Biomedical subjects

J L Wessale

Publications and source records attributed to J L Wessale.

At least 19 recordsLinked to original sources

PubMed1994

Nonpeptide renin inhibitors with good intraduodenal bioavailability and efficacy in dog.

The aim of this study was the discovery of nonpeptide renin inhibitors with much improved oral absorption, bioavailability, and efficacy, for use as antihypertensive agents. Our prior efforts led to the identification of A-74273 [1,R = 3-(4-morpholino)propyl], with a bioavailability of 26 +/- 10% [10 mg/kg intraduodenally (id), dog]. In vivo metabolism studies of A-74273 showed that the morpholino moiety underwent metabolic degradation. Computer modeling of A-74273 bound to renin indicated that the C-terminus was involved in a hydrogen-bonding network. New C-terminal groups were examined in two series of nonpeptides for effects on renin binding potency, lipophilicity (log P), and aqueous solubility. Those groups which possessed multiple hydrogen-bonding ability (3,5-diaminotriazole, cyanoguanidines, morpholino) provided particularly potent renin binding. Intraduodenal bioavailabilities of selected compounds, evaluated in rats, ferrets, and dogs, were higher for inhibitors with moderate solubility as well as moderate lipophilicity, in general. Although the absolute values varied substantially among species, the relative ordering of the inhibitors in terms of absorption and bioavailability was reasonably consistent. Such well absorbed inhibitors (e.g. 41, 44, and 51) were demonstrated as highly efficacious hypotensive agents in the salt-depleted dog. We report here the discovery of a series of efficacious nonpeptide renin inhibitors based on the 3-azaglutaramide P2-P4 replacement, the best of which showed id bioavailabilities > 50% in dog.

Amides↗

PubMed1993

Effects of renin inhibitor A-72517 on hemodynamics and cardiac function in sodium-depleted dogs.

A-72517 is a potent inhibitor of human renin (IC50 = 1.0 nmol/L, pH 7.4 in plasma) and, aside from displaying modest activity against canine plasma renin (IC50 = 110 nmol/L), has been shown to be orally active in the dog and other animals. Renin inhibitors, in general, are presumed to exert their hypotensive effect through a reduction in total peripheral resistance. To elucidate the hemodynamic mechanism of action of this new dipeptidic renin inhibitor, the cardiac and systemic hemodynamic effects of A-72517 were studied in sodium-depleted, pentobarbital-anesthetized dogs. Each dog received either vehicle (n = 8) or a single dose (n = 8/dose) of A-72517 administered intravenously as a priming bolus followed by a 30 min constant infusion; infusion doses were 0.01, 0.05, and 0.1 mg/kg/min. A-72517 elicited significant (P < .05) dose-related reductions in mean arterial pressure (MAP) and systemic vascular resistance (SVR) compared to baseline values and the vehicle-treated group, and the recoveries of MAP and SVR were also dose-related. Plasma renin activity, measured by radioimmunoassay, was nearly completely suppressed during drug infusion at all doses. The hypotensive responses did not alter cardiac output nor did they induce reflex tachycardia at any dose. Left ventricular dP/dtmax did not change during infusion of A-72517, but, when corrected for changes in afterload, showed dose-related increases with drug treatment. Moreover, left ventricular end-diastolic pressure and pulmonary arterial wedge pressure were significantly reduced at the high dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Cardiovascular effects and hemodynamic mechanism of action of the novel, nonpeptidic renin inhibitor A-74273 in dogs.

