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A Modin

Publications and source records attributed to A Modin.

At least 19 recordsLinked to original sources
PubMed2001

Nitrite-derived nitric oxide: a possible mediator of 'acidic-metabolic' vasodilation.

The fundamental, yet poorly understood, physiological mechanism known as 'acidic-metabolic' vasodilation, contributes to local blood flow regulation during hypoxia/ischaemia and increased metabolic activity. The vasodilator nitric oxide (NO) has been suggested to be involved in this event. Besides enzymatic production by NO synthases, a novel mechanism for generation of this gas in vivo was recently described. This involves non-enzymatic reduction of inorganic nitrite to NO, a reaction that takes place predominantly during acidic/reducing conditions. We have studied the effects of physiological amounts of nitrite on NO generation and relaxation of rat aorta in vitro in a situation where environmental pH was reduced to levels seen in tissues during hypoxia/ischaemia. The relaxatory effect of nitrite was increased in an acidic buffer solution (pH 6.6) compared with neutral pH; EC50 for nitrite was reduced from 200 to 40 microM. Nitrite-evoked relaxation was effectively prevented by coadministration of an inhibitor of soluble guanylyl cyclase. The relaxation was further potentiated by the addition of ascorbic acid. In parallel, NO was generated from nitrite in a pH dependent manner with even larger amounts seen after addition of ascorbic acid. NO generation from nitrite correlated to the the degree of relaxation of rat aorta. These results illustrate non-enzymatic release of NO from nitrite at physiological concentrations. This may be an important auto-regulated physiological mechanism involved in the regulation of vascular tone during hypoxia/ischaemia.

Acidosis↗
PubMed1999

Vascular neuropeptide Y Y1-receptors in the rat kidney: vasoconstrictor effects and expression of Y1-receptor mRNA.

Neuropeptide Y (NPY) -receptor subtypes were studied in the rat kidney in vivo by systemic administration of NPY, the two agonists [Leu(31), Pro(34)]NPY (Y1-receptor agonist) and NPY (13-36) (Y2-receptor agonist), or the Y1-receptor antagonist BIBP 3226. Effects on mean arterial blood pressure (MAP) and renal arterial blood flow were recorded. The Y1-receptor agonist evoked a dose-dependent increase in MAP concomitantly with a reduction in renal blood flow. At the largest dose administered (1.42 pmol/g), the Y1-agonist [Leu(31), Pro(34)] NPY increased MAP by 20 +/- 6 mmHg and reduced the renal vascular conductance by more than 50%. The same dose of the Y2-agonist NPY (13-36) did not evoke any clear-cut effects on the renal blood flow or MAP. Furthermore, administration of the Y1-receptor antagonist BIBP 3226 reduced the NPY-induced renal vasoconstriction, but did not affect the response to angiotensin II or phenylephrine. The effects evoked by 0.71 pmol/g NPY were almost abolished by 3 mg/kg BIBP 3226. In situ hybridization histochemistry was used to study the expression of Y1-receptor mRNA in the developing rat kidney. The levels of Y1-receptor mRNA expression in the vascular smooth muscle of the rat kidney varied at different ages, with low levels at postnatal day 10 and high levels at 20 days and again low levels at 40 days. In summary, the present study show a maturation-specific expression pattern of NPY Y1-receptor mRNA as well as functional effects of vascular NPY receptors of the Y1-subtype in the rat kidney.

Angiotensin II↗
PubMed1996

Effects of Ro 47-0203 and PD155080 on the plasma kinetics, receptor binding and vascular effects of endothelin in the pig.

