Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension.

We investigated the responses of canine coronary rings to endothelium-derived relaxing factor-nitric oxide- (EDRF-NO) dependent agonists and NO synthase (NOS) inhibitors 3 h after endotoxic shock was induced in dogs by lipopolysaccharide infusion (LPS; 2 mg/kg). EDRF-NO-dependent relaxation to thrombin [control maximum response produced after administration of thrombin (Emax) was -85.2 +/- 7.0% of the constrictor response produced by the thromboxane analogue U-46619], acetylcholine (control Emax -88.4 +/- 3.4%), or bradykinin (control Emax -80.5 +/- 2.2%) was not inhibited by LPS (Emax thrombin -75.9 +/- 9.5%; Emax acetylcholine -90.2 +/- 2.4%; Emax bradykinin -91.6 +/- 3.4%). The NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) (10(-6)-3 x 10(-4) M) caused constriction of rings with endothelium (Emax 36.3 +/- 5.6%), an effect that was greater after LPS (Emax 59.2 +/- 4.1%; P < 0.05). D-NMMA had no effect in control, but it increased tension after LPS (Emax 20.8 +/- 9.7%). Contrary to expectations, L- and D-NMMA relaxed endothelium-denuded rings (-30.4 +/- 8.7% L-NMMA; -45.1 +/- 11.7% D-NMMA; P < 0.05). However, neither agent caused relaxation after in vivo LPS (10.2 +/- 3.4% L-NMMA; 8.9 +/- 5.2% D-NMMA). N omega-nitro-L-arginine-methylester (L-NAME) and nitro-L-arginine (10(-6)-3 x 10(-4) M) increased tension (Emax 82.3 +/- 23.9 and 73.1 +/- 8.8%, respectively) but only when endothelium was present, and the increases were no greater in LPS-treated groups than in controls (with LPS: Emax L-NAME 87.3 +/- 16.5%; Emax nitro-L-arginine 65.7 +/- 3.3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1991.260.1.h242 ◽

1991 ◽

Vol 260 (1) ◽

pp. H242-H247 ◽

Cited By ~ 7

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.

Download Full-text

Influence of endothelium-derived relaxing factor on renal microvessels and pressure-dependent vasodilation

AJP Renal Physiology ◽

10.1152/ajprenal.1993.265.2.f285 ◽

1993 ◽

Vol 265 (2) ◽

pp. F285-F292 ◽

Cited By ~ 15

Author(s):

J. Hoffend ◽

A. Cavarape ◽

K. Endlich ◽

M. Steinhausen

Keyword(s):

Blood Flow ◽

Renal Perfusion ◽

Local Administration ◽

Relaxing Factor ◽

Female Wistar Rats ◽

Stepwise Reduction ◽

Afferent Arterioles ◽

Endothelium Derived Relaxing Factor ◽

Hydronephrotic Kidney

The influence of endothelium-derived relaxing factor (EDRF) on renal microvessels and autoregulation was visualized in vivo, in the split hydronephrotic kidney of rats. EDRF synthesis was inhibited by local administration of 10(-5) M NG-nitro-L-arginine methyl ester (L-NAME). Diameters of arcuate arteries decreased by 17%. In cortical vessels efferent arterioles constricted more (13-16%) than interlobular arteries and afferent arterioles (7-12%). Cortical glomerular blood flow (GBF) decreased by 46% after L-NAME. A similar behavior of blood flow and vascular diameters was also observed in juxtamedullary (JM) arterioles. The responses to acetylcholine but not to sodium nitroprusside were attenuated after L-NAME. After local administration of L-arginine (10(-3) M) diameters of all vessels and GBF increased, vascular responses to L-NAME were blunted. Stepwise reduction of renal perfusion pressure revealed that autoregulation was preserved in cortical vessels after L-NAME. In JM arterioles, which do not autoregulate in female Wistar rats, autoregulation of GBF was enhanced after L-NAME. These data suggest that tonic formation of EDRF influences basal renal hemodynamics to a considerable extent. EDRF may also impair autoregulation of JM glomeruli without disturbing autoregulation of cortical glomeruli.

Download Full-text

L-arginine suffusion restores response to acetylcholine in brain arterioles with damaged endothelium

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.262.4.h961 ◽

1992 ◽

Vol 262 (4) ◽

pp. H961-H964 ◽

Cited By ~ 1

Author(s):

W. I. Rosenblum ◽

G. H. Nelson ◽

T. Shimizu

Keyword(s):

Evans Blue ◽

Relaxing Factor ◽

Laser Injury ◽

Vascular Bed ◽

Brain Microvessels ◽

Time Period ◽

Pial Arterioles ◽

Vascular Beds ◽

Endothelium Derived Relaxing Factor

Minor endothelial injury was produced in pial arterioles by a laser-Evans blue technique. This technique previously has been shown to prevent relaxation of the arterioles by topical acetylcholine (ACh) or bradykinin, agonists whose actions are known to be endothelium dependent in most vascular beds. L-Arginine is thought to be the precursor of the endothelium-derived relaxing factor (EDRF) that mediates the response to ACh. To further test this hypothesis and to begin exploration of the intracellular effects of the laser injury, we used the laser to eliminate the response to ACh and then attempted to restore the responsivity by suffusing the arterioles with 10(-3) L-arginine for 10 min before testing with ACh. This treatment restored the response. In contrast, over the same time period, responses failed to recover in arterioles that were never exposed to L-arginine or in arterioles that were only exposed to L-arginine at the time of retest with ACh. D-Arginine failed to restore the response to ACh. L-Arginine failed to restore the response to bradykinin. The data support the hypothesis that L-arginine acts as a substrate for synthesis of “classical” EDRF in brain microvessels in vivo. The data suggest that laser-Evans blue injury either depletes the endothelium of L-arginine or interferes with conversion of L-arginine to EDRF. Increasing the substrate by exposing the vessels to L-arginine for 10 min permitted ACh to release sufficient EDRF to elicit dilatation. The data also support conclusions from earlier studies that in this vascular bed the dilations produced by ACh and bradykinin are mediated by different EDRF.

