Showing papers in "Circulation Research in 1978"

The ventricular pressure-volume diagram revisited

Abstract: The ventricular pressure-volume diagram revisited. Print ISSN: 0009-7330. Online ISSN: 1524-4571 Copyright © 1978 American Heart Association, Inc. All rights reserved. is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Circulation Research doi: 10.1161/01.RES.43.5.677 1978;43:677-687 Circ Res. http://circres.ahajournals.org/content/43/5/677.citation World Wide Web at: The online version of this article, along with updated information and services, is located on the

Direct evidence that the greater contractility of resistance vessels in spontaneously hypertensive rats is associated with a narrowed lumen, a thickened media, and an increased number of smooth muscle cell layers.

Abstract: The mechanical and morphological properties of segments of certain precisely defined resistance vessels (approximately 150 micrometer lumen diameter) in the mesenteric bed of spontaneously hypertensive (SHR) and normotensive (WKY) rats have been compared in vitro under carefully controlled conditions and also after fixation. At a given transmural pressure, the relaxed SHR vessels (compared with the WKY vessels) would have had a 16% smaller lumen diameter (P less than 0.01) and a 49% thicker media (P less than 0.005), so that the media volume per unit segment length was 31% greater (P less than 0.05). The smooth muscle cells were arranged circumferentially in about four layers in the SHR vessels and in about three layers in the WKY vessels. The SHR active wall tension in response to potassium was 53% greater (P less than 0.02) and to norepinephrine was 50% greater (P less than 0.01) than for WKY. However, the ED50 values for the norepinephrine dose-response curves were similar (approximately 5 micrometer). Activation with potassium plus norepinephrine gave greater responses in both vessel types, than with either agent alone, but the SHR responses were on average only 19% greater than the WKY (P less than 0.10). However, under these conditions, the SHR vessels would have been able to contract against 45% greater transmural pressures (P less than 0.001) because of their smaller lumen. On maximal activation, the mean force developed by each cell (approximately 3.85 micro N) was the same in both vessel types, even though on average (P = 0.10) the SHR cells had a 21% greater cross-sectional area. The results support the Folkow hypothesis that in genetic hypertension the increased peripheral resistance is associated with structural changes in the resistance vessels.

Mechanism and time course of S-T and T-Q segment changes during acute regional myocardial ischemia in the pig heart determined by extracellular and intracellular recordings.

Abstract: We recorded transmembrane potentials from subepicardial ventricular cells and local extracellular DC electrograms in isolated perfused pig hearts before and after occlusion of the left anterior descending artery. The first change was a decrease in the resting membrane potential, reflected by T-Q depression in the electrogram. After 3 minutes, action potentials shortened and their amplitude decreased, resulting in S-T elevation until, finally, cells in the center of the ischemic zone became totally unresponsive at resting potentials of about −65 mV. This rendered the extracellular complex monophasic. Determination of extracellular potential distribution at 150-250 epicardial sites after 15-30 minutes of occlusion showed an increase of T-Q depression and S-T elevation toward a central area, with maximum values of −15 and +35 mV, respectively. Comparison of amplitude and configuration of intramural and epicardial potential profiles revealed that the potential distribution was homogeneous throughout ischemic parts of the wall. Extracellular epicardial current originated, therefore, from the epicardial intracellular compartment. Maximal current density during late systole was 1 μA/mm 2, flowing in the border zone towards normal myocardium. After 1 hour of occlusion, there was a marked decrease of extracellular DC potentials which could be attributed to transient recovery of electrical activity in the ischemic zone. After 2 hours, the zone of unresponsiveness was larger than after 15 minutes of occlusion, and the overall amplitude of DC potentials had decreased further, possibly because of healing over.

The distribution of blood rheological parameters in the microvasculature of cat mesentery.

Abstract: In vivo studies of the rheological behavior of blood in the microcirculation were conducted by direct in situ measurements in cat mesentery. Upstream to downstream pressure drops were measured in unbranched arterioles, capillaries, and venules, with diameters from 7 to 58 micrometer. Simultaneous measurements of red cell velocity and vessel geometry facilitated computation of bulk velocity, pressure gradient, apparent viscosity, wall shear stress, and resistance. Arteriovenous distributions of these parameters revealed the following. Maximum pressure gradient (0.015 cm H20/micrometer) occurs in the true capillaries (7 micrometer in diameter); intravascular wall shear stress averaged 47.1 dynes/cm2 in arterioles and 29.0 dynes/cm2 in venules. Extreme values as great as 200 dynes/cm2 were observed in a few shunting arterioles. Apparent viscosity averaged 3.59 cP in arterioles, 5.15 cP in venules, and 4.22 cP overall. Intravascular resistance per unit length of microvessel varied with luminal diameter as a p...

Simulation studies of the electrocardiogram. I. The normal heart.

