroxynitrite acts to increase microvascular permeability and oedema formation. Therefore, peroxynitrite may mediate vascular pro-inflammatory effects in addition to its direct cytotoxic activity.     

Monkey central retinal artery is innervated by nitroxidergic vasodilator nerves

PURPOSE: To determine whether the monkey central retinal artery is innervated by vasodilator nerves and to analyze the mechanism underlying the neurogenic response. METHODS: Changes in isometric tension were recorded in helical strips of the arteries, which were stimulated by transmurally applied electrical pulses or nicotine. The presence of perivascular nerve fibers containing nitric oxide (NO) synthase immunoreactivity was determined histologically. RESULTS: Transmural electrical stimulation (5 Hz) and nicotine produced a relaxation of the arterial strips denuded of the endothelium, treated with prazosin, and contracted with prostaglandin F2 alpha. The response was not influenced by timolol, atropine, and indomethacin, but it was abolished by methylene blue and oxyhemoglobin. NG-nitro-L-arginine, a NO synthase inhibitor, abolished the neurogenic relaxation, and L-arginine restored the response. Antagonists of calcitonin gene-related peptide and vasoactive intestinal polypeptide in sufficient concentrations did not influence the response to nerve stimulation by nicotine. There were abundant nerve fibers and bundles containing NO synthase immunoreactivity in the adventitia. CONCLUSIONS: Monkey central retinal arteries are innervated by NO synthase-containing nerves that liberate NO possibly as a neurotransmitter on excitation to produce muscular relaxation.     

Blockade of endogenous nitric oxide production results in moderate hypertension, reducing sympathetic activity and shortening bleeding time in healthy volunteers

BACKGROUND: Short-term infusion of NG-monomethyl-L-arginine (L-NMMA) reversibly inhibits endogenous nitric oxide (NO) production in humans. We studied responses to more long-lasting (60 min) infusions, at doses high enough to cause effective inhibition of endogenous NO. METHODS: Eight healthy volunteers had catheters (pulmonary, arterial and venous) placed. Measurements included hemodynamics, endogenous NO levels in nasal air, bleeding time, and cyclic guanosine monophosphate (cGMP) and catecholamines in plasma. L-NMMA was infused at 0.3 mg.kg-1.min-1 during 30 min, followed by 0.15 (n = 6) or 0.3 (n = 2) mg.kg-1.min-1 during 30 min. RESULTS: L-NMMA significantly elevated mean arterial pressure by 12 +/- 3%, due to an increase in systemic vascular resistance. Cardiac output decreased by 23 +/- 3%, due to a decrease in stroke volume. Pulmonary vascular resistance (P < 0.05) increased, but mean pulmonary arterial pressure was stable. Forearm vascular resistance (P < 0.05) decreased. Bleeding time was shortened by 31 +/- 4% (P < 0.01). L-NMMA infusion reduced NO concentrations in nasal air by 64 +/- 2% (P < 0.01). Arterial pressure remained elevated and nasal NO remained depressed 90 min after the infusion, whereas most other responses were reversed at that time. Plasma cGMP showed only minor changes. Plasma norepinephrine decreased, suggesting reflexogenic inhibition of sympathetic activity, whereas epinephrine levels were low and stable throughout the experiment. CONCLUSION: Dosage of (13.5 mg.kg-1 in 60 min) L-NMMA infusion in humans was well tolerated. Pronounced and long-lasting inhibition of endogenous NO production, as evidenced by measurements in nasal air, resulted in unevenly distributed vasoconstriction, a transient decrease in cardiac output, and reflexogenic sympathetic withdrawal. Furthermore, bleeding time was shortened, suggesting platelet activation.     

Role of nitric oxide on cholinergic component of bronchial tone in pig

In vitro studies demonstrated that stimulation of intrinsic nerves of airway smooth muscle results in a predominantly contractile response, followed by a relaxant response which involves cholinergic, adrenergic and non-adrenergic non-cholinergic (NANC) nerve activation. Thus, in this paper it is determined whether endogenous nitric oxide (NO) modulates cholinergic neurotransmission in isolated pig airway smooth muscle. Bronchial rings were suspended in organ baths for isometric measurement of tension and the contractions were induced using electrical field stimulation (EFS) techniques. Then, the effects of L-NG-nitroarginine (L-NOARG, 10 microM), an inhibitor of NO synthase, and L-arginine (L-ARG, 1 mM), a precursor of NO synthesis, were evaluated. The cholinergic contractions induced by electrical field stimulation (EFS: 60 V, 2 ms, 60 Hz) of pig lobar bronchial preparations increased (29%) in the presence of L-NOARG (10 microM). This effect may be released by nerves in pig large airways during EFS.     

The Trypanosoma cruzi ribosomal RNA-encoding gene: analysis of promoter and upstream intergenic spacer sequences

The present study was designed to investigate the influence of endothelium-derived nitric oxide on the contractile responses of isolated human omental arteries to electrical field stimulation and noradrenaline. We measured isometric tension in artery rings obtained from portions of human omentum during the course of abdominal operations (32 patients). Electrical field stimulation induced frequency-dependent contractions which were abolished by tetrodotoxin (10(-6) M) and prazosin (10(-6) M), thus indicating that this effect was due to noradrenaline released from adrenergic nerves acting on alpha 1-adrenoceptors. The increases in tension induced by electrical field stimulation were of greater magnitude in arteries denuded of endothelium. NG-Nitro-L-arginine (L-NAME, 10(-4) M) potentiated the contractile response to electrical field stimulation in artery rings with endothelium but did not influence the contractile responses of endothelium-denuded arteries. The potentiation induced by L-NAME was completely reversed by L-arginine (10(-4) M), but not by D-arginine (10(-4) M). Contractile responses to noradrenaline were similar in arteries with and without endothelium. L-NAME (10(-4) M) had no significant effect on the contractile responses to noradrenaline. Our results suggest that electrical field stimulation releases endothelium-derived nitric oxide which inhibits the contractile responses of human omental arteries. The constrictor responses to noradrenaline are not modulated by the endothelium.