Download Full-text

Increased in vivo platelet activation and reduced intravascular endothelium-derived relaxing factor and nitrate/nitrite production in patients with insulin-dependent diabetes mellitus

Platelets ◽

10.1080/09537109876807 ◽

1998 ◽

Vol 9 (3-4) ◽

pp. 257-260 ◽

Cited By ~ 5

Author(s):

M. Udvardy ◽

M. Kaplar ◽

L. Rejto ◽

I. Tornai ◽

K. Palatka ◽

...

Keyword(s):

Diabetes Mellitus ◽

Platelet Activation ◽

Insulin Dependent Diabetes Mellitus ◽

Insulin Dependent Diabetes ◽

Dependent Diabetes Mellitus ◽

Relaxing Factor ◽

Nitrite Production ◽

Insulin Dependent ◽

Endothelium Derived Relaxing Factor

Download Full-text

In vitro and in vivo assessment of endothelium-derived relaxing factor during pregnancy in the ra.

10.1349/ddlp.2916 ◽

1991 ◽

Author(s):

Susan Whittemore

Keyword(s):

Relaxing Factor ◽

Endothelium Derived Relaxing Factor ◽

In Vivo Assessment

Download Full-text

Endothelium-derived relaxing factor inhibits norepinephrine contraction of fetal guinea pig arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.264.4.h1139 ◽

1993 ◽

Vol 264 (4) ◽

pp. H1139-H1145 ◽

Cited By ~ 2

Author(s):

L. P. Thompson ◽

C. P. Weiner

Keyword(s):

Vascular Tone ◽

Carotid Arteries ◽

Isometric Contractions ◽

Maximal Contraction ◽

Alpha Adrenoceptor ◽

Relaxing Factor ◽

Before And After ◽

Endothelium Derived Relaxing Factor ◽

Near Term

As in the adult circulation, the endothelium may play an important role in determining fetal vascular tone. The purpose of this study was to determine the influence of the endothelium on norepinephrine- and phenylephrine-induced contraction of pulmonary and carotid arteries from near-term fetal guinea pigs. Isometric contractions of isolated rings to the cumulative addition of norepinephrine (10(-9)-10(-5) M) were measured before and after 1) endothelium removal, 2) NG-monomethyl-L-arginine (L-NMMA; 10(-4) M) to inhibit endothelium-derived relaxing factor (EDRF), 3) methylene blue (10(-5) M) to inhibit guanylate cyclase, 4) oxyhemoglobin (3 x 10(-6) M) to bind EDRF, and 5) indomethacin (10(-5) M) to inhibit cyclooxygenase. All treatment effects were measured in endothelium-intact segments. The maximal norepinephrine contraction of fetal pulmonary (40 +/- 8% KCl, n = 7) and carotid (13 +/- 7% KCl, n = 7) arteries was much less (P < 0.05) than the maximal contraction to 120 mM KCl. Treatments that inhibit the action of EDRF increased contraction of both fetal pulmonary and carotid arteries. L-NMMA also increased contraction to phenylephrine. Indomethacin had no effect on the contractile responses to norepinephrine of either artery. Thus EDRF inhibits alpha-adrenoceptor-stimulated contraction of fetal pulmonary and carotid arteries and may attenuate the constrictor responsiveness of the fetal circulation in vivo.

Download Full-text

Inhibition of rat mesangial cell mitogenesis by nitric oxide-generating vasodilators

AJP Renal Physiology ◽

10.1152/ajprenal.1989.257.1.f60 ◽

1989 ◽

Vol 257 (1) ◽

pp. F60-F66 ◽

Cited By ~ 9

Author(s):

U. C. Garg ◽

A. Hassid

Keyword(s):

Nitric Oxide ◽

Sodium Nitroprusside ◽

Culture Medium ◽

Mesangial Cell ◽

Mesangial Cells ◽

Inhibitory Effect ◽

Relaxing Factor ◽

Growth Inhibitory ◽

Endothelium Derived Relaxing Factor

Recent studies indicate that endothelium-derived relaxing factor (EDRF) may be identical with nitric oxide (NO). The purpose of this study was to investigate the antimitogenic effect of NO-generating drugs in cultured mesangial cells. S-nitroso-N-acetylpenicillamine, sodium nitroprusside, and isosorbide dinitrate, which generate NO, dose dependently inhibited serum-stimulated DNA synthesis. All three drugs also inhibited the rate of cell proliferation, whereas sodium nitroprusside and S-nitroso-N-acetylpenicillamine decreased cell density at confluence. The antimitogenic activity of S-nitroso-N-acetylpenicillamine was labile in culture medium and could be inhibited by hemoglobin, supporting the view that NO, in free or bound form, was the ultimate effector. All three vasodilators increased cellular guanosine 3',5'-cyclic monophosphate (cGMP) levels dose dependently; moreover, 8-bromo-cGMP mimicked the effects of the NO-generating drugs, suggesting that cGMP may be an intracellular mediator of antimitogenesis. The growth-inhibitory effect of S-nitroso-N-acetylpenicillamine was reversible and was not due to cell toxicity as shown by several criteria of cell viability. The results raise the possibility that EDRF/NO may be a modulator of mesangial cell growth in vivo.

Download Full-text