Myocardial blood flow regulation relative to left ventricle pressure and volume in anesthetized dogs

The influence of left ventricle pressure and volume changes on coronary blood flow was investigated in eight anesthetized dogs. Coronary artery pressure-flow relationships were determined at two levels of left ventricular pressure and volume. The distribution of blood flow within the myocardium was also determined when these relationships varied. Reducing left ventricle pressures and volumes increased heart rate. Rate-pressure product, diastolic coronary pressure, myocardial O2 consumption, total, subendocardial and subepicardial flow decreased. Hematocrit and blood gas data were unchanged. The pressure-flow relationships were shifted leftward (p = 0.001) but the range of autoregulation was not altered. At low left ventricle pressures and volumes, the lower coronary artery pressure limit was shifted leftward (from 75 to 45 mm Hg (1 mm Hg = 133.3 Pa)), while total, subendocardial, and subepicardial blood flow did not change compared with the control. Below the lower coronary artery pressure limit, subendocardial but not subepicardial flow decreased, resulting in maldistribution of flow across the left ventricular wall. When coronary pressure was reset between control and the lower coronary artery pressure limit, subendocardial flow was restored. These results show that the lower coronary artery pressure limit can be shifted leftward while the distribution of blood flow across the left ventricular wall is preserved.     

Effects of coronary sinus pressure elevation on coronary blood flow distribution in dogs with normal preload

Coronary sinus pressure (Pcs) elevation shifts the diastolic coronary pressure-flow relation (PFR) of the entire left ventricular myocardium to a higher pressure intercept. This finding suggests that Pcs is one determinant of zero-flow pressure (Pzf) and challenges the existence of a vascular waterfall mechanism in the coronary circulation. To determine whether coronary sinus or tissue pressure is the effective coronary back pressure in different layers of the left ventricular myocardium, the effect of increasing Pcs was studied while left ventricular preload was low. PFRs were determined experimentally by graded constriction of the circumflex coronary artery while measuring flow using a flowmeter. Transmural myocardial blood flow distribution was studied (15-micron radioactive spheres) at steady state, during maximal coronary artery vasodilatation at three points on the linear portion of the circumflex PFR both at low and high diastolic Pcs (7 +/- 3 vs. 22 +/- 5 mmHg; p less than 0.0001) (1 mmHg = 133.322 Pa). In the uninstrumented anterior wall the blood flow measurements were obtained in triplicate at the two Pcs levels. From low to high Pcs, mean aortic (98 +/- 23 mmHg) and left atrial (5 +/- 3 mmHg) pressure, percent diastolic time (49 +/- 7%), percent left ventricular wall thickening (32 +/- 4%), and percent myocardial lactate extraction (15 +/- 12%) were not significantly changed. Increasing Pcs did not alter the slope of the PFR; however, the Pzf increased in the subepicardial layer (p less than 0.0001), whereas in the subendocardial layer Pzf did not change significantly. Similar slopes and Pzf were observed for the PFR of both total myocardial mass and subepicardial region at low and high Pcs. Subendocardial:subepicardial blood flow ratios increased for each set of measurements when Pcs was elevated (p less than 0.0001), owing to a reduction of subepicardial blood flow; however, subendocardial blood flow remained unchanged, while starting in the subepicardium toward midmyocardium blood flow decreased at high Pcs. This pattern was similar for the uninstrumented anterior wall as well as in the posterior wall. Thus as Pcs increases it becomes the effective coronary back pressure with decreasing magnitude from the subepicardium toward the subendocardium of the left ventricle. Assuming that elevating Pcs results in transmural elevation in coronary venous pressure, these findings support the hypothesis of a differential intramyocardial waterfall mechanism with greater subendo- than subepi-cardial tissue pressure.     

