Muscle microvascular oxygenation in chronic heart failure: role of nitric oxide availability.

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) proportional, variant O(2) delivery-to-uptake ratio) seen in healthy animals. METHODS: We superfused sodium nitroprusside (SNP; 300 microm), Krebs-Henseleit (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 = 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 = 15) and severe CHF (SEV; n = 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 Delta(L-NAME - CON) were: Baseline PO(2mv) [in mmHg, DeltaSham = -7.0 +/- 1.6 (P < 0.05); DeltaSEV =-1.2 +/- 2.1], end-contractions PO(2mv) [in mmHg, DeltaSham = -5.0 +/- 1.0 (P < 0.05); DeltaSEV = -2.5 +/- 0.5] and time constant of PO(2mv) decrease [in s, DeltaSham = -6.5 +/- 3.0 (P < 0.05); DeltaSEV = -3.2 +/- 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.

Effects of altered nitric oxide availability on rat muscle microvascular oxygenation during contractions.

AIM: To explore the role of nitric oxide (NO) in controlling microvascular O2 pressure (P(O2)mv) at rest and during contractions (1 Hz). We hypothesized that at the onset of contractions sodium nitroprusside (SNP) would raise P(O2)mv and slow the kinetics of P(O2)mv change whereas l-nitro arginine methyl ester (L-NAME) would decrease P(O2)mv and speed its kinetics. METHODS: We superfused the spinotrapezius muscle of female Sprague-Dawley rats (n = 7, body mass = 298 +/- 10 g) with SNP (300 microM) and L-NAME (1.5 mm) and measured P(O2)mv (phosphorescence quenching) during contractions. RESULTS: SNP decreased mean arterial pressure (92 +/- 5 mmHg) below that of control (CON, 124 +/- 4 mmHg) and L-NAME (120 +/- 4 mmHg) conditions. SNP did not raise P(O2)mv at rest but it did elevate the P(O2)mv-to-MAP ratio (50% increase, P < 0.05) and slow the kinetics by lengthening the time-delay (TD, 14.0 +/- 5.0 s) and time constant (tau, 24.0 +/- 10.0 s) of the response compared with CON (TD, 8.4 +/- 3.3 s; tau, 16.0 +/- 4.5 s, P < 0.05 vs. SNP). L-NAME decreased P(O2)mv at rest and tended to speed tau (10.1 +/- 3.8 s, P = 0.1), while TD (8.1 +/- 1.0 s) was not significantly different. L-NAME also caused P(O2)mv to fall transiently below steady-state contracting values. CONCLUSIONS: 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.

Effects of a specific endothelin-1A antagonist on exercise-induced pulmonary haemorrhage (EIPH) in thoroughbred horses.

REASONS FOR PERFORMING STUDY: During high intensity exercise, the very high pulmonary artery pressure (Ppa) experienced by Thoroughbred horses is considered a major factor in the aetiology of exercise-induced pulmonary haemorrhage (EIPH). Recently, endothelin-1 (ET-1), a potent vasoconstrictive hormone, has been found to increase Ppa in horses at rest via binding to its ET-1A receptor subtype. In addition, plasma concentrations of ET-1 are increased in horses during and after high intensity exercise. HYPOTHESIS: If ET-1 increases Ppa during exercise in the horse, administration of a specific ET-1A antagonist would decrease Ppa and therefore EIPH. METHODS: Saline (CON) or an ET-1A receptor antagonist, TBC3214 (3 mg/kg bwt i.v.; ANTAG) was administered to horses 1 h prior to maximal incremental exercise on a high-speed treadmill. Gas exchange measurements were made breath-by-breath and blood samples collected during each 1 min stage to determine blood gases, acid-base status and cardiac output. EIPH was determined via bronchoalveolar lavage (BAL) approximately 30 min after exercise. RESULTS: The time to fatigue, gas exchange and cardiovascular responses were not different between groups (P>0.05). Resting and peak Ppa did not differ significantly between treatments. Most importantly, ANTAG did not decrease EIPH. CONCLUSIONS: These results do not support a deterministic role for ET-1 in the increased Ppa and therefore EIPH, during maximal exercise in the equine athlete. POTENTIAL RELEVANCE: Treatment with an ET-1A receptor antagonist does not appear to be a viable therapeutic intervention in the prevention of EIPH.

Exercise-induced pulmonary haemorrhage during submaximal exercise.

REASONS FOR PERFORMING STUDY: Maximally exercising horses achieve mean pulmonary artery pressures (Ppa(mean)) that exceed the minimum threshold (75 mmHg) estimated for pulmonary capillary rupture and exercise-induced pulmonary haemorrhage (EIPH). EIPH is not expected to occur during moderate submaximal exercise (i.e. 40-60% VO2max) since Ppa(mean) remains well below this threshold. HYPOTHESIS: Prolonged submaximal exercise (trotting) would precipitate locomotory respiratory uncoupling and cause EIPH. This would be present as a result of the most negative intrapleural pressures (as estimated by the minimum oesophageal pressure; Poes(min)) occurring simultaneously with the most positive Ppa (Ppa(peak)) to produce estimated maximal pulmonary artery transmural pressures (PATMPmax) that surpass the EIPH threshold. METHODS: Five Thoroughbred horses trotted to fatigue (approximately 25 min) at 5 m/sec on a 10% incline. Ventilation (V(E)), Poes, and Ppa were measured at 5 min intervals, and bronchoalveolar lavage (BAL) red blood cells (RBCs) were quantified 45 min post exercise. RESULTS: BAL revealed an increased EIPH (rest: 2.0 +/- 1 x 10(5), exercise: 17 +/- 10 x 10(5) RBCs/ml BALF; P<0.05), despite the highest Ppamean reaching only mean +/- s.e. 55 +/- 3 mmHg, while V(E), tidal volume and Poes(min) approached 70-80% of the values achieved at maximal running speeds (10% incline: 12-13 m/sec) by these same horses. The resulting PATMPmax was well above the level considered causative of EIPH. CONCLUSIONS: The finding of significant EIPH during submaximal exercise broadens the spectrum of performance horses susceptible to EIPH and supports studies that suggest that extravascular factors are of primary importance in the aetiology of EIPH. POTENTIAL RELEVANCE: Consideration of strategies such as the equine nasal strip for reducing negative extravascular pressures is warranted even for exercise at moderate intensities.