Abstract: A digital computer model is presented for the simulation of the body surface electrocardiogram (ECG) during ventricular activation and recovery. The ventricles of the heart are represented in detail by a three-dimensional array of approximately 4000 points which is subdivided into 23 regions. Excitation sequence and cellular action potential data taken from the literature are used to determine the spatial distribution of intracellular potentials at each instant of time during a simulated cardiac cycle. The moment of the single dipole representing each region is determined by summing the spatial gradient of the intracellular potential distribution throughout the region. The resulting set of 23 dipoles is then used to calculate the potentials on the surface of a bounded homogeneous volume conductor with the shape of an adult torso. Simulated isopotential surface maps during both activation and recovery are in good agreement with data for humans reported in the literature.

Pressure-flow characteristics of coronary stenoses in unsedated dogs at rest and during coronary vasodilation.

Abstract: The pressure-flow characteristics of 100 left circumflex stenoses in 10 chronically instrumented unsedated dogs were studied under resting conditions and during pharmacological coronary vasodilation. At rest, the pressure loss (deltaP) due to a stenosis and arterial flow velocity (V) were related by the equation, deltaP = FV + SV2, where F is the coefficient of pressure loss due to viscous friction in the stenotic segment and S is the coefficient of pressure loss due to flow separation at the diverging end of the stenosis. The linear term due to viscous friction accounted for 65% and the nonlinear term due to flow separation accounted for 35% of the total pressure loss at resting coronary flow. At peak coronary flow after coronary vasodilation, the pressure loss due to viscous friction accounted for 33% and pressure loss due to flow separation accounted for 67% of the total pressure loss. The pressure gradient-velocity relationship at high flows was characterized by the same general equation but with proportionately larger values of the coefficient S and therefore greater pressure loss associated with flow separation than predicted by the resting gradient-velocity relationship. The pressure loss predicted for high coronary flow velocities on the basis of the gradient-velocity equation at rest was only 64% of the actual experimentally observed pressure gradient at peak coronary flow. The augmented separation loss following coronary vasodilation probably was due to dilation of the epicardial artery adjacent to the fixed stenotic segment which caused more severe relative percent narrowing and a larger divergence angle at the distal end of the stenosis, the primary geometric determinants of separation losses.

Factors which affect the diastolic pressure-volume curve.

Abstract: The nonlinear relationship between pressure and volume in the diastolic left ventricle is not fixed; interventions shift the pressure-volume curve within a few beats, and long-term changes in the heart's operating environment produce chronic shifts.'\"•' The fact that human diastolic pressure increases with little or no volume increase (or even a decrease) during ischemia 4 \" 9 is probably the most widely discussed acute reversible change in the pressurevolume relationship. Drugs that alter afterload 10 \" 13 also change the diastolic pressure-volume relationship. In addition to these acute reversible changes, the human diastolic pressure-volume curve exhibits long-term changes following coronary artery disease, 4 ' l4 ~ 18 hypertrophy, 17 \" 21 pressure 20 ' 22 and volume 22 overloading, cardiomyopathy, 15 \"\" 1 ' 20 and myocardial infarction. 14 - 23 Five potential mechanisms have been suggested to explain these changes in the pressure-volume relationship: changes in the heart's geometry, changes in the myocardium's passive mechanical properties, incomplete relaxation from the previous systole, engorgement of the coronary circulation, and interaction between the two ventricles. This review discusses the evidence concerning each of these mechanisms. Since the relationship between pressure and volume during diastole varies, one cannot use elevated end-diastolic pressure to indicate chronic systolic failure or enddiastolic pressure instead of volume when constructing left ventricular function curves. The diastolic pressurevolume curve's ability to change can produce shifts in traditional ventricular function curves, even with no change in systolic performance. The observation that the pressure-volume curve changes with disease motivated considerable effort to compute a clinical index of cardiac stiffness to quantify the extent and severity of ischemia

Diastolic coronary artery pressure-flow relations in the dog.

Abstract: Conscious dogs were used to investigate the relations between aortic (Pa) pressure and coronary flow (F) during individual diastoles. When the dogs were in a semibasal state, coronary pressure-flow relations were described by a family of lines, and diastolic flow was a linear function of aortic pressure. For a given perfusion pressure, higher flows were associated with lines of progressively greater slope and lower zero flow pressure intercept (Pf=0). Zero flow pressure intercepts were estimated by extrapolation and found to vary between 20 and 50 mm Hg, depending on the magnitude of flow. The zero flow pressure may represent the height of a vascular waterfall caused by vasomotor tone with the resistance-controlling coronary flow being (P-Pf=0).F-1. Interventions that decrease vasomotor tone increase coronary flow by both decreasing vascular resistance and increasing the perfusion pressure gradient. The gradient increases because the effective coronary back pressure is the height of the vascular waterfall and the latter is reduced when vasomotor tone falls. Passive changes in vessel dimensions, arterial recruitment, and autoregulation appear to be of little importance during individual diastoles.

The pericardium substantially affects the left ventricular diastolic pressure-volume relationship in the dog.

