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

Albert, Johanna; Schedin, Ulla; Lmdqvist, M.; Melcher, A.; Hjemdahl, Paul; Frostell, Claes

doi:10.1111/j.1399-6576.1997.tb04852.x

Cited by 28 publications

(26 citation statements)

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“…These investigations [45][46][47][48][49][50][51][52] agree on indicating that inhibition of NO synthesis results in hemodynamic changes qualitatively similar to those observed in the current study, i.e., increments of MAP and systemic vascular resistance and reductions in cardiac output, heart rate, and stroke volume. However, in healthy subjects inhibition of NOS had quite different renal effects from those observed in cirrhotic patients in our study because it induced reductions of variable degrees in RBF, GFR, and sodium excretion, which occurred despite an increase in MAP, 49,[52][53][54][55][56][57] indicating that NO acts as a regulator of renal hemodynamics and sodium excretion in healthy humans.…”

Section: Discussionsupporting

confidence: 84%

“…Several studies have been published investigating the effects of NOS inhibition on systemic hemodynamics [45][46][47][48][49][50][51][52] and renal function 49,[52][53][54][55][56][57] in healthy humans. These investigations [45][46][47][48][49][50][51][52] agree on indicating that inhibition of NO synthesis results in hemodynamic changes qualitatively similar to those observed in the current study, i.e., increments of MAP and systemic vascular resistance and reductions in cardiac output, heart rate, and stroke volume.…”

Section: Discussionmentioning

confidence: 99%

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Hemodynamic, Renal, and Endocrine Effects of Acute Inhibition of Nitric Oxide Synthase in Compensated Cirrhosis

et al. 2001

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To assess whether an increased production of nitric oxide is involved in the circulatory and renal alterations of cirrhosis, we evaluated systemic hemodynamics (echocardiography), renal hemodynamics, and sodium handling (lithium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 ؎ 2 years) with compensated cirrhosis, portal hypertension, and hyperdynamic circulation during intravenous N Gmonomethyl-L-arginine (L-NMMA) (3 mg/kg bolus plus 0.05 mg/kg ⅐ min for 120 minutes) or placebo (the vehicle) in a randomized, placebo-controlled, crossover study. Administration of L-NMMA resulted in significant reductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synthase. L-NMMA also significantly reduced cardiac index (؊13%) and increased systemic vascular resistance (؉26%), arterial pressure (؉9%), renal blood flow (؉12%), glomerular filtration rate (؉12%), and sodium excretion (؉25%). Changes in sodium excretion were caused by both enhanced filtered sodium load and reduced sodium reabsorption in the proximal tubule. Plasma norepinephrine significantly decreased in response to L-NMMA, and there was a trend for reductions in PRA and PAC. Placebo had no appreciable effect on any of the measured parameters. These results indicate that in patients with compensated cirrhosis, portal hypertension and hyperdynamic circulation inhibition of nitric oxide synthase corrects the altered systemic hemodynamics and improves re- Patients with cirrhosis and portal hypertension eventually develop a hyperdynamic circulation, with high cardiac output, reduced systemic vascular resistance, and a trend towards arterial hypotension. 1 This abnormality, that contributes to worsen portal hypertension and plays a major role in the pathogenesis of other complications, including ascites and renal failure, has been related to peripheral arterial vasodilation, mainly occurring in the splanchnic circulation. 2 The cause(s) and mechanism(s) of arterial vasodilation are still unknown, but available evidence suggests that an increased synthesis of nitric oxide (NO) participates in the pathogenesis of the altered systemic hemodynamics in cirrhosis. 3,4 Animals with experimental cirrhosis have increased expression of nitric oxide synthase (NOS) and increased synthesis of NO in the vasculature. 5-9 They also have impaired response to vasoconstrictors in isolated aortic rings or splanchnic vasculature preparations, which is reversed by NOS inhibitors, 10,11 and increased pressor response to systemic administration of NOS inhibitors. 12,13 In addition, normalization of NO production by low-dose N G -nitro-L-arginine methyl ester, a NOS inhibitor, corrected the altered systemic hemodynamics, normalized the activity of the main vasoconstricting and sodiumretaining systems, 14 and improved renal sodium and water excretion in cirrhotic rats with ascites. 15 Evidence of an increased synthesis of NO has also ...

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Hemodynamic, Renal, and Endocrine Effects of Acute Inhibition of Nitric Oxide Synthase in Compensated Cirrhosis

et al. 2001

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“…NO is also important for maintenance of normal pulmonary vascular tone, and NOS inhibition increases PVR in healthy and septic adults (15)(16)(17)(18)(19). Despite these observations, at the L-NMMA doses used in this study, we did not see any evidence of abnormal PVR by clinical or echocardiographic parameters in our preterm subjects.…”

Section: Discussioncontrasting

confidence: 51%

“…Inhibition of NO production produces increases in systemic blood pressure and vascular resistance in healthy adult volunteers (15,16). Its effects are more pronounced in adults with septic shock, in which systemic NO production is increased (17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