The effects of the mixed endothelin ET(A)/endothelin ET(B) receptor antagonist Ro 47-0203 (bosentan, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-( 2-methoxy -phenoxy)-2,2'-bipyrimidin-4-yl] -benzenesulfonamide) and the selective endothelin ET(A) receptor antagonist PD155080 (sodium 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-me thoxy-phenyl)-4-oxobut+ ++-2-enoate) on plasma half-life and regional extraction of exogenous endothelin-1 as well as on the regional vascular effects of endothelin-1 were investigated in the pig in vivo. Bosentan but not PD155080 (5 mg/kg, i.v. bolus, both drugs) increased the arterial plasma levels of endothelin-1-like immunoreactivity. Neither of the drugs affected the plasma half-life of infused endothelin-1. In the spleen, both the extraction and vascular effects of exogenous endothelin-1 were attenuated by both bosentan and PD155080 whereas renal extraction and vascular effects in the kidney were unaffected by both drugs. In the lung, only bosentan decreased pulmonary extraction of endothelin-1. In conclusion, the bosentan-induced increase of circulating endothelin-1 seems to be related to blockade of endothelin-1 binding to endothelin ET(B) receptors. Blockade of these receptors does not influence the overall elimination of endothelin-1, however.

Animals↗
PubMed1996

SR 120107A antagonizes neuropeptide Y Y1 receptor mediated sympathetic vasoconstriction in pigs in vivo.

The effects of the neuropeptide Y Y1 receptor antagonist SR 120107A (1-[2-[2-(2-naphtylsulfamoyl)-3-phenylpropionamido]-3-[4-[N- [4- (dimethylaminomethyl)-cis-cyclohexylmethyl]amidino]phenyl]propiony l] pyrrolidine, (S,R) stereoisomer) on sympathetic non-adrenergic vasoconstriction in a variety, of vascular beds were studied in reserpinized anesthetized pigs in vivo. The rapid vasoconstrictor response evoked by single impulse stimulation, in hind limb and nasal mucosa, was not affected by SR 120107A (1.5 mg kg-1 i.v.). In contrast, SR 120107A potently inhibited the long-lasting phase of vasoconstriction evoked by high frequency (60 impulses at 20 Hz) sympathetic nerve stimulation, in the main and deep femoral, the saphenous and the internal maxillary arteries, leaving merely the initial rapid peak of vasoconstriction in these vessels. Furthermore, the vasoconstrictor response was nearly abolished in the kidney and was attenuated in the spleen and main femoral artery, despite maintained neuropeptide Y overflow. The vasoconstrictor response evoked in the kidney by peptide YY, a neuropeptide Y Y1 and Y2 receptor agonist, was also nearly abolished in the presence of SR 120107A. This inhibitory effect on the response to exogenous agonist correlated well with the long-lasting inhibition of the response to nerve stimulation in the same tissue. The peptide YY-evoked vasoconstriction in the spleen was not altered by SR 120107A, in accordance with the view that the neuropeptide Y receptor population in this organ consists mainly of neuropeptide Y Y2 receptors. SR 120107A did not influence the vasoconstrictor effects of alpha, beta-methylene ATP (mATP) or phenylephrine in any of the tissues studied. We conclude that SR 120107A is a potent neuropeptide Y Y1 receptor antagonist with long duration of action in vivo. Endogenous neuropeptide Y acting on the neuropeptide Y Y1 receptor is likely to account for the long-lasting component of the reserpine-resistant sympathetic vasoconstriction upon high frequency stimulation in hind limb and nasal mucosa. Furthermore, the peak vasoconstriction in kidney, and to some extent in spleen, is also neuropeptide Y Y1 receptor mediated.

Adenosine Triphosphate↗
PubMed1996

Prejunctional regulation of reserpine-resistant sympathetic vasoconstriction and release of neuropeptide Y in the pig.

