Canine Preparation Research Articles

Potentiation of the cardiovascular effects of nicardipine by enflurane anesthesia in canine blood-perfused heart preparations.

The cardiovascular interaction between nicardipine (N) and enflurae (E) was examined with blood perfused isolated paplillary muscle preparations (PMP) and sinoatrial node preparations (SNP). Blood flow to these preparations was supplied by either conscious or 1.7% E-anesthetized-donor dogs. N was administered continuously at a rate of 2.0 microg.kg(-1).min(-1) into the donor dogs for 60 min. Measurements were as follows: mean arterial blood pressure (MAP), heart rate (DHR), PQ interval (PQ) in the electrocardiogram, developed tension (DT) in PMP, sinoatrial rate (SAR) in SNP and blood flow (BF) to PMP and SNP. There were no significant differences in PQ, SAR and BF between two groups. However, N further decreased MAP, DHR and DT that were already decreased by E significantly. The authors conclude that the cardiovascular interaction between N and E was generally additive but that concerning negative inotropism was synergistic.

Oxygen free radical-mediated selective endothelial dysfunction in isolated coronary artery.

To understand the direct involvement of free radicals causing reduction in endothelium-dependent relaxation of isolated canine coronary ring preparations, this study was undertaken to examine the effect of free radicals generated from dihydroxy fumarate (DHF) plus Fe(3+)-ADP or from H2O2 plus FeSO4. The vasodilators (acetylcholine, bradykinin, A23187, and nitroglycerin) were given after DHF/Fe(3+)-ADP or H2O2/FeSO4 was removed from the organ chamber. The earlier DHF/Fe(3+)-ADP exposure produced an attenuation of the relaxation of the rings induced by acetylcholine, bradykinin, or A23187 but not of the relaxation induced by nitroglycerin. The observed effect of previous DHF/Fe(3+)-ADP exposure was significantly protected in the vessels isolated from the dogs treated with alpha-tocopherol. In the experiments for assessing the effect of various scavengers, 1O2 scavenger histidine or iron chelator deferoxamine effectively protected the attenuation induced by DHF/Fe(3+)-ADP exposure of the relaxation elicited by acetylcholine; superoxide dismutase (SOD), catalase, or dimethyl sulfoxide (DMSO) had no effect on this system. Furthermore, the relaxation elicited by acetylcholine, but not nitroglycerin, was significantly attenuated by the earlier exposure to .OH generated by Fenton's reagent (H2O2+FeSO4); the attenuation was significantly protected by DMSO. These results are consistent with the view that .OH, 1O2, and/or iron-dependent reactive species selectively damage endothelium-dependent relaxation as opposed to endothelium-independent relaxation in endothelium-intact coronary ring preparations. It is also postulated that lipid peroxidation may be responsible for this effect.

Ischemia-induced depressed systolic thickening is transiently augmented by remote coronary occlusion.

To determine if ischemia-induced depressed myocardial thickening can be augmented by remote coronary occlusion, posterior wall function (pulsed Doppler crystal) was measured before and after left anterior descending coronary artery occlusion in the presence of reduced circumflex coronary artery flow (of sufficient severity to reduce resting function) in an anesthetized open-chest canine preparation in which the circumflex was pump-perfused with carotid arterial blood. Left anterior descending coronary occlusion elicited an immediate significant increase in posterior bed thickening fraction (TF%) (3.7 +/- 1.5 to 5.9 +/- 1.3%), but by 135 sec TF% had again deteriorated. The transient increase in thickening was not caused by increased flow to the posterior bed (microspheres, n = 3), nor was it related to a Frank-Starling mechanism (echocardiography, n = 3). Despite an ischemic-induced reduction in systolic shortening, systolic thickening can be transiently augmented by remote coronary occlusion. The etiology may be related to systolic unloading.

