Role Of Endothelium-derived Relaxing Factor Research Articles

The Role of Endothelium-Derived Relaxing Factor in The Regulation of SNP Induced Vasorelaxation: Sodium-Potassium-Chloride Cotransporter

Vascular endothelium plays a key role in the local regulation of vascular tone and vascular architecture. However, it is unclear whether the combination of NKCC cotransporter with endothelial mediated factor and potassium channel in rat aortic ring contributes in regulation of the vascular activity. In the current study, the potential role of endothelium-mediated relaxing factors and potassium channel in SNP induced vasorelaxation in precontracted isolated rat aortic rings in the presence of Bumetanide as NKCC blocker were investigated. The maximum vasorelaxation induced by SNP significantly blocked by the presence BUM. SNP induced relaxation was affected by combination of BUM with Indomethacin, Clotrimazole. TEA and BaCl2 significantly blocked of SNP induced relaxation in aorta preincubated with all blockers used, but BaCl2 showed a more potent effect as compared with others. These results indicate that SNP – induced vasorelaxation was mediated via EETs, Prostaglandin, BKCa and KIR pathways which ultimately enhanced the contribution of chloride transporter in aortic smooth muscle cells hyperpolarization and subsequent relaxation.

Repair of congenital diaphragmatic hernia under high-frequency oscillatory ventilation in high-risk patients: an opportunity for earlier repair while minimizing lung injury.

BACKGROUNDRepair of congenital diaphragmatic hernia (CDH) is ideally delayed until ventilatory parameters are stabilized and patients are switched to conventional ventilation. However, in selected high-risk patients, repair can be performed earlier while they are still on high-frequency oscillatory ventilation (HFOV).DESIGN AND SETTINGSA retrospective review of all CDH cases treated in our tertiary referral center between 1997 and 2013.METHODSIn 1997, we started repairing selected high-risk CDH cases under HFOV with or without inhaled nitric oxide (iNO). All repairs were performed once the infants’ blood gas levels were acceptable. The infants were gradually weaned to conventional ventilation followed by extubation as their ventilatory parameters improved. Their records were reviewed to determine the group-wide outcomes.RESULTSBetween 1997 and 2013, 55 infants with CDH were treated in our institute; of these 12 high-risk cases were repaired under HFOV/iNO combinations and 1 was repaired without iNO. All patients had significant pulmonary hypertension and 8 had herniated livers. The mean age at repair was 9.1 (6.3) days. Two mortalities occurred at the first and tenth postoperative days. Among the remaining 11 survivors, the median ventilation and hospitalization days were 29.5 (11–84) and 45.5 (25–107), respectively, and the median duration under HFOV and conventional ventilation days were 15 (9–40) and 12 (3–47), respectively.CONCLUSIONCDH repair can be performed earlier under HFOV and iNO. The possible advantages are earlier restoration of normal anatomy and earlier start of enteral feeding while minimizing the risk of lung injury.

ChemInform Abstract: Endothelial Modulation of Agonist‐Induced Vasoconstriction in Mesenteric Microcirculation

AbstractReview: 28 refs.

Endothelial Modulation of Agonist-induced Vasoconstriction in Mesenteric Microcirculation

It is widely accepted that vascular endothelium regulates vasoconstriction via release of endothelium-derived relaxing factors (EDRF). The mesenteric circulation, which is the largest vascular bed, influences regulation of systemic blood pressure. However, the role of EDRF in the modulation of vascular tone in peripheral mesenteric circulation has not been extensively studied. Therefore, our recent studies investigated the role of the vascular endothelium in the regulation of methoxamine (alpha(1)-adrenoceptor agonist)-induced vasoconstriction and their age-related changes in rat mesenteric vascular beds. In mesenteric vascular beds with intact endothelium isolated from 8 week-old rats, the initial maximum vasoconstriction induced by continuous perfusion of methoxamine was time-dependently decreased during 3 hour-perfusion. Neither nitric oxide synthase inhibitor nor cyclooxygenase inhibitor altered this time-dependent reduction of methoxamine-induced vasoconstriction. Endothelium removal, K(+)-channel inhibitors and gap junction inhibitor significantly inhibited the time-dependent reduction of methoxamine-induced vasoconstriction. In the preparations with intact endothelium from 16 week-old rats, the time-dependent reduction of methoxamine-induced vasoconstriction disappeared. Furthermore, endothelium removal and treatment with cyclooxygenase inhibitor, thromboxane A(2) receptor antagonist or superoxide dismutase mimetic significantly reduced the methoxamine-induced vasoconstriction in the preparations from 16 week-old rats. These findings suggest that vascular endothelium acts to depress methoxamine-induced vasoconstriction by releasing endothelium-derived hyperpolarizing factor (EDHF), and dysfunction in this endothelial modulation develops with ageing.

