Acetylcholine-induced vasodilatation in rabbit hindlimb in vivo is not inhibited by analogues of L-arginine

1991 ◽  
Vol 260 (1) ◽  
pp. H242-H247 ◽  
Author(s):  
A. Mugge ◽  
J. A. Lopez ◽  
D. J. Piegors ◽  
K. R. Breese ◽  
D. D. Heistad
Keyword(s):  
Substance P ◽  
Systemic Blood Pressure ◽  
Nitroso Compounds ◽  
Femoral Arteries ◽  
Relaxing Factor ◽  
Resistance Vessels ◽  
Basal Tone ◽  
Endothelium Derived Relaxing Factor

Nitric oxide (NO) or related nitroso compounds are an endothelium-derived relaxing factor (EDRF), originating from metabolism of L-arginine, L-Arginine analogues with chemically altered guanidino moity are potent and specific inhibitors of EDRF(NO) release. We evaluated effects of two L-arginine analogues, NG-monomethyl-L-arginine (L-NMMA, 100 microM) and N omega-nitro-L-arginine (L-NARG, 30 microM), on acetylcholine-, substance P-, and nitroglycerin-induced relaxation in the blood-perfused rabbit hindlimb in vivo and femoral arteries in vitro. L-NMMA and L-NARG selectively inhibited the vasodilator response to acetylcholine in rabbit femoral arteries in vitro, whereas endothelium-independent response to nitroprusside increased. L-NMMA (1.6 mg/min ia) in the blood-perfused rabbit hindlimb in vivo increased vascular resistance in the hindlimb by 23 +/- 3% (means +/- SE; n = 10) but did not inhibit the vasodilator responses to acetylcholine or substance P. L-NARG (10 mg/kg iv) increased systemic blood pressure by 26 +/- 3% (n = 7) and vascular hindlimb resistance by 22 +/- 9% (n = 8), and blood flow to hindlimb musculature, measured with microspheres, decreased by 46 +/- 5% (n = 6). Pretreatment with L-NARG, however, did not impair vasodilator responses to acetylcholine and substance P. These findings are consistent with the view that basal tone in resistance vessels in the rabbit hindlimb may be mediated by nitroso compounds, whereas agonist-stimulated vasodilation may be mediated by other mechanisms that do not involve the NO-synthesizing enzyme.

scholarly journals Endothelium-derived relaxing factor, nitric oxide: effects on and production by mesangial cells and the glomerulus.

1993 ◽  
Vol 3 (8) ◽  
pp. 1435-1441
Author(s):  
L Raij ◽  
P J Shultz
Keyword(s):  
Nitric Oxide ◽  
Vascular Tone ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Glomerular Mesangial Cells ◽  
Relaxing Factor ◽  
Endothelium Derived Relaxing Factor

The endothelium-derived relaxing factor nitric oxide (EDRF/NO) is a labile, endogenous vasodilator that is important in the control of systemic vascular tone. This review focuses on the effects of EDRF/NO on glomerular mesangial cells in vitro and on the role of EDRF/NO in mesangial and glomerular physiology and pathophysiology in vivo. It was concluded that EDRF/NO can stimulate increases in cGMP, inhibit mesangial cell contraction, and inhibit growth factor-induced proliferation of mesangial cells in culture. Furthermore, incubation with endotoxin or cytokines stimulates mesangial cells to produce EDRF/NO, via an inducible NO synthase enzyme. Therefore, it is likely that NO could play a role in the inflammatory response within the glomerulus. Finally, recent studies providing evidence that EDRF/NO is functional within the glomerulus in vivo, especially during endotoxemia and inflammation are also reviewed.

scholarly journals Inhibition of the release of endothelium-derived relaxing factor in vitro and in vivo by dipeptides containing NG-nitro-l-arginine

1991 ◽  
Vol 104 (1) ◽  
pp. 31-38 ◽  
Author(s):  
Christoph Thiemermann ◽  
Marina Mustafa ◽  
P. Achim Mester ◽  
Jane A. Mitchell ◽  
Markus Hecker ◽  
...  
Keyword(s):  
Relaxing Factor ◽  
Endothelium Derived Relaxing Factor

