Endothelial function of young healthy males following whole body resistance training.

Given the increasing emphasis on performance of resistance exercise as an essential component of health, we evaluated, using a prospective longitudinal design, the potential for resistance training to affect arterial endothelial function. Twenty-eight men (23 +/- 3.9 yr old; mean +/- SE) engaged in 12 wk of whole body resistance training five times per week using a repeating split-body 3-day cycle. Brachial endothelial function was measured using occlusion cuff-induced flow-mediated dilation. After occlusion of the forearm for 4.5 min, brachial artery dilation and postocclusion blood flow was measured continuously for 15 and 70 s, respectively. Peak and 10-s postocclusion blood flow, shear rate, and brachial artery flow-mediated dilation (relative and normalized to shear rate) were measured pretraining (Pre), at 6 wk of training (Mid), and at 13 wk of training (Post). Results indicated an increase of mean brachial artery diameter by Mid and Post vs. Pre. Peak and 10-s postocclusion blood flow increased by Mid and remained elevated at Post; however, shear rates were not different at any time point. Relative and normalized flow-mediated dilation was also not different at any time point. This study is the first to show that peripheral arterial remodeling does occur with resistance training in healthy young men. In addition, the increase in postocclusion blood flow may indicate improved resistance vessel function. However, unlike studies involving endurance training, flow-mediated dilation did not increase with resistance training. Thus arterial adaptations with high-pressure loads, such as those experienced during resistance exercise, may be quite different compared with endurance training.     

Direct observation of epicardial coronary capillary hemodynamics during reactive hyperemia and during adenosine administration by intravital video microscopy

Using high-resolution intravital charge-coupled device video microscopy, we visualized the epicardial capillary network of the beating canine heart in vivo to elucidate its functional role under control conditions, during reactive hyperemia (RH), and during intracoronary adenosine administration. The pencil-lens video-microscope probe was placed over capillaries fed by the left anterior descending artery in atrioventricular-blocked hearts of open-chest, anesthetized dogs paced at 60-90 beats/min (n = 17). In individual capillaries under control conditions, red blood cell flow was predominant during systole or diastole, indicating that the watershed between diastolic arterial and systolic venous flows is located within the capillaries. Capillary flow increased during RH and reached a peak flow velocity (2.1 +/- 0.6 mm/s), twice as high as control (1.2 +/- 0.5 mm/s), with enhancement of intercapillary cross-connection flow and enlargement of diameter (by 17%). With adenosine, capillary flow velocity significantly increased (1.8 +/- 0.7 mm/s). However, the increase in volumetric capillary flow with adenosine estimated from red blood cell velocity and diameter was less than the increase in arterial flow, whereas that during RH was nearly equivalent to the increase in arterial flow. There was a time lag of approximately 1.5 s for refilling of capillaries during RH, indicating their function as capacitance vessels. In conclusion, the coronary capillary network functions as 1) the major watershed between diastolic-dominant arterial and systolic-dominant venous flows, 2) a capacitor, and 3) a significant local flow amplifier and homogenizer of blood supply during RH, but with adenosine the increase in capillary flow velocity was less than the increase in arterial flow.     

Atrial natriuretic peptide (ANP) does not inhibit the basal vascular tone present in the in situ blood-perfused dog gracilis muscle

This study evaluated the effects of rat ANP(5-28) infusion into the blood-perfused dog gracilis muscle at concentrations ranging from 30 to 10,000 pg/ml. The vasculature of gracilis muscles from anesthetized beagle dogs was isolated and pump-perfused at constant flow with blood utilizing an extracorporeal circuit. Maximal vasodilatory capacity was determined by adenosine injection. ANP was infused into the arterial circuit to produce increasing arterial blood concentrations. Each infusion lasted 10 min. Systemic arterial pressure, central venous pressure, cardiac output and heart rate did not change during ANP infusion into the gracilis vasculature. ANP at arterial blood concentrations up to 10,000 pg/ml did not produce significant vasodilation although the vasculature showed pronounced vasodilation in response to adenosine. In vitro experiments showed that ANP had much less vasorelaxant activity in dog femoral artery and saphenous vein than in rabbit aorta. Therefore, rat ANP(5-28) at concentrations within and well above physiological and pharmacological ranges does not inhibit the basal vascular tone present in the innervated, blood-perfused dog gracilis muscle in situ.     