Effect of estrogen replacement therapy on distribution of myocardial blood flow in female anesthetized rabbits

Estrogen replacement therapy reduces risk of cardiovascular events by altering coronary vasoregulation and distribution of blood flow. Vessel reactivity and blood flow distribution were assessed in anesthetized female rabbits in the following groups: 1) sham, 2) ovariectomy, 3) ovariectomy + 17beta-estradiol, and 4) ovariectomy + dehydroepiandrosterone. After a 2-wk treatment, cardiac hemodynamics, vascular reserve, and blood flow were evaluated during the following infusions: 1) NaCl, or vehicle (0.5 ml/min), 2) acetylcholine (2 mg/kg), 3) isoproterenol (2 mg. kg(-1). min(-1)), and 4) chromonar (8 mg/kg). In hearts from ovariectomized rabbits, autoregulatory blood flow was preserved despite lower diastolic perfusion pressures (55 +/- 8 vs. 64 +/- 8 mmHg in sham) and rate-pressure product (14.4 +/- 0.8 vs. 19.3 +/- 0.8 beats/min. mmHg x 10(-3)). Estrogen replacement therapy restored coronary pressure and reserve, and all drugs increased vascular conductance. In conclusion, in hearts from ovariectomized rabbits, vascular reserve declined because coronary pressure was lower; however, blood flow was preserved at a higher level than expected for oxygen demand. Estrogen replacement therapy restores myocardial oxygen supply-demand indices and returns coronary pressure-flow data to levels observed in animals with intact ovaries.     

The energetic state within hibernating myocardium is normal during dobutamine despite inhibition of ATP-dependent potassium channel opening with glibenclamide

Within hibernating myocardium, it is uncertain whether a normal energetic state is present at baseline and whether maintaining that energy state during a catecholamine challenge is dependent on ATP-dependent potassium channel opening. In this study, 16 swine underwent a thoracotomy with placement of an external constrictor on the left anterior descending coronary artery (LAD) (hibernation model). Seven additional swine underwent a sham operation. At 10 wk, the myocardial energetic state in the LAD region was assessed by (31)P-NMR spectroscopy, and the ratio of phosphocreatine to ATP (PCr/ATP) was determined at baseline, during glibenclamide treatment (0.5 mg/kg bolus with 50 microg/min iv), and during addition of dobutamine (40 microg x kg(-1) x min(-1) iv). At baseline, transmural blood flow in the LAD and remote region was 0.75 +/- 0.11 and 0.88 +/- 0.09 ml x min(-1) x g(-1), respectively (P < 0.01), in hibernating hearts and 0.83 +/- 0.12 and 0.88 +/- 0.15 ml x min(-1) x g(-1), respectively (not significant), in sham-operated hearts. Under basal conditions, PCr/ATP in the LAD region of hibernating and sham pigs was 2.15 +/- 0.04 and 2.11 +/- 0.05, respectively (not significant). In sham pigs, addition of dobutamine to glibenclamide increased the double product from 10.4 +/- 0.8 to 23.9 +/- 4.0 mmHg x beats x min(-1) x 1,000 (P < 0.05) and decreased transmural PCr/ATP from 2.06 +/- 0.06 to 1.69 +/- 0.06 (P < 0.05). Dobutamine increased the double product in hibernating pigs in a similar fashion and, despite a 40% lower blood flow response, induced an equivalent decrease in PCr/ATP from 2.04 +/- 0.04 to 1.73 +/- 0.08 (P < 0.05). In conclusion, we found that, in chronic hibernating swine myocardium with reduced basal blood flow and perfusion reserve, the transmural energetic state, defined by PCr/ATP, is normal during addition of dobutamine, despite inhibition of ATP-dependent potassium channel opening with glibenclamide. These data suggest that important adaptations other than the ATP-dependent potassium channel opening allow hibernating myocardium to operate over a lower range of the oxygen supply-demand relationship to protect against myocardial ischemia.     

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.     