A-74273 is a nonpeptidic, potent inhibitor of human and canine renin (IC50 = 3.1 and 43 nM, respectively, in plasma at pH 7.4) and has been shown to be orally active in dogs. To determine the hemodynamic mechanism underlying this renin inhibitor's hypotensive activity, the cardiac and hemodynamic effects of A-74273 were studied in sodium-depleted and sodium-replete pentobarbital-anesthetized dogs. Vehicle [5% dextrose in water (V, D5W), n = 8] or a single dose of A-74273 was administered intravenously (i.v.) as a bolus followed by a 30-min infusion (one tenth the bolus dose per minute). Baseline mean arterial pressure (MAP) was similar among all treatment groups, but baseline plasma renin activity (PRA) was increased in the sodium-depleted dogs as compared with the sodium-replete dogs. In sodium-depleted dogs (n = 7-8/dose), MAP decreased maximally as compared with baseline by 4 +/- 1, 19 +/- 3, and 23 +/- 3% during infusion of A-74273 at doses of 0.001, 0.01, and 0.1 mg/kg/min, respectively (p < 0.05 vs. baseline or V). The two highest infusion doses also produced significant reductions (p < 0.05 vs. baseline and V) in systemic vascular resistance (SVR, 21 +/- 2 and 25 +/- 2%) and left ventricular end-diastolic pressure (LVEDP, 40 +/- 8 and 47 +/- 12%). In sodium-replete dogs (n = 4/dose), an infusion dose of 0.01 mg/kg/min elicited no hemodynamic response, whereas 0.1 mg/kg/min reduced MAP by 13 +/- 2% (p < 0.05 vs. baseline) and SVR by 7 +/- 6%.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1993

Detection of ventricular tachycardia and fibrillation using coronary sinus blood temperature: a feasibility study.

This study investigated the potential of coronary sinus blood temperature to detect ventricular arrhythmias. A rapid-response, thermistor-tipped catheter placed in the coronary venous system of anesthetized dogs was used to record the blood temperature during periods of induced bradycardia, tachycardia, and ventricular fibrillation. A second catheter was used to measure blood temperature in the aortic arch during these same episodes. A pulsatile component of venous blood temperature, typically 40 m degrees C in amplitude, was well correlated with the cardiac cycle, while another, slightly larger, pulsatile component was well correlated with respiration. The cardiac component peaked during ventricular systole, and the respiratory component peaked during expiration. As compared with sinus rhythm, the cardiac signal diminished during bradycardia and tachycardia and nearly disappeared during asystole and ventricular fibrillation. The baseline component of venous blood temperature rose during periods of tachycardia and fibrillation, while respiration proved to be an important factor in the baseline temperatures. The presence of small, cyclic, thermal variations in the coronary venous system was verified, and the concept of measuring metabolic activity to assess ventricular function was substantiated. These studies show promise that this concept could be incorporated into medical devices that use these temperature signals for diagnosis of ventricular arrhythmias.

Animals↗

PubMed1992

Comparison of rectangular and exponential current pulses for evoking sensation.

There exists a paucity of quantitative information comparing the stimulating currents for different waveforms. Thus, the objectives of this study was to compare the threshold peak current (I) for sensation using rectangular and exponential; that is, capacitor-discharge, cathodal pulses of equivalent pulse duration (d). In 10 human subjects, stimuli were applied to the skin of the forearm, and I was determined alternately for each current waveform at each of several pulse durations (d). Strength-duration curves for sensation were obtained using d of 0.01-50 ms. The threshold peak current (Ir) for a rectangular pulse of duration d was compared to the threshold peak current (Icd) for a capacitor-discharge pulse of duration d, where d was the time constant; that is, the time required for the current to decrease to 1/e, or 37% of its peak value. Chronaxie, the pulse duration at which I is twice the infinite-duration current asymptote (i.e., the rheobase), was calculated for each waveform and subject using the Weiss-Lapicque expression for excitability. Icd was found to be always higher than Ir of equivalent duration. Chronaxie for the capacitor-discharge pulse was, on the average, twice that for the rectangular pulse (p less than 0.01). Moreover, the ratio Icd/Ir increased with decreasing d. These results indicate that these two waveforms are not equivalent on the basis of an equal-charge requirement for excitation, particularly at the short pulse durations. Furthermore, they suggest the need of a better expression to describe the excitability characteristics of tissues.

Adult↗

PubMed1991

Use of electrical impedance for continuous measurement of stroke volume of a skeletal muscle-powered cardiac assist device.

