In this study, the nonselective nitric oxide synthase inhibitor 546C88 increased mortality in patients with septic shock.

A B S T R A C TFor purposes of quantitation these curves are approximated by a simple hyperbolic function, the parameters of which are evaluated by a least squares fit of the data. The parameter A denotes curve shape such that the higher the value of A, the greater the increase in ventilation for a given decrease in PAO2 and hence the greater the hypoxic drive. Curves are highly reproducible for each subject and curves from different subjects are similar. In 10 normal subjects at resting PAcO2, A = 180.2 +14.5 (SEM). When PACO, is adjusted to levels 5 mm Hg above and below control in six subjects A = 453.4 ±103 and 30.2 ±6.8 respectively. These latter values differed significantly from control (P < 0.05). These changes in curve shape provide a clear graphic description of interaction between hypercapnic and hypoxic ventilatory stimuli. At normal PACo2 the VE-PAO2 curve has an inflection zone located over the same P02 range as the inflection in the oxygenhemoglobin dissociation curve. This indicated that ventilation might be a linear function of arterial oxygen saturation or content. Studies in four subjects have

SUMMARY The role of a transmembrane calcium influx in hypoxic pulmonary vasoconstriction was studied in isolated, bloodperfused, rat lungs. We reasoned that, if the influx of extracellular calcium mediated the hypoxic mechanism, pressor responses to alveolar hypoxia (2.5% O 3 ) would be susceptible to inhibition by the calcium antagonists verapamil (2 x 10 5 to 2 x 10 ' HIM) and SKF 525 A (2.6 to 260 IDM). Susceptibility of hypoxic pressor responses to inhibition by these calcium antagonists was contrasted to that of pressor responses elicited by the humoral vasoconstrictors angiotensin II (1 or 0.5 fig) and prostaglandin F to (10 jig). Since neither saralasin (0.5 JJM), a competitive antagonist of angiotensin II, nor meclofenamate (6.8 HM), an inhibitor of prostaglandin synthesis, depressed hypoxic pressor responses, it was concluded that these humoral transmitters were not directly involved in the hypoxic mechanism, and therefore served as independent reference agonists. The order of susceptibility of pulmonary pressor responses to inhibition by verapamil was hypoxia > angiotensin II > prostaglandin F^. SKF 525A also reduced pressor responses to hypoxia more readily than those to angiotensin II. The greater inhibition of hypoxic pulmonary vasoconstriction by both calcium antagonists suggested that the hypoxic mechanism was critically dependent on the transmembrane influx of extracellular calcium. Mediation of the hypoxic response by this type of excitation-contraction coupling is consistent with the idea that hypoxia has a direct depolarizing effect on the vascular smooth muscle. It also provides a unifying explanation for inhibition of the hypoxic mechanism by various agents that have depressant or stabilizing actions on membranes in addition to other pharmacological effects.

In this study, treatment with the nitric oxide synthase inhibitor 546C88 promoted the resolution of shock in patients with severe sepsis. This was associated with an acceptable overall safety profile.