K(ATP)(+) channels, nitric oxide, and adenosine are not required for local metabolic coronary vasodilation

The role of ATP-sensitive K(+) (K(ATP)(+)) channels, nitric oxide, and adenosine in coronary exercise hyperemia was investigated. Dogs (n = 10) were chronically instrumented with catheters in the aorta and coronary sinus and instrumented with a flow transducer on the circumflex coronary artery. Cardiac interstitial adenosine concentration was estimated from arterial and coronary venous plasma concentrations using a previously tested mathematical model. Experiments were conducted at rest and during graded treadmill exercise with and without combined inhibition of K(ATP)(+) channels (glibenclamide, 1 mg/kg iv), nitric oxide synthesis (N(omega)-nitro-L-arginine, 35 mg/kg iv), and adenosine receptors (8-phenyltheophylline, 3 mg/kg iv). During control exercise, myocardial oxygen consumption increased ~2.9-fold, coronary blood flow increased ~2.6-fold, and coronary venous oxygen tension decreased from 19.9 +/- 0.4 to 13.7 +/- 0.6 mmHg. Triple blockade did not significantly change the myocardial oxygen consumption or coronary blood flow response during exercise but lowered the resting coronary venous oxygen tension to 10.0 +/- 0.4 mmHg and during exercise to 6.2 +/- 0.5 mmHg. Cardiac adenosine levels did not increase sufficiently to overcome the adenosine receptor blockade. These results indicate that combined inhibition of K(ATP)(+) channels, nitric oxide synthesis, and adenosine receptors lowers the balance between total oxygen supply and consumption at rest but that these factors are not required for local metabolic coronary vasodilation during exercise.     

Transmural distribution of metabolic abnormalities and glycolytic activity during dobutamine-induced demand ischemia

The heterogeneity across the left ventricular wall is characterized by higher rates of oxygen consumption, systolic thickening fraction, myocardial perfusion, and lower energetic state in the subendocardial layers (ENDO). During dobutamine stimulation-induced demand ischemia, the transmural distribution of energy demand and metabolic markers of ischemia are not known. In this study, hemodynamics, transmural high-energy phosphate (HEP), 2-deoxyglucose-6-phosphate (2-DGP) levels, and myocardial blood flow (MBF) were determined under basal conditions, during dobutamine infusion (DOB: 20 microg x kg(-1) x min(-1) iv), and during coronary stenosis + DOB + 2-deoxyglucose (2-DG) infusion. DOB increased rate pressure products (RPP) and MBF significantly without affecting the subendocardial-to-subepicardial blood flow ratio (ENDO/EPI) or HEP levels. During coronary stenosis + DOB + 2-DG infusion, RPP, ischemic zone (IZ) MBF, and ENDO/EPI decreased significantly. The IZ ratio of creatine phosphate-to-ATP decreased significantly [2.30 +/- 0.14, 2.06 +/- 0.13, and 2.04 +/- 0.11 to 1.77 +/- 0.12, 1.70 +/- 0.11, and 1.72 +/- 0.12 for EPI, midmyocardial (MID), and ENDO, respectively], and 2-DGP accumulated in all layers, as evidenced by the 2-DGP/PCr (0.55 +/- 0.12, 0.52 +/- 0.10, and 0.37 +/- 0.08 for EPI, MID, and ENDO, respectively; P < 0.05, EPI > ENDO). In the IZ the wet weight-to-dry weight ratio was significantly increased compared with the normal zone (5.9 +/- 0.5 vs. 4.4 +/- 0.4; P < 0.05). Thus, in the stenotic perfused bed, during dobutamine-induced high cardiac work state, despite higher blood flow, the subepicardial layers showed the greater metabolic changes characterized by a shift toward higher carbohydrate metabolism, suggesting that a homeostatic response to high-cardiac work state is characterized by more glucose utilization in energy metabolism.     