High-fat diet-induced reduction in nitric oxide-dependent arteriolar dilation in rats: role of xanthine oxidase-derived superoxide anion

Obesity frequently leads to the development of hypertension. We hypothesized that high-fat diet (HFD)-induced obesity impairs the endothelium-dependent dilation of arterioles. Male Wistar rats were fed with normal (control) or HFD (60% of saturated fat, for 10 wk). In rats with HFD, body weight, mean arterial blood pressure, and serum insulin, cholesterol, and glucose were elevated. In isolated gracilis muscle arterioles (diameter: approximately 160 microm) of HFD, rat dilations to ACh (at 1 microM, maximum: 83 +/- 3%) and histamine (at 10 microM, maximum: 16 +/- 4%) were significantly (P < 0.05) decreased compared with those of control responses (maximum: 90 +/- 2 and 46 +/- 4%, respectively). Dilations to the NO donor sodium nitroprusside were similar in the two groups. Inhibition of NO synthesis by N(omega)-nitro-l-arginine methyl ester reduced ACh- and histamine-induced dilations in control arterioles but had no effect on microvessels of HFD rats. The superoxide dismutase mimetic Tiron or xanthine oxidase inhibitor allopurinol enhanced ACh (maximum: 90 +/- 2 and 93 +/- 2%, respectively)- and histamine (maximum: 30 +/- 7 and 37 +/- 8%, respectively)-induced dilations in HFD arterioles, whereas the NAD(P)H oxidase inhibitor apocynin had no significant effect. Correspondingly, in carotid arteries of HFD rats, an enhanced superoxide production was shown by lucigenin-enhanced chemiluminescence, in association with an increased xanthine oxidase, but not NAD(P)H oxidase activity. In addition, a marked xanthine oxidase immunostaining was detected in the endothelial layer of the gracilis arterioles of HFD, but not in control rats. These findings suggest that, in obese rats, NO mediation of endothelium-dependent dilation of skeletal muscle arterioles is reduced because of an enhanced xanthine oxidase-derived superoxide production. These alterations demonstrate substantial dysregulation of arteriolar tone by the endothelium in HFD-induced obesity, which may contribute to disturbed tissue blood flow and development of increased peripheral resistance.     

WISE-2005: reduced cerebral blood flow velocity with nitroglycerin--comparison with common carotid artery blood flow

During the WISE-2005 study of 24 women, we observed a reduction (21.6 +/- 0.89%, mean +/- SEM) in cerebral blood flow velocity (CBV) measured by transcranial Doppler ultrasound, following 0.3 mg sublingual nitroglycerin (NG). In parallel, we observed quantitative reductions in leg blood flow (47.3 +/- 7.0%) and corresponding reductions in calculated conductance (Conductance = Femoral Flow / Mean Arterial Pressure; 45.7 +/- 7.2%). To determine if the reduction in CBV was the result of reduced cerebral blood flow or dilation of the middle cerebral artery (MCA), the change in CBV in the MCA was compared with changes in quantitative flow measured in the common carotid artery (CCA). The relationship between CBV and CCA blood flow was tested in five men and four women using hyper- and hypo-ventilation to manipulate arterial PCO2. Changes in CCA blood flow were positively correlated with changes in CBV (p<0.001). We then investigated the CBV and CCA flow responses to sublingual NG in an additional two men and six women. Concurrent with the reduction in CBV there was no change in blood flow through the CCA (p>0.05). These results indicate that the decrease in CBV observed in response to NG was probably the result of dilation of the MCA and that total cerebral blood flow was similar after administration of NG. These results suggest regional differences in the vascular responses to NG during the WISE bed rest. Conduit vessels of both the peripheral and cerebral vasculature dilated; however, the resistance vessels in skeletal muscle constricted causing a reduction in blood flow, while the resistance vessels of the brain appeared to be unaffected by NG so that cerebral blood flow remained constant. These results highlight the need to obtain quantitative measures of cerebral blood flow if there is reason to suspect that the diameter of the MCA might not remain constant.     