Abstract: We instrumented six dog hearts in vivo to study the relationship between left and right ventricular diastolic pressures with the pericardium closed and open. We measured left ventricular septum-to-free wall and anterior-posterior and right ventricular septum-to-free wall dimensions with implanted ultrasonic crystals, together with simultaneous high fidelity pressures. We varied diastolic pressure by infusing or withdrawing Mood or by increasing right ventricular afterload with transient pulmonary artery constriction. Although left and right ventricular diastolic pressures always correlated, this correlation was significantly higher with the pericardium closed than open. We fit left ventricular dfautolic pressure to an equation whkh included first order right ventricular pressure and fourth order left ventricular dimension terms. With the pericardium closed, the right ventricular pressure term dominated; with the pericardium open, left ventricular dimension terms dominated. Therefore, with the pericardium closed, right ventricular pressure was a more powerful predictor of left ventricular pressure than were left ventricular dimensions. In addition, the left ventricle appears much more compliant with the pericardium open. These results led us to modify the traditional view of the diastolic left ventricle as an unconstrained elastic shell of myocardium and replace it with a concept of the diastolic heart as a composite shell of stiff pericardium and compliant muscle, divided into subcompartments (ventricles) by the relatively compliant septum. The influence of the pericardium on the diastolic pressure-volume relationship should be considered in experiments on animals and patient management when the pericardium is open or closeab.

Competition between sympathetic vasoconstriction and metabolic vasodilation in the canine coronary circulation.

Abstract: The role of a-receptor constriction of coronary vessels in response to cardiac sympathetic activation was evaluated in closed-chest, chloralose-anesthetized dogs. Cardiac sympathetic activation was produced (1) directly by intracoronary norepinephrine infusion at several different rates and (2) reflexly by carotid sinus hypotension. The resulting changes in coronary blood flow and myocardial oxygen consumption were recorded before and after a-receptor blockade with dibozane (3.0 mg/kg, iv) or phenoxybenzamine (0.5 mg/kg, intracoronary). The changes in coronary blood flow were normalized to changes in myocardial metabolism by division of the oxygen delivery (coro- nary flow times arterial oxygen content) by the change in myocardial oxygen consumption per 100 g of myocardium. Before a-receptor blockade, either intracoronary norepinephrine infusion or reflex sympathetic activation from the carotid sinus resulted in an increase of only 0.85 ml/100 g mirr+- in oxygen delivery for each increase of 1 ml/100 g min\"1 in cardiac oxygen consumption. Under these circumstances, myocardial oxygen extraction increased and coro- nary venous oxygen content fell. After a-receptor blockade, either intracoronary norepinephrine infusion or a carotid sinus reflex resulted in an increase of 1.23 ml/100 g min +- in oxygen delivery for each increase of 1 ml/100 g min+-1 in cardiac oxygen consumption. Myocardial oxygen extraction and coronary venous oxygen content changed only slightly after a-receptor blockade. The greater coronary vasodilation and lesser change in cardiac oxygen extraction after a-receptor blockade were significantly different (P < 0.001) from the values before blockade. It is concluded that the coronary a-receptor constrictor mechanism competes with metabolic vasodilation during sympathetic activation even when there are large increases in myocardial metabolism. The net effect of the a-receptor constrictor influence is to restrict the metabolically related flow increase by about 30%, thus increasing oxygen extraction and decreasing coronary venous oxygen content.

Effects of excess free fatty acids on mechanical and metabolic function in normal and ischemic myocardium in swine.

Abstract: We evaluated the consequences of excess free fatty acids (FFA) on mechanical and metabolic functions in globally perfused working swine hearts. In one group of eight hearts, treatments with heparin and 10% fat emulsion (Intralipid) produced a 3- to 5-fold elevation in serum FFA levels as contrasted with levels in 10 untreated hearts. At control flows, excess FFA caused declines in aortic pressure (−31.4%, P < 0.05), left ventricular systolic pressure (−24.8, P < 0.05), left ventricular work (−69.8%, P < 0.001), and epicardial motion (−57.8%, P < 0.001), together with an increase in myocardial oxygen consumption (+16.5%, P < 0.05) as compared to pretreatment values. Ischemia in untreated hearts also decreased mean aortic pressure (−46.2%, P < 0.005), left ventricular systolic pressure (−19.5%, P < 0.001), left ventricular max dp/dt (−27.9%, P < 0.001), left ventricular work (−49.1%, P < 0.025), myocardial oxygen consumption (−21.2%, P < 0.001) as compared with preischemic values. Excess FFA during ischemia resulted in even greater deteriorations in hemodynamic and metabolic functions. Tissue metabolites in the two groups of ischemic hearts were compared with those in six untreated hearts maintained at control flows. Tissue levels (mfiM/g dry weight) of long-chain acyl coenzyme A (CoA) esters were 70.1 ± 6.5, 121.4 ± 11.1 (P < 0.001), and 174.7 ± 13.7 (P < 0.001) in control, ischemic with normal FFA, and ischemic with excess FFA hearts, respectively. Tissue fatty acyl carnitine levels (imiM/g dry) were 20.6 ± 9.8, 380.1 ± 51.6 (P< 0.001), and 685.1 ± 115.7 (P< 0.001) in control, ischemic with normal FFA, and ischemic with excess FFA hearts, respectively. Thus, excess FFA caused significant impairments in cardiac function in association with elevations in tissue acyl CoA and acyl carnitine derivatives during ischemia. Accumulations of these products of fatty acid metabolism may interfere with enzyme functions and membrane transport systems.