AT1-receptor antagonism reverses the blood pressure elevation associated with diet-induced obesity

Previous studies in our laboratory demonstrated that rats exhibiting obesity in response to a moderately high-fat (MHF) diet developed hypertension associated with activation of the local and systemic renin-angiotensin system. In this study, we examined the effect of the angiotensin type 1 (AT(1))-receptor antagonist, losartan, on blood pressure in obesity-prone (OP) and obesity-resistant (OR) rats fed a MHF diet. Using telemetry monitoring, we characterized the evolution of blood pressure elevations during the development of obesity. Male Sprague-Dawley rats were implanted with telemetry transducers for chronic monitoring of blood pressure, and baseline measurements were obtained. Rats were then switched to the MHF diet (32% kcal as fat) and were segregated into OP and OR groups at week 5. At week 9 on the MHF diet, OP rats exhibited significantly greater 24-h mean arterial blood pressure compared with OR rats (OP: 105 +/- 4 mmHg, OR: 96 +/- 2 mmHg; P < 0.05). Elevations in blood pressure in OP rats were manifest as an increase in systolic pressure. Administration of losartan to all rats at week 9 resulted in a reduction in blood pressure; however, losartan had the greatest effect in OP rats (percent decrease in mean arterial pressure by losartan; OP: 19 +/- 4, OR: 10 +/- 2%; P < 0.05). These results demonstrate that elevations in blood pressure occur subsequent to established obesity in rats fed a high-fat diet. Moreover, these results demonstrate the ability of losartan to reverse the blood pressure increase from diet-induced obesity, supporting a primary role for the renin-angiotensin system in obesity-associated hypertension.     

Myocardial tissue pressure and blood flow during coronary sinus pressure modulation in anesthetized dogs.

To determine whether coronary sinus outflow pressure (Pcs) or intramyocardial tissue pressure (IMP) is the effective back pressure in the different layers of the left ventricular (LV) myocardium, we increased Pcs in 14 open-chest dogs under maximal coronary artery vasodilation. Circumflex arterial (flowmeter), LV total, and subendocardial and subepicardial (15-microns radioactive spheres) pressure-flow relationships (PFR) and IMP (needle-tip pressure transducers) were recorded during graded constriction of the artery at two diastolic Pcs levels (7 +/- 3 vs. 23 +/- 4 mmHg). At high Pcs, LV, aortic and diastolic circumflex arterial pressure, heart rate, myocardial oxygen consumption, and lactate extraction were unchanged; IMP in the subendocardium did not change (130/19 mmHg), whereas IMP in the subepicardium increased by 17 mmHg during systole and 10 mmHg during diastole (P < or = 0.001), independently of circumflex arterial pressure. Increasing Pcs did not change the slope of the PFR; however, coronary pressure at zero flow increased in the subepicardium (P < or = 0.008), whereas in the subendocardium it remained unchanged at 24 +/- 3 mmHg. Thus Pcs can regulate IMP independently of circumflex arterial pressure and consequently influence myocardial perfusion, especially in the subepicardial tissue layer of the LV.     

Chronic angiotensin II AT1 receptor blockade increases cerebral cortical microvessel density

Angiotensin II is known to stimulate angiogenesis in the peripheral circulation through activation of the angiotensin II type 1 (AT1) receptor. This study investigated the effect of angiotensin receptor blockade on cerebral cortical microvessel density. Rats (6-7 wk old, n = 5-17) were instrumented with femoral arterial and venous indwelling catheters for arterial blood pressure measurement and drug administration. Rats were treated for 3 or 14 days with the AT1 receptor blocker losartan (50 mg/day in drinking water) or vehicle. Brains were sectioned and immunostained for CD31, and microvessel density was measured. Treatment with losartan for 3 or 14 days resulted in a slight decrease in mean arterial blood pressure (3 days, 92 +/- 1 mmHg; and 14 days, 99 +/- 2 mmHg) compared with vehicle (109 +/- 3 and 125 +/- 4 mmHg, respectively). A furosemide + captopril 14-day treatment group was added to control for the blood pressure change (96 +/- 3 mmHg). Microvessel density increased in groups treated with losartan for 14 days (429 +/- 13 vessels/mm2) compared with vehicle (383 +/- 11 vessels/mm2) but did not change with furosemide + captopril (364 +/- 7 vessels/mm2). Thus AT1 receptor blockade for 14 days resulted in increased cerebral microvessel density in a blood pressure-independent manner.     