This study describes the use of electrical impedance Z to continuously measure the stroke volume SV of a skeletal muscle-powered ventricle (SMV). An SMV was constructed surgically in four anaesthetised dogs. The rectus abdominis (two dogs) or latissimus dorsi (two dogs) muscle was wrapped around a compressible pouch, the ends of which were connected to a saline-filled (0.9 per cent) mock circulation. The motor nerves to the muscle were stimulated to produce tetanic contractions at a rate of 10 min-1. Z was measured between brass sleeve electrodes within the end conduits of the pouch. To derive a simple expression relating pouch volume V to Z, the pouch was represented as two truncated cones with their bases joined. For V ranging from 53 to 103 ml, the relationship between Z and 1/square root of V was nearly linear; i.e. Z = m(1/square root of V) + b. Impedance-derived stroke volume SV (delta Z) was calculated using this linear approximation and the impedance measured just before and after muscle contraction. The stroke volume SV (EM) ejected by the pouch during muscle contraction was measured with an electromagnetic flowmeter. The linear regression coefficients ranged from 0.99 to 2.55; the correlation coefficients ranged from 0.90 to 0.98. In general, SV(delta Z) tracked SV(EM) very well, although SV(delta Z) tended to overestimate SV(EM).

Animals↗

PubMed1990

Impedance cardiography by use of a spot-electrode array to track changes in cardiac output in anesthetized dogs.

Transthoracic impedance cardiography is a noninvasive method to determine changes in cardiac output on the basis of the cardiac-induced impedance change measured across the thorax. In this report, we describe a new, easily applied, tetrapolar spot-electrode configuration for use in canine transthoracic impedance cardiography. The array is a convenient alternative to use of the traditional circumferential band-electrode array which, in the dog, is prohibitive because of the extensive skin preparation required. The spot-electrode array was used to compare changes in cardiac output measured by transthoracic impedance cardiography, with changes measured by a reference indicator-dilution technique. A spot-electrode array, composed of 4 standard ECG electrodes, was used to measure transthoracic impedance in 10 anesthetized dogs. Variations in cardiac output were produced by controlled hemorrhage (200- to 250-ml increments). Simultaneous reference measurements of cardiac output were made before hemorrhage (control) and at each level of hemorrhage, using the saline-dilution method. The beat-by-beat impedance changes were measured by use of a Minnesota impedance cardiograph, which also recorded the first derivative of impedance (dZ/dt). An index of cardiac output was defined as the product of the maximal value of the first time derivative of impedance, ejection time, and heart rate for each beat during inscription of a saline-dilution curve. The average of the beat-by-beat indices was calculated and then normalized relative to the initial control value. Linear regression analysis was performed to evaluate the correlation of the index of cardiac output with the reference cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

PubMed1990

Stroke volume and the three phase cardiac output rate relationship with ventricular pacing.

Knowledge of how stroke volume (SV), and hence cardiac output (CO), changes with ventricular pacing rate (R) constitutes a key aspect of sensor driven, variable rate pacemakers. It has been established that the relationship between CO and pacing rate exhibits three phases for rest and constant exercise. At low rates (phase 1), CO increases with increasing R; with additional rate increase (phase 2), CO either remains constant or increases slightly; and above some critical rate, CO decreases (phase 3). However, the nature of the relationship between SV and pacing rate has not been as clearly described. Therefore, the objectives of this study were (1) to describe and document the relationship between SV and R, and (2) to demonstrate the consequence of this relationship in terms of the three phase CO versus R relationship. In six anesthetized dogs, right ventricular SV was determined from pulmonary artery blood flow measured using an electromagnetic flow meter, and the right ventricle was paced over a range of rates. In general, SV decreased with increasing R, although the exact nature of the relationship varied from animal to animal. The results demonstrate that it is the manner in which SV decreases with increasing R that determines the three phase relationship between CO and R. The relationships described in this study have important implications for choosing pacing rates for patients receiving sensor driven, variable rate pacemakers.

Animals↗

PubMed1990

The use of an electrically activated valve to control preload and provide maximal muscle blood flow with a skeletal-muscle ventricle.

