Aim: To test the hypothesis that diminished vascular nitric oxide availability might explain the inability of individuals with chronic heart failure (CHF) to maintain the microvascular PO 2 's (PO 2mv µ O 2 delivery-to-uptake ratio) seen in healthy animals. Methods: We superfused sodium nitroprusside (SNP; 300 lm), KrebsHenseleit (control, CON) and l-nitro arginine methyl ester (l-NAME; 1.5 mm) onto the spinotrapezius muscle and measured PO 2mv by phosphorescence quenching in female Sprague-Dawley rats (n ¼ 26) at rest and during twitch contractions (1 Hz). Seven rats served as controls (Sham) while CHF was induced by myocardial infarction. CHF rats were grouped as moderate (MOD; n ¼ 15) and severe CHF (SEV; n ¼ 4) according to morphological data and baseline PO 2mv . Results: In contrast to Sham and MOD, l-NAME did not affect the PO 2mv response (dynamics and steady-state) of SEV when compared with CON. SNP restored the PO 2mv profile of SEV to that seen in Sham animals during CON. Specifically, the effect of l-NAME expressed as D(l-NAME -CON) were: Baseline PO 2mv [in mmHg, DSham ¼ )7.0 AE 1.6 (P < 0.05); DSEV ¼ )1.2 AE 2.1], end-contractions PO 2mv [in mmHg, DSham ¼ )5.0 AE 1.0 (P < 0.05); DSEV ¼ )2.5 AE 0.5] and time constant of PO 2mv decrease [in s, DSham ¼ )6.5 AE 3.0 (P < 0.05); DSEV ¼ )3.2 AE 1.8]. Conclusion: These data provide the first direct evidence that the pathological profiles of PO 2mv associated with severe CHF can be explained, in part, by a diminished vascular NO availability.

These results indicate that NO availability can significantly affect P(O2)mv at rest and during contractions and suggests that P(O2)mv derangements in ageing and chronic disease conditions may potentially result from impairments in NO availability.

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There are currently no models of exercise that recruit and train muscles, such as the rat spinotrapezius, that are suitable for transmission intravital microscopic investigation of the microcirculation. Recent experimental evidence supports the concept that running downhill on a motorized treadmill recruits the spinotrapezius muscle of the rat. Based on these results, we tested the hypothesis that 6 wk of downhill running (-14 degrees grade) for 1 h/day, 5 days/wk, at a speed of up to 35 m/min, would 1) increase whole body peak oxygen uptake (Vo(2 peak)), 2) increase spinotrapezius citrate synthase activity, and 3) reduce the fatigability of the spinotrapezius during electrically induced 1-Hz submaximal tetanic contractions. Trained rats (n = 6) elicited a 24% higher Vo(2 peak) (in ml.min(-1).kg(-1): sedentary 58.5 +/- 2.0, trained 72.7 +/- 2.0; P < 0.001) and a 41% greater spinotrapezius citrate synthase activity (in mumol.min(-1).g(-1): sedentary 14.1 +/- 0.7, trained 19.9 +/- 0.9; P < 0.001) compared with sedentary controls (n = 6). In addition, at the end of 15 min of electrical stimulation, trained rats sustained a greater percentage of the initial tension than their sedentary counterparts (control 34.3 +/- 3.1%, trained 59.0 +/- 7.2%; P < 0.05). These results demonstrate that downhill running is successful in promoting training adaptations in the spinotrapezius muscle, including increased oxidative capacity and resistance to fatigue. Since the spinotrapezius muscle is commonly used in studies using intravital microscopy to examine microcirculatory function at rest and during contractions, our results suggest that downhill running is an effective training paradigm that can be used to investigate the mechanisms for improved microcirculatory function following exercise training in health and disease.

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