Intradermal angiotensin II administration attenuates the local cutaneous vasodilator heating response

The vasodilation response to local cutaneous heating is nitric oxide (NO) dependent and blunted in postural tachycardia but reversed by angiotensin II (ANG II) type 1 receptor (AT(1)R) blockade. We tested the hypothesis that a localized infusion of ANG II attenuates vasodilation to local heating in healthy volunteers. We heated the skin of a calf to 42 degrees C and measured local blood flow to assess the percentage of maximum cutaneous vascular conductance (%CVC(max)) in eight healthy volunteers aged 19.5-25.5 years. Initially, two experiments were performed; in one, Ringer solution was perfused in three catheters, the response to heating was measured, 2 microg/l losartan, 10 mM nitro-l-arginine (NLA), or NLA + losartan was added to perfusate, and the heat response was remeasured; in another, 10 microM ANG II was given, the heat response was measured, losartan, NLA, or NLA + losartan was added to ANG II, and the heat response was reassessed. The heat response decreased with ANG II, particularly the plateau phase (47 +/- 5 vs. 84 +/- 3 %CVC(max)). Losartan increased baseline conductance in both experiments (from 8 +/- 1 to 20 +/- 2 and 12 +/- 1 to 24 +/- 3). Losartan increased the ANG II response (83 +/- 4 vs. 91 +/- 6 in Ringer). NLA decreased both angiotensin and Ringer responses (31 +/- 4 vs. 43 +/- 3). NLA + losartan blunted the Ringer response (48 +/- 2), but the ANG II response (74 +/- 5) increased. In a second set of experiments, we used dose responses to ANG II (0.1 nM to 10 microM) with and without NLA + losartan to confirm graded responses. Sodium ascorbate (10 mM) restored the ANG II-blunted heating plateau. NO synthase and AT(1)R inhibition cause an NO-independent angiotensin-mediated vasodilation with local heating. ANG II mediates the AT(1)R blunting of local heating, which is not exclusively NO dependent, and is improved by antioxidant supplementation.     

Progressive loss of perfusion-contraction matching during sustained moderate ischemia in pigs

It is unclear whether perfusion-contraction matching (PCM) is maintained during prolonged myocardial ischemia. In 27 anesthetized pigs, left anterior descending coronary arterial inflow was reduced to decrease an anterior work index (WI) at 5 min of hypoperfusion by 40% and then maintained at this level for 12 or 24 h. With 12 h of hypoperfusion, the myocardium remained viable in 6 of 7 pigs (with triphenyltetrazolium chloride; TTC) and with 24 h of hypoperfusion in 5 of 11 pigs (TTC, histology). The reduction in WI to 62 +/- 4 and 62 +/- 3% of baseline in the two groups was matched to the reduction of transmural blood flow (TBF; microspheres) at 5 min of hypoperfusion, averaging 59 +/- 4 and 60 +/- 2% of baseline. With prolonged hypoperfusion, WI decreased to 30 +/- 5% at 12 h and 18 +/- 3% at 24 h; TBF remained unchanged (53 +/- 4 and 54 +/- 4%). The added calcium concentration required for the half-maximal increase in WI increased from 121 +/- 25 microg/ml blood at baseline to 192 +/- 26 microg/ml blood at 12 h of hypoperfusion. Thus, with hypoperfusion for 24 h, PCM is progressively lost, and calcium responsiveness is reduced.     