Characterization of agonist‐induced endothelium‐dependent vasodilatory responses in the vascular bed of the equine digit

The role of endothelium-derived relaxing factors was studied in the regulation of vascular responses in the Krebs perfused equine isolated digit. Perfusion pressure was recorded in response to bolus doses of 5-hydroxytryptamine (6 nmol) alone or co-administered with carbachol (CCh; 0.2 micromol), bradykinin (BK; 0.2 nmol), substance P (SP; 0.2 nmol) or sodium nitroprusside (SNP; 0.2 micromol). N(omega)-Nitro-L-Arginine methyl ester hydrochloride (L-NAME; 300 microm) caused partial but significant inhibition of CCh-induced vasodilatory response, whereas BK and SP-induced responses were resistant to L-NAME. High potassium (K(+), 30 mm) and the cytochrome P-450 (CYP) epoxygenase inhibitor, clotrimazole (10 microm) plus L-NAME (100 microm), completely abolished the CCh, BK and SP-induced vasodilatory responses, whereas the response to SNP was unaffected. In contrast, the L-NAME-resistant proportion of CCh, BK and SP-induced vasodilatory response was not inhibited by the highly selective CYP2C9 inhibitor, sulphaphenazole (10 microm). The cyclo-oxygenase inhibitor, ibuprofen (10 microm) did not affect the CCh, BK and SP-induced responses. These data demonstrate that CCh, BK and SP-induced relaxation in the equine digit involve a combination of the NO and endothelium-derived hyperpolarizing factor (EDHF) pathways. These results do not support the evidence for the involvement of CYP-derived epoxyeicosatrienoic acids and the exact nature of EDHF in the equine digit remains to be established.

Gender difference in the role of endothelium-derived relaxing factors modulating renal vascular reactivity

This study analyzed the role of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in gender differences in the renal vascular reactivity of rats. Renal responses to vasoconstrictors and vasodilators were studied in isolated kidneys from male and female rats under basal conditions, after NO and EDHF blockade or after endothelium removal. Female rat kidneys had reduced responsiveness to vasoconstrictors. The blockade of NO or of EDHF did not completely abolish the differences, but the simultaneous blockade of both factors or endothelium removal abolished gender differences. Male and female kidneys showed a similar responsiveness to endothelium-dependent and -independent vasodilators under basal conditions and after NO or EDHF blockade. In conclusion: (a) the attenuated response to vasoconstrictors in female kidneys is related to an increased production of NO and EDHF; and (b), the contributions of NO and EDHF to endothelium-dependent vasodilation are similar in the male and female renal vasculature.

Role of endothelium-derived relaxing factors in the renal response to vasoactive agents in hypothyroid rats.

This study analyzed the role of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in the abnormal renal vascular reactivity of hypothyroid rats. Renal responses to vasoconstrictors [VC: phenylephrine (PHE) and ANG II] and vasodilators [VD: ACh, sodium nitroprusside (SNP), and papaverine (PV)] were studied in kidneys from control and hypothyroid rats under normal conditions and after NO or EDHF blockade. NO was blocked by the administration of Nomega-nitro-l-arginine methyl ester (l-NAME) and EDHF by the administration of tetraethylammonium (TEA) or by an increased extracellular K+. The response to VC was also evaluated after endothelium removal. Hypothyroid kidneys showed reduced responsiveness to PHE and a normal response to ANG II. l-NAME and TEA administration produced an increased sensitivity to PHE and to ANG II in control preparations. l-NAME also increased the response to PHE in hypothyroid kidneys, but the differences between control and hypothyroid kidneys were maintained. TEA administration did not change the response to either VC in hypothyroid preparations. In endothelium-removed preparations, TEA was unable to increase pressor responsiveness to VC. Hypothyroid kidneys showed reduced responsiveness to ACh and SNP and normal response to PV. The differences between hypothyroid and control preparations in the responses to ACh and SNP were maintained after l-NAME or increased K+. In conclusion, this study shows that 1) the attenuated response to PHE in hypothyroidism is not related to an increased production of endothelium-derived relaxing factors NO and EDHF; 2) the response to VC in hypothyroid preparations is insensitive to EDHF blockade; and 3) hypothyroid preparations have a reduced reactivity to the NO donor, and NO-independent vasodilatation remains unaffected.