Effect of Superoxide Dismutase on Endothelium-Dependent Relaxation of Aorta from Endotoxin-Treated Rabbits

1994 ◽  
Vol 22 (2) ◽  
pp. 113-120 ◽  
Author(s):  
H Yaku ◽  
K Mikawa ◽  
K Nishina ◽  
N Maekawa ◽  
H Obara
Keyword(s):  
Superoxide Dismutase ◽  
Protective Effect ◽  
Treated Group ◽  
Endothelial Damage ◽  
Histological Studies ◽  
Relaxing Factor ◽  
Endothelium Derived Relaxing Factor ◽  
Endothelium Dependent Relaxation

To assess the protective effect of superoxide dismutase (SOD) on the endothelium of aorta in endotoxaemia, we investigated the production of endothelium-derived relaxing factor in aorta obtained from endotoxin-treated rabbits concomitantly receiving SOD or not. Thirty-two male Japanese white rabbits were randomly divided into four groups ( n = 8 for each group): one group receiving saline as a placebo, a second receiving 5 mg/kg endotoxin intravenously, a third receiving 5 mg/kg endotoxin intravenously plus SOD, and a fourth receiving SOD alone. SOD was injected intravenously at a dose of 10 000 U/kg before the endotoxin and was infused continuously at a rate of 15 000 units/kg/h throughout the experiment. The tension of the aorta was recorded in vitro 6 h after the start of in vivo treatment with endotoxin or saline. In the aorta of rabbits receiving endotoxin alone, acetylcholine-induced relaxation was reduced by 50%. The SOD fully restored the reduction of acetylcholine-induced relaxation by endotoxin. Histological studies using photomicroscopy revealed endothelial damage in the endotoxin-treated aorta, which was attenuated in the SOD-treated group. These data suggest that intravenous SOD may be an effective treatment for unstable haemodynamics in endotoxaemia.

Effects of a stabilized endothelium-derived relaxing factor on the coronary vasculature in awake dogs

1989 ◽  
Vol 257 (6) ◽  
pp. H1895-H1899
Author(s):  
A. Chu ◽  
F. R. Cobb ◽  
P. O. Hagen ◽  
J. J. Murray
Keyword(s):  
Endothelial Cells ◽  
Biological Effects ◽  
Calcium Ionophore ◽  
Left Ventricular ◽  
Ionophore A23187 ◽  
Relaxing Factor ◽  
Endothelium Derived Relaxing Factor ◽  
Distal Flow

The effects of a partially purified endothelium-derived relaxing factor (EDRF) stabilized by acidification from cultured bovine aortic endothelial cells stimulated with the calcium ionophore A23187 on coronary and peripheral vasculature were examined in five awake dogs. The dogs were chronically instrumented with miniature arterial dimension crystals and Doppler flow probes. Intracoronary or intra-arterial infusions of this EDRF induced a rapid (less than 15 s) significant increase in the proximal vessel diameter (P less than 0.02). The duration of proximal dilation response to this EDRF persisted up to 6 min, whereas the smaller changes in distal flow were more transient (less than 1 min). Similar but more pronounced changes in the proximal arterial dilation and distal flow occurred with infusion of nitroglycerin (0.4 mg). No vasoactive changes were observed during infusions of the control vehicle. The vasodilatory effects to this EDRF occurred in the absence of changes in aortic and left ventricular pressure, rate of pressure development (dP/dt), and heart rate. These data demonstrate that infusion of this partially purified relaxing factor from cultured endothelial cells causes vasodilation in vivo with a vasoactive profile similar to nitroglycerin. The biological effects of this EDRF persist significantly longer than the extreme lability of EDRF at neutral pH (approximately 6 s), consistent with its in vitro effects. Despite the demonstration of rapid inactivation of EDRF in vitro by hemoglobin, high oxygen tension, and plasma, the study shows that this EDRF can have significant in vivo vasoactive effects.