Effects of age on brachial artery myogenic responses in humans

The myogenic response, the inherent ability of blood vessels to rapidly respond to changes in transmural pressure, is involved in local blood flow autoregulation. Animal studies suggest that aging impairs the myogenic response. The purpose of this study was to compare the effects of changes in transmural pressure on mean blood velocity (MBV, cm/s) in young and older subjects. Twelve younger men and women (25 +/- 1 yr) were gender and body composition matched to twelve older men and women (65 +/- 1 yr). A specially designed tank raised or lowered forearm pressure by 50 mmHg within 0.2 s. Brachial artery MBV was measured directly above the site of forearm pressure change using Doppler methods. In response to increasing transmural pressure (i.e., release of +50 mmHg), older subjects compared with younger subjects had significantly lower peak MBV (Delta 12.43 +/- 1.16 vs. Delta 17.97 +/- 2.01 cm/s; P < 0.05), reduced rates in the dynamic fall of MBV after peak values were achieved (vasoconstriction) (-1.88 +/- 0.17 vs. -2.90 +/- 0.28 cm.s(-1).s(-1); P < 0.05), and lower MBV values with sustained suction. In response to decreasing transmural pressure (i.e., change to +50 mmHg), there was a significantly greater increase in MBV (Delta peak flow from trough 7.71 +/- 1.32 vs. 4.38 +/- 0.71 cm/s; P < 0.05) and a trend toward a greater rate of rise in MBV (vasodilation; 1.61 +/- 0.29 vs. 0.96 +/- 0.21 cm.s(-1).s(-1); P = 0.08) in the older subjects. Older subjects compared with the younger subjects exhibited decreased dynamic vasoconstriction, enhanced steady-state constriction, as well as evidence for enhanced dynamic vasodilation responses to sustained alterations in forearm transmural pressure.     

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.     

Evaluation of transmural distribution of viable muscle by myocardial strain profile and dobutamine stress echocardiography

Transmural distribution of viable myocardium in the ischemic myocardium has not been quantified and fully elucidated. To address this issue, we evaluated transmural myocardial strain profile (TMSP) in dogs with myocardial infarction using a newly developed tissue strain imaging. TMSP was obtained from the posterior wall at the epicardial left ventricular short-axis view in 13 anesthetized open-chest dogs. After control measurements, the left circumflex coronary artery was occluded for 90 min to induce subendocardial infarction (SMI). Subsequently, latex microbeads (90 microm) were injected in the same artery to create transmural infarction (TMI). In each stage, measurements were done before and after dobutamine challenge (10 microg.kg(-1).min(-1) for 10 min) to estimate transmural myocardial viability. Strain in the subendocardium in the control stage increased by dobutamine (from 53.6 +/- 17.1 to 73.3 +/- 21.8%, P < 0.001), whereas that in SMI and TMI stages was almost zero at baseline and did not increase significantly by dobutamine [from 0.8 +/- 8.8 to 1.3 +/- 7.0%, P = not significant (NS) for SMI, from -3.9 +/- 5.6 to -1.9 +/- 6.0%, P = NS for TMI]. Strain in the subepicardium increased by dobutamine in the control stage (from 23.9 +/- 6.1 to 26.3 +/- 6.4%, P < 0.05) and in the SMI stage (from 12.4 +/- 7.3 to 27.1 +/- 8.8%, P < 0.005), whereas that in the TMI stage did not change (from -1.0 +/- 7.8 to -0.7 +/- 8.3%, P = NS). In SMI, the subendocardial contraction was lost, but the subepicardium showed a significant increase in contraction with dobutamine. However, in TMI, even the subepicardial increase was not seen. Assessment of transmural strain profile using tissue strain imaging was a new and useful method to estimate transmural distribution of the viable myocardium in myocardial infarction.     

