Effect of Molsidomine and Linsidomine on the Human Isolated Bronchus and the Guinea-pig Isolated Trachea

Abstract— The effects of molsidomine and its metabolite linsidomine were studied on the guinea-pig isolated trachea and on the human isolated bronchus. These effects were compared with those of nitrate derivatives (sodium nitroprusside, isosorbide dinitrate), theophylline, zardaverine and isoprenaline. Linsidomine exerted a relaxant effect similar to that of sodium nitroprusside on the two types of preparations precontracted with acetylcholine, histamine or potassium chloride. Molsidomine was about one-hundredth as potent as linsidomine, and less efficacious. The effects of the two substances were not modified by removal of the human bronchial epithelium. The concentration-response curves of linsidomine and sodium nitroprusside were significantly shifted to the right by methylene blue (3 × 10^?5 m ) but the effects of isoprenaline were unmodified. The effects of linsidomine and sodium nitroprusside were potentiated specifically by zaprinast (10^?6-10^?5 m ), an inhibitor of type Ia or V phosphodiesterases, whereas the effects of isoprenaline were potentiated by zardaverine (10^?9-10^?8 m ), an inhibitor of class III and IV phosphodiesterases. The effects of all three substances (linsidomine, isoprenaline and sodium nitroprusside) were potentiated equally by theophylline (10^?5-10^?4 m ), a nonspecific inhibitor of phosphodiesterases. It is concluded that linsidomine is a potent relaxant of the smooth muscle of the guinea-pig isolated trachea and human isolated bronchus. In terms of potency and efficacy, its effect is much superior to that of the parent compound molsidomine. It is suggested that linsidomine acts, like nitrate derivatives, through the guanylate cyclase-cGMP system.     

The Effect of External Cardiac Pacing on Stroke Volume

To evaluate the hemodynamic effects of external cardiac pacing, ten subjects with normal left ventricular function were paced at rates approximating their resting heart rates using an external pacemaker while continuous-wave Doppler measurements from the aortic outflow were recorded. The Doppler flow velocity integral was used as an index of stroke volume and the product of heart rate and flow velocity integral was used as an index of cardiac output. At a pacing rate 13% faster (range -5% to 32%) than the rate during sinus rhythm, the mean index of stroke volume was reduced 24% from 17.7 cm to 13.5 cm (P less than 0.0002). However, the faster rate during external pacing partially compensated for the reduced stroke volume resulting in an index of cardiac output that was 14% lower compared to the prepaced index (1,297 vs 1,121 cm [P less than 0.02]). Thus, in subjects with normal LV function, external pacing results in a small drop in cardiac output that may be partially overcome by increasing the pacing rate.     

Differential Ontogenesis of Three DOI-Induced Behaviors in Mice

Our previous studies have shown that intraperitoneal administration of DOI [(±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] simultaneously produces the head-twitch and ear-scratch responses (HTR and ESR, respectively) in mice via activation of 5-HT_2A receptors. In the present study, we have investigated the ontogeny of these DOI-induced behaviors in both male and female mice across a wide age range (i.e., postnatal days 7, 14, 18, 22, 28, 35, 42, 63, 120, and 180). We also measured the effects of DOI on the locomotor activity of these mice. In addition to the vehicle, 2 doses of DOI (1 and 2.5 mg/kg) were used in age-matched different male and female groups. The age of onset for significant production of HTR and ESR by both doses of DOI were between postpartum days 14–18 and 18–22, respectively. Maximal HTR frequency to both doses of DOI (66 and 94 HTRs) occurred on postpartum day 28. Thereafter, the HTR frequency tended to decrease with increasing age, but the attenuation did not attain significance. On the other hand, maximal ESR score (37 and 60 ESRs) generally developed between postpartum days 22–35 for the cited doses of DOI. After 35 days of age, the ESR frequency dramatically decreased and, by postnatal day 180, no significant response was obtained to either dose of DOI. Age-matched vehicle-treated male and female control groups exhibited few (1–8) HTRs and ESRs across the age range tested. DOI dose-dependently enhanced locomotor activity in both male and female mice relative to their age- and sex-matched vehicle-treated controls for the first 28 days of life. Thereafter, no significant effect was observed. None of the cited behaviors exhibited gender differences across the age range tested. The present results suggest that DOI-induced changes in HTR, ESR, and locomotor activity develop and mature differentially, but in a similar manner, in male and female mice. Furthermore, unlike DOI-induced HTR, the ability of DOI to produce ear-scratches and to enhance locomotor activity in mice disappears with old age.     

Brief Report: Bilirubin Formation in the Liver from Nonhemoglobin Sources: Experiments with Isolated, Perfused Rat Liver

Rapid formation of C¹⁴-bilirubin from glycine-2-C¹⁴ or -aminolevulinicacid-4-C¹⁴ has been demonstrated in isolated, perfused rat liver. The kineticsof labeled bilirubin production in vitro were similar to those of the "earlylabeling" pigment fraction observed in intact rats. The magnitude of bilepigment formation from C¹⁴-ALA by isolated liver was comparable to that inintact animals. Derivation of the C¹⁴-bilirubin from hepatic degradation oflabeled hemoglobin was excluded by perfusion of the liver with blood poor inreticulocytes, or with plasma. The findings identify the liver as an importantsource of the "early-labeling" pigment fraction.

Submitted on April 15, 1965 Accepted on June 18, 1965