Compression induced by RV pressure overload decreases regional coronary blood flow in anesthetized dogs

Pulmonary artery constriction (PAC), a model of right ventricular (RV) pressure overload, flattens or inverts the septum and may flatten the left ventricular (LV) free wall. Finite element (FE) analysis predicts that such deformations may cause substantial compression. This study tests the hypothesis that deformation-induced myocardial compressive stress impedes coronary blood flow (CBF). Colored microspheres ( approximately 2 x 10(6)) were injected into the left atrium of 13 open-chest, anesthetized dogs under control conditions and during PAC, which decreased the end-diastolic transseptal pressure gradient (LV - RV) from 1.6 +/- 1.3 to -3.4 +/- 1.7 mmHg. Septal and LV deformation was assessed with the use of two-dimensional echocardiography, and by FE analysis, the hydrostatic component of stress was assessed. Postmortem, a 2.5-cm wide, LV equatorial ring was divided into 16 endocardial and epicardial samples. PAC decreased CBF in the FE-predicted compression zones, areas with the greatest compression having the greatest reductions in CBF. During PAC, compression reached a maximum of 25.3 +/- 1.8 mmHg on the (LV) endocardial sides of the RV insertion points, areas that saw CBF decrease from 1.05 +/- 0.08 to 0.68 +/- 0.05 ml.min(-1).g(-1) (P < 0.001), more than 30%. CBF decreased (from 1.08 +/- 0.07 to 0.81 +/- 0.07 ml.min(-1).g(-1); P < 0.001) on the RV side of the midseptum, an area with as much as 16.0 +/- 1.0 mmHg of compression. Overall, average compressions of 10 mmHg decreased CBF by approximately 30%. We conclude that acute RV pressure overload deforms the septum and LV and induces compressive stresses that reduce CBF substantially. This may help explain why some patients with pulmonary hypertension and no critical coronary disease have chest discomfort indistinguishable from angina pectoris.     

NO supports right ventricular flow dominance and whole body O(2) utilization in midgestation fetal lambs

It is unknown if nitric oxide (NO) modulates the relative levels of left (LV) and right (RV) ventricular output, fetal O2 consumption, or blood flow distribution between the body and placenta at midgestation. To address these questions, six fetal lambs were instrumented at 89-96 days gestation (term 147 days), and blood flows were measured with radioactive microspheres 3-4 days later at baseline and after inhibition of NO synthesis with 10 mg/kg (L-NNA10) and 25 mg/kg (L-NNA25) N(omega)-nitro-L-arginine. LV output fell by 74 +/- 15 ml. min(-1). kg(-1) at L-NNA10 (P < 0.005), whereas RV output decreased by 90 +/- 18 ml. min(-1). kg(-1) at L-NNA10 (P < 0.02) and by a further 80 +/- 22 ml. min(-1). kg(-1) at L-NNA25 (P < 0.05). As a result, RV output exceeded LV output at baseline (P = 0.03) and L-NNA10 (P < 0.02) but not at L-NNA25. Fetal body blood flow fell by 95 +/- 25 ml. min(-1). kg(-1) at L-NNA10 (P < 0.01), but because placental blood flow decreased by 70 +/- 22 ml. min(-1). kg(-1) at L-NNA10 (P < 0.01) and a further 71 +/- 21 ml. min(-1). kg(-1) at L-NNA25 (P < 0.01), the fetal body-to-placental blood flow ratio was near unity at baseline and L-NNA10 but rose to 1.5 +/- 0.3 at L-NNA25 (P < 0.05). In association with these flow changes, fetal O2 consumption declined by 1.4 +/- 0.3 ml. min(-1). kg(-1) at L-NNA10 (P < 0.05) and by a further 1.5 +/- 0.6 ml. min(-1). kg(-1) at L-NNA25 (P < 0.02). These findings suggest that, in midgestation fetal lambs, NO supports an RV flow dominance, whole body O2 utilization, and the maintenance of a near-equal fetoplacental blood flow distribution.     