Stimulation of cardiac sympathetic nerve activity by central angiotensinergic mechanisms in conscious sheep

Central actions of angiotensin play an important role in cardiovascular control and have been implicated in the pathogenesis of hypertension and heart failure. One feature of centrally or peripherally administered angiotensin is that the bradycardia in response to an acute pressor effect is blunted. It is unknown whether after central angiotensin this is due partly to increased cardiac sympathetic nerve activity (CSNA). We recorded CSNA and arterial pressure in conscious sheep, at least 3 days after electrode implantation. The effects of intracerebroventricular infusions of ANG II (3 nmol/h for 30 min) and artificial cerebrospinal fluid (CSF) (1 ml/h) were determined. The response to intracerebroventricular hypertonic saline (0.6 M NaCl in CSF at 1 ml/h) was examined as there is evidence that hypertonic saline acts via angiotensinergic pathways. Intracerebroventricular angiotensin increased CSNA by 23 +/- 7% (P < 0.001) and mean arterial pressure (MAP) by 7.6 +/- 1.2 mmHg (P < 0.001) but did not significantly change heart rate (n = 5). During intracerebroventricular ANG II the reflex relation between CSNA and diastolic blood pressure was significantly shifted to the right (P < 0.01). Intracerebroventricular hypertonic saline increased CSNA (+9.4 +/- 6.6%, P < 0.05) and MAP but did not alter heart rate. The responses to angiotensin and hypertonic saline were prevented by intracerebroventricular losartan (1 mg/h). In conclusion, in conscious sheep angiotensin acts within the brain to increase CSNA, despite increased MAP. The increase in CSNA may account partly for the lack of bradycardia in response to the increased arterial pressure. The responses to angiotensin and hypertonic saline were losartan sensitive, indicating they were mediated by angiotensin AT-1 receptors.     

Redistribution in left ventricular regional flow following acute right ventricular pressure overload

The left ventricular dysfunction following acute pulmowary hypertension remains unexplained. We wondered if acute pulmonary hypertension could alter the transmural flow distribution within the left ventricular myocardium, independent of coronary flow and perfusion pressure. We used a canine preparation in which the left coronary system was perfused at constant flow and induced a two- to three-fold increase in pulmonary artery pressure by banding the pulmonary artery. Regional myocardial blood flow of the left coronary system was measured using radioactive microspheres, injected into the left coronary system before and after 10-30 min of banding of the pulmonary artery. The left ventricular subendocardial:epicardial ratio fell by 12 and 31% (p less than 0.05) of control value, 10 and 30 min, respectively, after banding of the pulmonary artery, the total flow to the left coronary system being kept constant. Left atrial mean pressure increased from 2.9 +/- 2.4 to 3.6 +/- 1.9 and 6.0 +/- 2.1 (p less than 0.05) following banding. The mechanism of the redistribution of coronary flow may relate to inappropriate vasodilation of the right septal myocardium with consequent relative left ventricular subendocardial hypoperfusion which might aggravate left ventricular ischemia in the presence of hypotension and hypoxia.     

Coronary microcirculatory vasoconstriction is heterogeneously distributed in acutely ischemic myocardium

The classical model of coronary physiology implies the presence of maximal microcirculatory vasodilation during myocardial ischemia. However, Doppler monitoring of coronary blood flow (CBF) documented severe microcirculatory vasoconstriction during pacing-induced ischemia in patients with coronary artery disease. This study investigates the mechanisms that underlie this paradoxical behavior in nine patients with stable angina and single-vessel coronary disease who were candidates for stenting. While transstenotic pressures were continuously monitored, input CBF (in ml/min) to the poststenotic myocardium was measured by Doppler catheter and angiographic cross-sectional area. Simultaneously, specific myocardial blood flow (MBF, in ml.min(-1).g(-1)) was measured by 133Xe washout. Perfused tissue mass was calculated as CBF/MBF. Measurements were obtained at baseline, during pacing-induced ischemia, and after stenting. CBF and distal coronary pressure values were also measured during pacing with intracoronary adenosine administration. During pacing, CBF decreased to 64 +/- 24% of baseline and increased to 265 +/- 100% of ischemic flow after adenosine administration. In contrast, pacing increased MBF to 184 +/- 66% of baseline, measured as a function of the increased rate-pressure product (r = 0.69; P < 0.05). Thus, during pacing, perfused myocardial mass drastically decreased from 30 +/- 23 to 12 +/- 11 g (P < 0.01). Distal coronary pressure remained stable during pacing but decreased after adenosine administration. Stenting increased perfused myocardial mass to 39 +/- 23 g (P < 0.05 vs. baseline) as a function of the increase in distal coronary pressure (r = 0.71; P < 0.02). In conclusion, the vasoconstrictor response to pacing-induced ischemia is heterogeneously distributed and excludes a tissue fraction from perfusion. Within perfused tissue, the metabolic demand still controls the vasomotor tone.     