A new method for optimally loading a skeletal muscle-wrapped pouch to act as a blood pump is described. The method takes advantage of the fact that the high preload pressure required for a forceful contraction needs to be present for only a short time. By using an electrically controlled valve to delay pouch filling until just before muscle contraction, pouch diastolic pressure can be kept low, which in turn maintains a high muscle capillary blood flow. The intrapouch precontraction pressure can be controlled by selecting the appropriate valve-open time (VOT). The pumping capabilities of untrained rectus abdominis and latissimus dorsi muscles were evaluated using a hydraulic circulatory system in a ten dog study (weight range 20-32.7 kg). The afterload was constant at 100 mmHg, and the pouch precontraction pressure, selected by choice of the VOT, was the test variable. It was found that for maximum pouch output, a precontraction pressure of 60-100 mmHg was required, being attained in this hydraulic model with a VOT of 400-500 msec. Typical pouch outputs were 400-600 mL/min with a muscle contraction rate of 40/min. Muscle capillary blood flow, measured with a periarterial electromagnetic flowmeter, varied inversely with pouch diastolic pressure and was near zero during tetanic muscle contraction. In one animal, a pouch output of 200 mL/min or more was maintained for more than 20 hours of continuous pumping without fatigue. In a related experiment, the method was applied to pump blood in a 32.7 kg dog, in which the muscle-wrapped pouch was connected between the descending thoracic aorta and the abdominal aorta. A pouch output of about 400 mL/min was obtained when the muscle was contracted 30 times/min and the VOT was 400 msec. This flow represented about 20% of the animal's cardiac output. This study demonstrates that by delaying pouch filling until just before the muscle is to be contracted, a low pouch diastolic pressure can be maintained, thereby maximizing muscle capillary blood flow and, in turn, providing the best opportunity for prolonged pumping.

Animals↗

PubMed1990

Tracking cardiac output by a saline dilution technique using esophageal catheter electrodes.

This paper presents preliminary results of a study in which saline indicator dilution curves were obtained by measuring impedance dilution curves using a tetrapolar catheter-based electrode placed in the esophagus of anesthetized dogs. Cardiac output (CO) was calculated from the area under the impedance-derived saline dilution curve, and compared to CO calculated from the saline dilution curve obtained by a cylindrical external conductivity cell placed in an arterio-venous shunt. The results revealed an approximately two-third overestimation in CO determined using the esophageal electrodes. However, the esophageal impedance CO tracked CO determined by the conventional indicator dilution method very well. When the data were pooled, a cumulative correlation coefficient of 0.96 was obtained. Although the esophageal impedance CO method overestimates CO, it tracks changes in CO well. Further investigation is indicated to determine an optimal electrode configuration for the tetrapolar esophageal electrode.

Animals↗

PubMed1988

Cardiac output versus pacing rate at rest and with exercise in dogs with AV block.

To achieve maximum benefit from exercise (rate)-responsive pacing in subjects with sinus node dysfunction and AV block, it is necessary to determine the pacing rate (HR) which produces maximum cardiac output (CO) under specified exercise conditions. However, the CO-HR relationship for exercise has not been systematically investigated. To permit determination of the optimum HR, CO was measured at rest and with exercise for different pacing rates. Seven dogs with complete AV block and permanently implanted ventricular pacemakers were exercised on a treadmill for 5 min at each of four pacing rates (55, 76, 101, 116/min) and at two constant exercise levels (225 and 560 kg.m/min). CO was determined by impedance cardiography during the resting state preceding exercise and during a brief period (10-20 s) immediately after exercise, and was expressed as a percent of the CO determined at rest with HR = 55/min. A three-phase pattern of CO versus HR appears to exist for exercise as for rest. For exercise, starting from a low HR, CO increases markedly; a "plateau" is reached during which moderate increase in CO is achieved by increasing HR. At very rapid pacing rates, CO may actually decrease with further increase in HR. The results of this study suggest that a subject-specific optimum HR exists for each constant exercise level. Moreover, the methodology employed in the study is applicable to the identification of optimum HR for any exercise (rate)-responsive pacemaker.

Animals↗

PubMed1988

Relationship between tracheal air flow and induced changes in intrathoracic volume. A basis for calibration of pneumocardiogram.

The volume of air moved into the trachea due to ventricular activity--a record of which is the pneumocardiogram (PNCG)--is always less than true stroke volume. A new method of investigating this relationship consists of inducing a known volume change (delta V in) within the thorax and measuring the volume of air (delta V out) recorded with a pneumotachograph connected to the trachea. The range of delta V in was from 4 ml to 36 ml. A linear relationship (mean r = 0.98, p less than 0.001) between delta V out and delta V in was observed in 19 anesthetized, intubated dogs: delta V out = (f) delta V in, where f = 0.53 +/- 0.09 (mean +/- SD). The coefficient, f, ranged from 0.40 to 0.71. These results demonstrate that although f is subject-dependent, delta V out reliably reflects changes in delta V in. It is suggested that the technique of inducing a known volume change within the thorax and measuring the volume of air recovered from the trachea could be used as a method for calibrating the pneumocardiogram to obtain stroke volume.

