COMPARISON OF THE ABILITY OF NICARDIPINE, THEOPHYLLINE AND ZAPRINAST TO RESTORE CARDIOVASCULAR HEMODYNAMICS FOLLOWING INHIBITION OF NITRIC-OXIDE SYNTHESIS

1 The use of pharmacological inhibitors of nitric oxide (NO) synthesis to treat patients with septic shock is limited by the observation tha t they cause a fall in cardiac output in some subjects. The aim of thi s work was to investigate this fall and to test whether it was reversi ble by subsequent administration of nicardipine, theophylline or the c yclic GMP-selective phosphodiesterase inhibitor, zaprinast (M&B 22948) . 2 In pentobarbitone-anaesthetized pigs, haemodynamic indices were me asured before and after intravenous administration of NG-nitro-L-argin ine 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 follow ed by increasing doses of nicardipine, theophylline or zaprinast (n = 8 in each group). 3 L-NAME caused a dose-dependent rise in systemic va scular resistance and mean systemic arterial pressure and a dose-depen dent fall in cardiac output. A single bolus of L-NAME (10 mg kg(-1)) p roduced these effects within 15 min. 4 Subsequent administration of ni cardipine (0.05-0.2 mg kg(-1)) caused complete reversal of systemic va soconstriction and hypertension and in doing so completely restored ca rdiac output. Theophylline (7.5-10 mg kg(-1)) partially reversed the r ise in systemic vascular resistance and partially restored cardiac out put but the effect was small compared to that of nicardipine. Zaprinas t (1-5 mg kg(-1)) had no significant effect on any of these variables. 5 These results suggest that reduced cardiac output following inhibit ion of NO synthesis is an effect of increased afterload on the heart a nd 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.