Mechanisms of vasorelaxation to testosterone in the rat aorta

We have investigated the role of endothelium-derived relaxing factors, K + channels and steroid receptors in vasorelaxation to testosterone in the rat aorta. Testosterone (1 nM–mM) caused acute concentration-dependent vasorelaxation. Both indomethacin (10 μM) and flurbiprofen (10 μM) uncovered relaxant responses to testosterone. The action of indomethacin was inhibited by endothelial removal. N G-nitro- l-arginine methyl ester ( l-NAME, 300 μM) had no effects on testosterone-induced responses. In the presence of indomethacin, the vasorelaxant potency of testosterone was reduced by depolarization with 60 mM KCl or charybdotoxin (100 nM), but not by glibenclamide (10 μM), 4-aminopyridine (1 mM) or barium chloride (30 μM). The responses to testosterone were not inhibited by flutamide (10 μM) or mifepristone (30 μM). Pre-treatment of the aorta with testosterone (100 μM) inhibited CaCl 2-induced contraction. In the present study, we have demonstrated that testosterone causes acute vasorelaxations, which are modulated via endothelium-derived prostanoids. The responses uncovered by cyclooxygenase inhibitors are due to the activation of K Ca channels, while at higher concentrations, testosterone inhibits Ca 2+ influx.

Role of endothelium-derived relaxing factors in adrenomedullin-induced vasodilation in the rat kidney

The present study aimed to evaluate the contributions of endothelium-derived hyperpolarizing factor (EDHF), the nitric oxide (NO)-cGMP pathway, and prostaglandins to adrenomedullin-induced vasodilation in isolated rat kidney. Inhibition of the NO-cGMP pathway with N ω-nitro- l-arginine methyl ester ( l-NAME) or 1 H-[1,2,4]oxadiazolo-[4,3 a]quinoxalin-1-one (ODQ) reduced the maximal vasodilator response to adrenomedullin by approximately 50%. Pretreatment of the vessels with the potassium channel inhibitor, tetraethylammonium or increased extracellular K +, also decreased the maximal response to adrenomedullin by approximately 50%. The simultaneous administration of blockers of both endothelium-derived relaxing factors had a combined effect that almost suppressed adrenomedullin-induced vasodilation. The administration of indomethacin did not modify the renal response to adrenomedullin. Our results suggest that the vasodilator response to adrenomedullin in the isolated perfused kidney of rats is mediated by EDHF and NO to a similar extent. Our data also provide evidence that prostaglandins play no role in the vasodilator response to adrenomedullin in the renal vasculature.

Role of EDRF in Pulmonary Circulation During Sustained Hypoxia

The pulmonary artery pressure (PAP) response to hypoxia is characterized by an initial vasoconstriction followed by vasodilation. Pulmonary vessels can release endothelium-derived relaxing factor (EDRF), which is considered to be nitric oxide (NO), but the role of EDRF in the regulation of normal and hypoxic pulmonary vascular tone is still uncertain. We designed this study to address the in vivo role of EDRF in vasodilation during sustained hypoxia. We studied the effects of an EDRF-synthesis inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), on the pulmonary vascular response to sustained hypoxia (10% O2, 20 min) in normoxic (N) and chronically hypoxic (CH) rats. Biphasic PAP response was observed in N rats, whereas PAP was unchanged in CH rats during sustained hypoxic exposure. The L-NAME-induced PAP increase during normoxia was greater in CH than in N rats, suggesting that basal EDRF plays an important role in attenuating the severity of pulmonary hypertension in CH rats. Administration of L-NAME increased the initial increment in PAP by acute hypoxia and shifted the PAP response upward throughout sustained hypoxia, while still showing the biphasic pattern, in N rats. In contrast, PAP increased acutely and remained elevated with little recovery in the late phase in CH rats. The inducible NO synthase messenger RNA (mRNA) expression and protein showed greater increases in the lungs of CH than in N rats. These results suggest that EDRF release during sustained hypoxia may partly contribute to the roll-off in PAP response during sustained hypoxia in N rats, and that augmented EDRF may prevent a further increase in PAP during chronic hypoxia.