Effect of Breathing Pattern and Level of Ventilation on Pulmonary Fluid Filtration in Dog Lung

The effect of breathing pattern and level of ventilation on fluid filtration in the lung under edema forming conditions was studied in an in situ left upper lobe (LUL) canine preparation. LUL weight was continuously monitored. In Group 1, rate of edema formation (delta W/delta t) was measured In seven dogs at two vascular pressures (35 and 45 mm Hg) while the LUL was randomly ventilated under six conditions. At equivalent vascular pressures and mean airway pressures (Paw) (and hence, mean operating lung volume), increasing respiratory frequency (f) enhanced delta W/delta t. This was reversed when minute ventilation (VE) was returned to baseline by reducing tidal volume (VT), even when Paw were matched to baseline. Increasing VT also enhanced delta W/delta t whether VE was increased (J Appl Physiol 1988; 64:1900) or not (present study) and whether Paw was matched to baseline. In Group 2 delta W/delta t was measured at fixed VT and f while inspiratory/expiratory time ratio (TI/TE) was switched from 1:1 to 1:6. Shortening inspiratory time by increasing inspiratory flow rate had no effect on delta W/delta t. We conclude that increasing VE, whether by raising VT or f, promotes greater edema formation by mechanisms that are independent of vascular pressure or operating lung volume. Increasing VT appears to have an additional adverse effect over and above that of increased VE.

Effects of sympathetic stimulation on use dependence of lidocaine, mexiletine, and quinidine in an intact canine model.

The use- or rate-dependent effects of a continuous infusion of lidocaine (n = 6, serum level 3.1 +/- 0.34 micrograms/mL), mexiletine (n = 8, serum level 7.08 +/- 0.90 micrograms/mL), and quinidine (n = 6, serum level 6.8 +/- 1.22 micrograms/mL) were studied in an open chest canine preparation. A use-dependent effect on conduction was assessed by measuring the change in the His to surface ventricular activation (HV) time at differing atrial paced rates during drug infusion. Global sympathetic activation was achieved by nondecentralized left stellate ganglion stimulation (4-10 Hz, 6-12 V, 2 ms) and use dependence at the same cycle lengths was compared. Repolarization times were measured from epicardial monophasic action potentials recorded from the anterior left ventricle throughout the study. There was no significant change in the HV time during control studies with or without left stellate stimulation. Use-dependent slowing of conduction was seen in all studies during drug infusion. This was evident at cycle lengths of 300-190 ms for quinidine and at cycle lengths less than 250 ms for lidocaine and mexiletine. Stellate stimulation attenuated use dependence in all studies. This effect was significant from cycle lengths of 300-190 ms for lidocaine and quinidine and at cycle lengths shorter than 230 ms for mexiletine (p less than 0.05). Stellate stimulation significantly reduced use-dependent prolongation of the HV interval by an average of 60%. During stellate stimulation there was a nonsignificant trend towards cycle length independent shortening of action potential duration both at baseline and in the presence of drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hydralazine on vascular mechanics in a canine lobar preparation of pulmonary embolism

We studied the effect of hydralazine (H) on pulmonary vascular mechanics in an isolated, in situ, canine lobe model of normal and increased pulmonary vascular resistance (Rp) produced by Gelfoam embolization (GE). Pulmonary pressure-flow (P-Q) curves from 24 lobes were obtained at baseline and after each intervention. Hemodynamic parameters for analysis included: the mean critical closing pressure (Ppai), vascular conductance (1/Rp), lobar flow (QL), and the pulmonary inflow pressure (Ppa) at different levels (50, 100, 200, 400, and 600 ml/min) of a fixed flow. After the preparation was stabilized, the 24 lobes were classified into 2 groups. For group 1 (n = 8) we studied the effect of H on the normal pulmonary vasculature. In group 2 (n = 16) we studied the effect of GE. Following GE, this group was further divided in half. For group 2A (n = 8) we followed the natural history of GE with measurements at 15 and 60 min. For group 2B (n = 8) measurements were done 15 min after GE and repeated again 15 min after the infusion of H. For group 1 lobes, H promoted a significant decrease (p less than 0.001) in Ppa at fixed flows of 200, 400, and 600 ml/min compared to baseline, with no change in Ppa for flows below 100 ml/min. QL and 1/Rp increased (p less than 0.01), and there was not any significant change in Ppai. In group 2A lobes, GE produced an increase in Ppa at all levels of flow (p less than 0.01), QL and 1/Rp decreased (p less than 0.05), and there was an increase in Ppai (p less than 0.05). These changes remained stable over the 60 min of observation. For group 2B lobes, GE produced the same hemodynamic changes as in group 2A, and the infusion of H caused a decrease in Ppa at flows between 100 and 300 ml/min. (p less than 0.01) with no change in Ppa at flows below 100 ml/min. QL and 1/Rp increased (p less than 0.01) and Ppai did not change compared to 15 min after GE. We conclude that in the normal canine pulmonary vasculature as well as in the model of GE, H decreased Rp and did not affect mean critical closing pressure, all of which may be explained by an increase in vascular conductance due to an increase in vascular distensibility.