Influence of serotonin on myocardial blood flow in the presence and absence of a coronary arterial stenosis: observations in domestic swine

This study tested the hypothesis that 5-HT may impair coronary flow regulation by inappropriately increasing arteriolar tone in the coronary circulation. Ten closed chest, domestic swine were studied both in the presence and in the absence of a severe artificial intraluminal coronary stenosis. A 5-French micromanometer catheter with fluid lumen was placed in the left anterior descending coronary artery and used to record pressure and infuse 5-HT (40 and 100 micrograms/min) into the coronary circulation. For the stenosis phase of the protocol the catheter was embedded in the artificial stenosis. Hemodynamics, regional myocardial blood flow (microsphere technique), coronary vascular resistance, lactate consumption, and oxygen metabolism were measured at control and at 5 min of each 5-HT dose. In the absence of coronary artery stenosis (i.e., full vasodilatory reserve), there was no change in regional myocardial blood flow or coronary vascular resistance during 5-HT infusion. In the presence of a severe coronary stenosis (i.e., limited vasodilator reserve) 5-HT produced a significant (P less than 0.05) decrease versus control in the distal left anterior descending: circumflex zone endocardial blood flow ratio (0.63 +/- 0.19, mean +/- 1 SD, to 0.55 +/- 0.15) and a significant (P less than 0.05) increase versus control in endocardial (50.6 +/- 16.6 to 61.2 +/- 19.8 mm Hg/ml/min/g) and transmural (49.9 +/- 9.5 to 57.2 +/- 12.8) coronary vascular resistance. Thus, 5-HT does not impair coronary flow regulation when full vasodilatory reserve is present. When coronary vasodilatory reserve is impaired by the presence of a severe proximal stenosis, 5-HT causes modest impairment of endocardial flow regulation.     

Ovine fetal electrocortical activity and regional cerebral blood flow

Fetuses of 12 near-term sheep were prepared for microsphere determination of cerebral blood flow. Experiments were performed 5 days postsurgery. The regional blood flows were measured in successive high (HV), low (LV) and high voltage electrocorticographic states. Comparisons were made between the observations made in the LV and averaged flanking HV cycles. Total cerebral blood flow was 95 +/- 8, 119 +/- 11 and 100 +/- 9 ml/min/100 g in HV, LV and HV, respectively. Low voltage electrocortical activity increased average cerebral blood flow by 22% (P less than 0.01). Significant changes were seen in all regions except the occipital cortex. The maximum change was observed in the thalamus in which the flows were 152 +/- 23, 243 +/- 35 and 138 +/- 20 ml/min/per 100 g tissue, respectively. The increase was 68% (P less than 0.001). The percent changes seen in the cerebrum are as follows: Frontal grey + 18%, frontal white + 22%, parietal white + 22%, temporal + 18%. A + 17% change was seen in the cord (P less than 0.03). It is concluded that in low voltage electrocortical activity all of the brain, except the occipital region, shows an increase in cerebral blood flow. This is probably secondary to a variance in cerebral activity. This preparation may be useful in localizing function in the fetal brain.     

Right and left ventricular function after chronic pulmonary artery banding in rats assessed with biventricular pressure-volume loops

In many patients with congenital heart disease, the right ventricle (RV) is subjected to abnormal loading conditions. To better understand the state of compensated RV hypertrophy, which could eventually progress to decompensation, we studied the effects of RV pressure overload in rats. In the present study, we report the biventricular adaptation to 6 wk of pulmonary artery banding (PAB). PAB resulted in an RV pressure overload to approximately 60% of systemic level and a twofold increase in RV mass (P < 0.01). Systemic hemodynamic parameters were not altered, and overt signs of heart failure were absent. Load-independent measures of ventricular function (end-systolic pressure-volume relation, preload recruitable stroke work relation, maximum first time derivative of pressure divided by end-diastolic volume), assessed by means of pressure-volume (PV) loops, demonstrated a two- to threefold increase in RV contractility under baseline conditions in PAB rats. RV contractility increased in response to dobutamine stimulation (2.5 microg.kg(-1).min(-1)) both in PAB and sham-operated rats in a similar fashion, indicating preserved RV contractile reserve in PAB rats. Left ventricular (LV) contractility at baseline was unaffected in PAB rats, although LV volume in PAB rats was slightly decreased. LV contractility increased in response to dobutamine (2.5 microg.kg(-1).min(-1)), both in PAB and sham rats, whereas the response to a higher dose of dobutamine (5 microg.kg(-1).min(-1)) was blunted in PAB rats. RV pressure overload (6 wk) in rats resulted in a state of compensated RV hypertrophy with preserved RV contractile reserve, whereas LV contractile state at baseline was not affected. Furthermore, this study demonstrates the feasibility of performing biventricular PV-loop measurements in rats.     