The prejunctional regulation of non-adrenergic sympathetic vasoconstriction and release of neuropeptide Y (NPY) was investigated in vivo. In reserpinized pigs (with depleted noradrenaline (NA)), it was demonstrated that brief sympathetic nerve stimulation (2 pulses of 20 Hz) of the spleen, kidney and hind limb in the presence of the alpha 2-adrenoceptor agonist UK 14,304 (1 micrograms/kg per min i.v.) evoked reproducible vasoconstrictor responses which were reduced by 40-80% in comparison to that in the absence of UK 14,304. In addition, the splenic overflow of NPY-like immunoreactivity (-LI) was reduced. After cessation of the UK 14,304 infusion all these effects were reversed by addition of the alpha 2-adrenoceptor antagonist yohimbine (0.2 mg/kg i.v.). Also the Y2 receptor agonist NPY(13-36) reduced the splenic overflow of NPY-LI. Splenic vasoconstriction per se was evoked by another Y2 receptor agonist N-acetyl[Leu28Leu31]NPY(24-36), while no vascular effects in the kidney or hind limb were observed. Both Y2 agonists displaced [125I]NPY binding to splenic membranes with higher potency than the Y1-receptor agonist [Leu31Pro34]NPY(1-36). No evidence was obtained for angiotensin II mechanisms being important for the enhanced NPY release after reserpine in spite of elevated renin release. The present results show that in the absence of NA, repetition of brief sympathetic nerve stimulation evokes vascular effects and NPY-LI release which are repeatable and these effects are efficiently modulated via alpha 2-adrenoceptors. Furthermore, the Y2 receptors may mediate both prejunctional inhibition of NPY release, as well as postjunctional vasoconstrictor effects in the pig spleen.

Animals↗
PubMed1996

Increased concentrations of endothelin-1 messenger RNA in tissues and endothelin-1 peptide in plasma in septic pigs: modulation by betamethasone.

OBJECTIVES: To study the expression of preproendothelin-1 messenger RNA (mRNA) in tissue after Escherichia coli lipopolysaccharide challenge and to evaluate the possible effects of betamethasone both regarding endothelin-1 production as well as hemodynamic and vascular effects during E. coli lipopolysaccharide infusion in pigs in vivo. DESIGN: Prospective trial. SETTING: Laboratory at a university medical center. SUBJECTS: Ten domestic pigs, weighing 18 to 25 kg. INTERVENTIONS: Anesthetized pigs were given continuous infusions of E. coli lipopolysaccharide (15 micrograms/kg/hr for 3 hrs), with or without prior treatment with betamethasone (0.5 mg/kg im 12 hrs before the start of the surgical preparation and 0.5/kg iv at the start of the preparation). MEASUREMENTS AND MAIN RESULTS: The E. coli lipopolysaccharide infusion evoked the characteristic cardiovascular changes observed in septic shock: decreased mean arterial pressure and cardiac output; increased heart rate and increased pulmonary vascular resistance. Large increases in both arterial plasma concentrations of endothelin-1-like immunoreactivity, as well as preproendothelin-1 mRNA concentrations in tissues, were also observed during the E. coli lipopolysaccharide infusion. Treatment with betamethasone significantly attenuated the E. coli lipopolysaccharide-induced increase in endothelin-1 plasma concentrations, whereas the increased mRNA concentrations were only slightly affected. Furthermore, betamethasone treatment also affected cardiovascular parameters, with significant attenuation of the E. coli lipopolysaccharide-induced increase in heart rate and a higher cardiac output after 60 mins of the E. coli lipopolysaccharide infusion. The urine production, which was markedly decreased during the E. coli lipopolysaccharide infusion, was significantly higher in the betamethasone-treated group compared with the control group. CONCLUSIONS: The present results indicate that the increased concentrations of endothelin-1-like immunoreactivity that are observed in septic shock may have negative effects on both cardiovascular parameters as well as renal function, which is in agreement with a possible role for endothelin-1 in the pathogenesis of septic shock.

Animals↗
PubMed1996

Bosentan-improved cardiopulmonary vascular performance and increased plasma levels of endothelin-1 in porcine endotoxin shock.