Influence of short atrioventricular delay on late diastolic transmitral flow and stroke volume.

Atrial transport function and the corresponding transmitral flow and stroke volume depend on the timing of atrial contraction. To study the influence of short atrioventricular delay (AVD) on these hemodynamic parameters, transmitral flow velocity (by pulsed wave Doppler) and aortic flow (by electromagnetic technique) were studied and compared (paired t test) during normal and short AVD at fixed rate DDD pacing (80 bpm) in AV-blocked, open-chest canine preparations (n:16). The short AVD resulted in a shorter acceleration (difference 4.1 +/- 4.9 msec, mean +/- SD, p less than 0.05), a lower peak velocity (difference: 7.1 +/- 3.2 cm/sec, p less than 0.001), a shorter (difference: 26.9 +/- 16.2 msec, p less than 0.001) and more rapid deceleration (difference: 220.7 +/- 291.7 cm/sec2, p less than 0.005) of the late diastolic transmitral flow elicited by atrial systole. Stroke volume decreased (7.8 +/- 5.2%, p less than 0.001) during short AVD as a consequence of a reduced left ventricular filling due to the interruption of the active atrial transport by the onset of the ventricular contraction.

Equivalent pressure-volume area accounts for oxygen consumption of fibrillating heart

We attempted to find cardiac mechanical parameters to account for myocardial O2 consumption (VO2) during ventricular fibrillation (VF). We fully utilized the concept of pressure-volume (P-V) area (PVA), which is equivalent to the total mechanical energy generated by a ventricular contraction. We also utilized a multicompartment model consisting of multiple asynchronously contracting compartments, which we previously proposed to simulate the mechanics of a fibrillating ventricle. The model analysis had already validated the application of PVA to VF in terms of "equivalent PVA" (ePVA). ePVA is the area surrounded by the end-systolic and end-diastolic P-V relations in beating state and the isobaric P-V line at the VF pressure. ePVA is supposed to represent the total mechanical energy generated by single contractions of each compartment (or myocyte) in a fibrillating ventricle. We determined ePVA and correlated it with measured VO2 per minute (mVO2) at various ventricular volumes in electrically induced fibrillating left ventricles of the excised cross-circulated canine heart preparation. Correlation coefficient (r) of the mVO2-ePVA relation during VF was high (r = 0.95, P less than 0.01). Comparing mVO2 during VF with that in beating state at an unloaded ventricular volume, we calculated equivalent heart rate (eHR) as an estimate of the frequency of contractions of individual compartments (myocytes). With the use of both ePVA and eHR, mVO2 during VF at various ventricular volumes was estimated. The relation between estimated mVO2 and directly measured mVO2 was highly linear (r = 0.88, P less than 0.01), and the regression line almost agreed with the identity line (regression coefficient = 1.05). We conclude that the new ePVA and eHR concepts can reasonably account for VO2 during VF.

