Stephen F. Flaim

Alterations in vasomotor tone in congestive heart failure.

T HE changes that occur in the regional circulations with congestive heart failure depend on a number of variables: (A) the stimulus for heart failure; (B) the severity of heart disease; (C) the stage of development of heart failure; (D) the stress placed on the cardiovascular system (exercise, thermal); and (E) the species in which heart failure is studied.‘,’ These variables interact by means of normal physiologic modulators of cardiocirculatory function (reflexes, hormones) operating normally or in excess, and by nonphysiologic abnormalities characteristic of the heart failure state. The reflexes frequently activated include those stimulated via systemic arterial and atria1 baroreceptars, ventricular mechanoreceptors, and somatic afferent and pulmonary afTerent nerve fibers. The hormonal response to heart failure can include activation of the renin-angiotensinaldosterone system, the release of vasopressin, and the secretion of epinephrine and norepinephrine from adrenal medulary and/or peripheral vascular sites. Moreover, interaction between these neurohumoral modulators occurs frequently. Nonphysiologic modulators of circulatory function include salt and water retention which can alter vascular stiffness and externally compress vessels by deforming the interstitial space, and structural changes in afferent nerve fibers and vascular basement membranes. Perturbation of this complex system is caused by medical therapy (digitalis, diuretics, vasodilatars), which may affect the blood vessels directly or alter the modulators. Drugs may interrupt reflexes at multiple levels in the nervous system and can also interfere with hormonal responses at multiple levels. What generalizations can be made regarding vasomotor tone in heart failure? First, blood vessels are constricted. If not present at rest, an abnormal pattern of vasoconstriction almost invariably results during exercise. Second, this vasoconstriction is part of a total cardiocirculatory response designed to maintain optimal circulatory efficiency.‘,3.4 Two sets of cardiocirculatory compensatory mechanisms are activated in heart failure. The first is designed to maintain a normal cardiac output at rest and under conditions of stress. Both cardiac factors (cardioacceleration, myocardial hypertrophy, ventricular dilatation) and circulatory factors (plasma volume expansion and “endogenous impedance reduction”) contribute toward maintaining an adequate cardiac output. The second mechanism is invoked if total flow of the regional circulations cannot be maintained normally. Vasoconstriction is the hallmark of this second response. initially, the vasoconstriction is minimal and selective. The body strives to redistribute blood flow between and within organs, and circulatory efficiency is enhanced. Later, however, vasoconstriction is excessive in order to maintain blood pressure at a normal level. This results in a marked reduction of flow to nonessential circulations (renal, splanchnic, cutaneous), especially during exercise stress. The vasoconstrictor mechanisms thus activated usually spare the coronary and cerebral circulations, which are the main beneficiaries of the body’s effort to maintain a normal blood pressure.’ Third, at some point, the vasoconstriction of congestive heart failure becomes inappropriate. By increasing aortic impedance, vasoconstriction places a further burden on the already failing heart, and the decline in cardiac function is accelerated.‘~’ It is this vicious cycle of inappropriately high vasoconstriction leading to further cardiac dysfunction that vasodilator therapy is intended to interrupt.‘.’ ’ In the remainder of this review, we will first present some examples to illustrate how the type of heart disease. its severity, and its time course of development can alter the vasomotor response. Next, we will review the normal mechanisms regulating regional blood flow at rest and during __-__

Multiple simultaneous determinations of hemodynamics and flow distribution in conscious rat

A method for multiple simultaneous determinations of cardiocirculatory dynamics, regional blood flow, and total cardiac output distribution in the conscious rat preparation is described. The preparation allows for intravenous administration of agents and can be performed on animals either at rest or during treadmill exercise. Instrumentation procedures involve placement of fluid-filled catheters in the left ventricle, right atria, right jugular vein, and caudal artery. Left ventricular pressures are recorded via a modified 4F Millar transducer-tipped manometer containing a 10-cm extension of fluid-filled PE 50 placed into the left ventricle via the right carotid artery. Radionuclide-labeled microspheres (15 +/- 5 mu) are injected into the left ventricle through the fluid-filled PE 50 at selected times for determination of cardiac output and regional blood flows using the caudal artery catheter as the source of the reference blood sample. Details and selected validation data for procedures involving anesthesia, instrumentation, recovery from anesthesia, data gathering, and data analysis are presented. Emphasis is placed on the procedures required for use of the radioactive microsphere technique in this model with special attention given to quality control of the microsphere stock, counting procedures, and computer analysis of these data.