Local heat produces a shear-mediated biphasic response in the thermoregulatory microcirculation of the Pallid bat wing

Investigators report that local heat causes an increase in skin blood flow consisting of two phases. The first is solely sensory neural, and the second is nitric oxide mediated. We hypothesize that mechanisms behind these two phases are causally linked by shear stress. Because microvascular blood flow, endothelial shear stress, and vessel diameters cannot be measured in humans, bat wing arterioles (26.6 +/- 0.3, 42.0 +/- 0.4, and 58.7 +/- 2.2 microm) were visualized noninvasively on a transparent heat plate via intravital microscopy. Increasing plate temperature from 25 to 37 degrees C increased flow in all three arterial sizes (137.1 +/- 0.3, 251.9 +/- 0.5, and 184.3 +/- 0.6%) in a biphasic manner. With heat, diameter increased in large arterioles (n = 6) by 8.7 +/- 0.03% within 6 min, medium arterioles (n = 8) by 19.7 +/- 0.5% within 4 min, and small arterioles (n = 8) by 31.6 +/- 2.2% in the first minute. Lidocaine (0.2 ml, 2% wt/vol) and NG-nitro-L-arginine methyl ester (0.2 ml, 1% wt/vol) were applied topically to arterioles (approximately 40 microm) to block sensory nerves, modulate shear stress, and block nitric oxide generation. Local heat caused only a 10.4 +/- 5.5% increase in diameter with neural blockade (n = 8) and only a 7.5 +/- 4.1% increase in diameter when flow was reduced (n = 8), both significantly lower than control (P < 0.001). Diameter and flow increases were significantly reduced with NG-nitro-L-arginine methyl ester application (P < 0.05). Our novel thermoregulatory animal model illustrates 1) regulation of shear stress, 2) a nonneural component of the first phase, and 3) a shear-mediated second phase. The time course of dilation suggests that early dilation of small arterioles increases flow and enhances second-phase dilation of the large arterioles.     

The use of 8-phenyltheophylline as a competitive antagonist of adenosine and an inhibitor of the intrinsic regulatory mechanism of the hepatic artery

Reduction of portal blood flow results in compensatory vasodilation of the hepatic artery, the hepatic arterial buffer response. The hypothesis tested is that the regulation of the buffer response is mediated by adenosine, where the local concentration of adenosine in the region of the hepatic arterial resistance vessels is regulated by washout of adenosine into portal venules that are in intimate contact with hepatic arterioles. In anesthetized cats, portal flow was reduced to zero by complete occlusion of all arterial supply to the guts. The resultant dilation of the hepatic artery compensated for 23.9 +/- 4.9% of the decrease in portal flow. Dose-response curves were obtained for the effect of intraportal adenosine infusion on hepatic arterial conductance in doses that did not lead to recirculation and secondary effects on the hepatic artery via altered portal blood flow. The dose to produce one-half maximal response for adenosine is 0.19 mg X kg-1 X min-1 (intraportal) and the estimated maximal dilation is equivalent to an increase in hepatic arterial conductance to 245% of the basal (100%) level. The adenosine antagonist, 8-phenyltheophylline, produced dose-related competitive antagonism of the dilator response to infused adenosine (but not to isoproterenol) and a similar, parallel antagonism of the hepatic arterial buffer response. If supramaximal blocking doses were used, the hepatic artery showed massive and prolonged constriction with blood flow decreasing to zero. The data strongly support the hypothesis that intrinsic hepatic arterial buffer response is mediated entirely by local adenosine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Microvascular remodeling and accelerated hyperemia blood flow restoration in arterially occluded skeletal muscle exposed to ultrasonic microbubble destruction

We showed previously that microbubble destruction with pulsed 1-MHz ultrasound creates a bioeffect that stimulates arteriogenesis and a chronic increase in hyperemia blood flow in normal rat muscle. Here we tested whether ultrasonic microbubble destruction can be used to create a microvascular remodeling response that restores hyperemia blood flow to rat skeletal muscle affected by arterial occlusion. Pulsed ultrasound (1 MHz) was applied to gracilis muscles in which the lateral feed artery was occluded but the medial feed artery was left intact. Control muscles were similarly occluded but did not receive ultrasound, microbubbles, or both. Hyperemia blood flow and number of smooth muscle (SM) alpha-actin-positive vessels, >30-mum arterioles, and capillaries per fiber were determined 7, 14, and 28 days after treatment. In ultrasound-microbubble-treated muscles, lateral region hyperemia blood flow was increased at all time points and restored to normal at day 28. The number of SM alpha-actin vessels per fiber was increased over control in this region at days 7 and 14 but decreased by day 28, when larger-diameter arterioles became more prevalent in the medial region. The number of capillaries per fiber was increased over control only at day 7 in the lateral region and only at days 7 and 14 in the medial region, indicating that the angiogenesis response was transient and likely did not contribute significantly to flow restoration at day 28. We conclude that ultrasonic microbubble destruction can be tailored to stimulate an arteriogenesis response that restores hyperemia blood flow to skeletal muscle in a rat model of arterial occlusion.     