1. To evaluate the possible contribution of endothelin-1 (ET-1) to the pathophysiology of porcine septic shock, the non-peptide, mixed ET-receptor antagonist, bosentan (RO 47-0203) was administered (5 mg kg-1, i.v.) 30 min before infusion of lipopolysaccharide (LPS) (E. coli., serotype 0111:B4) (15 micrograms kg-1 h-1) and at 3.5 h of endotoxaemia in six anaesthetized and mechanically ventilated pigs. Six other pigs served as controls and received only LPS infusion. Pulmonary and systemic haemodynamics as well as splenic, renal and intestinal blood flows were measured continuously. Release and synthesis of ET-1 and Big ET-1 were also measured. 2. Only three of the six pigs in the control group survived 3 h of LPS infusion while in the bosentantreated group all six pigs were alive at that time. A biphasic increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR) was seen in control pigs. Pretreatment with bosentan did not influence the first peak but markedly attenuated the second, more prolonged increase in MPAP and PVR. The second dose of bosentan completely restored these parameters to pre-LPS levels. The LPS-induced changes in mean arterial blood pressure, heart rate and systemic vascular resistance were similar in both groups, while cardiac output (CO) was significantly higher in the bosentan-treated group. The second bosentan dose increased CO and splenic and intestinal blood flow without further lowering of blood pressure. 3. Bosentan caused an increase of the basal arterial plasma levels of ET-1-like immunoreactivity (LI), from 16.8 +/- 1.3 pM to 49.6 +/- 10.0 pM (n = 6, P < 0.01). However, the rate of the increase of ET-1 levels during the LPS infusion was not affected by bosentan. Repeated administration of bosentan during LPS infusion caused an additional increase of ET-1-LI levels. Neither the basal levels of Big ET-LI nor the LPS induced 8 fold increase in Big ET-LI were changed by bosentan. The level of preproET-1 mRNA in the lung was increased about 3 fold after 4.5 h of LPS treatment. This elevation was not influenced by bosentan. 4. From these studies using bosentan, a non-peptide, selective and mixed ET-receptor antagonist, we conclude that during LPS-induced shock bosentan can abolish the late phase pulmonary hypertension and improve cardiac output as well as increase blood flow to the splenic and intestinal vascular beds without causing a further decrease in mean arterial blood pressure. Further investigations in the clinical setting are needed to evaluate the use of ET-receptor antagonists, such as bosentan, in treatment of septic shock.

Animals↗
PubMed1995

Effect of combined nitric oxide inhalation and NG-nitro-L-arginine infusion in porcine endotoxin shock.

OBJECTIVE: To evaluate the possible effects of a combination of systemic nitric oxide synthesis inhibition (to increase mean arterial blood pressure) and nitric oxide inhalation (to decrease pulmonary vascular pressure) in porcine endotoxin shock. DESIGN: Prospective trial. SETTING: Laboratory at a large university medical center. SUBJECTS: Ten pathogen-free pigs weighing 19 to 25 kg. INTERVENTIONS: After surgical preparation, all pigs received a continuous infusion of Escherichia coli lipopolysaccharide endotoxin (15 micrograms/kg/hr) for 2 hrs. After 1 hr of endotoxemia, nitric oxide inhalation (50 parts per million) and NG-nitro-L-arginine infusion (50 mg/kg/hr) were initiated in six pigs. Four pigs served as controls and received only a lipopolysaccharide infusion. MEASUREMENTS AND MAIN RESULTS: NG-nitro-L-arginine infusion and nitric oxide inhalation prevented the further decrease in mean arterial blood pressure seen in the control pigs (p < .05), but did not restore mean arterial blood pressure back to basal values. Cardiac output decreased significantly compared with controls during NG-nitro-L-arginine infusion/nitric oxide inhalation (p < .01). Systemic vascular resistance, which was below basal values in the controls after 2 hrs of endotoxemia, was markedly increased by NG-nitro-L-arginine/nitric oxide, to higher values than those observed in the basal state (p < .01). In the control pigs, mean pulmonary arterial pressure and pulmonary vascular resistance showed a biphasic increase. In the NG-nitro-L-arginine/nitric oxide treated group, the second phase increase in mean pulmonary arterial pressure did not occur (p < .01). However, there was no difference in pulmonary vascular resistance between the groups. Renal vascular resistance was unchanged in controls, while NG-nitro-L-arginine/nitric oxide induced a four-fold increase in renal vascular resistance (p < .001). There was no statistical difference in urine production between the groups. PaO2 values were higher and PaCO2 tensions were lower in the treated pigs than in the controls. Arterial pH and base excess did not differ. Arterial plasma epinephrine, norepinephrine, and neuropeptide Y concentrations increased during the lipopolysaccharide infusion in both groups, with a tendency toward higher concentrations in the pigs receiving NG-nitro-L-arginine/nitric oxide. Arterial plasma endothelin-1-like immunoreactivity in these pigs was significantly higher at the end of the treatment than in the controls. CONCLUSIONS: In this model of porcine endotoxin shock, the combination of NG-nitro-L-arginine infusion and nitric oxide inhalation attenuated pulmonary hypertension and improved gas exchange; it also prevented development of further systemic hypotension, but impaired cardiac output and increased systemic and renal vascular resistances to supranormal levels. NG-nitro-L-arginine/nitric oxide did not reduce sympathetic nervous system activation or metabolic acidosis.