Phorbol ester contracts rabbit thoracic aorta by increasing intracellular calcium and by activating calcium influx

The ability of the phorbol ester tumor promoter, PDB, to activate contraction and stimulate calcium influx was investigated in rabbit thoracic aorta. PDB caused a strong, slowly-developing sustained contraction in physiological salt solution which was concentration-related (0.01 to 10.0 microM). PDB-induced contractions (0.1 microM) in calcium-free medium were attenuated but not prevented. PDB (1.0 microM) maximally stimulated Ca influx above basal control, vehicle = 39.2 +/- 2.2; PDB 1.0 microM = 70.7 +/- 6.7 mumoles Ca/kg tissue; N = 16, p less than 0.01). These data suggest that PDB activates rabbit thoracic aorta by a combination of intracellular and extracellular calcium dependent mechanisms.

Ischemia-Reperfusion Injury at the Microvascular Level Treatment by Endothelin A–Selective Antagonist and Evaluation by Myocardial Contrast Echocardiography

Background—The purpose of this study was to verify whether endothelin A–antagonist administration at the time of coronary reperfusion preserves postischemic microvasculature and whether myocardial contrast echo (MCE) is able to detect pharmacologically induced changes in microvascular reflow. Methods and Results—Twenty dogs underwent 90 minutes of LAD occlusion (OCC) followed by 180 minutes of reperfusion (RP). Five minutes before LAD reopening, an intravenous bolus (5 mg/kg) of LU 135252 was given in 10 dogs and vehicle in the remaining 10. At baseline (BSL), OCC, and 90 and 180 minutes of RP, microvascular flow (BF) was assessed by microspheres, and MCE was performed with intravenous echo contrast. MCE videointensity and BF were expressed as risk area/control ratio. Myocardial thickness of the risk area was calculated by 2D echo. No differences in BF between the 2 groups were observed at BSL, OCC, and 90 minutes of RP. At 180 minutes of RP, BF was decreased in controls (70±7.4% of BSL;P <0.005 versus BSL) and preserved in LU 135252–treated animals (89±4% of BSL;P =NS versus BSL;P <0.05 versus controls). Videointensity at MCE closely followed the changes in BF observed in both groups throughout the protocol. Myocardial thickness at 180 minutes of RP increased to 138.6±9.9% of BSL in controls and remained at 108.9±7.4% of BSL in treated dogs (P <0.05). Conclusions—Endothelin A–antagonist treatment at the time of reperfusion significantly limited the progressive decrease in postischemic microvascular reflow and the increase in myocardial thickness. MCE allowed a reliable evaluation of pharmacologically induced changes in microvascular flow.