Impaired resting perfusion in viable myocardium distal to chronic coronary stenosis in rats

Chronic coronary artery stenosis results in patchy necrosis in the dependent myocardium and impairs global and regional left ventricular (LV) function in rats in vivo. The aim of the present study was to compare regional myocardial blood flow (RMBF) and function (F) in poststenotic myocardium by using magnetic resonance imaging (MRI) and to compare MRI blood flow changes to histological alterations to assess whether RMBF in the viable poststenotic tissue remains normal. MRI was performed in 11 anesthetized Wistar rats with 2-wk stenosis of the left coronary artery. Postmortem, the extent of fibrotic tissue was quantified. Poststenotic RMBF was significantly reduced to 2.21 +/- 0.30 ml.g(-1).min(-1) compared with RMBF in the remote myocardium (4.05 +/- 0.50 ml.g(-1).min(-1)). A significant relationship between the poststenotic RMBF (%remote area) and the poststenotic F (%remote myocardium) was calculated (r = 0.61, P < 0.05). Assuming perfusion in scar tissue to be 32 +/- 5% of perfusion of remote myocardium, as measured in five additional rats, and that in remote myocardium to be 114 +/- 25% of that in normal myocardium, as assessed in five sham rats, the calculated perfusion in partially fibrotic tissue samples (35.7 +/- 5.2% of analyzed area) was 2.88 +/- 0.18 ml.g(-1).min(-1), whereas measured MRI perfusion was only 1.86 +/- 0.24 ml.g(-1).min(-1) (P < 0.05). These results indicate that resting perfusion in viable poststenotic myocardium is moderately reduced. Alterations in global and regional LV function are therefore secondary to both patchy fibrosis and reduced resting perfusion.     

Fatigability and blood flow in the rat gastrocnemius-plantaris-soleus after hindlimb suspension.

The purpose of this study was to test the hypothesis that hindlimb suspension increases the fatigability of the soleus during intense contractile activity and determine whether the increased fatigue is associated with a reduced muscle blood flow. Cage-control (C) and 15-day hindlimb-suspended (HS) rats were anesthetized, and either the gastrocnemius-plantaris-soleus (G-P-S) muscle group or the soleus was stimulated (100 Hz, 100-ms trains at 120/min) for 10 min in situ. In the G-P-S preparation, blood flow was measured with radiolabeled microspheres before and at 2 and 10 min of contractile activity. The G-P-S fatigued markedly at this stimulation frequency, and the differences between C and HS animals were not significant until the 9th min of contractile activity. In contrast, the stimulation resulted in faster rates and significantly larger amounts of fatigue in the soleus from HS than from C animals. The atrophied soleus showed significant differences by 1 min of stimulation (C = 70 +/- 1% vs. HS = 57 +/- 2% of peak train force) and remained different at 10 min (C = 64 +/- 4% vs. HS = 45 +/- 2% peak train force). Relative blood flow to the soleus was similar between groups before and during contractile activity (rest: C = 20 +/- 3 vs. HS = 12 +/- 3; 2 min: C = 128 +/- 6 vs. HS = 118 +/- 4; 10 min: C = 123 +/- 11 vs. HS = 105 +/- 11 ml.min-1.100 g-1). In conclusion, these results established that 15 days of HS increased the fatigability of the soleus, but the effect was not caused by a reduced muscle blood flow.     

Blood flow to the placenta and lower body in the growth-retarded guinea pig fetus