Bradykinin-induced chemoreflexes from skeletal muscle: implications for the exercise reflex

We examined the cardiovascular response to bradykinin stimulation of skeletal muscle afferents and the effect of prostaglandins on this response. Intra-arterial injection of 1 microgram bradykinin into the gracilis muscle of cats reflexly increased mean arterial pressure by 16 +/- 2 mmHg, left ventricular end-diastolic pressure by 1.6 +/- 0.6 mmHg, maximal dP/dt by 785 +/- 136 mmHg/s, heart rate by 11 +/- 2 beats/min, and mean aortic flow by 22 +/- 3 ml/min. The hemodynamic responses were abolished following denervation of the gracilis muscle. The increases in mean arterial pressure and maximal dP/dt were reduced by 68 and 45%, respectively, following inhibition of prostaglandin synthesis with indomethacin (2-8 mg/kg iv). Treatment with prostaglandin E2 (PGE2, 15-25 micrograms ia) restored the initial increase in mean arterial pressure, but not dP/dt, caused by bradykinin stimulation. Injection of PGE2 (15-30 micrograms ia) into the gracilis, without prior treatment with indomethacin, augmented the bradykinin-induced increases in mean arterial pressure and dP/dt. We conclude that small doses of bradykinin injected into skeletal muscle are capable of reflexly activating the cardiovascular system and that prostaglandins are necessary for the full manifestation of the corresponding hemodynamic response. The pattern of hemodynamic adjustment following bradykinin injection into skeletal muscle is very similar to that induced by static exercise. Therefore, it is possible that intense exercise provides a stimulus for this bradykinin-induced reflex in vivo.     

Gradual increase in leg oxygen uptake during repeated submaximal contractions in humans

We examine whether muscle oxygen consumption (VO2) increases gradually during repeated submaximal isometric contractions. Six subjects made two-legged isometric quadriceps contractions at 30% maximal voluntary contraction for 6 s with 4 s of rest between until exhaustion (58 +/- 8 min). Blood samples were taken from the femoral vein and artery, and blood velocity was recorded by ultrasound-Doppler technique in the femoral artery. Blood flow was calculated from velocity and artery diameter values. Leg VO2 increased sixfold within the 1st min of exercise. A further doubling of the VO2 was seen during the remainder of the exercise, reaching 307 +/- 22 ml/min at exhaustion. This latter increase was due to a 54% increase in blood flow and a 34% increase in oxygen extraction. After 20 min of recovery VO2 was still 75% higher than preexercise values. The results show a twofold increase in energy demand of the working muscle during repeated constant-force isometric contractions. The increased energy cost of contraction is probably localized at the cellular level, and it parallels fatigue determined as decreased force-generating capacity.     

Vascular adaptation to 4 wk of deconditioning by unilateral lower limb suspension

Physical inactivity or deconditioning is an independent risk factor for atherosclerosis and cardiovascular disease. In contrast to exercise, the vascular changes that occur as a result of deconditioning have not been characterized. We used 4 wk of unilateral lower limb suspension (ULLS) to study arterial and venous adaptations to deconditioning. In contrast to previous studies, this model is not confounded by denervation or microgravity. Seven healthy subjects participated in the study. Arterial and venous characteristics of the legs were assessed by echo Doppler ultrasound and venous occlusion plethysmography. The diameter of the common and superficial femoral artery decreased by 12% after 4 wk of ULLS. Baseline calf blood flow, as measured by plethysmography, decreased from 2.1 +/- 0.2 to 1.6 +/- 0.2 ml.min(-1).dl tissue(-1). Both arterial diameter and calf blood flow returned to baseline values after 4 wk of recovery. There was no indication of a decrease in flow-mediated dilation of the superficial femoral artery after ULLS deconditioning. This means that functional adaptations to inactivity are not simply the inverse of adaptations to exercise. The venous pressure-volume curve is shifted downward after ULLS, without any effect on compliance. In conclusion, deconditioning by 4 wk of ULLS causes significant changes in both the arterial and the venous system.     