Diastolic mechanics and the origin of the third heart sound

The third heart sound (S3) is observed for various hemodynamic conditions in both the normal and diseased heart. A theory is proposed in which myocardial viscoelasticity is primarily responsible for S3. A mathematical model is developed based on the mechanical aspects of diastolic function: nonlinear elasticity, viscoelasticity, and pressure generation. The model is provided as an electrical analogy of the left ventricle and circulatory system. S3 is predicted for the normal heart and the heart with dilated cardiomyopathy. An elevation of S3 intensity is indicated for cardiomyopathy, as is often observed in the clinic. S3 is produced experimentally by volume loading of the open-chest canine preparation and mathematically by imposing the conditions of volume loading on the model. Consistency of theory and experiment imply that it is valid to attribute S3 to myocardial viscoelasticity. The animal whose heart possessed the largest constant of viscoelasticity produced the greatest level of S3, in both cases. Nonlinear ventricular compliance is not found to be an essential requirement for sound generation, although increased compliance led to an increase in sound. S3 is predicted to change in response to venous return, ventricular stiffness, contractility, heart rate, and duration of contraction, as observed by others. In general, the coupling of these quantities to S3 is explained in terms of an excitation of viscous properties of the ventricle.

Influence of histaminergic receptors on denervated canine gracilis muscle vascular tone during endotoxemia

The purpose of this study was to determine if endogenously released histamine and its non-neural interaction with the H1- and H2-histaminergic receptors in the peripheral vasculature can account for the decompensatory loss of peripheral vascular tone associated with the hypotension occurring during endotoxemia. A denervated in situ constant flow double canine gracilis muscle preparation that permitted one muscle to serve as a control (GMc) for the contralateral experimental muscle (GMe) was used. Endotoxemia was induced by intravenous infusion of 2 mg.kg-1.30 min-1 endotoxin. The specific H1 and H2 antagonists diphen-hydramine and cimetidine were infused either together or separately in both high and low dosages into the GMe. Blockades were validated by intra-arterial injection of histamine or the specific agonists betahistine for H1 and dimaprit for H2 receptors. The results suggest that the high-dose diphenhydramine produced a nonspecific dilation not seen with the lower dose. Because both the blocked and unblocked vascular beds exhibited the same degree of vasodilation after endotoxin, these studies do not support the hypothesis that endogenously released histamine is responsible for the loss of vascular tone. These studies do verify, however, that a nonneurally mediated loss of skeletal muscle vascular tone is an important factor to consider in the overall cardiovascular hypotension occurring during endotoxin shock.

Electrophysiological properties of a new antiarrhythmic agent, bisaramil on guinea-pig, rabbit and canine cardiac preparations

Electrophysiological effects of bisaramil, a novel antiarrhythmic agent, were examined using the conventional microelectrode technique applied to cardiac multicellular preparations from guinea-pigs, rabbits and dogs and the whole-cell patch-clamp technique applied to guinea-pig ventricular myocytes. Bisaramil at 10(-6) M or higher concentrations produced a dose-dependent decrease in the maximum rate of rise (Vmax) of action potentials of guinea-pig papillary muscles without changes in resting membrane potentials. In the presence of bisaramil, trains of stimuli at rates greater than 0.1 Hz led to the use-dependent block of Vmax, which was enhanced at higher frequencies. At a concentration of 3 x 10(-6) M, the degree of use-dependent block was about 35% at 3.3 Hz, of which degree was comparable to those of 10(-4) M disopyramide and lidocaine. The development of Vmax block by bisaramil was expressed by a single exponential function in the same manner as flecainide, whereas the time courses of the block development by disopyramide and lidocaine were described by two exponentials. Recovery time constants from Vmax block were 44.1 +/- 3.4 s and 20.3 +/- 2.3 s for bisaramil and flecainide, respectively. Bisaramil at 10(-6) and 3 x 10(6) M did not change the action potential duration of guinea-pig papillary muscles and rabbit atrial muscles with a significant reduction of Vmax. No change in action potential duration can be explained by depression of both the Ca2+ and the delayed outward K+ currents by bisaramil. On the other hand, 10(-6) M bisaramil shortened action potential duration of canine Purkinje fibers at 50% and 90% of repolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the effects of prostaglandins E2 and I2 on testicular nociceptor activities studied in vitro