Blood flow to the placenta and lower body of control and growth retarded (IUGR) guinea pig fetuses was measured between 60-64 days of pregnancy by the microsphere technique. Further information about the hepatic blood supply and its interlobular distribution was obtained by injecting microspheres into the umbilical vein and a branch of the portal vein. Liver weight was reduced by 60% in IUGR fetuses from 5.0 +/- 0.2 to 2.0 +/- 0.1 g, compared to a decrease in body weight of 50% from 91.6 +/- 3.0 to 45.4 +/- 2.6 g. In addition, there was a proportionately greater reduction in the size of the right liver lobe. Umbilical blood flow was 10.8 +/- 1.0 ml min-1 in control fetuses and 4.9 +/- 1.2 ml.min-1 in IUGR fetuses, whilst blood flow in the portal vein was reduced from 1.4 +/- 0.1 to 0.8 +/- 0.3 ml min-1 and that in the hepatic artery from 0.6 +/- 0.1 to 0.3 +/- 0.1 ml.min-1. Since ductus venosus flow was absent or negligible, the umbilical venous return accounted for greater than 80% of the hepatic blood supply in both control and IUGR fetuses. Blood flows were, however, unequally distributed between the liver lobes. The right lobe was supplied mainly by the portal vein in IUGR fetuses as well as the controls, and received less than 6% of the umbilical venous return. No significant change occurred in total liver perfusion, which was 2.8 +/- 0.2 ml min-1 per g in control fetuses and 2.6 +/- 0.4 ml min-1 per g in IUGR fetuses. It is therefore suggested that a high rate of liver metabolism is maintained in IUGR, but by a smaller tissue mass, and that the rate of umbilical blood flow may be one factor determining the size of the liver. The relatively greater reduction in size of the right lobe in IUGR is probably the result of poor oxygenation of the portal venous blood.     

Myocardial perfusion reserve in adults with cyanotic congenital heart disease

In patients with cyanotic congenital heart disease (CCHD), a right-to-left shunt results in systemic hypoxemia. Systemic hypoxemia incites a compensatory erythrocytosis, which increases whole blood viscosity. We considered that these changes might adversely influence myocardial perfusion in CCHD patients. Basal and hyperemic (intravenous dipyridamole) perfusion measurements were obtained with [13N]ammonia positron emission tomographic imaging in left (LV) and right (RV) ventricular and septal myocardium in 14 adults with CCHD [age: 34.1 yr (SD 6.5)]; hematocrit: 62.2% (SD 4.8)] and 10 healthy controls [age: 34.1 yr (SD 6.5)]. In patients, basal perfusion measurements were higher in LV [0.77 (SD 0.24) vs. 0.55 ml x min(-1) x g(-1) (SD 0.09), P < 0.02], septum [0.71 (SD 0.16) vs. 0.49 ml x min(-1) x g(-1) (SD 0.09), P < 0.001], and RV [0.77 (SD 0.30) vs. 0.38 ml x min(-1) x g(-1) (SD 0.09), P < 0.001]. However, basal measurements normalized for the rate-pressure product were similar to those of controls. Calculated oxygen delivery relative to rate-pressure product was higher in the patients [2.2 (SD 0.8) vs. 1.6 (SD 0.4) x 10(-5) ml O2 x min(-1) x g tissue(-1) x (beats x mmHg)(-1) in the LV, P < 0.05, and 2.0 (SD 0.7) vs. 1.4 (SD 0.3) x 10(-5) ml O2 x min(-1) x g tissue(-1) x (beats x mmHg)(-1) in the septum, P < 0.01]. Hyperemic perfusion measurements in CCHD patients did not differ from controls [LV, 1.67 (SD 0.60) vs. 1.95 ml x min(-1) x g(-1) (SD 0.46); septum, 1.44 (SD 0.56) vs. 1.98 ml x min(-1) x g(-1) (SD 0.69); RV, 1.56 (SD 0.56) vs. 1.65 ml x min(-1) x g(-1) (SD 0.64), P = not significant], and coronary vascular resistances were comparable [LV, 55 (SD 25) vs. 48 mmHg x ml(-1) x g x min (SD 16); septum, 67 (SD 35) vs. 50 mmHg x ml(-1) x g x min (SD 21); RV, 59 (SD 26) vs. 61 mmHg x ml(-1) x g x min (SD 27), P = not significant]. These findings suggest that adult CCHD patients have remodeling of the coronary circulation to compensate for the rheologic changes attending chronic hypoxemia.     

