Comparison of the ability of nicardipine, theophylline and zaprinast to restore cardiovascular haemodynamics following inhibition of nitric oxide synthesis

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Abstract
1 The use of pharmacological inhibitors of nitric oxide (NO) synthesis to treat patients with septic shock is limited by the observation that they cause a fall in cardiac output in some subjects. The aim of this work was to investigate this fall and to test whether it was reversible by subsequent administration of nicardipine, theophylline or the cyclic GMP-selective phosphodiesterase inhibitor, zaprinast (M&B 22948). 2 In pentobarbitone-anaesthetized pigs, haemodynamic indices were measured before and after intravenous administration of NG-nitro-l-arginine methyl ester (l-NAME) in a dose-response protocol (0.2–20 mg kg−1; n = 6) and as a single bolus of 10 mg kg−1 either alone or followed by increasing doses of nicardipine, theophylline or zaprinast (n = 8 in each group). 3 l-NAME caused a dose-dependent rise in systemic vascular resistance and mean systemic arterial pressure and a dose-dependent fall in cardiac output. A single bolus of l-NAME (10 mg kg−1) produced these effects within 15 min. 4 Subsequent administration of nicardipine (0.05–0.2 mg kg−1) caused complete reversal of systemic vasoconstriction and hypertension and in doing so completely restored cardiac output. Theophylline (7.5–10 mg kg−1) partially reversed the rise in systemic vascular resistance and partially restored cardiac output but the effect was small compared to that of nicardipine. Zaprinast (1–5 mg kg−1) had no significant effect on any of these variables. 5 These results suggest that reduced cardiac output following inhibition of NO synthesis is an effect of increased afterload on the heart and is reversible by nicardipine and to a lesser extent by theophylline. These findings may have potential value for those using NO synthase inhibitors to treat patients with septic shock.