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PubMed1994

Sympathetic activity and blood pressure are tightly coupled at 0.4 Hz in conscious rats.

Interactions of sympathetic nerve activity (SNA) with blood pressure (BP) and heart rate (HR) were assessed in conscious rats while they rested quietly in a cloth sock (n = 7), roamed freely in their home cage (n = 6), and then after anesthesia with pentobarbital (30 mg/kg; n = 7). The power and coherence spectra below 3 Hz were calculated from data collected for 9.56 min. In the conscious rat, SNA spectral power peaked at 0.4 Hz, whereas the majority of spectral power for both BP and HR occurred at frequencies lower than 0.4 Hz. However, there was an inconspicuous peak in the BP power spectra at 0.4 Hz that was not seen in the HR spectra. Coherence between SNA and BP peaked at a frequency of approximately 0.4 Hz, the same frequency at which the SNA spectral peaks occurred. In contrast, at frequencies below 0.4 Hz where maximum BP power occurred, the coherence was considerably lower. Anesthesia with pentobarbital lowered spectral power for BP, SNA, and HR but essentially did not change the coherence between SNA and BP. Interactions between respiration and each of the other variables were weak in the conscious rat. However, prominent respiratory interactions at approximately 1.2 Hz were evident after anesthesia. These data indicate a close coupling between SNA and BP at 0.4 Hz, raising the possibility that the BP spectral power at 0.4 Hz reliably reflects sympathetic activity.

Anesthesia, General↗
PubMed1985

Effects of volume expansion on renal nerve activity, renal blood flow, and sodium and water excretion in conscious dogs.

Effects of acute volume expansion with isotonic isoncotic 3% dextran in saline were examined on renal nerve activity (RNA), renal blood flow, vascular resistance, and sodium and water excretion in conscious dogs. In intact dogs, acute volume expansion increased mean arterial pressure 15 +/- 3 mmHg, left atrial pressure 5.5 +/- 0.6 mmHg, and decreased RNA 88 +/- 2%, whereas renal blood flow did not change and renal vascular resistance increased slightly. When renal perfusion pressure was maintained at control levels, volume expansion decreased RNA 87 +/- 2% and renal vascular resistance 15 +/- 4%. During the 80-min period after volume expansion, urine flow rate increased 0.66 +/- 0.13 ml/min and sodium excretion rose 3.89 +/- 0.54 mueq X min-1 X kg-1, whereas RNA remained depressed. Arterial baroreceptor denervation (ABD) did not diminish responses of RNA, renal blood flow, renal vascular resistance, or sodium and water excretion to volume expansion. After ABD plus bilateral cervical vagotomy, volume expansion did not decrease RNA, and diuretic and natriuretic responses were significantly attenuated (P less than 0.025). However, responses of renal blood flow to volume expansion were not altered significantly. In conscious dogs with renal denervation, responses of renal blood flow to volume expansion were not impaired, whereas diuretic and natriuretic responses were attenuated (P less than 0.025). Thus, in intact conscious dogs, vagally mediated reflex decreases in RNA induced by acute volume expansion exerted a significant effect on sodium and water excretion but little control of renal blood flow and renal vascular resistance.

Animals↗
PubMed1999

Endothelin mediates renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats.

Profound vasodilation of the kidneys and other nonreproductive organs transpires during early pregnancy. Because nitric oxide (NO) was found to mediate renal vasodilation and hyperfiltration in conscious pregnant rats, and endogenous endothelin (ET) was suggested to be vasodilatory in the renal circulation of nonpregnant rats, we tested whether endothelin mediates the NO-dependent changes in the renal circulation during pregnancy. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured in conscious pregnant and virgin rats before and during infusion of 30 micrograms/min RES-701-1 (a selective ETB receptor subtype antagonist). Baseline GFR and ERPF were significantly increased by 35% in gravid rats relative to virgin controls. During infusion of RES-701-1, the pregnant rats responded more robustly, showing a greater decline in both GFR and ERPF such that renal function converged in the two groups of rats. ERPF also converged in pregnant and virgin rats during infusion of SB-209760, a nonselective ETA/B receptor subtype antagonist. Combined infusion of Nomega-nitro-L-arginine methyl ester [L-NAME, an NO synthase (NOS) inhibitor] and RES-701-1 reduced GFR and ERPF to levels comparable to those reached with either agent given alone, suggesting inhibition of a common vasodilatory pathway. RES-701-1 and SB-209670 significantly lowered the cGMP content of small renal arteries from gravid and virgin rats in vitro, strengthening the link between the renal endothelial ETB receptor subtype and NO. Importantly, we showed that RES-701-1 is not a direct inhibitor of NOS. We conclude that endothelin mediates the NO-dependent changes in the renal circulation of conscious rats during pregnancy.

Animals↗
PubMed1983

Inhibition of hypoxia-induced ADH release by meclofenamate in the conscious dog.