The effects of ethanol on pancreatic blood flow in awake and anesthetized dogs

The pathophysiology of alcohol-induced acute pancreatitis is not clear. Ischemic injury has been suggested as a possible mechanism. To examine the effects of ethanol on pancreatic and splanchnic blood flow, measurements were made in fasted, conditioned awake dogs before and after iv infusion of ethanol (1.7 g/kg). At 30 min blood ethanol concentration ranged between 60 and 150 mg/dl and at 60 min between 166 and 350 mg/dl. Although cardiac output, aortic pressure, left atrial pressure, and arterial pH did not change, pancreatic flow declined by 39 +/- 12 ml/min/100 g, P less than 0.05 (from 173 +/- 10 ml/min/100 g) at 30 min and was still depressed (by 27 +/- 12 ml/min/100 g, P less than 0.05) at 60 min. Concomitantly, hepatic arterial flow increased. While hepatic and pancreatic flow changed inversely, the correlation (r = -0.17) of these changes was not significant. At comparable blood ethanol concentrations in pentobarbital-anesthetized dogs hepatic arterial flow increased by 11 +/- 3 ml/min/100 g, P less than 0.01 (from 24 +/- 5 ml/min/100 g), but pancreatic flow did not change. Thus, in the awake dog at blood levels that would produce mild to moderate alcoholic intoxication in man, ethanol reduces pancreatic flow. Although hepatic flow increases concomitantly, the relationship of these changes appears to be independent.     

Effects of chronic reduction in uterine blood flow on fetal and placental growth in the sheep

Pregnancy is associated with a significant increase in uteroplacental blood flow (UBF), which is responsible for delivering adequate nutrients and oxygen for fetal and placental growth. The present study was designed to determine the effects of vascular insufficiency on fetal and placental growth. Thirty-nine late-term pregnant ewes were instrumented to investigate the effects of chronic UBF reduction. Animals were split into three groups based on uterine blood flow, and all animals were killed on gestational day 138. UBF, which began at 851 +/- 74 ml/min (n = 39), increased in controls (C) to 1,409 +/- 98 ml/min (day 138 of gestation) and in the moderately restricted (R(M)) group to 986 +/- 69 ml/min. In the severely restricted (R(S)) group, UBF was only 779 +/- 79 ml/min on gestational day 138. This reduction in UBF significantly affected fetal body weight with R(M) fetuses weighing 3,685 +/- 178 g and R(S) fetuses weighing 2,920 +/- 164 g compared with C fetal weights of 4,318 +/- 208 g. Fetal brain weight was not affected, whereas ponderal index was significantly reduced in R(M) (2.94 +/- 0.09) and R(S) fetuses (2.49 +/- 0.08) compared with the value of the C fetuses (3.31 +/- 0.08). Placental weight was also significantly reduced in the R(M) group, being 302 +/- 24 g, whereas the R(S) group placenta weighed 274 +/- 61 g compared with the C values of 414 +/- 57 g. Fetal heart, liver, lung, and thymus were all significantly smaller in the R(S) group. Thus the present study shows a clear relationship between the level of UBF and both fetal and placental size. Furthermore, the observation that fetal brain weight was not affected, whereas fetal body weight was significantly reduced suggests that this experimental preparation may provide a useful model in which to study asymmetric fetal growth restriction.     

Regional blood flow during exercise in humans measured by near-infrared spectroscopy and indocyanine green.

Using near-infrared spectroscopy (NIRS) and the tracer indocyanine green (ICG), we quantified blood flow in calf muscle and around the Achilles tendon during plantar flexion (1-9 W). For comparison, blood flow in calf muscle was determined by dye dilution in combination with magnetic resonance imaging measures of muscle volume, and, for the peritendon region, blood flow was measured by (133)Xe washout. From rest to a peak load of 9 W, NIRS-ICG blood flow in calf muscle increased from 2.4+/-0.2 to 74+/-5 ml x 100 ml tissue(-1) x min(-1), similar to that measured by reverse dye (77+/-6 ml x 100 ml tissue(-1) x min(-1)). Achilles peritendon blood flow measured by NIRS-ICG rose with exercise from 2.2+/-0.5 to 15.1+/-0.2 ml x 100 ml(-1) x min(-1), which was similar to that determined by (133)Xe washout (2.0+/-0.6 to 14.6+/-0.3 ml x 100 ml tissue(-1) x min(-1)). This is the first study using NIRS and ICG to quantify regional tissue blood flow during exercise in humans. Due to its high spatial and temporal resolution, the technique may be useful for determining regional blood flow distribution and regulation during exercise in humans.     

Negative metabolic and coronary flow effects of decreases in cAMP and increases in cGMP in control and renal hypertensive rabbit hearts.