EDRF in pulmonary resistance vessels from fetal lamb: stimulation by oxygen and bradykinin

1994 ◽  
Vol 266 (3) ◽  
pp. H936-H943 ◽  
Author(s):  
Y. Wang ◽  
F. Coceani
Keyword(s):  
Nitric Oxide ◽  
Thromboxane A2 ◽  
Pulmonary Resistance ◽  
Relaxing Factor ◽  
Resistance Vessels ◽  
Basal Tone ◽  
Fetal Lamb ◽  
Endothelium Derived Relaxing Factor ◽  
Arteries And Veins ◽  
Thromboxane A2 Analogue

Endothelium-derived relaxing factor-nitric oxide (EDRF-NO) has been studied in isolated, pulmonary resistance vessels from term fetal lambs at a fetal (21 +/- 0.2 mmHg) and neonatal (69 +/- 0.4 mmHg) PO2. Bradykinin dose dependently (0.1-100 nM) relaxed arteries and veins that had been precontracted with a thromboxane A2 analogue. Their response did not differ at low PO2, whereas the response of the arteries was greater at high PO2. Sodium nitroprusside was almost as potent as bradykinin on the arteries, but its action did not vary with PO2. Acetylcholine also relaxed the arteries at higher concentrations (0.1-100 microM). N omega-mono-methyl-L-arginine (L-NMMA) and N omega-nitro-L-arginine methyl ester (L-NAME) (both at 100 microM) weakly contracted arteries at low PO2. The contraction to L-NAME, but not L-NMMA, increased with the PO2. In the arteries, L-NAME had no effect on bradykinin relaxation at low PO2, whereas it was an inhibitor at high PO2. Conversely, L-NMMA slightly inhibited bradykinin relaxation regardless of PO2. In the veins, L-NAME transiently increased basal tone and inhibited bradykinin relaxation at either PO2. Indomethacin (2.8 microM) had no effect on arteries at low PO2, whereas it was a constrictor at high PO2. No indomethacin constriction occurred in the veins. We conclude that fetal pulmonary resistance vessels possess an EDRF-NO relaxing mechanism that is stimulated by bradykinin. In the arteries, this mechanism is more effective at high PO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of endothelium-derived relaxing factor in renal autoregulation in conscious dogs

1992 ◽  
Vol 263 (2) ◽  
pp. F208-F213 ◽  
Author(s):  
J. E. Baumann ◽  
P. B. Persson ◽  
H. Ehmke ◽  
B. Nafz ◽  
H. R. Kirchheim
Keyword(s):  
Perfusion Pressure ◽  
Systemic Blood Pressure ◽  
Renal Perfusion ◽  
Conscious Dogs ◽  
Renal Autoregulation ◽  
Relaxing Factor ◽  
Resistance Vessels ◽  
Endothelium Derived Relaxing Factor ◽  
Aortic Cuff

In six chronically instrumented, conscious dogs the hypothesis was tested that the release of endothelium-derived relaxing factor (EDRF) is important for autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR). RBF was measured by a Transonic flowmeter. Renal perfusion pressure was servo-controlled by an aortic cuff. EDRF synthesis was inhibited by NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg iv). L-NAME increased mean systemic blood pressure (30 mmHg) and decreased heart rate (-40 beats/min), but it left autoregulation of RBF and GFR intact. However, basal RBF decreased markedly (2.24 +/- 0.32 ml.min-1.g-1 with L-NAME vs. 3.91 +/- 0.64 ml.min-1.g-1 for control, P less than 0.01), whereas basal GFR was not significantly influenced (0.37 +/- 0.05 ml.min-1.g-1 with L-NAME vs. 0.42 +/- 0.06 ml.min-1.g-1 for control). Hence filtration fraction increased with L-NAME [27.6 +/- 1.7% vs. 19.3 +/- 1.3% (P less than 0.01)]. The lower limit of autoregulation remained unchanged for RBF (64 +/- 5 mmHg with L-NAME vs. 63 +/- 3 mmHg for control) and increased slightly for GFR (74 +/- 2 mmHg with L-NAME vs. 67 +/- 1 mmHg for control, P less than 0.01). In conclusion, basal EDRF activity tonically influences renal resistance vessels; however, EDRF release is not primarily involved in the process of renal autoregulation. The maintenance of GFR suggests that this effect is localized in preglomerular as well as in postglomerular arterioles.