Airway Resistance↗

PubMed1985

Correlation of the cardiogenic air flow in the respiratory airway (i.e. the pneumocardiogram) with left ventricular stroke volume in dogs.

The pneumocardiogram (PNCG) is a record of the pulsatile flow of air in the trachea coincident with each heart beat. In 5 anesthetized mongrel dogs, the cardiogenic air flow through an endotracheal tube was measured with a research pneumotachograph. The correlation between the pneumocardiographic volume of air, obtained by integrating the PNCG over the period of ventricular ejection, and stroke volume (SV), measured by the saline-dilution method, was determined for a physiologic range of SV. Although the pneumocardiographic volume tracked measured SV, the former was always less. The range of correlation coefficients was 0.60 to 0.91. The results suggest that the PNCG may be suitable for continuous tracking of changes in SV on a noninvasive, beat-by-beat basis. The technique is ideally applicable to intubated human subjects, particularly those undergoing closed-chest surgical procedures.

Animals↗

PubMed1985

Indirect auscultatory systolic and diastolic pressures in the anesthetized dog.

The auscultatory method was used to obtain indirect systolic and diastolic pressures in 13 dogs anesthetized with either halothane or sodium pentobarbital (30 mg/kg of body weight). Korotkoff sounds were obtained, using a 1-cm (diameter) piezoelectric element cemented to the inner surface of a pediatric cuff (width 5.5 cm) which was placed on a shaved thoracic limb (membrum thoracicum). The signal from the piezoelement was amplified by a differential amplifier (30 to 200 Hz) and a commercially available audio amplifier. Indirect pressure (I) was compared with direct pressure (D) in the brachial, femoral, or carotid artery. The linear regression lines and correlation coefficients (r) for the data were as follows: systolic, I = 0.94 (D) + 1.1, r = 0.98; diastolic, I = 0.99 (D) + 3.2, r = 0.99. The quality of the Korotkoff sounds and the accuracy of the determinations were best in the halothane-anesthetized dogs. These results indicate that indirect auscultatory systolic and diastolic pressures are in excellent agreement with the directly measured pressures.

Anesthesia↗

PubMed1980

Bipolar catheter defibrillation in dogs using trapezoidal waveforms of various tilts.

The choice of defibrillating waveform is critical in determining the size, battery life, and effectiveness of an automatic implantable defibrillator (AID). The trapezoidal (truncated exponential) waveform is well suited for the AID and its use can be optimized by the selection of appropriate values of pulse duration and tilt. The purpose of this study was to determine the dependence of the threshold peak current (the minimum peak current necessary to defibrillate the ventricles) on pulse duration and tilt for a bipolar catheter electrode configuration. Successive fibrillation-defibrillation trials were performed in 30 dogs anesthetized with sodium pentobarbital (30 mg/kg). The defibrillating pulse was applied via a bipolar-electrode catheter positioned such that the electrodes were located in the right ventricle at the apex and in the superior vena cava. The threshold peak current was determined in each dog for trapezoidal waveforms with 80%, 65%, 50%, and less than 5% tilt and with pulse durations of 2, 5, 10, 15, and 20 milliseconds. From a total of 600 threshold peak-current values, a strength-duration curve was derived for each value of tilt. The threshold peak current dose (peak current divided by body weight) increased with increasing tilt and decreasing duration. The threshold average current dose (average current over the duration of the defibrillating pulse divided by body weight) was IAV = 0.26 + 0.47/d, where d is the pulse duration in milliseconds and IAV is the average current in amperes per kilogram. If catheter apparent impedance is known, the minimum capacitance and output voltage necessary for defibrillation can be inferred from the strength-duration curves. From these data one can quantitatively assess the effect of trapezoidal waveform shape on the design criteria for the AID.

Animals↗

PubMedDate not supplied

Pumping capabilities of the latissimus dorsi and rectus abdominis muscles wrapped around a valved pouch in a mock circulatory system.