Coordinate changes of renin and brain-type nitric-oxide-synthase (b-NOS) mRNA levels in rat kidneys.

In our study we have examined the mRNA levels of nitric-oxide-(NO-)synthases in rat kidneys during states of stimulated and reduced renin gene expression, to find out whether renal mRNA levels of NO-synthases are correlated with the activity of the renin system. Stimulation of the renin system was achieved by unilateral renal artery clipping (2-kidney/1-clip rats), treatment with the angiotensin II (ANG II) antagonist losartan (40 mg/kg), application of furosemide (12 mg x kg-1 x day-1) and a low-sodium diet (0.02% w/w Na+), which increased renin mRNA levels to 464%, 495%, 309% and 219% of those of control animals, respectively. Inhibition of the renin system was achieved in the nonclipped (contralateral) kidneys of 2-kidney/1-clip rats and in the kidneys of rats which were fed a high-sodium diet (4% w/w Na+); in both cases renin mRNA levels decreased to about 50% of the control values. First screening of the gene expression of brain-type NO-synthase (b-NOS), endothelial NOS (e-NOS) and inducible NOS (i-NOS) during all these alterations of the renin system was done using the reverse transcriptase-polymerase chain reaction (RT-PCR) technique. Results from such noncompetitive PCR experiments indicated that only b-NOS mRNA levels change concordantly with the levels of renin. These changes in b-NOS mRNA levels were checked by the more reliable method of RNase protection assay. Results of the RNase protection assay proved that the renal levels of b-NOS mRNA were significantly increased by about 50% after a low-sodium diet and hypoperfusion of the kidney. Given a stimulatory role of endothelium-derived relaxing factor (EDRF)/NO on the renin system our findings may provide the first evidence that increases of renal levels of b-NOS mRNA and, as a consequence, of renal EDRF/NO formation could be important mediators of the well-known effect of salt intake and hypoperfusion on the renin system.

Significance of endothelium-derived relaxing factor (EDRF) on pulmonary vasoconstriction induced by hypoxia and hypercapnia.

Distribution of pulmonary blood flow is physiologically regulated by alveolar PO2 and PCO2 surrounding the microcirculation in the lung (Fishman, 1976; Yamaguchi et al., 1994). Decrease in PO2 and/or increase in PC02 has been considered to evoke a rise in the pulmonary microvascular resistance to blood flow (Sylvester et al., 1986; Rodman and Voelkel, 1991). It has been suggested that hypoxic pulmonary vasoconstriction (HPV) as well as hypercapnic-induced vasoconstriction may divert blood flow away from the poorly ventilated areas (Fishman, 1976). The importance of the endothelial-derived vasoactive agents in modulating blood flow has been increasingly recognized since the discovery of endothelium-derived relaxing factor (EDRF), a noble vasodilator of both the systemic and pulmonary circulation (Palmer et al., 1987; Ignaro et al., 1987; Moncada et al., 1991). Many authors have attempted to clarify a possible role of EDRF in the occurrence of HPV, however definite conclusion has not been attained. Although hypercapnia caused by alveolar hypoventilation is considered as the additionally important factor affecting pulmonary hemodynamics (O’Brodovich et al., 1982; Marshall et al., 1984; Sylvester et al., 1986; Yamaguchi et al., 1994), there have been no systematic studies showing the potential effects of hypercapnic-induced acidosis on EDRF modulation for pulmonary circulation. The first aim of this study is systematically to reinvestigate the effects of EDRF on HPV applying varied inhibitors or inactivators for EDRF acting on different levels of EDRF metabolic pathway. The second aim is to make clear the possible roles of EDRF modulating the pulmonary vascular response to acute hypercapnia.