Administration, Inhalation↗
PubMed1995

Inhibition of sympathetic vasoconstriction in pigs in vivo by the neuropeptide Y-Y1 receptor antagonist BIBP 3226.

1. Recently, a potent non-peptide antagonist of neuropeptide Y (NPY)-Y1 receptors has been developed. In this study, the selectivity of this compound, BIBP 3226, as a functional Y1 receptor antagonist, and the possible role of endogenous NPY in sympathetic vasoconstriction in different vascular beds have been investigated in anaesthetized pigs. 2. BIBP 3226 specifically displaced [125I]-NPY binding with an IC50 value of 7 nM in membranes of pig renal arteries, which also were responsive to a Y1 receptor agonist, but had only minor effects in the pig spleen (IC50 55 microM), where instead [125I]-NPY binding was markedly inhibited by a Y2 receptor agonist. IC50 values in the same nM range for BIBP 3226 were also observed in rat and bovine cortex and dog spleen. 3. In anaesthetized control pigs in vivo BIBP 3226 (1 and 3 mg kg-1) markedly inhibited the vasoconstrictor effects of the Y1 receptor agonist [Leu31, Pro34] NPY(1-36), without influencing the responses to the Y2 receptor agonist N-acetyl [Leu28, Leu31] NPY(24-36), or to noradrenaline, phenylephrine, alpha,beta-methylene adenosine triphosphate or angiotensin II. 4. High frequency stimulation of the sympathetic trunk in control pigs caused a biphasic vasoconstrictor response in nasal mucosa, hind limb and skin: there was an immediate, peak response, followed by a long-lasting vasoconstriction. BIBP 3226 (1 and 3 mg kg-1) reduced the second phase by about 50% but had no effect on the peak response. In the spleen, kidney and mesenteric circulation (which lack the protracted response) BIBP 3226 was likewise without effect on the maximal vasoconstriction, and did not influence noradrenaline overflow from spleen and kidney. 5. The corresponding S-enantiomer BIBP 3435 had only marginal influence on [125I]-NPY binding (microM range) and did not inhibit the vasoconstrictor effects of any of the agonists used, including the Y1 receptor peptide agonist. Furthermore, BIBP 3435 did not affect the response to sympathetic nerve stimulation. Both BIBP 3435 and BIBP 3226 caused a slight transient decrease in mean arterial blood pressure (by about 5 and 15 mmHg at 1 mg kg-1 and 3 mg kg-1, respectively), accompanied by splenic and mesenteric vasodilatation, suggesting that this effect was unrelated to Y1 receptor blockade. 6. The peptide YY (PYY)- and NPY-evoked vasoconstriction in the kidney of reserpine-treated pigs was markedly reduced (by 95%) by BIBP 3226 while the vasoconstrictor effect in the spleen was attenuated by only 20%. BIBP 3226 did not influence stimulation-evoked NPY release. The vasoconstrictor response in reserpine-treated pigs to single impulse stimulation, which is observed only in nasal mucosa and hind limb, was unchanged regarding maximal amplitude and the integrated effect was only moderately reduced (by about 25%) in the presence of BIBP 3226 (1 mg kg-1). BIBP 3226 (1 mg kg-1) markedly reduced (by 55-70%) the long-lasting vascular response (total integrated blood flow reduction) evoked by sympathetic nerve stimulation at high frequency (40 impulses at 20 Hz) in spleen, kidney, nasal mucosa and hind limb. Furthermore, the maximal amplitude of the vasoconstriction was reduced mainly in the kidney (by 60%) and also in the spleen (by 40%). 7. It is concluded that BIBP 3226 can act as a selective Y1 receptor antagonist in the pig. Endogenous NPY via Y1 receptor activation may play a role in evoking the long-lasting vasoconstriction seen in nasal mucosa, hind limb and skin after high frequency stimulation of sympathetic nerves in control pigs. Furthermore, NPY via Y1 receptor mechanisms seems to be of major importance for the long-lasting component of the reserpine resistant sympathetic vasoconstriction in many vascular beds, and for the maximal vasoconstrictor response in the kidney. Circulating NPY and PYY induce splenic vasoconstriction via Y2-receptors in contrast to neuronally released NPY which mainly activates Y1 receptors.

