nitroarginine and Cardiac-Output--Low

Fluid loading is an essential part of cardiovascular resuscitation in septic shock. We hypothesized that fluid administration increases blood flow velocity and thus endothelial shear stress, causing the release of nitric oxide by the vascular endothelium. Because of endothelial dysfunction in sepsis, this mechanism would be less effective in septic animals. Fluid loading may have different effects in septic compared with control animals.. Prospective, randomized, controlled study.. Animal research laboratory.. Male Sprague-Dawley rats.. We tested the involvement of nitric oxide in the fluid-induced cardiovascular response after administration of lipopolysaccharide (5 mg/kg, n = 10) or vehicle (control, n = 10) in rats subsequently randomized after 165 mins to receive L-N(G)-nitroarginine (7.5 mg/kg) or saline (n = 5 in each group). At 180 mins, all animals received hydroxyethyl starch (fluid loading, 15 mL/kg in 15 mins). Reversal of L-N(G)-nitroarginine was studied with an intravenous bolus of L-arginine (300 mg/kg).. Lipopolysaccharide injection induced a hypokinetic shock (low blood pressure: -30% +/- 9%, p < .05), low cardiac output (aortic pulsed-Doppler probe: -20% +/- 8, p < .05), and unchanged systemic conductance, which turned into a hyperkinetic shock by fluid loading. Pretreatment with L-N(G)-nitroarginine totally abolished this fluid loading-induced vasodilation in control rats but only partially in lipopolysaccharide-treated rats, suggesting an altered endothelial response after lipopolysaccharide injection. Maximal aortic blood flow acceleration was used as an index of left ventricular systolic function. The improvement of maximal aortic blood flow acceleration observed during fluid loading in lipopolysaccharide-treated or control animals was blunted by L-N(G)-nitroarginine pretreatment, suggesting the involvement of nitric oxide in the myocardial response to fluid loading.. These results suggest that the endothelium participates in the hemodynamic response to fluid loading in control rats, but less in rats with septic shock, secondary to an altered nitric oxide-dependent vasodilation.

Topics: Animals; Aorta; Blood Flow Velocity; Cardiac Output, Low; Disease Models, Animal; Endothelium, Vascular; Enzyme Inhibitors; Escherichia coli; Injections, Intravenous; Lipopolysaccharides; Male; Nitric Oxide; Nitroarginine; Prospective Studies; Random Allocation; Rats; Rats, Sprague-Dawley; Resuscitation; Shock, Septic; Vasodilation

We performed experiments to test the hypothesis that experimental heart failure (HF) is associated with altered nitric oxide (NO)-dependent influences on the renal microvasculature, including diminished modulation of constrictor responses to ANG II. Eight to ten weeks after inducing HF in rats by coronary artery ligation, we administered enalaprilat to suppress ANG II synthesis and studied renal arteriolar function using the in vitro blood-perfused juxtamedullary nephron technique. In kidneys from sham-operated rats, NO synthase inhibition [100 microM Nomega-nitro-L-arginine (L-NNA)] reduced afferent arteriolar diameter by 4.1 +/- 0.6 microm and enhanced ANG II responsiveness (10 nM ANG II decreased afferent diameter by 10.1 +/- 1.4 micrometer before and 12.8 +/- 1.6 micrometer during L-NNA treatment; P < 0.05). In kidneys from HF rats, L-NNA did not alter afferent arteriolar baseline diameter or ANG II responsiveness (10 nM ANG II decreased diameter by 12.5 +/- 1.5 micrometer before and 12.5 +/- 2.3 micrometer during L-NNA). The effects of L-NNA on efferent arteriolar function were also abated in HF rats. In renal cortex of HF rats, NO synthase activity was decreased by 63% and superoxide dismutase activity was diminished by 39% relative to tissue from sham-operated rats. Urinary nitrate/nitrite excretion was also reduced in HF rats. Thus both diminished synthesis and augmented degradation are likely to contribute to a decreased renal microvascular impact of endogenous NO during chronic HF, the consequences of which include loss of NO-dependent modulation of ANG II-induced vasoconstriction.

Topics: Animals; Arterioles; Cardiac Output, Low; Chronic Disease; Enzyme Inhibitors; Kidney; Male; Microcirculation; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley; Renal Circulation; Superoxide Dismutase