The interaction during stimulation of cGMP and inhibition of cAMP was investigated in control and renal hypertensive hearts. Control and hypertensive [1 kidney, 1 clip (1K1C)] rabbits were used. The anesthetized open-chest groups were vehicle, 8-bromo-cGMP (8-Br-cGMP; 10(-3)M), propranolol (Prop; 2 mg/kg), and Prop + 8-Br-cGMP. O(2) consumption levels (Vo(2)) in the subepicardium (Epi) and subendocardium (Endo) were determined from coronary flow (microspheres) and O(2) extraction (microspectrophotometry). Wall thickening and cAMP levels were also determined. In control, no significant change in Vo(2) was seen for the 8-Br-cGMP group, but Vo(2) was decreased from Epi (9.7 +/- 1.5 ml O(2) x min(-1) x 100 g(-1)) and Endo (10.5 +/- 0.4 ml O(2) x min(-1) x 100 g(-1)) to 6.8 +/- 0.6/7.8 +/- 0.5 ml O(2) x min(-1) x 100 g(-1) in the control Prop group. Control Prop + 8-Br-cGMP did not cause a further fall in Vo(2) but lowered Endo flow. In 1K1C, Vo(2) decreased from Epi/Endo (10.8 +/- 1.3/11 +/- 1.0 ml O(2).min(-1).100 g(-1)) to 7.8 +/- 1.1/8.7 +/- 0.5 ml O(2) x min(-1) x 100 g(-1) in the 1K1C 8-Br-cGMP group and to 7 +/- 0.5/8.1 +/- 0.5 ml O(2) x min(-1) x 100 g(-1) in the 1K1C Prop group. 1K1C Prop + 8-Br-cGMP did not cause a further fall in Vo(2) but lowered blood flow. No significant changes in cAMP levels were present with 8-Br-cGMP in control or 1K1C rabbits, but significant decreases were seen with Prop in both control and 1K1C rabbits. No further change was seen in Prop + 8-Br-cGMP for either control or 1K1C. Thus the negative metabolic effect of stimulating cGMP was seen only in the hypertensive rabbit heart. The negative metabolic effect of inhibiting cAMP was seen in both the control and the hypertensive rabbit heart. However, the negative metabolic effects of cGMP and cAMP were nonadditive.     

Dose-dependent effect of bradykinin on muscular blood flow and glucose uptake in man

Using the forearm technique, the effect of bradykinin on muscular blood flow and glucose uptake in healthy man in the postabsorptive state (n = 8) was studied at different doses of an intra-arterial infusion of bradykinin (2.5-150 ng/min). The blood flow of the forearm was increased dose-dependently from basal 2.8 +/- 0.3 up to 14.7 +/- 2.8 ml/(100 g X min). At lower bradykinin concentrations (2.5-25 ng/min), muscular glucose uptake was raised parallel to the increased blood flow from basal 0.71 +/- 0.30 to 2.93 +/- 0.50 mumol/(100 g X min). However, at higher doses (50-150 ng/min) glucose uptake was decreased again. Thus, the greatest metabolic effect of bradykinin was seen at a calculated bradykinin concentration of approximately 1 X 10(-9)M in the blood.     

VEGF(121)- and bFGF-induced increase in collateral blood flow requires normal nitric oxide production

The angiogenic proteins basic fibroblast growth factor (bFGF; FGF-2) and vascular endothelial growth factor 121 (VEGF(121)) are each able to enhance the collateral-dependent blood flow after bilateral femoral artery ligation in rats. To study the effect of nitric oxide (NO) synthase (NOS) inhibition on bFGF- or VEGF(121)-induced blood flow expansion, the femoral arteries of male Sprague-Dawley rats were ligated bilaterally, and the animals were given tap water [non-N(G)-nitro-L-arginine methyl ester (L-NAME) group; n = 36] or water that contained L-NAME (L-NAME group; 2 mg/ml, n = 36). Animals from each group were further divided into three subgroups: vehicle (n = 12), bFGF (5 microg x kg(-1) x day(-1), n = 12), or VEGF(121) (10 microg x kg(-1) x day(-1), n = 12). Growth factors were delivered via intra-arterial infusion with osmotic pumps over days 1-14. On day 16, after a 2-day delay to permit clearance of bFGF and VEGF from the circulation, maximal collateral blood flow was determined by (85)Sr- and (141)Ce-labeled microspheres during treadmill running. L-NAME (approximately 137 mg x kg(-1) x day(-1)) for 18 days increased systemic blood pressure (approximately 26%, P<0.001). In the absence of L-NAME, collateral-dependent blood flows to the calf muscles were greater in the VEGF(121)- and bFGF-treated subgroups (85 +/- 4.5 and 80 +/- 2.9 ml x min(-1) x 100 g(-1), respectively) than in the vehicle subgroup (49 +/- 3.0 ml x min(-1) x 100 g(-1), P<0.001). In the presence of NOS inhibition by L-NAME, blood flows to the calf muscles were essentially equivalent among the three subgroups (54 +/- 3.0, 56 +/- 5.1, and 47 +/- 2.0 ml x min(-1) x 100 g(-1) in the bFGF-, VEGF(121)-, and vehicle-treated subgroups, respectively) and were not different from the blood flow in the non-L-NAME vehicle subgroup. Our results therefore indicate that normal NO production is essential for the enhanced vascular remodeling induced by exogenous bFGF or VEGF(121) in this rat model of experimental peripheral arterial insufficiency. These results imply that a blunted endothelial NO production could temper vascular remodeling in response to these angiogenic growth factors.     