Effects of exogenous prostaglandin (PG) E2 and PGI2 on testicular polymodal receptor activities were compared in in vitro recordings of single- or multi-fiber discharges from canine testis-spermatic nerve preparations. PGI2 up to 1.4 x 10(-6) mol/l (cumulative method) or 1.0 x 10(-5) mol/l (non-cumulative method) excited only weakly some of the receptors, and similar observations were made with PGE2. Both PGs applied cumulatively or non-cumulatively at concentrations above 1.4 x 10(-8) mol/l augmented the response to bradykinin (9.4 x 10(-8) mol/l) in more than half of the cases tested. The augmenting effect of PGE2 lasted longer than that of PGI2 both with the cumulative and the non-cumulative method. The degree of augmentation tended to increase dependent on concentration, but some cases showed no further increase or rather a decrease in augmentation by PGs at a ten times higher concentration, especially when PGs were applied cumulatively. A second challenge by PG after a short interval (2 min) did not induce augmentation. These phenomena were considered to be tachyphylaxis to PGs. Cross-tachyphylaxis to PGE2 and PGI2 was also observed. There was not much difference in excitatory and augmenting potencies between these two PGs, but there was a clear difference in the concentrations of the PGs necessary to induce excitation of polymodal receptors and to facilitate their response to bradykinin.

Does pentobarbital anesthesia depress left ventricular contractility in dogs?

Although pentobarbital sodium (NP) anesthesia has been shown to depress left ventricular (LV) contractility in dogs, measurements of LV contractility in previous studies have been made soon after a bolus of NP was given when serum concentrations would be extremely high. In this study, we compared indexes of LV contractility during awake and anesthetized conditions. During anesthesia, measurements were obtained 1 h after an intravenous bolus of NP was given when serum concentrations were approximately 25 mg/l and above that reported to abolish pain. In 13 dogs, subendocardial ultrasonic crystal transducers and a high-fidelity pressure transducer were implanted into the LV. Measurements were obtained with and without prior treatment with propranolol to produce beta-adrenergic blockade. LV contractility was assessed by ejection fraction and the end-systolic pressure-volume relationship. The effect of NP on ventricular myocardium was also examined in an in vitro canine right trabecular preparation to compare in vivo and in vitro effects. In the in vivo study, the results showed no decrease in LV contractility during anesthesia regardless of whether propranolol was administered. The in vitro preparation showed only a minimal decrease in isometric tension at the concentrations used in the in vivo study. We conclude that NP anesthesia does not depress LV contractility when concentrations are maintained at approximately 25 mg/l.

Effects of Tetrodotoxin and Imipramine on the Cardiac Responses to Nicotine in Isolated, Blood-Perfused Canine Heart Preparations

The effects of nicotine on the sinus rate and atrial or left ventricular contractile force were investigated in the isolated, blood-perfused dog right atrium and left ventricle. Nicotine (3-300 nmol) in the right atrium induced dose-dependent negative followed by positive chronotropic and inotropic responses, whereas nicotine caused only a positive inotropic response in the left ventricle. The negative responses to nicotine were blocked by atropine, hexamethonium (C6), and tetrodotoxin (TTX). The positive effects of nicotine were abolished by propranolol and C6. TTX significantly inhibited the positive responses to nicotine by about 50% in the atrial preparation and totally suppressed them in the left ventricle. Imipramine inhibited the positive cardiac responses to nicotine and tyramine, but potentiated the responses to noradrenaline (NA) in atrial and ventricular preparations. These results suggest that (a) nicotine induces negative and positive cardiac effects mediated by parasympathetic ganglionic nicotinic receptors and presynaptic nicotinic receptors of the postganglionic sympathetic nerves, respectively, in the dog heart; (b) there are few parasympathetic ganglionic cells in the dog left ventricle; (c) the positive cardiac responses to nicotine are caused by both TTX-sensitive and TTX-insensitive NA release mechanisms; and (d) imipramine inhibits the positive cardiac responses to nicotine at the presynaptic nicotinic receptor sites of the postganglionic sympathetic nerves.