Modulatory role of endothelium-derived relaxing factors on the response to vasoconstrictors and flow-pressure curve in the isolated perfused rat kidney.

The aim of this study was to compare the effects of the blockade of nitric oxide (NO) and of endothelium-derived hyperpolarizing factor (EDHF) on the response to vasoconstrictors (VC) and on the flow-pressure curve in the isolated perfused rat kidney. To this end, dose-response curves to phenylephrine and BaCl2 were studied in the renal vasculature under basal conditions and after the infusion of N(omega)-nitro-L-arginine methyl ester (L-NAME) and tetraethylammonium (TEA) in endothelium-intact and endothelium-denuded (CHAPS-treated) preparations. In another experiment, renal flow-pressure curves were obtained under basal conditions and after the infusion of L-NAME or TEA. The flow-pressure curve was obtained by increasing renal perfusion flow (RPF) from 2.5 to 15 ml/min/g kidney weight (KW) over the basal level (5 ml/min/g KW). L-NAME or TEA produced a leftward shift of the dose-response curves of both VC, and the simultaneous administration of L-NAME and TEA produced a greater shift to the left in the pressor response curves. CHAPS treatment produced a leftward shift of the dose-response curves of both VC, and the dose-response curves were not significantly modified by the infusion of L-NAME or TEA. L-NAME markedly shifted the flow-pressure curve upward, especially at higher levels of RPF. However, the administration of TEA, perfusate solution (Tyrode) or D-NAME did not significantly change the flow-pressure curve. These results suggest that NO is released in response to VC as well as to increased perfusion flow in the isolated renal vascular bed. However, EDHF release seems to be stimulated by VC but not by increased perfusion flow.

Endothelial modulation of pH-dependent pressor response in isolated perfused rabbit lungs.

With the use of isolated perfused rabbit lungs (n = 152), roles of endothelium-derived relaxing factor (EDRF) in pulmonary vascular responses to hypocapnia and hypercapnia were studied. Lungs were ventilated with a gas mixture containing 1, 5, or 10% CO2 and 21% O2, adjusting the perfusate pH to 7.8, 7.4, or 7.1, respectively. Methemoglobin (MetHb), hemoglobin (Hb), methylene blue (MB), and L-argininosuccinic acid (L-ASA) were used as modulators of EDRF. To eliminate augmented shear stress, we used papaverine during hypercapnia. As a measure of EDRF, we spectrophotometrically examined nitric oxide (NO) metabolites in the perfusate. Hypocapnia and hypercapnia evoked, respectively, unsustainable vasodilatation and vasoconstriction. Hb, MB, and L-ASA, but not MetHb, produced an increase in baseline pulmonary arterial pressure (Ppa). These agents also exacerbated vasoconstriction during hypercapnia. Hypercapnia and hypocapnia caused an increase and decrease, respectively, in EDRF production. L-ASA suppressed EDRF production in hypercapnic lungs. Papaverine did not suppress EDRF production under hypercapnia. In conclusion, 1) the effects of pH on pulmonary circulation are transient, 2) the increase in Ppa caused by hypercapnia is modulated by EDRF, and 3) the pulmonary EDRF genesis is activated by hypercapnic acidosis but suppressed by hypocapnic alkalosis.

The role of nω-nitro-L-arginine in modulation of pulmonary vascular tone in the maturing newborn pig