Changes in regional myocardial volume during the cardiac cycle: implications for transmural blood flow and cardiac structure

Although previous studies report a reduction in myocardial volume during systole, myocardial volume changes during the cardiac cycle have not been quantitatively analyzed with high spatiotemporal resolution. We studied the time course of myocardial volume in the anterior mid-left ventricular (LV) wall of normal canine heart in vivo (n = 14) during atrial or LV pacing using transmurally implanted markers and biplane cineradiography (8 ms/frame). During atrial pacing, there was a significant transmural gradient in maximum volume decrease (4.1, 6.8, and 10.3% at subepi, midwall, and subendo layer, respectively, P = 0.002). The rate of myocardial volume increase during diastole was 4.7 +/- 5.8, 6.8 +/- 6.1, and 10.8 +/- 7.7 ml.min(-1).g(-1), respectively, which is substantially larger than the average myocardial blood flow in the literature measured by the microsphere method (0.7-1.3 ml.min(-1).g(-1)). In the early activated region during LV pacing, myocardial volume began to decrease before the LV pressure upstroke. We conclude that the volume change is greater than would be estimated from the known average transmural blood flow. This implies the existence of blood-filled spaces within the myocardium, which could communicate with the ventricular lumen. Our data in the early activated region also suggest that myocardial volume change is caused not by the intramyocardial tissue pressure but by direct impingement of the contracting myocytes on the microvasculature.     

The differential effects of alpha 2-adrenergic stimulation on the myocardium and coronary vessels in the isolated rat heart

The differential effects of alpha 2-adrenoceptor stimulation on myocardial contractility and coronary circulation were examined in the isolated perfused rat heart. We studied 20 Sprague-Dawley rats of similar age (26-28 weeks) and body weight (500-550 gm). Myocardial contractility (LV +dp/dt and developed pressure, LVP) and coronary flow resistance (CFR) were tested in the isolated isovolumic hearts using Langendorff preparation at a constant perfusion rate (2.5 ml/min/100 g BW) of Krebs-Henseleit bicarbonate solution. Group I (N-7) received B-HT 920 (specific alpha 2-adrenergic agonist, 0.6 to 58 micrograms/min), Group II (N-7) received B-HT 920+Yohimbine (300 nM in the perfusate). Group III (N-6) received vehicle only. Baseline LVP, LV +dP/dt and CFR were not significantly different among the 3 groups. During drug or vehicle administration, LVP and LV +dP/dt remained unchanged in all the groups. Coronary flow resistance increased in a dose-response fashion with a maximum increase of 22.7 +/- 3.6 (SE) mmHg/ml/min/g LV in Group I, and 10.5 +/- 2.0 mmHg/ml/min/g LV in Group II (p less than 0.02). We conclude that in the Sprague-Dawley rat heart, the physiologic effects of alpha 2-adrenoceptors are predominant in the coronary circulation but not in the myocardium itself possibly because of absence of post-synaptic alpha 2-adrenergic receptors in the rat myocardium.     