Combined Treatment With a Nonselective Nitric Oxide Synthase Inhibitor (L-NMMA) and Indomethacin Increases Ductus Constriction in Extremely Premature Newborns

et al. 2005

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Studies in premature animals suggest that 1) prolonged tight constriction of the ductus arteriosus is necessary for permanent anatomic closure and 2) endogenous nitric oxide (NO) and prostaglandins both play a role in ductus patency. We hypothesized that combination therapy with an NO synthase (NOS) inhibitor [N G -monomethyl-L-arginine (L-NMMA)] and indomethacin would produce tighter ductus constriction than indomethacin alone. Therefore, we conducted a phase I and II study of combined treatment with indomethacin and L-NMMA in newborns born at Ͻ28 weeks' gestation who had persistent ductus flow by Doppler after an initial three-dose prophylactic indomethacin course (0.2, 0.1, 0.1 mg/kg/24 h). Twelve infants were treated with the combined treatment protocol [three additional indomethacin doses (0.1 mg/kg/24 h) plus a 72-hour L-NMMA infusion]. Thirty-eight newborns received three additional indomethacin doses (without L-NMMA) and served as a comparison group. Ninety-two percent (11/12) of the combined treatment group had tight ductus constriction with elimination of Doppler flow. In contrast, only 42% (16/38) of the comparison group had a similar degree of constriction. L-NMMA infusions were limited in dose and duration by acute side effects. Doses of 10 -20 mg/kg/h increased serum creatinine and systemic blood pressure. At 5 mg/kg/h, serum creatinine was stable but systemic hypertension still limited L-NMMA dose. We conclude that combined inhibition of NO and prostaglandin synthesis increased the degree of ductus constriction in newborns born at Ͻ28 weeks' gestation. However, the combined administration of L-NMMA and indomethacin was limited by acute side effects in this treatment protocol. Studies in premature animals demonstrate that prolonged, tight constriction of the ductus arteriosus is necessary to produce ischemia of the ductus wall, anatomic remodeling, and permanent closure (1-3). A persistent patent ductus arteriosus (PDA) in premature infants is due in large part to the increased sensitivity of the ductus to endogenous vasodilators like prostaglandins. Prostaglandin synthesis inhibitors, such as indomethacin, are the only drugs currently approved for treatment of PDA. Unfortunately, a three-dose course of indomethacin frequently fails to close the PDA in infants of Ͻ28 weeks gestational age (GA). Previous studies have shown that infants delivered before 28 weeks GA who still have evidence of ductus flow on Doppler examination (performed after a standard three-dose course of indomethacin), are unlikely to eliminate Doppler flow through their ductus even if a prolonged six-dose indomethacin course is administered (2).

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“…DUCTUS ARTERIOSUS REMODELING (44), and pulmonary vascular pressure (39,40). Similar studies are not available in the extremely preterm newborn.…”

mentioning

confidence: 99%

Combined Prostaglandin and Nitric Oxide Inhibition Produces Anatomic Remodeling and Closure of the Ductus Arteriosus in the Premature Newborn Baboon

Seidner¹,

Chen

Oprysko

et al. 2001

Pediatr Res

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After birth, the full-term ductus arteriosus actively constricts and undergoes extensive histologic changes that prevent subsequent reopening. These changes are thought to occur only if a region of intense hypoxia develops within the ductus wall after the initial active constriction. In preterm infants, indomethacininduced constriction of the ductus is often transient and is followed by reopening. Prostaglandins and nitric oxide both play a role in inhibiting ductus closure in vitro. We hypothesized that combined inhibition of both prostaglandin and nitric oxide production (with indomethacin and N-nitro-L-arginine (L-NA), respectively) may be required to produce the degree of functional closure that is needed to cause intense hypoxia. We used preterm (0.67 gestation) newborn baboons that were mechanically ventilated for 6 d: 6 received indomethacin alone, 7 received indomethacin plus L-NA, and 16 received no treatment (control). Just before necropsy, only 25% of control ductus and 33% of indomethacin-treated ductus were closed on Doppler examination; in contrast, 100% of the indomethacin-plus-L-NA-treated ductus were closed. Control and indomethacin-treated baboons developed negligible-to-mild ductus hypoxia (EF5 technique). Similarly, there was minimal evidence of ductus remodeling. In contrast, indomethacin-plus-L-NA-treated baboons developed intense hypoxia in regions where the ductus was most constricted. The hypoxic muscle strongly expressed vascular endothelial growth factor, and proliferating luminal endothelial cells filled and occluded the lumen. In addition, cells in the most hypoxic regions were undergoing DNA fragmentation. In conclusion, preterm newborns are capable of remodeling their ductus, just like the full-term newborn, if they can reduce their luminal blood flow to a point that produces intense ductus wall hypoxia. Combined prostaglandin and nitric oxide inhibition may be necessary to produce permanent closure of the ductus and prevent reopening in preterm infants. In the full-term infant, closure of the DA occurs in two phases: 1) initial "functional" closure of the DA lumen by smooth muscle constriction, and 2) "anatomic" occlusion of the lumen resulting from endothelial proliferation, neointimal thickening, and loss of smooth muscle cells from the inner muscle media (1, 2). Hypoxia of the DA wall seems to be the required stimulus for irreversible, anatomic closure (3). Anatomic remodeling occurs only in the presence of moderate to intense hypoxia (3).

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

Cited by 28 publications

References 0 publications

Hemodynamic, Renal, and Endocrine Effects of Acute Inhibition of Nitric Oxide Synthase in Compensated Cirrhosis

Hemodynamic, Renal, and Endocrine Effects of Acute Inhibition of Nitric Oxide Synthase in Compensated Cirrhosis

Combined Treatment With a Nonselective Nitric Oxide Synthase Inhibitor (L-NMMA) and Indomethacin Increases Ductus Constriction in Extremely Premature Newborns

Combined Prostaglandin and Nitric Oxide Inhibition Produces Anatomic Remodeling and Closure of the Ductus Arteriosus in the Premature Newborn Baboon

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