Studies of the Release from Human Platelets of the Growth Factor for Cultured Human Arterial Smooth Muscle Cells

Abstract: SUMMARY Platelets contain a growth-promoting factor for arterial smooth muscle cells (SMC) that may play a major role in atberogenesis. We have studied some of the effects of the platelet-derived growth factor (PDGF) on human arterial SMC in culture and the release of PDGF from human platelets in relationship to other released substances. Material released from platelets was highly potent in stimulating human SMC to proliferate. A substantial portion of the growth-promoting activity of human serum could be attributed to a factor(s) released from platelets. Similar dose-response patterns to PDGF were observed with human SMC and with mouse 3T3 cells. The time-course of release of PDGF and its concentration dependence on human thrombin were determined in comparison with serotonin, ADP, ATP, an acid bydrolase, platelet factor 4 (PF4), and /3-thromboglobulln (/JTG). PDGF activity was assayed by stimulation of the incorporation of 'H-thymidine into DNA of 3T3 cells; PF4 and /JTG were measured by newly developed radioimmunoassays. PDGF, PF4, and /JTG were released from platelets by lower concentrations of thrombin than those required for release of the other components. The results suggest that PDGF, PF4, and /3TG are localized in the platelet in granules different from either the dense bodies (that contain serotonin, ADP, ATP) or the acid hydrolase-containing granules, possibly in a-granules. The contents of these PDGFcontainlng a-granules are actively released during the release reaction and are particularly sensitive to release by low doses of thrombin.

Changes in central catecholaminergic neurons in the spontaneously (genetic) hypertensive rat.

Abstract: Catecholamines and catecholamine-synthesizing enzymes have been examined in specific brain areas during the development of spontaneously (genetic) hypertensive (SH) rats. Changes in catecholamine metabolism were localized to regions of the brain implicated in the regulation of blood pressure. Norepinephrine levels and dopamine-beta-hydroxylase (DBH) activities were decreased in specific nuclei of the hypothalamus and in the nucleus interstitialis striae terminalis ventralis, in both young and adult rats. The decrease in the formation of norepinephrine can result in a reduced activation of central alpha-adrenergic receptors which may be related causally to the onset of hypertension. The activity of the epinephrine-forming enzyme, phenylethanolamine-N-methyltransferase (PNMT), was increased in the A1 and A2 areas of the brainstem in young SH rats, but it was normal in adult hypertensive animals. These results implicate adrenergic neurons in the brainstem and noradrenergic neurons in the hypothalamus in the development of spontaneous (genetic) hypertension in rats.

Effects of nifedipine on myocardial perfusion and ischemic injury in dogs.

Abstract: To determine whether nifedipine, a calcium antagonist, protects ischemic myocardium, conscious dogs were subjected to coronary occlusion and given nifedipine by intravenous infusion beginning 30 minutes after the onset of ischemia and lasting for 24 hours while systemic arterial pressure, left atrial pressure, and cardiac output were monitored. Local myocardial perfusion at selected intervals after coronary occlusion was assessed with radioactive microspheres injected into the left atrium. In regions of myocardium exhibiting moderately depressed flow 29 minutes after occlusion in control dogs (n = 8), flow was significantly greater 3 and 23.5 hours later, reflecting increases in collateral perfusion. Corresponding zones of myocardium in treated dogs (n = 9) exhibited significantly greater increases in flow at each interval after occlusion (P less than 0.05). Furthermore, myocardial creatine kinase depletion (which correlated well with morphometric estimates of necrosis) in myocardium matched for ischemia prior to treatment was 1.5 to 3 times less in treated than in control dogs (P less than 0.05). Thus, nifedipine produced sustained increases in collateral flow and reduced myocardial ischemic injury.

Coronary blood flow in experimental canine left ventricular hypertrophy.

Abstract: To determine whether left ventricular hypertrophy [LVH] altered total and regional coronary blood flow, we inflated a balloon around the ascending aorta of nine dogs; six acute and six sham-operated dogs were controls. After 6 weeks, all dogs were studied with an open chest under anesthesia; the balloons were deflated. There was moderate LVH as shown by increased left ventricular weight and fiber diameter. At rest there were no major differences of coronary flow or resistance per gram of muscle. With maximal coronary vasodilation due to adenosine or carbochrome, mean coronary vascular resistance was 84% higher in LVH than in normal hearts; with isoproterenol, resistance was 54% higher in LVH. These changes were similar in right and left ventricles. Minimal coronary resistance at end diastole also was higher in LVH--64% and 94% for the two sets of vasodilators, respectively. There were no significant differences in capillary or large vessel proportional volumes in LVH and control dogs, but arterial capacity could not be estimated. The raised minimal coronary resistance suggests the possibility that, with stress, coronary flow, especially to subendocardial muscle, might be inappropriate and perhaps cause ischemic damage. However, the changes noted might have been due to coronary arterial responses to raised coronary pressures rather than to hypertrophy itself.