To study the role of nitric oxide in the cardiovascular response to a model of a low output syndrome.. Prospective animal study.. Animal research laboratory.. Sheep anesthetized with pentobarbital, mechanically ventilated, and monitored with pulmonary arterial and peripheral arterial catheters.. A low output state was induced by inflating a balloon-tip catheter placed in the right atrium. Cardiac index was maintained at 1 L/min/m2 throughout the experiment in three groups of sheep: a) control (n=6) b)LNNA group (pretreated with the nitric oxide synthase inhibitor N omega-nitro-L-arginine [LNNA, 100 mg/kg, iv bolus, n=6); and c) dexamethasone group (pretreated with dexamethasone (6 mg/kg, intravenous bolus, n=6). Dexamethasone is an inhibitor of the induction of nitric oxide synthase. LNNA or dexamethasone were administered 15 mins before inducing the low output state.. Hemodynamic and oxygen transport variables, and plasma lactate and pyruvate concentrations, were measured at baseline and during the next 3 hrs. For a comparable decrease in cardiac index and oxygen delivery in all groups, the LNNA group had less hypotension and a more marked increase in systemic vascular resistance as compared with the control group. Oxygen consumption and oxygen extraction were higher in the LNNA group as compared with the control group at 30 and 60 mins. Plasma lactate concentration increased significantly less in the LNNA group than in the control and the dexamethasone groups during the observation period.. Inhibition of nitric oxide synthesis during a severe low output state in sheep is associated with a better hemodynamic response, as evidenced by a greater vasoconstriction, and signs of less marked tissue hypoxia. It is likely that inhibition of nitric oxide synthesis in this model leads to an imbalance between the tonic relaxing action of nitric oxide and the influences of vasoconstrictor agents.

Topics: Analysis of Variance; Animals; Arginine; Cardiac Output, Low; Cardiovascular System; Dexamethasone; Disease Models, Animal; Nitric Oxide Synthase; Nitroarginine; Prospective Studies; Sheep; Shock, Cardiogenic

Enhanced production of nitric oxide has been implicated in cardiac and vascular dysfunction associated with septic and endotoxic shock. To test this hypothesis, conscious rats were administered endotoxin. 6 h later, the rats were anesthetized, arterial pressure was measured, and hearts were removed for Langendorff perfusion in the absence and presence of .01 microM isoproterenol. Left ventricular developed pressure was 61 +/- 6 mmHg in control rats 39 +/- 5 mmHg in endotoxin-treated rats. Inotropic responses to isoproterenol were unaffected by endotoxin treatment. Administration of nitric oxide synthase (NOS) inhibitors (NG-nitro-L-arginine and aminoguanidine) prior to endotoxin did not improve left ventricular function in endotoxin-treated rats. Dexamethasone pretreatment, however, prevented endotoxin-induced cardiac depression. These results suggest that cardiac depression during endotoxemia is not caused by NOS activation and increased nitric oxide production. Furthermore, the cardioprotectant actions of dexamethasone are not related to its ability to inhibit inducible NOS expression.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Cardiac Output, Low; Dexamethasone; Guanidines; Heart Rate; Hemodynamics; Hypotension; Isoproterenol; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley; Shock, Septic

Activation in conscious dogs of the carotid chemoreflex or cardiac receptors results in coronary vasodilation that is mediated by a vagal cholinergic mechanism. Our previous study showed that the coronary vasodilation following activation of carotid chemoreflex is also mediated by nitric oxide (NO). In addition, NO production is depressed after the development of heart failure. Therefore, we hypothesized that the coronary vasodilation after activation of reflexes that elicit efferent vagal coronary vasodilation would be blunted in conscious dogs after pacing-induced heart failure due to the disappearance of NO.. Mongrel dogs were chronically instrumented using sterile techniques for measurements of systemic hemodynamics and left circumflex coronary blood flow (CBF). Without the heart rate controlled, intra-atrial injection of veratrine (4 micrograms/kg) caused bradycardia (-36 +/- 3 beats per minute). With the heart rate controlled, veratrine increased CBF in a dose-dependent manner: for example, 4 micrograms/kg of veratrine increased CBF by 54 +/- 5% from 38 +/- 4.9 mL/min (P < .05). The increases in CBF induced by veratrine were markedly blunted by nitro-L-arginine (NLA). Activation of carotid chemoreflex by nicotine increased CBF by 121 +/- 9% from 32 +/- 4 mL++/min (P < .05) with the heart rate controlled and caused bradycardia (-32 +/- 5 beats per minute) without the heart rate controlled. After the development of heart failure, in response to activation of carotid chemoreflex or cardiac receptors the coronary vasodilation was almost abolished (CBF increased by only 23 +/- 8% or 11 +/- 3%, P < .05 compared with control). There still was a marked bradycardia after injections of nicotine or veratrine (-50 +/- 11 or -48 +/- 7 beats per minute).. Our results indicate that vagally mediated coronary vasodilation is selectively attenuated in conscious dogs after pacing-induced heart failure, whereas the vagally mediated bradycardia is preserved. Since muscarinic receptor-induced coronary vasodilation is mediated by NO, the disappearance of NO from blood vessels leads to a defect in the integrated neural regulation of coronary blood flow and myocardial function during heart failure.

Topics: Acetylcholine; Adenosine; Animals; Arginine; Cardiac Output, Low; Cardiac Pacing, Artificial; Chemoreceptor Cells; Coronary Circulation; Dogs; Heart Rate; Hemodynamics; Nicotine; Nitric Oxide; Nitroarginine; Reflex; Vagus Nerve; Vasodilation; Veratrine