Is the Pressure Rate Quotient a Predictor or Indicator of Myocardial Ischemia as Measured by ST-Segment Changes in Patients Undergoing Coronary Artery Bypass Surgery?

Perioperative myocardial ischemia is associated with an increased risk of perioperative myocardial infarction (PMI). Several attempts have been made to define intraoperative hemodynamic predictors of myocardial ischemia. In a canine preparation with coronary stenosis, a pressure rate quotient (PRQ = mean arterial pressure/heart rate) less than one (PRQ less than 1) indicated subendocardial myocardial ischemia. The authors tested this hypothesis in patients undergoing elective coronary artery bypass graft operation (CABG), using electrocardiogram (ECG) ST-segment changes (leads II/V5) to diagnose myocardial ischemia. Sixty (n = 60) patients having CABG surgery were prospectively studied before initiation of cardiopulmonary bypass. Calibrated ECG leads II and V5 (diagnostic mode) were monitored continuously and recorded with the use of a Hewlett-Packard computer ST-segment analyzer. In addition, arterial and pulmonary artery pressures were monitored. Ischemia was defined as new-onset ST deviation (greater than or equal to 1 mm from the baseline ECG). ECG and hemodynamic data were stored at 2-min intervals for subsequent computer analysis. Serial creatinine phosphokinase (CPK) X MB (%) determinations and 12-lead ECGs were collected for the initial 3 postoperative days. Of the 3,463 intervals (2 min) available for study, 3,322 (96%) were satisfactorily recorded for 60 patients. Ischemia occurred during 65 intervals in 9 patients (9 of 60), of which only 34% (22 of 65) were associated with a PRQ less than 1 (P less than 0.01). In contrast, there were 466 intervals during which PRQ was less than 1, but without ECG evidence of ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of gastric antisecretory and prostaglandin E receptor binding activity of misoprostol by misoprostol free acid

In enriched canine parietal cell preparations, misoprostol, an analog of prostaglandin E1 methyl ester, was rapidly deesterified to misoprostol free acid. Under this circumstance, misoprostol and misoprostol free acid exhibited equal antisecretory potency against histamine-stimulated acid secretion and bound equally well to prostaglandin E receptors. When the deesterification of misoprostol was inhibited by paraoxon, an esterase inhibitor, the antisecretory and receptor binding activity of misoprostol was markedly reduced, with potency much less than misoprostol free acid. These results indicate that misoprostol free acid is the active biological form of misoprostol that binds to prostaglandin E receptors and mediates the antisecretory action of misoprostol.

Effects of left atrial pressure on the pulmonary vascular response to hypoxic ventilation

We investigated the effects of hypoxic ventilation on the pulmonary arterial pressure- (P) flow (Q) relationship in an intact canine preparation. Mean pulmonary P-Q coordinates were obtained during hypoxic ventilation and during ventilation with 100% O2 at normal and at increased left atrial pressure. Specifically, we tested the hypothesis that, over a wide range, changes in left atrial pressure would alter the effects of hypoxic ventilation on pulmonary P-Q characteristics. Seven dogs were studied. When left atrial pressure was normal (5 mmHg), the mean value of the extrapolated intercept (PI) of the linear P-Q relationship was 10.9 mmHg and the slope (incremental vascular resistance, IR) of the P-Q relationship was 2.2 mmHg.l-1.min. Hypoxic ventilation increased PI to 18 mmHg (P less than 0.01) but did not affect IR. Subsequently, during ventilation with 100% O2, when left atrial pressure was increased to 14 mmHg by inflation of left atrial balloon, PI increased to 18 mmHg. IR was 1.6 mmHg.l-1.min. Again, hypoxic ventilation caused an isolated change in PI. Hypoxia increased PI from 18 to 28 mmHg (P less than 0.01). As in the condition of normal left atrial pressure, hypoxic ventilation did not affect IR. We conclude that, in an anesthetized intact canine preparation, hypoxic ventilation causes an isolated increase in the extrapolated pressure intercept of the pulmonary P-Q relationship. Furthermore the effects of hypoxic ventilation on pulmonary P-Q characteristics are not affected by the resting left atrial pressure.