Animals↗
PubMed1994

Nitric oxide regulates peptide release from parasympathetic nerves and vascular reactivity to vasoactive intestinal polypeptide in vivo.

The possible involvement of nitric oxide (NO) in the vasodilator response to parasympathetic nerve stimulation in the pig submandibular gland in vivo was studied using the NO synthase inhibitor, NG-nitro-L-arginine. The atropine-resistant vasodilation elicited by parasympathetic stimulation (10 Hz, 30 s) and the response elicited by i.v. injection of vasoactive intestinal polypeptide (VIP) were markedly reduced by NG-nitro-L-arginine. Furthermore, peptide release from the gland elicited by nerve stimulation was attenuated after NG-nitro-L-arginine administration. Addition of the NO donor, nitroprusside, reversed the NG-nitro-L-arginine evoked attenuation of the response to nerve stimulation and VIP. Also the cholinergic parasympathetic component and the vascular effect of acetylcholine were reduced by NG-nitro-L-arginine. Furthermore, the NG-nitro-L-arginine-induced attenuation of the vascular responses was partially prevented by milrinone, an inhibitor of the cyclic GMP-regulated phosphodiesterase III. The present results suggest that NO may be crucial for parasympathetic vasodilatation by regulating peptide release and second messenger systems for VIP and acetylcholine.

Animals↗
PubMed1994

Repeated renal and splenic sympathetic nerve stimulation in anaesthetized pigs: maintained overflow of neuropeptide Y in controls but not after reserpine.

The overflow and the arterial vascular effects of neuropeptide Y (NPY) in response to repeated sympathetic nerve stimulation of kidney and spleen were investigated in anaesthetized pigs. The responses under control conditions were compared to those evoked in pigs with tissue stores of noradrenaline (NA) selectively depleted by reserpine pretreatment combined with sympathetic nerve transection. The renal and splenic sympathetic nerves were repeatedly stimulated at 1 h intervals with one 5 Hz stimulation for 48 s and transmitter overflow determined. Between these stimulations, 5 min stimulations with bursts of 20 Hz (for 1 s every 10 s) were given in order to induce a depletion of nerve transmitter. In the control group, overflow of NPY and NA and vasoconstrictor responses were almost identical for the 5 consecutive stimulations in the kidney, whereas in the spleen the parameters showed a slight tendency to be reduced. In the reserpine-treated group, the initial evoked overflow of NPY was increased 8-fold and 3-fold in the kidney and spleen, respectively, compared to the control group. Upon each subsequent stimulation the overflow decreased gradually, in parallel with the evoked vasoconstrictor response. After a 2 h recovery period no change in evoked overflow of NPY compared to the amount released by the previous stimulation was observed. The present study illustrates, the high capacity of maintenance of not only NA but also NPY overflow and vascular responses in control conditions, whereas the enhanced release of NPY in the absence of NA cannot be maintained. It is therefore possible that the NA-mediated prejunctional feedback mechanism is important for the maintenance of a constant NPY release in situations of high sympathetic activation.

Anesthesia↗
PubMed1994

Nitric oxide synthase in the pig autonomic nervous system in relation to the influence of NG--nitro-L-arginine on sympathetic and parasympathetic vascular control in vivo.