Fluid dynamics of coronary artery stenosis.

Abstract: A large-scale model of the coronary circulation, instrumented to permit detailed pressure and velocity measurements, has been used to study flow through isolated stenotic elements in large coronary arteries. Pulsatile aortic and instantaneous peripheral resistance were stimulated with servovalves. A variety of axisymmetric and asymmetric stenoses were studied and flow separation was found to occur for all but very mild stenoses. Pressure recovery downstream of the stenosis throat was limited and, in some cases, no recovery was observed. Pressure drop was primarily dependent upon the minimum area of the stenosis and relatively independent of stenosis geometry. Flow was quasi-steady at normal heart rates, and simple steady flow theory proved adequate to describe the pressure drop through the stenosis. The theory yielded results that agreed well with published data for dogs and appears promising for predicting effects of hemodynamic variables on a given stenotic lesion. Thus, principal findings of the study are that a relatively severe stenosis behaves essentially like an orifice and that a simple quasi-steady theory appears adequate to predict effects of a stenosis on coronary flow.

Effect of renal hypertension and left ventricular hypertrophy on the coronary circulation in dogs

Abstract: SUMMARY The purpose of this study was to investigate the effects of pressure-induced left ventricular hypertrophy on the coronary circulation. Hypertrophy was induced by single-kidney renal vascular hypertension in 12 dogs. Ventricular mass in the dogs with hypertrophy was about 50% greater than in 11 controls. A third group of six dogs, with a similar amount of left ventricular hypertrophy but normal blood pressure after repair of the renal artery stenosis, also was studied. Total and regional myocardial blood flow was measured with radioactive microspheres at rest, during pacing at a rate of 200 (in the control and hypertensive dogs), and during maximal vasodilation induced with adenosine (4.7 juM/kg x min). Results were as follows. (1) Regional distribution of coronary flow was normal at rest in dogs with hypertension and left ventricular hypertrophy and in dogs with hypertrophy alone. (2) Pacing caused at 16% decrease in the endocardial-epicardial perfusion ratio only in the hypertrophied ventricles of the hypertensive dogs. (3) During maximal coronary vasodilation, the coronary vascular resistance of the entire left ventricle was no different among the three groups: the controls, the hypertensive dogs with left ventricular hypertrophy, and the normotensive dogs with left ventricular hypertrophy (0.14 ± 0.02 SEM, 0.16 ± 0.02, and 0.14 ± 0.02 mm Hg/ml x min, respectively). The use of the minimal coronary vascular resistance measured during maximal vasodilation as an index of the functional cross-sectional area of the coronary bed suggests that the cross-sectional area does not increase with hypertrophy. This failure of the cross-sectional area of the coronary bed to increase commensurate with the degree of hypertrophy is due to an anatomical or architectural alteration of the relationship between the coronary bed and the cardiac muscle and is not due to a functional alteration caused by hypertension alone. Thus, the hypertrophied ventricle may be at greater risk of ischemic injury. CLINICAL SUSPICION of inadequate myocardial perfusion due to pressure-induced hypertrophy of the left ventricle has existed for many years.'" 4 Although several investigators have found that blood flow per unit mass of the myocardium of hypertrophied ventricles is normal, 5 " 8 the decreases in capillary density described in hypertrophied myocardium 9 ''" and preliminary reports suggesting relative endocardial hypoperfusion"' 12 imply that the regional distribution of coronary flow may be abnormal in hypertrophied ventricles and that such ventricles might be at increased risk for ischemic injury. To study possible physiological limitations of the coronary circulation in pressure-induced hypertrophy, we produced single-kidney renal vascular hypertension in mongrel dogs. After left ventricular hypertrophy developed, we assessed regional myocardial perfusion at rest, during pacing, and during maximal vasodilation produced by an iv adenosine infusion. We also studied another group of dogs at rest and during adenosine infusion which had ventricular hypertrophy induced in the same manner but were rendered normotensive by repair of the renal artery stenosis. In this manner we were able to isolate the effects of hypertrophy

Preferential distribution of inhibitory cardiac receptors with vagal afferents to the inferoposterior wall of the left ventricle activated during coronary occlusion in the dog.

Abstract: The purpose of this study was to determine the relative magnitudes of the reflex effects mediated by cardiac receptors during anterior as opposed to inferoposterior ischemia of the left ventricle of the dog. Cessation of perfusion (coronary "occlusion") of the circumflex coronary artery (Cx) in 29 chloralose-anesthetized dogs with common carotids ligated (group I) resulted in significant bradycardia and hypotension, but in no significant change in perfusion pressure in the gracilis muscle perfused at constant flow. Occlusion of the left anterior descending coronary artery (LAD) produced less hypotension, no change in heart rate, and vasoconstriction in the gracilis. After vagotomy and aortic nerve section, no significant change in heart rate or gracilis perfusion pressure was observed during lad or Cx occlusion, and the blood pressure responses to LAD and Cx occlusion were not different. In nine dogs with sinoaortic denervation (group II), brief Cx occlusion resulted in bradycardia, hypotension, and vasodilation in the gracilis muscle. LAD occlusion in group II dogs caused less hypotension and no change in heart rate or gracilis perfusion pressure. After vagotomy, the bradycardia and vasodilation resulting from Cx occlusion were abolished and the blood pressure responses to LAD and Cx occlusion were not different. The weights of left ventricle perfused by each occluded vessel were not different. These data show that left ventricular receptors with vagal afferents which are activated during coronary occlusion and which mediate cardioinhibitory and vasodepressor responses are located mainly in the inferoposterior left ventricle of the dog heart.

