Beneficial effects of two new verapamil analogs, anipamil and ronipamil, in circulatory shock

Intracellular calcium overload has been reported to mediate a number of detrimental cytolytic actions involved in the pathophysiology of shock. We studied the effects of both anipamil and ronipamil at 1.0 mg/kg on pentobarbital anesthetized rats subjected to Noble-Collip drum trauma. Neither substance at this dose influenced MABP or HR in non-shocked, anesthetized rats. Neither verapamil analog had any significant effect on attenuating the eight-fold (p<0.01) increase in plasma cathepsin D activity occuring during traumatic shock. However, both anipamil (50 ± 8, P<0.01) and ronipamil (74 ± 11 U/h, p<0.01) significantly blunted the rate of accumulation of the cardiotoxic peptide myocardial depressant factor (MDF) in shock plasma when compared to the vehicle (169 ± 18 U/h). In addition, both anipamil (0.74 ± 0.09 vs 1.12 ± 0.07 μmoles serine x 10^-2/mg protein, p<0.001), and ronipamil (0.91 ± 0.1 vs 1.16 ± 0.09 p<0.02) significantly retarded the rate of proteolysis in pancreatic homogenates suggesting a strong anti-proteolytic effect. Both analogs also significantly prolonged survival time (p<0.01) when compared to vehicle treatment, however, anipamil provided a significantly greater degree of protection than ronipamil (4.4 ± 0.3 vs 1.9 ± 0.1 h and 3.1 ± 0.3 vs 1.8 ± 0.4 h respectively p < 0.02). Anipamil appears to provide a greater degree of protection tection in this severe shock model, however both verpamil derivatives possess promising anti-shock potential.