Current therapeutic modalities for treatment of newborn pulmonary hypertensive crisis include but are not limited to the administration of nitric oxide (endothelium-derived relaxing factor). However, few data are available on the role of endogenously produced endothelium-derived relaxing factor in the modulation of pulmonary vascular tone in the neonate. In the current study, we investigated the acute effects of Nω-nitro- L -arginine (a potent competitive inhibitor of endothelium-derived relaxing factor synthase) on the pulmonary vasculature of anesthetized open-chest 48-hour-old ( n = 8) and 2-week-old ( n = 7) Yorkshire pigs. After baseline data were acquired, all animals received a 10 mg/kg per minute infusion of Nω-nitro- L -arginine for 10 minutes. To discern distal and proximal pulmonary arterial vessel changes, input mean and characteristic impedance were respectively determined. Pulmonary vascular resistance was also calculated (units determined in dyne • sec • cm -5 plus or minus the standard errorof the mean). Results showed Nω-nitro- L -arginine infusion did not significantly alter baseline pulmonary arterial pressure (22,370 ±1473 dyne/cm 2 ), pulmonary vascular resistance (5171 ±805 dyne • sec • cm -5 ), input impedance (6343 ±806 dyne • sec • cm -5 ), or characteristic impedance (2073 ±418 dyne • sec • cm -5 ) in 48-hour-old pigs. In 2-week-old pigs, infusion of Nω-nitro- L -arginine elevated pulmonary arterial pressure (18,162 ±1415 dyne/cm 2 versus 23,838 ±1810 dyne/cm 2 , p = 0.015), pulmonary vascular resistance (810 ±137 dyne • sec • cm -5 versus 1519 dyne • sec • cm -5 , p = 0.030), and input impedance (2302 ±251 dyne • sec • cm -5 versus 2900 ±255 dyne • sec • cm -5 , p = 0.018). Characteristic impedance was not altered in 2-week-old pigs. These data indicate that Nω-nitro- L -arginine infusion resulted in pulmonary arteriolar vasoconstriction in 2-week-old pigs, but not in 48-hour-old pigs. This finding suggests that endothelium-derived relaxing factor does not modulate basal pulmonary arteriolar tone during the early newborn period, but does play a significant role in 2-week-old pigs. These data also suggest that the functional role for endothelium-derived relaxing factor is confined to the distal arteriolar pulmonary bed and does not extend to the larger proximal arterial vessels. (J THORAC CARDIOVASC SURG 1995;110:1486-92)

Role of endothelium-derived relaxing factor in the maintenance of renal blood flow in a rodent model of chronic hydronephrosis

Objectives To define the role of endothelium-derived relaxing factor (EDRF) in the regulation of renal hemodynamics in the hydronephrotic kidney. Methods Experiments were performed in control rats and in rats that had undergone unilateral ureteral ligation 6 weeks before. Renal blood flow was monitored before and after inhibition of EDRF synthesis in the control and hydronephrotic animals. Videomicroscopy was also performed in hydronephrotic animals to observe directly the effect of inhibition of EDRF synthesis on the renal microcirculation. Results Inhibition of EDRF synthesis resulted in a 61% decrease in renal blood flow in the control animals compared with only a 27% decrease for the hydronephrotic animals. The videomicroscopy studies demonstrated that inhibition of EDRF synthesis results in significant vasoconstriction of the preglomerular and postglomerular resistance vessels. Conclusions Although EDRF continues to play a significant role in the maintenance of renal blood flow in the chronically obstructed kidney, EDRF synthesis by the renal vascular endothelium may be reduced in this setting, contributing to ischemic renal atrophy.

Endothelium-mediated control of coronary vascular tone after chronic exercise training

The purpose of this paper is to examine the role of endothelium-derived relaxing factors in the control of coronary vascular resistance in conditioned subjects (i.e., after exercise training for a period of time sufficient to complete adaptation processes). Results from studies with exercise trained (EX) dogs, miniature swine, and rats are summarized. Since the relative importance of vascular control mechanisms differ in various segments of the coronary arterial tree, the effects of EX on conduit arteries and the coronary arterial microcirculation are discussed separately. Results indicate that endothelium-mediated vasodilator responses are normal in conduit coronary arteries of EX dogs, miniature swine, and rats. It is proposed that endothelium-mediated vasodilation of conduit coronary arteries is enhanced early in the exercise-adaptive process but returns to normal as adaptation to EX is complete, when structural adaptations produce a relative decrease in coronary shear during exercise. EX miniature swine manifest enhanced endothelium-mediated vasodilation stimulated by bradykinin and flow in isolated coronary resistance arteries and appear to have increased expression of NO synthase (ecNOS). Brief training also appears to increase the expression of ecNOS. The role of endothelium-mediated vasodilation in regulation of coronary blood flow in EX animals remains uncertain.