The pumping capabilities of nine unconditioned canine rectus abdominus muscles (93-163 gm) and six latissimus dorsi muscles (99-146 gm) were measured. The muscles were wrapped around a 100 ml ellipsoidal pouch in a mock circulatory system in which the afterload was 100 mmHg. Pouch diastolic pressure was kept low by an electrically controlled inlet valve to maximize muscle capillary blood flow. Immediately before tetanic contraction of the pouch-encircling muscle, the inlet valve opened for 450 msec to increase pouch pressure to 100 mmHg, thereby providing a high preload and ensuring a forceful muscle contraction. The motor nerves to the muscles were stimulated with 450 msec trains of 0.1 msec stimuli, using a frequency of 40/sec. The train rates (muscle contractions/min) were 10-50/min. In this circulatory model it was found that the maximum output for both muscle types occurred between 20 and 40 contractions/min. It was also found that for both muscle types, the maximum output (L/min) was dependent upon muscle weight. The data revealed that an output of 4 ml/min was obtained per gram of muscle. The power (mW/gm) developed was related to the output (L) in L/min. For the rectus muscle W = 0.47L, and for the latissimus muscle W = 0.41L mW/gm. Pumping periods lasted approximately 4 hours, with no evidence of fatigue. When viewed as a potential cardiac assist device, the muscles were able to provide a flow equivalent to approximately 25% of the cardiac output. However, it is important to note that the pumping capability is directly related to muscle weight, indicating that a higher output can be achieved with a larger muscle.

Abdominal Muscles↗

PubMedDate not supplied

Detection of ventricular fibrillation with a ventricular monopolar catheter electrode.

This report describes the use of right ventricular impedance (RVZ) sensing with a monopolar electrode to identify the cessation of pumping with the onset of ventricular fibrillation. RVZ, ECG (lead II), and femoral artery pressure were monitored in seven anesthetized dogs. An impedance recorder (10-kHz, 100-microA peak-to-peak current) was used to measure RVZ between a monopolar, catheter-mounted electrode placed in the right ventricle and an indifferent electrode (8.5-cm diameter plate) sutured to the right chest wall. The catheter electrode was either 0.4 cm or 1.2 cm long and had a surface area of 0.50 cm2 or 1.50 cm2, respectively. A monopolar electrode was positioned at the apex of the right ventricle or midway between the apex and the tricuspid valve. The peak-to-peak amplitude of the pulsatile cardiac-induced impedance change was measured prior to and throughout an episode of ventricular fibrillation lasting up to 1 minute. On the average, the amplitude of the pulsatile RVZ signal after 10 seconds of fibrillation decreased by 79% of the prefibrillation amplitude. The 1.2-cm electrode located at the middle of the ventricle showed the largest reduction in pulsatile impedance, the amplitude being very small at 10 seconds. It is concluded that sensing RVZ by a monopolar electrode located on a catheter in the mid-ventricle can provide the mechanical information needed to identify the onset of ventricular fibrillation.

Animals↗

PubMedDate not supplied

Sequential pulse defibrillation for implantable defibrillators.

A technique is described that reduces defibrillation threshold for automatic implantable defibrillators, permits either reducing the size of the pulse generator or increasing the effectiveness of the pulse generator, and provides an increased safety factor. Defibrillation threshold was compared in 12 anesthetized dogs with mean (+/- SD) body weight of 21.6 +/- 3.4 kg for two defibrillating modalities: 1) single pulse technique with current flowing from electrodes in the right ventricle to electrodes either in the superior vena cava or on the left ventricular epicardium, and 2) sequential pulse technique. The sequential pulse technique tested uses two pulses and three or four electrodes. Current of the first 5-ms pulse flows from the superior vena caval electrode to an electrode in the right ventricle, and after a 1-ms interval, current of the second pulse flows from electrodes on the left ventricular epicardium to the right ventricular electrode. Ventricular defibrillation threshold was reduced by 56% to 6.3 +/- 1.03 joules (mean +/- SEM) (P less than 0.01). Because defibrillation threshold is less for sequential pulse defibrillation than for conventional techniques, sequential pulse defibrillators can be smaller and more effective than previously available devices.

Animals↗