The long-term effect of adenosine and of a new xanthine derivative, 1-(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 mumol.h-1 iv) reduced the heart rate and produced an increase in coronary blood flow (studied using 15 micrometers 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 mumol.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 less than 0.001) and 18% (p less than 0.02) respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

SUMMARY1. Rabbit fast muscles (tibialis anterior, t.a.; extensor digitorum longus, e.d.l.; and peroneal muscles) were stimulated for up to 28 days by electrodes implanted in the vicinity of the lateral popliteal (peroneal) nerve for 8 h/day, using either intermittent high-frequency (three trains at 40 Hz/min, each 5 s duration), or continuous stimulation at 10 Hz. This did not result in muscle hypertrophy even after 28 days.2. Capillary density (number of capillaries/mm2) was increased in e.d.l. from 251 ± 3 to 366 + 6 after 14 days of stimulation and from 251 + 3 to 514 + 13 after 28 days of stimulation at 40 Hz. In t.a., capillary density increased from 373 + 5 to 583 + 10 after 14 days of stimulation at 40 Hz. The capillary/fibre ratio increased in e.d.l. from 1-25+0102 to 1-86+0-04 at 14 days and to 2-07+0-06 at 28 days. In t.a., capillary/fibre ratio increased from 1-40 + 0-03 to 1-83 + 0-05 at 14 days. All these changes were significant (P < 010005).3. Analysis of capillary density, capillary/fibre ratio, fibre areas and proportion of different fibre types in muscles stimulated for shorter periods showed no changes in capillary density, capillary/fibre ratio or fibre areas in e.d.l. or t.a. stimulated for 4 days; there was a decrease in the proportion of fast glycolytic fibres from 42 to 32 % (P < 010025) and increase in fast oxidative from 37-6 to 41-2 % in e.d.l. Muscles stimulated for 7 days showed increases in capillary density and capillary/fibre ratio in fast predominantly glycolytic fibres in e.d.l., and a decrease in capillary density in fast and slow oxidative fibres in t.a. This was partly due to the increase in fibre areas in these groups (capillary/fibre ratio in t.a. was not significantly changed). No changes were observed in fibre areas in e.d.l. Stimulation at 10 Hz produced increase in capillary/fibre ratio in the vicinity of glycolytic fibres after only 4 days.4. High-frequency intermittent stimulation leads to a massive capillary growth which starts first in the muscle with a higher proportion of glycolytic fibres (e.d.l.), has a later onset than continuous low-frequency stimulation, and may be due to a combination of high blood flow and metabolic factors.

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The effect of prazosin on heart and muscle blood flow and capillary density was studied in rats. In acute experiments, alpha 1-blocker prazosin almost trebled blood flow in fast skeletal muscles [tibialis anterior (TA) and extensor digitorum longus (EDL)], but did not affect coronary flow when infused i.v. at a dose of 0.5 microgram.ml-1.min-1 for 30 min. Prazosin in an equivalent dose was then given orally over a period of 5 weeks to investigate its effect on capillarisation in heart and skeletal muscle. Capillary density (CD, capillaries.mm-2), estimated in frozen sections stained for alkaline phosphatase, was similar in the hearts of prazosin-treated and control rats. Capillary/fibre ratio in skeletal muscles increased from 1.52 +/- 0.019 in control EDL to 1.69 +/- 0.01 (P less than 0.001) and from 1.56 +/- 0.04 in control TA to 2.16 +/- 0.04 (P less than 0.001). In TA, the increase was greater than in EDL both in the glycolytic periphery (from 1.30 +/- 0.13 to 1.75 +/- 0.11, P less than 0.025) and the oxidative core of the muscle (from 1.837 +/- 0.14 to 2.51 +/- 0.12, P less than 0.005). Unilateral crush of the lateral peroneal nerve and subsequent reinnervation over the next 7 weeks resulted in redistribution of fibre types from a typical mosaic pattern into groups composed of fibres of similar oxidative capacity. Capillary density as well as capillary/fibre ratio in purely glycolytic areas was lower when compared to supply of glycolytic fibres in normal muscles.(ABSTRACT TRUNCATED AT 250 WORDS)