Pharmacology of bepridil

Bepridil is an antianginal agent with multiple therapeutic actions. It decreases calcium influx through potential-dependent and receptor-operated sarcolemmic calcium channels and acts intracellularly as a calmodulin antagonist and calcium sensitizer. Thus, in cardiac muscle it enhances the sensitivity of troponin C to calcium, stimulates myofibrillar adenosine triphosphatase activity, removes calmodulins inhibitory effect on sarcoplasmic reticulum calcium release, and inhibits sodium-calcium exchange--actions that tend to offset the effects of calcium influx blockade on cardiac contractile force. However, in vascular smooth muscle where the calcium-calmodulin complex promotes muscle contraction by activating myosin light-chain kinase phosphorylation of contractile proteins, calmodulin antagonism, coupled with bepridils blockade of calcium influx, leads to vasorelaxation. In animal models of ischemia, bepridil and other calmodulin inhibitors show antiarrhythmic efficacy following reperfusion. Additionally, interfering with calmodulins role in sympathetic nerve terminal function may help to limit the ischemia-induced catecholamine release that contributes to arrhythmogenesis. Bepridil shows a lidocaine-like fast kinetic block of inward sodium current (as distinct from the slow or intermediate kinetic inhibition expressed by encainide or quinidine, respectively). This inhibition is pH-dependent; activity is expressed to a greater degree at lower pH levels. This, this potentially antiarrhythmic mechanism is activated by conditions of ischemia. Bepridils blockade of outward potassium currents and its inhibition of sodium-calcium exchange increase action potential duration and ventricular refractoriness, prolong the QT interval, and form the basis for a class III antiarrhythmic mechanism. Because hypokalemia also prolongs the QT interval, the addition of bepridil in the presence of hypokalemia can lead to excessive prolongation. Bepridil both increases myocardial oxygen supply through coronary vasodilation and decreases myocardial oxygen demand through mild heart rate and afterload reduction, and shows potential antiarrhythmic activity through class IB, III, and IV mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of dynamic changes in microvascular flow during ischemia-reperfusion by myocardial contrast echocardiography

BACKGROUND Dynamic changes of myocardial blood flow have been observed after reperfusion of an occluded coronary artery. MCE performed by intracoronary contrast injection can provide an estimate of microvascular flow. We hypothesized that MCE performed using intravenous infusion of a new generation contrast agent and electrocardiogram-gated harmonic imaging would be able to assess serial changes of microvascular perfusion. OBJECTIVE To study the potential of myocardial contrast echocardiography (MCE) to assess serial changes of microvascular flow during ischemia-reperfusion. METHODS Sixteen dogs underwent 90 or 180 min of left anterior descending coronary occlusion, followed by 180 min of reperfusion. Regional blood flow (RBF) was measured with fluorescent microspheres at baseline, during coronary occlusion, and at 5, 30, 90, and 180 min during reperfusion. At the same time points, MCE was performed with intravenous infusion of AF0150 (4 mg/min). Gated end-systolic images in short axis were acquired in harmonic mode and digitized on-line. Background-subtracted videointensity measured from MCE and RBF obtained from fluorescent microspheres were calculated for the risk area and for a control area, and were expressed as the ratio of the two areas. RESULTS After initial hyperemia, a progressive reduction in flow was observed during reperfusion. MCE correctly detected the time course of changes in flow during occlusion-reperfusion. Videointensity ratio significantly correlated with RBF data (r=0.79; p < 0.0001). CONCLUSIONS The progressive reduction in blood flow occurring within the postischemic microcirculation was accurately detected by MCE. This approach has potential application in the evaluation and management of postischemic reperfusion in humans.

Effects of diltiazem on cardiac function and regional blood flow at rest and during exercise in a conscious rat preparation of chronic heart failure (myocardial infarction).

The effects of intravenous infusion of diltiazem on regional blood flow (radioactive microspheres), hemodynamics, and maximum rate of oxygen consumption were evaluated in conscious rats with congestive heart failure caused by large myocardial infarction (n = 10, infarct size 41.8% of left ventricle) and compared with data obtained from rats subjected to sham surgical procedures (n = 9). In both groups data were obtained at rest and during submaximal treadmill exercise during alternate infusion of diltiazem and saline. In the group with heart failure, diltiazem increased stroke volume at rest and during exercise (p less than .05), reduced heart rate (p less than .05), and improved cardiac output during exercise (p less than .05) without increasing left ventricular end-diastolic pressure in any of the animals. Blood flow to renal and splanchnic circulations was reduced in the group with heart failure but was increased by diltiazem to values similar to those observed in sham-operated animals. Although skeletal muscle flow during exercise was significantly increased by the drug, maximal rate of oxygen consumption was not, indicating unchanged oxygen availability within working muscle. Thus diltiazem caused redistribution of blood flow to kidney and gut in animals with myocardial infarction and failure, thereby restoring blood flow to circulatory beds known to be impaired in this setting.