Dynamic properties of left ventricular response to changes in coronary perfusion

To determine the dynamic property of cardiac function response to alterations in coronary perfusion, we varied coronary arterial pressure (CAP) sinusoidally around one of four mean CAP levels with a constant amplitude at several frequencies in isolated, isovolumically contracting canine heart preparations. From the frequency spectrum of the peak left ventricular pressure (PLVP) response, we arrived at a phenomenological model with two components coupled in parallel and estimated the parameter values. One component is a first-order delay system having a short time constant (approximately 1 s) and a small gain (range 0.08-0.16); it probably represents a hydraulic effect of coronary perfusion. The other component is a second-order delay system with longer time constants (approximately 15 and 6 s) and a larger gain (range 0.14-0.69); this probably represents a metabolic effect. The gain value of the slow component varied inversely with the mean CAP level, and studies with adenosine suggested that this dependence was due to the coronary autoregulation. The model prediction of the transient responses of PLVP to step changes in CAP agreed reasonably well with those experimental data of transient responses obtained in the identical hearts but not used to determine the model parameter values.

Kistrin, a polypeptide platelet GPIIb/IIIa receptor antagonist, enhances and sustains coronary arterial thrombolysis with recombinant tissue-type plasminogen activator in a canine preparation.

Kistrin is a 68-amino acid polypeptide from the venom of the Malayan pit viper Agkistrodon rhodostoma, which inhibits the platelet GPIIb/IIIa receptor. Its effect on thrombolysis, reocclusion, and bleeding associated with administration of recombinant tissue-type plasminogen activator (rt-PA) was studied in a canine model of coronary artery thrombosis. Coronary patency was monitored for 2 hours by ultrasonic flow probe and repeated coronary angiography. The rt-PA was given as 0.45-mg/kg bolus injections at 15-minute intervals until recanalization or to a maximum of four boluses. Four groups of four or five dogs were studied: a control group that received intravenous heparin (4,000-unit bolus and 1,000 units each hour) and three groups that received heparin and 0.48, 0.24, or 0.12 mg/kg kistrin, administered as a 10% bolus injection and an infusion during a 60-minute period. In the control group, reflow occurred in four of five dogs within 37 +/- 47 minutes but was followed by cyclic reflow and reocclusion. Kistrin at a dose of 0.48 and 0.24 mg/kg reduced the time to reflow to 6 +/- 5 and 10 +/- 3 minutes, respectively, and abolished reocclusion. With 0.12 mg/kg kistrin, reflow occurred in all four animals, within 27 +/- 23 minutes, and reocclusion occurred in two animals. Kistrin induced a dose-related prolongation of the template bleeding time: with 0.48 mg/kg kistrin, the bleeding time was prolonged from 3.8 +/- 1.3 minutes before infusion to 29 +/- 2 minutes during infusion, but it was shortened to 8.3 +/- 2.6 minutes at 90 minutes after the end of infusion. Kistrin also caused a dose-related inhibition of platelet aggregation with ADP and collagen: with 0.48 mg/kg kistrin, platelet aggregation was abolished during the infusion but had partially recovered toward the end of the observation period. Pathological examination of recanalized coronary arterial segments of dogs given 0.48 or 0.24 mg/kg kistrin revealed widely patent arteries with some platelets layered on the damaged intimal surface. Kistrin increases the rate and extent of thrombolysis with a reduced dose of rt-PA, and it prevents reocclusion. At an effective dose, it is associated with a transient prolongation of the bleeding time and inhibition of platelet aggregation. Kistrin may offer promise as adjunctive treatment to thrombolytic agents in patients with acute myocardial infarction.

Comparison of Cardiovascular Effects of a Novel Class Ic Antiarrhythmic Agent, NIK-244, with Those of Flecainide in Isolated Canine Heart Preparations Cross-Circulated with a Donor Dog

Comparison of Cardiovascular Effects of a Novel Class Ic Antiarrhythmic Agent, NIK-244, with Those of Flecainide in Isolated Canine Heart Preparations Cross-Circulated with a Donor Dog