High-dose Almitrine Bismesylate Inhibits Hypoxic Pulmonary Vasoconstriction in Closed-chest Dogs

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Abstract
The effect of almitrine bismesylate on the hypoxic pulmonary vasoconstrictor (HPV) response was studied in seven closed-chest dogs anesthetized with pentobarbital and paralyzed with pancuronium. The right lung was ventilated continuously with 100% O2, while the left lung was ventilated with either 100% O2 ("hyperoxia") or with an hypoxic gas mixture ("hypoxia": end-tidal PO2 = 50.1 .+-. 0.1 mmHg). Cardiac output (CO) was altered from a "normal" value of 3.10 .+-. 0.18 l .cntdot. min-1 to a "high" value of 3.92 .+-. 0.16 l .cntdot. min-1 by opening arteriovenous fistulae which allowed measurements of two points along a pressure-flow line. These four phases of left lung hypoxia or hyperoxia with normal and high cardiac output were repeated in the presence and absence of almitrine. Almitrine bismesylate was administered as a constant infusion of 14.3 .mu.g .cntdot. kg-1 .cntdot. min-1 for a mean plasma concentration of 21.5 .+-. 26.4 ng .cntdot. ml-1. Relative blood flow to each lung was measured with a differential CO2 excretion (.ovrhdot.VCO2) method corrected for the Haldane effect. With both lungs hyperoxic, the percent left lung blood flow (%.ovrhdot.QI-.ovrhdot.VCO2 was 44 .+-. 1%. When the left lung was exposed to hypoxia, the %.ovrhdot.QL-.ovrhdot.VCO2 decreased significantly to 22 .+-. 1%. However, with the administration of almitrine, the %.ovrhdot.QL-.ovrhdot.VCO2 during left lung hypoxia increased significantly to 36 .+-. 2%. The arterial oxygen tension decreased significantly between hyperoxia (PaO2 = 633 .+-. 6 mmHg) and hypoxia (271 .+-. 31 mmHg). With the addition of almitrine, there was no change during hyperoxia; however, during hypoxia, the PaO2 decreased significantly to 124 .+-. 15 mmHg. Cardiac output did not influence these findings. The pulmonary vascular conductance (G) is the slope of the pressure-flow line. The pulmonary vascular conductance of the right lung (GR .times. 103) (1.6 .+-. 0.1 dyn-1 .cntdot. cm5 .cntdot. s-1) did not change significantly during hyperoxia or hypoxia when no drug was given. With the administration of almitrine, GR decreased significantly to 1.0 .+-. 0.1 dyn-1 .cntdot. cm5 .cntdot. s-1 during both hyperoxia and hypoxia. The same was true at normal and high cardiac output. The pulmonary vascular conductance of the left lung (GL) decreased significantly between hyperoxia (1.24 .+-. 0.1 dyn-1 .cntdot. cm5 .cntdot. s-1) and hypoxia (0.7 .+-. 0.1 dyn-1 .cntdot. cm5 .cntdot. s-1). However, with the addition of almitrine, GL decreased significantly during hyperoxia (0.8 .+-. 0.1 dyn-1 .cntdot. cm5 .cntdot. s-1), but not during hypoxia (0.8 .+-. 0.1 dyn-1 .cntdot. cm5 .cntdot. s-1). The same was true at normal and high cardiac output. It is concluded that almitrine bismesylate caused nonspecific pulmonary vasoconstriction that was greater in the 100% O2 ventilated lung than in the hypoxic lung regions. Therefore, blood flow was diverted from the hyperoxic back to the hypoxic lung causing a reduction of the HPV response.