Nitric oxide synthase, the enzyme responsible for the formation of nitric oxide, was demonstrated by an indirect immunofluorescence technique to be present in both the sympathetic and parasympathetic nervous system of the domestic pig. In the sympathetic nervous system, nitric oxide synthase was mainly present in preganglionic neurons projecting to postganglionic neurons, some of which contained neuropeptide Y in the superior cervical, the coeliac and the lumbar ganglia of the sympathetic chain. A minor population of postganglionic sympathetic neurons contained nitric oxide synthase, vasoactive intestinal polypeptide and peptide histidine isoleucine. In the densely sympathetically innervated vascular beds such as the spleen, kidney and skeletal muscle, many neuropeptide Y- but no nitric oxide synthase-positive fibres were found. The nitric oxide synthase inhibitor NG-nitro-L-arginine reduced cardiac output by 40% and caused profound vasoconstriction in a variety of vascular beds. Furthermore, no or minor changes in plasma catecholamines, neuropeptide Y or endothelin-1 were observed up to 20 min after NG-nitro-L-arginine. Milrinone (a phosphodiesterase III inhibitor) prevented this NG-nitro-L-arginine-induced reduction in cardiac output, and the regional vasoconstriction was reduced, whereas some elevation of the blood pressure was still observed. Sympathetic nerve stimulation, with single impulses of 10 Hz for 1 s in the presence of NG-nitro-L-arginine, evoked vasoconstrictor responses which were largely in the same range as in control conditions. Parasympathetic postganglionic neurons to the submandibular salivary gland contained nitric oxide synthase, vasoactive intestinal polypeptide, peptide histidine isoleucine and neuropeptide Y. The vasodilatation evoked by parasympathetic nerve stimulation (10 Hz for 1 s) in the presence as well as in the absence of atropine was, on the other hand, markedly reduced by NG-nitro-L-arginine administration. Milrinone attenuated the inhibitory effect of NG-nitro-L-arginine on the parasympathetic vasodilation. In conclusion, nitric oxide synthase can be demonstrated in preganglionic sympathetic and postganglionic parasympathetic neurons. The main effect of nitric oxide synthase inhibition seems to be related to attenuation of basal endothelial nitric oxide production and parasympathetic transmission. Inhibition of phosphodiesterase counteracts both the haemodynamic and the neuronal effects of NG-nitro-L-arginine.

Amino Acid Oxidoreductases↗
PubMed1994

Non-adrenergic, non-cholinergic vascular control with reference to neuropeptide Y, vasoactive intestinal polypeptide and nitric oxide.

1. NOS-immunoreactivity was shown to be colocalized with vasoactive peptides such as VIP, PHI and NPY in postganglionic parasympathetic neurons to the submandibular gland. NOS-immunoreactivity was on the other hand found in preganglionic neurons in sympathetic ganglia but only in few postganglionic sympathetic neurons. These latter neurons also contained VIP and PHI. NPY was present in postganglionic perivascular sympathetic nerves in all organs studied. 2. Large vasoconstrictor responses were evoked by sympathetic nerve stimulation in the pig and dog after depletion of NA by reserpine treatment combined with interruption of nerve activity. Reserpine resistant vascular responses were obtained already at single pulse stimulation in pig skeletal muscle but the sensitivity to nerve stimulation varied with type of vascular bed. In general, the maximal vasoconstriction obtained after reserpine treatment was smaller than in controls but the duration of the response was prolonged. 3. In control condition NPY overflow was relatively well maintained. The severalfold larger NPY-overflow obtained after reserpine treatment compared to control conditions contributes to the gradual peptide depletion upon repeated stimulation and is likely to be related to lack of prejunctional alpha 2-adrenoceptor inhibition of transmitter release. NPY also regulated transmitter release via a prejunctional action. The NPY-LI in splenic venous effluent upon sympathetic stimulation after reserpine reached levels where exogenous NPY causes vasoconstriction. 4. NPY and NPY analogues caused long-lasting vasoconstriction. The dominating vascular NPY receptor seemed to be of the Y1 type, which mediated vasoconstriction in all vascular beds investigated and also increased MABP. A population of postjunctional Y2 receptors was also present in the splenic vascular bed in addition to its prejunctional localization on sympathetic nerves. 5. Inhibition of NO production by L-NNA caused general vasoconstriction, reduction in cardiac output and increase in MABP. L-NNA caused larger vasoconstriction in intact than in sympathetically denervated hind limb. After inhibition of NO production, preganglionic sympathetic nerve stimulation of the hind limb and nasal mucosa had vasoconstrictor effects only slightly different from those seen in control conditions. Both the cholinergic and non-cholinergic components of the parasympathetic nerve-mediated vasodilatation in the submandibular salivary gland were on the other hand markedly suppressed by L-NNA. 6. VIP- and ACh-evoked vasodilatory effects in the submandibular salivary gland were reduced after NOS-inhibition. Also the overflow of NPY-LI evoked by parasympathetic nerve stimulation of the submandibular salivary gland was suppressed by L-NNA.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Oxidoreductases↗
PubMed1993