Velocity distribution and intimal proliferation in autologous vein grafts in dogs.

Abstract: SUMMARY Autologous femoral veins grafted between the external iliac arteries in 18 dogs provided a model for studying the hemodynamics and histopathology of vein graft bypasses. The angle of proximal anastomosis was varied by groups (<90°, 90°, >90°) to produce a wide range of flow conditions within the grafts. Four months after implantation, point velocity measurements of blood flow and histological examination of the superior and inferior walls were made at proximal, middle, and distal locations in each graft. Hot-film velocity measurements revealed outwardly skewed velocity profiles in the proximal locations in all grafts, and flow visualization models showed secondary fluid motions and separation zones at those regions. Velocity profiles in the middle and distal regions of the grafts were more symmetrical and showed no flow separation. Histological examination of wall sections along the graft length showed that intimal proliferation occurred focally and ranged from 1 to 100 fita in thickness. No signficant correlation between graft angle and degree of intimal proliferation was found. However, there was a weak inverse correlation between the apparent fluid shear rate and the corresponding degree of intimal proliferation, with the greatest proliferation occurring in the regions experiencing the lowest shearing forces. Regions of low shear rate should be avoided by maintaining adequate flow rates through the grafts and thus minimising losses of patency due to both thrombus formation and intimal proliferation.

Liver and ductus venosus blood flows in fetal lambs in utero.

Abstract: SUMMARY We evaluated the circulation of the liver and ductus venosus, using the radionuclide-labeled mkrosphere technique, in 24 chronically prepared fetal lambs. We placed catheters in fetal descending aorta and inferior vena cava, and hi a carotid artery and an umbilical vein; in 11 fetuses, we aho Inserted a catheter hi a mesenteric vein that drained into the portal vein. After allowing 2-4 days for recovery from the stresses of anesthesia and operation, we measured blood flow to the fetal liver and hs various lobes and through the ductus venosus. Total Mood flow to the liver was 435 ± 122 ml/min per 100 g liver (mean ± SD), of which hepatic arterial flow represented 9%, portal venous flow 18%, and umbilical venous flow 73%. Hepatic arterial and umbilical venous flows were approximately equally divided between left and right lobes, although portal blood flow was directed almost exclusively to the right lobe. The right lobe received 40% more total blood flow than the left, even though the left lobe weighed more than the right. Approximately 53% of umbilical venous blood flow but less than 9% of portal venous blood flow entered the ductus venosus; umbilical venous flow therefore accounted for more than 98% of ductus venosus blood flow. Ductus venosus flow showed a strong linear correlation with umbilical blood flow. However, there was no relationship between ductus venosus flow and gestational age. The results suggest that the liver receives a large Mood flow primarily because of a large umbilical venous contribution. It is not dear whether the fetal liver requires this large flow and peculiar lobar distribution for normal function and growth. It is unlikely, however, that the ductus venosus functions actively to maintain a stable blood flow to the fetal liver. THE LIVER of the fetus receives its blood supply from the hepatic artery, portal vein, and umbilical vein. Total blood flow to the fetal liver must be high, because a large umbilical venous blood flow passes through the liver. Nevertheless, the actual flow that reaches the liver from all three vascular sources has not been measured previously. The relative contributions of hepatic arterial and portal and umbilical venous blood flows to the various lobes of the liver also have not been studied quantitatively. Anatomically, the left lobe of the liver is supplied by branches of the umbilical vein, while the right lobe is supplied by portal venous branches 11 (Fig. 1). Except for occasional small branches, no umbilical blood vessels extend into the right lobe, and no portal blood vessels reach the left lobe. Branches of the hepatic artery supply both lobes, but arterial flow to the whole liver is small.

Metabolic responses to cardiac hypoxia. Increased production of succinate by rabbit papillary muscles.