Venous occlusion plethysmography reduces arterial diameter and flow velocity

The measurement of peripheral blood flow by plethysmography assumes that the cuff pressure required for venous occlusion does not decrease arterial inflow. However, studies in five normal subjects suggested that calf blood flow measured with a plethysmograph was less than arterial inflow calculated from Doppler velocity measurements. We hypothesized that the pressure required for venous occlusion may have decreased arterial velocity. Further studies revealed that systolic diameter of the superficial femoral artery under a thigh cuff decreased from 7.7 +/- 0.4 to 5.6 +/- 0.7 mm (P less than 0.05) when the inflation pressure was increased from 0 to 40 mmHg. Cuff inflation to 40 mmHg also reduced mean velocity 38% in the common femoral artery and 47% in the popliteal artery. Inflation of a cuff on the arm reduced mean velocity in the radial artery 22% at 20 mmHg, 26% at 40 mmHg, and 33% at 60 mmHg. We conclude that inflation of a cuff on an extremity to low pressures for venous occlusion also caused a reduction in arterial diameter and flow velocity.     

Influence of vascular dimension on gender difference in flow-dependent dilatation of peripheral conduit arteries

To assess the influence of initial diameter on the gender difference in flow-dependent dilatation (FDD) of the conduit artery, we measured radial artery internal diameter (echotracking), flow (Doppler) and total blood viscosity in 24 healthy (25 +/- 0.8 yr) men and women during reactive hyperemia (RH) and during a gradual hand skin heating (SH). At baseline, mean diameter (men, 2.76 +/- 0.09 vs. women, 2.32 +/- 0.07 mm, P < 0.05), flow (men, 21 +/- 4 vs. women, 10 +/- 1 ml/min, P < 0.05), and blood viscosity (men, 4.13 +/- 0.07 vs. women, 3.92 +/- 0.13 cP, P < 0.05) were higher in men but mean shear stress (MSS) was not different between groups. During RH, the percent increase in diameter was lower in men (men, 9 +/- 1 vs. women, 13 +/- 1%, P < 0.05). This difference was suppressed after correction for baseline diameter. During SH, the increase in diameter with flow was higher in women (P < 0.01). However, the increase in MSS was higher in women because of their smaller diameter at each level of flow (P < 0.01) and there was no difference between groups for the increase in diameter at each level of MSS. These results demonstrate in a direct manner that initial diameter influences the magnitude of FDD of conduit arteries in humans by modifying the value of the arterial wall shear stress at each level of flow and support the interest of the heating method in presence of heterogeneous groups.     

Modulation of endothelial nitric oxide synthase expression by red blood cell aggregation

The effects of enhanced red blood cell (RBC) aggregation on nitric oxide (NO)-dependent vascular control mechanisms have been investigated in a rat exchange transfusion model. RBC aggregation for cells in native plasma was increased via a novel method using RBCs covalently coated with a 13-kDa poloxamer copolymer (Pluronic F-98); control experiments used RBCs coated with a nonaggregating 8.4-kDa poloxamer (Pluronic F-68). Rats exchange transfused with aggregating RBC suspensions demonstrated significantly enhanced RBC aggregation throughout the 5-day follow-up period, with mean arterial blood pressure increasing gradually over this period. Arterial segments ( approximately 300 microm in diameter) were isolated from gracilis muscle on the fifth day and mounted between two glass micropipettes in a special chamber equipped with pressure servo-control system. Dose-dependent dilation by ACh and flow-mediated dilation of arterial segments pressurized to 30 mmHg and preconstricted to 45-55% of the original diameter by phenylephrine were significantly blunted in rats with enhanced RBC aggregation. Both responses were totally abolished by nonspecific NO synthase (NOS) inhibitor (Nomega-nitro-l-arginine methyl ester) treatment of arterial segments, indicating that the responses were NO related. Additionally, expression of endothelial NOS protein was found to be decreased in muscle samples obtained from rats exchanged with aggregating cell suspensions. These results imply that enhanced RBC aggregation results in suppressed expression of NO synthesizing mechanisms, thereby leading to altered vasomotor tonus; the mechanisms involved most likely relate to decreased wall shear stresses due to decreased blood flow and/or increased axial accumulation of RBCs.     

