Noradrenaline and Nω-monomethyl-L-arginine (L-NMMA): effects on haemodynamics and regional blood flow in healthy and septic sheep

Abstract

This prospective, non-randomized, controlled experimental study looks at the effects of N(omega)-monomethyl-L-arginine (L-NMMA) on haemodynamics, oxygen transport and regional blood flow in healthy and septic sheep, and compares these effects with those of noradrenaline (NA; norepinephrine). All sheep were chronically instrumented. Six sheep received L-NMMA (7 mg.kg(-1).h(-1)), six sheep received NA, and seven sheep received the carrier alone (0.9% NaCl). The NA dosage was continuously and individually adjusted to achieve the same increase in blood pressure as observed in matched sheep of the L-NMMA group (non-septic phase). Treatment was discontinued after 3 h. Sepsis was initiated and maintained by a continuous infusion of live Pseudomonas aeruginosa. After 24 h of sepsis, the sheep were again challenged over a treatment period of 3 h with their previously assigned drug (septic phase). During the non-septic phase of the experiment, NA and L-NMMA both caused an increase in mean arterial pressure (MAP) through vasoconstriction. Ater 24 h of sepsis, all sheep developed a hyperdynamic circulatory state. While L-NMMA caused an increase in MAP through intense vasoconstriction, NA caused MAP to increase through a further elevation of the cardiac index. The NA dosage needed was significantly higher in the septic phase compared with the non-septic phase, reflecting a reduced vascular responsiveness to catecholamines during sepsis. Renal blood flow remained unchanged during either treatment in both the non-septic and the septic phases. Nevertheless, urine output increased during NA treatment in both the non-septic and the septic phases, while L-NMMA caused urine output to increase only under septic conditions.

Nitric Oxide Regulates Local Arterial Distensibility In Vivo

“…The ovine 22 and human 9 systemic responses to L-NMMA, however, are similar. The use of general anesthesia may also have influenced our results to some degree, as may the introduction of an arterial catheter.…”

“…When hemodynamics returned to baseline, after a minimum period of 30 minutes, L-NMMA was infused through the sheath and then the catheter in turn, at a dose based on previous data. 8,9,22 Main Study A further 7 sheep were used for the remaining studies. After baseline recordings had been obtained, 2 doses of ACh (60 and 120 nmol/min) were infused through the catheter.…”

Renal Vascular Resistance in Sepsis

“…Of these articles, 52 (38.0%) showed a decreased RVR [25, 28, 30, 31, 32, 33, 34, 36, 45, 46, 47, 51, 52, 53, 58, 62, 63, 68, 69, 70, 71, 72, 73, 74, 75, 78, 84, 85, 87, 92, 95, 98, 99, 100, 101, 109, 111, 112, 114, 115, 120, 122, 124, 125, 126, 130, 131, 135, 143, 144, 154, 155], 16 (11.7%) an unchanged RVR [23, 29, 35, 37, 60, 64, 80, 97, 106, 108, 110, 113, 116, 119, 140, 145,] and 69 (50.3%) an increased RVR [20, 21, 22, 24, 26, 27, 38, 39, 40, 41, 42, 43, 44, 48, 49, 50, 54, 55, 56, 57, 59, 61, 65, …”

Controversial Issues Concerning Norepinephrine and Intensive Care Following Severe Traumatic Brain Injury

“…Apart from volume administration, norepinephrine is beneficial, especially in face of nitric oxide (NO)-mediated vasodilation and diseaserelated vasoparalysis which disturbs various modulators (catecholamines, NO, angiotensin II, vasopressin, and endothelin-1) and intracellular pathways [29]. Despite norepinephrine-induced reduction in renal perfusion observed in healthy volunteers at 0.118 ± 0.03 µg/kg/min [30], norepinephrine pressure-dependently elevates renal perfusion, increases urine output and creatinine clearance in healthy [7,31] and septic animals [31]. Adverse effects were ruled out in a retrospective study including 200 cardiac surgery patients in whom norepinephrine infusion did not increase serum creatinine levels [32].…”

“…Adverse effects were ruled out in a retrospective study including 200 cardiac surgery patients in whom norepinephrine infusion did not increase serum creatinine levels [32]. Under experimental and clinical septic conditions norepinephrine required to elevate MABP to 70 mmHg needs to be increased severalfold [31,11], reaching values as high as 1.3 ± 0.3 µg/kg/min (97.5 ± 22.5 µg/75 kg/min) in humans [11] Figure 3. Schematic drawing of different organ systems with their complex intra-and interorgan influences involved in norepinephrine-mediated functional circuits.…”