Comparison between selective and nonselective nitric oxide synthase inhibition and phenylephrine in normal and endotoxic swine

Objective: To compare the cardiopulmonary and peripheral circulatory effect s of the nonselective nitric oxide synthase (NOS) inhibitor NG-nitro-L-argi nine methyl ester (L-NAME) to the more selective inducible NOS inhibitor S- methylisothiourea (SMT) and to phenylephrine (PE) in endotoxic and normal s wine. Design:Prospective, randomized, unblinded study. Setting: Research laboratory of academic medical center. Subjects: Nonanesthetized, sedated, mechanically ventilated, minimally inva sive swine model. Interventions: Animals received either lipopolysaccharide (LPS, LPS groups) or equivalent volume of saline (normal groups). LPS animals were further r andomized into four groups when mean arterial pressure (MAP) had dropped to <60 mm Hg: the LPS/saline group received saline only; the other groups rec eived either L-NAME, SMT, or PE. These were titrated to elevate MAP by 20-2 5 mm Hg, and animals were followed for another 3 hrs. Pulmonary artery occl usion pressure was maintained at one to two times baseline with the infusio n of saline. Normal groups received the same agents 1 hr after baseline mea surements, and drugs were titrated to achieve similar increases in MAP. We measured gastric-arterial P-CO2, gradient by tonometry as an index of gastr ic mucosal perfusion. Left ventricular volumes were determined echocardiogr aphically; right ventricular volumes were determined by a pulmonary arteria l catheter equipped with a rapid thermistor. Plasma nitrite/nitrate (NOx) c oncentrations were measured hourly. Measurements and Main Results:ln the LPS groups, all agents elevated MAP and systemic vascul ar resistance similarly. By hr 4, cardiac output had decreased in all group s, but the decrease with L-NAME (35% +/- 16%) occurred earlier (at hr 3) an d was larger than the decrease with SMT at hrs 3 and 5 and larger than the decrease with saline at hrs 3 to 5. L-NAME resulted in a larger increase in mean pulmonary arterial pressure (MPAP) when compared with saline (130% +/ - 44% vs. 61% +/- 25%; p < .001) and SMT groups (130% vs. 97% +/- 80%; p < .007). Only L-NAME had detrimental effects on right ventricular function as indicated by an increase in right ventricular end-systolic volume (54 +/- 10 to 87 +/- 6 mt; p < .05) and right ventricular end-diastolic volume (90 +/- 11 to 128 +/- 18 mL; p < .05). SMT decreased both left ventricular end- systolic volume (10.4 +/- 2 to 7.7 +/- 4 mt; p <.05) and left ventricular e nd-diastolic volume (18.5 +/- 3 to 14.2 +/- 5 mt; p < .05), indicating impr oved left ventricular function, whereas L-NAME did not affect left ventricu lar volumes. Both SMT and PE corrected LPS-induced gastric mucosal acidosis , but L-NAME did not. We did not detect changes in plasma NOx concentration s in any of LPS groups. In the normal groups, all agents increased MAP without changes in plasma NO x concentrations. L-NAME caused a larger decrease in cardiac output, but th e increase in MPAP was higher with SMT. Both NOS inhibitors led to left ven tricular dilation, but PE did not. Only L-NAME caused right ventricular dil ation. There were no changes in gastric-arterial P-CO2 gradient. Conclusions; In LPS animals, we failed to detect changes in plasma NOx conc entrations. Furthermore, for similar increases in MAP, SMT improved gastric mucosal acidosis, had less adverse effects on right ventricular function a nd MPAP, and may have improved left ventricular function. However, apart fr om its beneficial effects on left ventricular function, SMT was not superio r to PE. The results from normal animals indicate that both NOS inhibitors have adverse effects on cardiac function beyond those attributed to increas ed MAP.