Myogenic responses and compliance of mesenteric and splenic vasculature in the rat

In the rat, the spleen is a major site of fluid efflux out of the blood. By contrast, the mesenteric vasculature serves as a blood reservoir. We proposed that the compliance and myogenic responses of these vascular beds would reflect their different functional demands. Mesenteric and splenic arterioles ( approximately 150-200 microm) and venules (<250 microm) from rats anesthetized with pentobarbital sodium were mounted in a pressurized myograph. Mesenteric arterial diameter decreased from 146 +/- 6 to 133 +/- 6 microm on raising intraluminal pressures from 80 to 120 mmHg. This response was enhanced in the presence of N(omega)-nitro-l-arginine methyl ester (l-NAME; 139 +/- 6 to 112 +/- 7 microm). There was no such myogenic response in the splenic arterioles, except in the presence of l-NAME (194 +/- 4 to 164 +/- 4.2 microm). We propose that, whereas mesenteric arterioles exhibit myogenic responses, this is normally masked by NO-mediated dilation in the splenic vessels. The mesenteric venules were highly distensible (active, 184 +/- 15 to 320 +/- 30.9 microm; passive in Ca(2+)-free media, 209 +/- 31 to 344 +/- 27 microm; 4-8 mmHg) compared with the splenic vessels (active, 169 +/- 11 to 184 +/- 16 microm; passive, 187 +/- 12 to 207 +/- 17 microm). We conclude that, in response to an increase in perfusion pressure, mesenteric arterial diameter would decrease to limit the changes in flow and microvascular pressure. In addition, mesenteric venous capacitance would increase. By contrast, splenic arterial diameter would increase, while there would be little change in venous diameter. This would enhance the increase in intrasplenic microvascular pressure and increase fluid extravasation.     

In vitro diameter response of rat femoral artery to flow in the presence and absence of endothelium.

We have examined the diameter response of rat femoral artery segments in the presence and absence of endothelium to changes in flow rate. The segments were isolated, mounted on microcannulae, maintained at 37 degrees C, and perfused at 90 mmHg with Tyrode's solution. The external arterial diameter was measured using video-microscopy. The mean control diameter was 741+/-22 microm (mean+/-SEM,n=7). The arteries were preconstricted to 75+/-1% of the control diameter with a superfusion of 1 microM norepinephrine (NE). Endothelial function was verified by perfusion of 1 micro;M acetylcholine (ACh). Two different flow protocols were employed: step changes in flow (n=7) and low-frequency sinusoidal flow changes (0.01Hz0.05). Sinusoidal flow oscillations resulted in sinusoidal diameter oscillations, whose amplitude and phase lag were inversely proportional to the frequency of the flow oscillations. A first-order low-pass filter, with a time constant of 28+/-3 and 30+/-5s for arteries with and without functional endothelium, respectively, was used to describe the relation between oscillatory flow and diameter. The response of the rat femoral arteries to changes in flow was not found to be different whether the endothelium was intact or removed.     

Rapid force recovery in contracting skeletal muscle after brief ischemia is dependent on O(2) availability.

We tested the hypothesis that contracting skeletal muscle can rapidly restore force development during reperfusion after brief total ischemia and that this rapid recovery depends on O(2) availability and not an alternate factor related to blood flow. Isolated canine gastrocnemius muscle (n = 5) was stimulated to contract tetanically (isometric contraction elicited by 8 V, 0.2-ms duration, 200-ms trains, at 50-Hz stimulation) every 2 s until steady-state conditions of muscle blood flow (controlled by pump perfusion) and developed force were attained (3 min). While maintaining the same stimulation pattern, muscle blood flow was then reduced to zero (complete ischemia) for 2 min. Normal blood flow was then restored to the contracting muscle; however, two distinct conditions of oxygenation (at the same blood flow) were sequentially imposed: deoxygenated blood (30 s), blood with normal arterial O(2) content (30 s), a return to deoxygenated blood (30 s), and finally a return to normal arterial O(2) content (90 s). During the ischemic period, force development fell to 39 +/- 6 (SE)% of normal (from 460 +/- 40 to 170 +/- 20 N/100 g). When muscle blood flow was restored to normal by perfusion with deoxygenated blood, developed force continued to decline to 140 +/- 20 N/100 g. Muscle force rapidly recovered to 310 +/- 30 N/100 g (P < 0.05) during the 30 s in which the contracting muscle was perfused with oxygenated blood and then fell again to 180 +/- 30 N/100 g when perfused with blood with low PO(2). These findings demonstrate that contracting skeletal muscle has the capacity for rapid recovery of force development during reperfusion after a short period of complete ischemia and that this recovery depends on O(2) availability and not an alternate factor related to blood flow restoration.     