Clinical evidence for myocardial derecruitment downstream from severe stenosis: pressure-flow control interaction

To verify the interaction between coronary pressure (CP) and blood flow (CBF) control, we studied nine candidates for angioplasty of an isolated lesion of the left anterior descending coronary artery [i.e. , percutaneous transluminal coronary angioplasty (PTCA)]. CBF (i.e., flow velocity x coronary cross-sectional area at the Doppler tip) and CP were monitored during washout of 2-5 mCi of (133)Xe after bolus injection into the left main artery before and after PTCA. Xe mean transit time (MTT) was calculated as the area under the time-activity curve, acquired by a gamma camera, divided by the dose obtained from a model fit of the Xe curve in the anterior wall. CBF response to intracoronary adenosine (2 mg) was also assessed. PTCA increased baseline CBF (from 14.5 +/- 9.4 to 20 +/- 8 ml/min, P < 0.01), coronary flow reserve (from 1.52 +/- 0.24 to 2.33 +/- 0.8, P < 0.01), and CP (from 64 +/- 9 to 100 +/- 10 mmHg, P < 0.05). MTT decreased from 89 +/- 32 to 70 +/- 19 s (P < 0.05) after PTCA; however, MTT and CBF changes were not correlated (r = -0.09, not significant). Inasmuch as MTT is the ratio of distribution volume to CBF, MTT x CBF was used as an index of perfused myocardial volume. Volume increased after PTCA from 23 +/- 18 to 56 +/- 30 ml. A direct correlation was observed between the percent increase in distal CP and percent increase in perfused volume (r = 0.91, P < 0.01). Thus low CP was not associated with exhaustion of flow reserve but, rather, with reduction of perfused myocardial volume. These data suggest that, in the presence of a severe coronary stenosis, derecruitment of vascular units occurs that is proportional to the decrease in driving pressure. Residual perfused units maintain a vasomotor tone, thus explaining the paradoxical persistence of coronary reserve.     

Distribution of blood flow during exercise after blood volume expansion in swine

To study the distribution of blood flow after blood volume expansion, seven miniature swine ran at high speed (17.6-20 km/h, estimated to require 115% of maximal O2 uptake) on a motor-driven treadmill on two occasions: once during normovolemia and once after an acute 15% blood volume expansion (homologous whole blood). O2 uptake, cardiac output, heart rate, mean arterial pressure, and distribution of blood flow (with radiolabeled microspheres) were measured at the same time during each of the exercise bouts. Maximal heart rate was identical between conditions (mean 266); mean arterial pressure was elevated during the hypovolemic exercise (149 +/- 5 vs. 137 +/- 6 mmHg). Although cardiac output was higher and arterial O2 saturation was maintained during the hypervolemic condition (10.5 +/- 0.7 vs. 9.3 +/- 0.6 l/min), O2 uptake was not different (1.74 +/- 0.08 vs. 1.74 +/- 0.09 l/min). Mean blood flows to cardiac (+12.9%), locomotory (+9.8%), and respiratory (+7.5%) muscles were all elevated during hypervolemic exercise, while visceral and brain blood flows were unchanged. Calculated resistances to flow in skeletal and cardiac muscle were not different between conditions. Under the experimental conditions of this study, O2 uptake in the miniature swine was limited at the level of the muscles during hypervolemic exercise. The results also indicate that neither intrinsic contractile properties of the heart nor coronary blood flow limits myocardial performance during normovolemic exercise, because both the pumping capacity of the heart and the coronary blood flow were elevated in the hypervolemic condition.