Plasma viscosity and cerebral blood flow

We hypothesized that the response of cerebral blood flow (CBF) to changing viscosity would be dependent on "baseline" CBF, with a greater influence of viscosity during high-flow conditions. Plasma viscosity was adjusted to 1.0 or 3.0 cP in rats by exchange transfusion with red blood cells diluted in lactated Ringer solution or with dextran. Cortical CBF was measured by H(2) clearance. Two groups of animals remained normoxic and normocarbic and served as controls. Other groups were made anemic, hypercapnic, or hypoxic to increase CBF. Under baseline conditions before intervention, CBF did not differ between groups and averaged 49.4 +/- 10.2 ml. 100 g(-1). min(-1) (+/-SD). In control animals, changing plasma viscosity to 1. 0 or 3.0 cP resulted in CBF of 55.9 +/- 8.6 and 42.5 +/- 12.7 ml. 100 g(-1). min(-1), respectively (not significant). During hemodilution, hypercapnia, and hypoxia with a plasma viscosity of 1. 0 cP, CBF varied from 98 to 115 ml. 100 g(-1). min(-1). When plasma viscosity was 3.0 cP during hemodilution, hypercapnia, and hypoxia, CBF ranged from 56 to 58 ml. 100 g(-1). min(-1) and was significantly reduced in each case (P < 0.05). These results support the hypothesis that viscosity has a greater role in regulation of CBF when CBF is increased. In addition, because CBF more closely followed changes in plasma viscosity (rather than whole blood viscosity), we believe that plasma viscosity may be the more important factor in controlling CBF.     

Blood flow response to muscle contractions is more closely related to metabolic rate than contractile work.

The magnitude of the blood flow response to exercise has been linked to both the contractile work performed and the metabolic cost of the activity. Under certain conditions, contractile work and metabolic cost may be dissociated. This study examined the blood flow response to trains of contractions when contraction duration was manipulated under conditions of similar tension-time indexes (isometric analog of work). Previous investigations have shown that trains of short-duration contractions have a greater ATP utilization, which may result from an augmented ion transport required for muscle activation and relaxation. On the basis of these findings, we hypothesized that the blood flow response would be greater to a train of short-duration contractions than a train of long-duration contractions. Canine gastrocnemius-plantaris muscle (n = 8) was isolated, and blood flow assessed with an ultrasound flow probe placed around the popliteal artery. The sciatic nerve was stimulated to produce two contraction protocols that resulted in similar contraction-to-rest ratios: short duration: 0.25 s/0.75 s vs. long duration: 1 s /3 s. In accord with the design of the experiment, the tension-time indexes were identical for the two contraction protocols (short: 18.6 +/- 1.0 vs. long: 18.6 +/- 1.0 kN.s). Steady-state oxygen consumption was greater in the short-duration contractions (17.2 +/- 0.9 ml.100 g(-1).min(-1)) than in the long-duration contractions (11.7 +/- 0.7 ml.100 g(-1).min(-1)). Similarly, the steady-state blood flow was greater in contractions of short duration (125 +/- 7 ml/min) compared with long-duration contractions (92 +/- 7 ml/min). Contractions of short duration resulted in significantly higher oxygen consumptions and blood flows compared with contractions of long duration despite the same total contractile work. The blood flow response to muscle contraction appears to be more closely associated with muscle metabolism than contractile work performed.     

Regional measurement of canine skeletal muscle blood flow by positron emission tomography with H2(15)O.

Positron emission tomography (PET) with H2(15)O was used as an in vivo, relatively noninvasive, quantitative method for measuring regional blood flow to hindlimb skeletal muscle of anesthetized dogs. A hydrooccluder positioned on the femoral artery was used to reduce flow, and high-flow states were produced by local infusion of adenosine. Three to four measurements were made in each animal. Approximately 40 mCi of H2(15)O were injected intravenously, and serial images and arterial blood samples were acquired over 2.5 min. Data analysis was performed by fitting tissue and arterial blood time-activity curves to a modified, single-compartment Kety model. The model equation was also solved on a pixel-by-pixel basis to yield maps of regional skeletal muscle blood flow. After each PET determination, flow was measured with radioactive microspheres. Results of the PET measurements demonstrated that basal flow to hindlimb skeletal muscle was 3.83 +/- 0.36 ml x min(-1) x 100 g(-1) (mean +/- SE). This value was in excellent agreement with the microsphere data, 3.73 +/- 0.32 ml x min(-1) x 100 g(-1) (P = 0.69, not significant). Adenosine infusion resulted in flows as high as 30 ml x min(-1) x 100 g(-1), and the PET and microsphere data were highly correlated over the entire range of flows (r2 = 0.98, P < 0.0001). We conclude that muscle blood flow can be accurately measured in vivo by PET with H2(15)O and that this approach offers promise for application in human studies of muscle metabolism under varying pathophysiological states.