scholarly journals Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses

1990 ◽  
Vol 258 (3) ◽  
pp. H655-H662 ◽  
Author(s):  
J. P. Tolins ◽  
R. M. Palmer ◽  
S. Moncada ◽  
L. Raij
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Intravenous Infusion ◽  
Soluble Guanylate Cyclase ◽  
Hemodynamic Responses ◽  
Relaxing Factor ◽  
Renal Hemodynamic ◽  
Endothelium Derived Relaxing Factor

An endothelium-derived relaxing factor (EDRF) has recently been identified as nitric oxide (NO), originating from endothelial cell metabolism of L-arginine. In vitro studies suggest that EDRF/NO stimulates soluble guanylate cyclase and increases guanosine 3',5'-cyclic monophosphate (cGMP) levels in vascular smooth muscle cells, resulting in the vasorelaxant effects of endothelium-dependent vasodilators such as acetylcholine (ACh). The importance of EDRF/NO in normal physiology or disease states remains uncertain. We therefore investigated the relationship between ACh-induced hemodynamic responses, synthesis of EDRF/NO, and changes in the rate of urinary cGMP excretion in the anesthetized rat in vivo. Intravenous infusion of ACh resulted in hypotension, maintenance of glomerular filtration rate, and renal vasodilatation. ACh induced a dose-dependent increase in urinary cGMP excretion, an effect that was not observed with equihypotensive doses of the endothelium-independent vasodilator, prostacyclin. Rates of cGMP excretion were significantly correlated with the fall in systemic blood pressure induced by ACh. Treatment with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of enzymatic synthesis of nitric oxide from L-arginine, prevented the ACh-induced increase in urinary cGMP excretion as well as the systemic and renal hemodynamic effects of ACh. Plasma levels of atrial natriuretic peptide were unchanged by ACh infusion. Intravenous infusion of L-NMMA was associated with increased blood pressure and decreased basal rates of urinary cGMP excretion. This hypertensive effect was reversed by administration of L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

Methylprednisolone on circulating eicosanoids and vasomotor tone after endotoxin

1986 ◽  
Vol 61 (1) ◽  
pp. 185-191 ◽  
Author(s):  
C. A. Hales ◽  
R. D. Brandstetter ◽  
C. F. Neely ◽  
M. B. Peterson ◽  
D. Kong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Resistance ◽  
Systemic Blood Pressure ◽  
Physiological Effect ◽  
High Dose ◽  
Systemic Blood ◽  
Eicosanoid Production ◽  
Circulating Levels

Acute pulmonary and systemic vasomotor changes induced by endotoxin in dogs have been related, at least in part, to the production of eicosanoids such as the vasoconstrictor thromboxane and the vasodilator prostacyclin. Steroids in high doses, in vitro, inhibit activation of phospholipase A2 and prevent fatty acid release from cell membranes to enter the arachidonic acid cascade. We, therefore, administered methylprednisolone (40 mg/kg) to dogs to see if eicosanoid production and the ensuing vasomotor changes could be prevented after administration of 150 micrograms/kg of endotoxin. The stable metabolites of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured by radioimmunoassay. Methylprednisolone by itself did not alter circulating eicosanoids but when given 2.5 h before endotoxin not only failed to inhibit endotoxin-induced eicosanoid production but actually resulted in higher circulating levels of 6-keto-PGF1 alpha (P less than 0.05) compared with animals receiving endotoxin alone. Indomethacin prevented the steroid-enhanced concentrations of 6-keto-PGF1 alpha after endotoxin and prevented the greater fall (P less than 0.05) in systemic blood pressure and systemic vascular resistance with steroid plus endotoxin than occurred with endotoxin alone. Administration of methylprednisolone immediately before endotoxin resulted in enhanced levels (P less than 0.05) of both TxB2 and 6-keto-PGF1 alpha but with a fall in systemic blood pressure and vascular resistance similar to the animals pretreated by 2.5 h. In contrast to the early steroid group in which all of the hypotensive effect was due to eicosanoids, in the latter group steroids had an additional nonspecific effect. Thus, in vivo, high-dose steroids did not prevent endotoxin-induced increases in eicosanoids but actually increased circulating levels of TxB2 and 6-keto-PGF1 alpha with a physiological effect favoring vasodilation.

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