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The long-term effect of adenosine and of a new xanthine derivative, l-(5-oxohexyl)-3-methyl- 7-propylxanthine (HWA 285) on capillary density was studied in rabbits. Doses of both agents were established in acute experiments such that they would produce a prolonged increase in coronary and skeletal muscle blood flows without significantly affecting blood pressure or cardiac output. These doses were then chronically administered (3 to 5 weeks) by continuous intravenous infusion from portable infusion pumps carried by the rabbits. Control animals were infused with saline. Long-term administration of adenosine and HWA 285 was well tolerated by the animals. In the acute experiments, adenosine (42 μmol·h−1 iv) reduced the heart rate and produced an increase in coronary blood flow (studied using 15μm radioactive microspheres) and conductance of 38% and 65% respectively, with increases in skeletal muscle of 65% and 92%. Blood pressure, cardiac output and cardiac minute work were not affected. HWA 285 (57 μmol·h−1) slightly but significantly increased blood pressure, but did not affect heart rate, cardiac output or minute work. Coronary and skeletal muscle blood flow were increased by 41% and 72%, with conductance increases of 33% and 62% respectively. The number of all capillaries present was studied in the heart and skeletal muscle using histochemical staining for alkaline phosphatase. Myocardial capillary density (capillaries per mm2, means±SE) was 3092±97 in the adenosine infused group and 2870+153 in the HWA 285 infused group compared with 2426±93 in the controls, ie an increase of 27% (p<0.001) and 18% (p<0.02) respectively. Capillary/fibre ratio in extensor digitorum longus (EDL) muscle was increased from 1.13±0.09 in saline infused control rabbits to 1.42±0.04 (p<0.01) with adenosine and 1.38±0.05 (p<0.01) with HWA 285. Resting cardiac minute and stroke work, and maximal cardiac minute work and stroke work under the effect of noradrenaline were not significantly affected by long-term infusion of either drug. Peak isometric tension and fatiguability in the extensor digitorum longus (EDL) muscles of the vasodilator-infused animals showed no significant difference from control values. Long-term administration of adenosine and the xanthine derivative, in doses which produce marked increases in coronary and muscle blood flow, thus produces an increase in capillarity in both heart and skeletal muscle without any effect on their performance.
Ziada et al. (Sat,) studied this question.