Diltiazem pretreatment reduces experimental myocardial infarct size in rat.

Diltiazem (DZ) is a calcium channel blocking drug which has been shown to be a potent coronary artery dilating agent in the rat. Since this agent has been shown to reduce heart rate and contractility as well as to inhibit calcium transport in the ischemic myocardium, the present study was conducted to determine if DZ is effective in reducing myocardial infarct (MI) size in a rat model utilizing experimental left coronary artery ligation. Rats were pretreated (30 min presurgery) with either DZ (20 mg/kg i.p.) or saline (SA). At 48 h postsurgery, left ventricles were removed and assayed for total creatine kinase activity (CK). Percent infarct size was calculated and found to be significantly reduced from 14.8% in control SA to 6.7% of the total left ventricle in the DZ-treated group (p less than 0.01). Thus, pretreatment with DZ significantly preserves total CK activity and reduces % infarct size in the left ventricle of rats 48 h after experimental MI.

Regional vascular adjustments during recovery from myocardial infarction in rats

Left ventricular function and systemic regional blood flow (radioactive microspheres, 15 +/- 5 mu) were studied 1, 3, 10 or 42 days after left coronary occlusion in conscious rats. One day after coronary occlusion, vascular resistance in the skeletal muscle and cutaneous beds increased while stroke work and left ventricular systolic pressure were depressed. Regional blood flow and hemodynamic data were similar for sham and infarction groups at 3 and 10 days after surgery, except for left ventricular end-diastolic pressure, which was significantly increased in rats with infarction (sham versus infarct: 11.5 +/- 1.0 versus 18.4 +/- 3.2 at day 3 and 12.2 +/- 1.4 versus 19.9 +/- 3.2 at day 10) (p less than 0.05). At 42 days after myocardial infarction, manifest heart failure occurred as documented by decreased cardiac output and left ventricular systolic pressure and elevated left ventricular end-diastolic pressure and vascular resistance in the cutaneous, skeletal muscle and renal beds. In a separate group of animals with moderate (33.2 +/- 2% of left ventricle) and large infarctions (45 +/- 1.3% of left ventricle), regional blood flow was compared with the sham group. Rats with a large infarct demonstrated significant (p less than 0.05) reduction in flow to kidney, gut and liver. In rats with a medium sized infarct, only renal blood flow was significantly reduced. It is concluded that in this model of myocardial infarction, early cardiocirculatory depression is followed by a partially compensated state with increased left ventricular end-diastolic pressure and subsequent systemic and regional vasoconstriction which, in turn, may contribute to late deterioration of heart failure.

Acute effects of arterio-venous shunt on cardiovascular hemodynamics in rat

The cardiovascular effects of an acute high cardiac output state (Acute HCO) were determined in rats 24 h after opening an abdominal aorta-caval shunt equal to 50% of total cardiac output (CO). Heart rate (HR), left ventricular peak (LVP), end diastolic (LVEDP), and arterial (AP) pressures, CO, stroke volume (SV), total systemic and regional vascular resistance (VR), regional blood flow (BF) (radioactive microspheres), and tissue fluid content data were collected. In Acute HCO, AP and LVP were reduced while LVEDP was elevated, total CO was increased and total VR was decreased while systemic CO and VR were unchanged. In Acute HCO, HR did not change significantly and SV was significantly increased. Lung water in Acute HCO was significantly greater than control. Regional BF changes in Acute HCO include skeletal muscle reflex vasoconstriction and splanchnic and cerebral dilation. The results in conjunction with previous data on chronic HCO indicate that in the rat (1) increased lung water which is absent after cardiovascular compensation is an acute result of HCO, and (2) the acute phase of cardiac compensation to HCO occurs in the absence of a tachycardia response.