Abstract: In oxygen-deprived heart muscle tissue, alanine levels increase, whereas levels of glutamate and aspartate decline, and it is therefore postulated that free tissue amino acids participate in the metabolic response to cardiac hypoxia. Succinate is a hypothetical end product of anaerobic metabolism of glutamate and aspartate. To test this hypothesis in vitro isolated right ventricular papillary muscles from rabbits were individually incubated under oxygenated and hypoxic conditions. Lack of oxygen significantly augmented succinate, lactate, and alanine production, while levels of glutamate fell. Increased succinate production also was seen when various metabolic precursors were present in the oxygenated incubation medium. In hypoxic muscles, succinate production could be enhanced further when these precursors were present. The aminotransferase inhibitor, aminooxyacetate, reduced succinate production by hypoxic papillary muscles. This finding demonstrated a close relationship between transamination of amino acids and succinate production. In addition, it is suggested that anaerobic metabolism of the amino acids glutamate and aspartate, anaerobic glycolysis, and alanine production are quantitatively related. Moreover, the two reactions responsible for succinate production during hypoxia, 2-oxoglutarate dehydrogenase and fumarate reductase, are in oxidation-reduction balance and lead to substrate level phosphorylation in the citric acid cycle. Anaerobic mitochondrial metabolism, resulting in increased synthesis of succinate, must be considered when one estimates the energy production by oxygen-deprived heart muscle.

Postnatal changes in the circulation and responses to volume loading in sheep.

Abstract: SUMMARY We examined postnatal circulatory changes in three groups of lambs at 1, 4, and 6 weeks after birth. Five lambs in each group were instrumented chronically with electromagnetic flow transducers on the ascending aorta and catheters in the aorta, left ventricle, left atrium, and superior vena cava. After recovery for 2 days, measurements were made daily at rest and during intravenous infusion of 0.9% NaCI solution (25 ml/kg per min) for 2 minutes into the superior vena cava to increase mean left alrial pressure to about 25 mm Hg. Resting heart rate fell progressively, from 210 ± 27/min (mean ± SD) at 1 week to 141 ± 26 at 6 weeks, whereas arterial pressure increased from 71 ± 8 mm Hg during the 4th week to 80 ± 10 at 6 weeks. Aortic flow per kilogram body weight fell from the high level of 425 ± 86 ml during the 1st week to 147 ± 28 ml by the 6th week. This reduction in cardiac output probably is associated with alterations of oxygen consumption per kilogram body weight in the neonatal period. During infusion of saline, left ventricular output increased by a modest 35% over control levels in the 1-week-old lambs, but rose more (58%) in the other two groups. The maximal cardiac output achieved during saline infusion was greater during isoproterenol and less after propranolol administration in each group. We, therefore, suggest that since the neonatal lamb has a high resting cardiac output it has less capacity to respond to volume loading than does the older lamb.

Adenosine production in the ischemic kidney.

Abstract: We conducted experiments to determine (1) tissue, blood, and urine levels of adenosine produced by the ischemic kidney under conditions of renal artery occlusion, and (2) the site(s) of production and release of adenosine by the kidney. Concentrations of adenosine, inosine, and hypoxanthine in the dog urine were found to increase after 2 minutes of renal artery occlusion as were concentrations of these metabolites in renal tissue after 10 minutes of renal artery occlusion. Renal venous plasma levels of inosine and hypoxanthine also were elevated after 3 minutes of arterial occlusion. In modified stop-flow experiments, adenosine appeared in the urine in a peak that corresponded most closely with proximal tubule fluid. 5'-Nucleotidase, the enzyme which catalyzes the dephosphorylation of 5'-AMP or 5'-IMP to adenosine or inosine, respectively, was found to be located primarily on the external membranes and mitochondria of proximal tubule cells, but not in distal tubule or collecting duct cells. Since adenosine has been demonstrated to elicit renal vasoconstriction and is produced by the ischemic kidney, it is suggested that adenosine may be involved in the mediation of postocclusion renal ischemia.

Effects of substrates on tissue metabolic changes in the isolated rat heart during underperfusion and on release of lactate dehydrogenase and arrhythmias during reperfusion.

Abstract: In Langendorff-perfused rat hearts, the perfusion pressure was reduced from 100 cm H2O to 20 cm H2O for 30 minutes to produce a model of global ischemia with a residual oxygen uptake. The release of lactate dehydrogenase (LDH) and the occurrence of ventricular arrhythmias during reperfusion were dependent on the substrate. Glucose-perfused hearts had the highest rates of glycolytic ATP production (2.5 mumol/g per min) during ischemia with normal contents of tissue cyclic adenosine 3',5'-monophosphate (cAMP) and, during reperfusion, the release of LDH was lowest and severe ventricular arrhythmias did not occur. In pyruvate-perfused hearts, glycolysis was inhibited during ischemia, the rate of production of glycolytic ATP was only 0.5 mumol/g per min. and tissue cAMP doubled; during reperfusion, LDH release was 14-fold higher and ventricular arrhythmias were more severe. Total tissue contents of ATP and phosphocreatine were similar in glucose- and in pyruvate-perfused hearts. In hearts perfused with acetate, there was virtually no glycolytic ATP synthesized during the last 5 minutes of ischemia and cAMP increased further. Acetate- and palmitate-perfused hearts showed greatest release of LDH and had severest arrhythmias during reperfusion, suggesting that it was the metabolic and not the detergent effects of palmitate that were operating. Lipolysis was not a major factor in the cause of reperfusion LDH release. A role of glycolytic ATP in the maintenance of membrane integrity is postulated.

Evidence that neural mechanisms do not have important effects on cerebral blood flow.