EDRF and norepinephrine-induced vasodilation in the canine coronary circulation

Experiments were performed to characterize the role of endothelium-derived relaxing factor (EDRF) in coronary vasodilation caused by norepinephrine. The circumflex or left anterior descending coronary artery was cannulated and pump perfused with constant pressure or constant flow in closed-chest anesthetized dogs. Prostaglandin synthesis was blocked with ibuprofen. During constant-pressure perfusion, EDRF inhibition with intracoronary N omega-nitro-L-arginine (L-NNA) did not affect the vasodilation due to nitroglycerin (an endothelium-independent process). However, L-NNA did significantly inhibit (P < 0.001) the vasodilation due to acetylcholine (an endothelium-dependent process). In response to bolus injections of norepinephrine, EDRF inhibition with L-NNA significantly reduced coronary vasodilation (P < 0.001). This inhibition was partially reversed with L-arginine infusion. To determine whether an increase in shear stress due to an increase in flow was the stimulus for EDRF release, experiments were performed during constant-flow conditions. Vasodilation caused by nitroglycerin was not inhibited by L-NNA, but EDRF inhibition did blunt acetylcholine-induced vasodilation significantly (P < 0.001) during constant-flow perfusion. During EDRF inhibition with L-NNA, vasodilation due to norepinephrine was not significantly altered when coronary flow was held constant (P = 0.19). In conclusion, EDRF plays a role in norepinephrine-induced coronary vasodilation that is largely flow dependent.

Role of EDRF in the cardiopulmonary dysfunction produced by massive sympathetic activation.

This study was undertaken to determine whether endothelium-derived relaxing factor (EDRF) modulates the pulmonary and systemic hemodynamic responses to massive sympathetic nervous system (SNS) activation and, in so doing, also modulates the degree of SNS-induced left ventricular (LV) dysfunction and the likelihood for pulmonary edema formation. The SNS of 13 anesthetized untreated rabbits and 14 anesthetized rabbits pretreated with the EDRF inhibitor, N omega-nitro-L-arginine (L-NNA, 20 mg/kg), was massively activated with an intracisternal injection of veratrine. Pulmonary and systemic arterial pressures increased to the same extent in both groups, but LV end-diastolic pressure was significantly lower in untreated rabbits. During this time, cardiac output decreased by 37% in L-NNA pretreated rabbits compared with 8% in untreated animals. Peak systemic and pulmonary vascular resistances increased significantly in L-NNA rabbits, whereas only systemic vascular resistance increased significantly in untreated rabbits. However, this increase in systemic vascular resistance was threefold less than that observed for L-NNA-treated animals. Although the degree of LV dysfunction was greater in the L-NNA rabbits, pulmonary edema developed less frequently in this group. We suggest that when EDRF release is inhibited during massive SNS activity, pulmonary vascular resistance increases markedly, which causes the right ventricle to fail. We further suggest that the reduced right ventricular output maintains pulmonary microvascular pressure below levels required for edema development.

Role of nitric oxide (EDRF) in radiocontrast acute renal failure in rats.

This study was undertaken to examine the possible role of endothelium-derived relaxing factor (EDRF), identified as nitric oxide (NO), in the pathogenesis of radiocontrast-induced acute renal failure in rats. Normal and salt-depleted rats were monitored for 60 min or 24 h after radiocontrast administration. The administration of L-arginine to normal rats abolished the immediate decrease in p-aminohippurate clearance (CPAH) and attenuated the decrease in inulin clearance (CIn). The administration of NO synthase inhibitor to the salt-depleted animals resulted in a significantly more pronounced decrease in CPAH compared with both the control and the L-arginine-treated animals. The recovery of CIn 24 h after radiocontrast administration to the salt-depleted rats was significantly better in the L-arginine-treated rats than in either the control or inhibitor-treated groups. The administration of radiocontrast material resulted in a significant decrease in urinary guanosine 3',5'-cyclic monophosphate as well as NO2 + NO3 excretion. This decrease was significantly attenuated by L-arginine. Our results 1) suggest that NO plays a major role in the pathogenesis of radiocontrast-induced acute renal failure and 2) suggest a novel therapeutic approach, i.e., the use of L-arginine in this form of acute renal failure.