MCA Vmean and the arterial lactate-to-pyruvate ratio correlate during rhythmic handgrip.

Regulation of cerebral blood flow during physiological activation including exercise remains unknown but may be related to the arterial lactate-to-pyruvate (L/P) ratio. We evaluated whether an exercise-induced increase in middle cerebral artery mean velocity (MCA Vmean) relates to the arterial L/P ratio at two plasma lactate levels. MCA Vmean was determined by ultrasound Doppler sonography at rest, during 10 min of rhythmic handgrip exercise at approximately 65% of maximal voluntary contraction force, and during 20 min of recovery in seven healthy male volunteers during control and a approximately 15 mmol/l hyperglycemic clamp. Cerebral arteriovenous differences for metabolites were obtained by brachial artery and retrograde jugular venous catheterization. Control resting arterial lactate was 0.78 +/- 0.09 mmol/l (mean +/- SE) and pyruvate 55.7 +/- 12.0 micromol/l (L/P ratio 16.4 +/- 1.0) with a corresponding MCA Vmean of 46.7 +/- 4.5 cm/s. During rhythmic handgrip the increase in MCA Vmean to 51.2 +/- 4.6 cm/s was related to the increased L/P ratio (23.8 +/- 2.5; r2 = 0.79; P < 0.01). Hyperglycemia increased arterial lactate and pyruvate to 1.9 +/- 0.2 mmol/l and 115 +/- 4 micromol/l, respectively, but it did not significantly influence the L/P ratio or MCA Vmean at rest or during exercise. Conversely, MCA Vmean did not correlate significantly, neither to the arterial lactate nor to the pyruvate concentrations. These results support that the arterial plasma L/P ratio modulates cerebral blood flow during cerebral activation independently from the plasma glucose concentration.     

Effect of sildenafil on coronary active and reactive hyperemia

Sildenafil, a selective inhibitor of phosphodiesterase type 5, produces relaxation of isolated epicardial coronary artery segments by causing accumulation of cGMP. Because shear-induced nitric oxide-dependent vasodilation is mediated by cGMP, this study was performed to determine whether sildenafil would augment the coronary resistance vessel dilation that occurs during the high-flow states of exercise or reactive hyperemia. In chronically instrumented dogs, sildenafil (2 mg/kg per os) augmented the vasodilator response to acetylcholine, with a leftward shift of the dose-response curve relating coronary flow to acetylcholine dose. Sildenafil caused a 6. 7 +/- 2.1 mmHg decrease of mean aortic pressure, which was similar at rest and during treadmill exercise (P < 0.05), with no change of heart rate, left ventricular (LV) systolic pressure, or LV maximal first time derivative of LV pressure. Sildenafil tended to increase myocardial blood flow at rest and during exercise (mean increase = 14 +/- 3%; P < 0.05 by ANOVA), but this was associated with a significant decrease in hemoglobin, so that the relationship between myocardial oxygen consumption and oxygen delivery to the myocardium (myocardial blood flow x arterial O(2) content) was unchanged. Furthermore, sildenafil did not alter coronary venous PO(2), indicating that the coupling between myocardial blood flow and myocardial oxygen demands was not altered. In addition, sildenafil did not alter the peak coronary flow rate, debt repayment, or duration of reactive hyperemia that followed a 10-s coronary occlusion. The findings suggest that cGMP-mediated resistance vessel dilation contributes little to the increase in myocardial flow that occurs during exercise or reactive hyperemia.