Endothelial regulation of coronary vascular tone in vitro: contribution of endothelin receptor subtypes and nitric oxide.

The functional effects of endothelin-1, endothelin-3 and the ETB receptor agonist [Ala1,3,11,15]endothelin-1 on pig coronary arteries were characterized in vitro by using the ETA receptor antagonist BQ-123 and the nitric oxide synthesis inhibitor N-nitro-L-arginine. Endothelin-1 (EC50 value 8.8 nM), endothelin-3 (EC50 11.6 nM) and [Ala1,3,11,15]endothelin-1 (EC50 42 nM) evoked concentration-dependent contractions with maximal responses that were 151 +/- 21, 85 +/- 12 and 11 +/- 2%, respectively, of contractions evoked by 127 mM K+. BQ-123 (0.1-10 microM) induced concentration-related rightward shift of the response to endothelin-1. The response to the highest concentration of endothelin-1 was reduced by 62% in the presence of 10 microM BQ-123. Application of BQ-123 to vessels precontracted with endothelin-1 caused relaxation by 53%. BQ-123 also inhibited the contractile effect of endothelin-3, whereas the contractile responses to [Ala1,3,11,15]endothelin-1, serotonin or neuropeptide Y (Y1 receptor-mediated) were unaffected. In the presence of N-nitro-L-arginine (50 microM) the responses to [Ala1,3,11,15]endothelin-1 and low concentrations of endothelin-3 were significantly enhanced. The present results show that endothelin-induced contractions of porcine coronary arteries are efficiently prevented and reversed by BQ-123 indicating that the responses are evoked by ETA receptors. A portion of the contraction seems to be mediated by ETB receptors. The contractile response to ETB stimulation is in part counteracted by release of nitric oxide.

Amino Acid Sequence↗
PubMed1993

Comparison of the acute influence of neuropeptide Y and sympathetic stimulation on the composition of blood cells in the splenic vein in vivo.

The acute influence of exogenous transmitters and sympathetic nerve stimulation on the composition of blood cells in the splenic vein in relation to the splenic vascular effects was investigated in anaesthetized pigs. Intra arterial bolus injections of 720 pmol neuropeptide Y (NPY), 4.9 nmol noradrenaline (NA) and 20 nmol alpha,beta-methylene adenosine triphosphate (mATP) in the spleen were given and these doses caused arterial vasoconstriction in the same range, and increase in splenic venous haematocrit. NPY administration evoked a decrease in splenic venous blood flow and an unchanged leukocyte outflow from the spleen. mATP and NA, on the other hand, evoked increases in splenic venous blood flow and leukocyte outflow. Sympathetic nerve stimulation caused increases in haematocrit and leukocyte outflow in control pigs as well as in pigs with reserpine-induced depletion of tissue NA, although these effects, as well as the vascular effects, were significantly reduced after reserpine treatment. For comparison, the vasodilator calcitonin gene-related peptide increased leukocyte outflow without change in haematocrit. It is concluded that haematocrit and leukocyte concentration in the splenic venous blood are acutely modulated in different ways by vascular changes evoked by different sympathetic mediators. Furthermore, the capacitance function seems to be regulated by adrenergic and possibly purinergic transmission, whereas the non-adrenergic mediator NPY seems to be involved mainly in splenic arterial vasoconstriction.

Adenosine Triphosphate↗