Abstract: CEREBRAL blood flow may be regulated by four major factors: chemical stimuli (blood gases and extracellular fluid pH), autoregulation, metabolic factors, and neural stimuli. The first three factors are clearly important in control of cerebral vessels. In contrast, we propose that, despite many years of intensive study, there is no convincing evidence that neural control plays an important role in regulation of cerebral blood flow. Before accepting this conclusion, we must address three major questions, which will be the theme of this review: First, why are cerebral vessels richly innervated if the innervation has no important function? In most vascular beds the density of adrenergic innervation correlates with responsiveness of vessels to neural stimuli. Because cerebral vessels are extensively innervated, one might expect important neural effects. If, however, the mechanism of neuromuscular transmission were unusual in cerebral vessels, the vessels might be relatively unresponsive to the neurotransmitter. There is good evidence that neuromuscular transmission is unusual and that cerebral vessels are relatively unresponsive to the adrenergic neurotransmitter, norepinephrine. Second, if in fact neural stimuli do not have significant effects, why have numerous studies indicated important effects of neural stimuli on cerebral blood vessels? We suggest that, in the studies that have indicated important effects of neural stimuli on cerebral vessels, the methods for measuring cerebral blood flow and the experimental protocols have had serious limitations. Third, could nerves have important cerebral vascular effects other than in regulation of blood flow? It is possible, for example, that nerves may affect capillary surface area without affecting blood flow significantly.

Inverse calculation of QRS-T epicardial potentials from body surface potential distributions for normal and ectopic beats in the intact dog.

Abstract: Inverse epicardial potential distributions were calculated from potential distributions measured from the body surface in 12 intact dogs, divided into six pairs. The calculation procedure made use of measurements from the initial dog of each pair, giving the geometric location of each epicardial and body surface electrode and the approximate variance of the epicardial potentials and of the body surface noise. The same calculation procedure subsequently was applied to the other dog of the pair. For all dogs, inverse solutions were calculated throughout QRS-T for several sequences of excitation and repolarization which were produced by stimulating singly and in pairs any of eight ventricular sites. All calculated inverse results were checked by detailed quantitative comparison to the corresponding measured epicardial potential distributions, which were obtained from chronically implanted epicardial electrodes. The root mean square (RMS) numerical differences between the inverse computed and the measured epicardial distributions were a substantial fraction of the RMS measured epicardial voltages, often 0.7 or more, and the correlation coefficients between measured and computed epicardial distributions were in the range 0.6-0.8. Nonetheless, the major epicardial electrical events of excitation and repolarization easily were seen in all of the inverse maps in the initial dogs of each pair, and with only slightly less clarity in the subsequent dogs. Events readily observed included the initial minimum around the stimulus site as excitation began, the movement of the zero contour line across the epicardium as excitation progressed, and the characteristic pattern of repolarization with a maximum near the stimulus site. The results demonstrated that specific physical features of epicardial potential distributions can be determined from body surface measurements and can be verified by comparison with direct epicardial measurements.

Baroreceptor reflexes in human hypertension.

Abstract: We studied the control of arterial pressure by the carotid sinus baroreceptors in 35 hypertensive humans, using a variable pressure neck chamber to alter carotid sinus transmural pressure in a graded fashion. The results were compared with those obtained from 11 normotensives. As in normotensives, reduction in carotid transmural pressure caused a linearly related pressor response and vice versa. However, whereas in normotensives the pressure response was greater than the depressor, the reverse was the case in hypertensives. Furthermore, the pressor response decreased and the depressor response increased progressively with an increase in severity of the hypertension. Thus while in normotensives the carotid baroreflex is more effective in protecting against hypotension, in hypertensives the antihypertensive function of the reflex is favored. Similar differences between hypertensives and normotensives were found with respect to the carotid baroreceptor control of heart rate. In eight hypertensives, reflex changes in heart rate also were studied by injection of phenylephrine and trinitroglycerine to vary not only carotid baroreceptor activity, but also activity of extracarotid baroreceptors. The results were compared with results of similar studies on eight normotensives. These comparisons suggest that, whereas the carotid baroreceptor reflex remains active in hypertension, reflexes stemming from extracarotid baroreceptor areas are much diminished.

Morphometry of the small pulmonary arteries in man.

Abstract: From a resin cast of a normal pulmonary arterial tree, the diameter, length, and number of branches in each order were determined for arteries from 25 to 300 micrometer in diameter. Histological sections 120-micrometer thick were cut from a normal human lung in which the pulmonary artery had been injected with a mixture of ink and gelatin. Similar measurements were made on arteries from 10 to 70 micrometer in diameter, and the mode of origin of the capillaries was studied. The data thus obtained were found to correspond reasonably well to values previously estimated by extrapolation from data for arteries of 100 micrometer or more in diameter. The branching rules apply down to arteries of about 10-15 micrometer in diameter, the estimated number of which is 73 million. Distal to these vessels, capillaries arise either directly from small arteries or indirectly via precapillaries which are given off in great numbers and diverse patterns from the small arteries