Release of antidiuretic hormone (ADH) due to hypoxic stimuli has been documented in several in vivo models. The current study was performed to determine whether 1) hypoxia causes ADH release in the conscious normovolemic dog and 2) whether endogenous prostaglandins are involved in hypoxic ADH release. Five conscious dogs were made hypoxic by inhalation of 10% O2. Dogs were studied both with and without pretreatment with meclofenamate (2 mg/kg iv and 2 mg . kg-1 . h-1). Hypoxic exposure resulted in elevated plasma ADH; however, meclofenamate totally blocked this response. Hemodynamic responses to hypoxia were unaffected by meclofenamate. In addition, plasma osmolality was unchanged by hypoxia in both groups. Since meclofenamate does not cross the blood-brain barrier, it is concluded that the release of ADH by hypoxia in the conscious dog may be mediated by endogenous prostaglandins produced outside the central nervous system. It appears that elevated renal prostaglandin release, increased ADH, and hemodynamic alterations could all interact to determine the final renal response to hypoxia.

Animals↗
PubMed1984

Effects of hypoxia on ventilation during postnatal development in conscious kittens.

Effects of steady-state hypoxia (inspired O2 fraction = 0.11) on ventilation and breathing pattern were studied during postnatal development in unanesthetized kittens. Studies were done from 2 days to 8 mo of age, every week during the first month and every month thereafter. During the first 2 months, states of consciousness were determined. In the first month, minute ventilation (VE) was depressed in hypoxia compared with control values in air, whereas in the older kittens VE was increased in hypoxia, as in adult cats. The inhibitory effect of hypoxia was observed in all three states of consciousness in 7- and 14-day-old kittens. In the 21- and 28-day-old kittens, VE could not be reliably related to the state of consciousness. In the 2-mo-old kittens, VE increased in all states. Tidal volume (VT) was markedly decreased in kittens up to 14 days of age, and respiratory frequency increased. In the 21- and 28-day-old kittens, changes in breathing pattern were variable. In the oldest, the increase of VE was mainly due to an increase of VT. We conclude that in unanesthetized kittens, the ventilatory response to hypoxia is mature at 2 mo of age. The hypoxic tachypnea observed at 7 and 14 days resembles that previously seen in adult carotid-denervated cats, and may be due to a low level of carotid chemoreceptor drive and to a central excitatory effect of hypoxia on respiratory frequency. The complex response observed during the first month of life must reflect the development of peripheral and central mechanisms and their interactions.

Aging↗
PubMed2000

Systemic hypoxia increases leukocyte emigration and vascular permeability in conscious rats.

We recently observed that acute systemic hypoxia produces rapid increases in leukocyte adherence in the mesenteric microcirculation of the anesthetized rat Wood JG, Johnson JS, Mattioli LF, and Gonzalez NC. J Appl Physiol 87: 1734-1740, 1999; Wood JG, Mattioli LF, and Gonzalez NC. J Appl Physiol 87: 873-881, 1999. Hypoxia-induced leukocyte adherence is associated with an increase in reactive oxygen species (ROS) generation and is attenuated by antioxidants or interventions that increase tissue levels of nitric oxide (NO). These results suggest that the acute effects of hypoxia on leukocyte-endothelial interactions are caused by a change in the ROS-NO balance. The present experiments were designed to extend our observations of the initial microcirculatory response to hypoxia; specifically, we wanted to determine whether the response to systemic hypoxia involves increased microvascular permeability and leukocyte emigration and whether ROS generation and decreased NO levels contribute to these responses. At this time, there is conflicting evidence, from in vitro studies, regarding the effect of hypoxia on these indexes of vascular function. Our studies were carried out in the physiological setting of the conscious animal, in which a prolonged hypoxic exposure is possible without the adverse effects that may develop under anesthesia. The central observation of these studies is that conscious animals exposed for 4 h to environmental hypoxia show increased microvascular permeability and emigration of leukocytes into the extravascular space of the mesenteric circulation. Furthermore, these events are dependent on increased ROS generation and, possibly, a subsequent decrease in tissue NO levels during systemic hypoxia. Our results show that systemic hypoxia profoundly affects vascular endothelial function through changes in the ROS-NO balance in the conscious animal.

Animals↗
PubMed2004

Effects of relaxin on systemic arterial hemodynamics and mechanical properties in conscious rats: sex dependency and dose response.

We previously showed that chronic administration of recombinant human relaxin (rhRLX; 4 microg/h) to conscious female, nonpregnant rats to reach serum levels corresponding to early to midgestation (approximately 20 ng/ml) increases cardiac output (CO) and global arterial compliance (AC) and decreases systemic vascular resistance (SVR), comparable to changes observed in midterm pregnancy. The goals of this study were to test whether chronic administration of rhRLX (4 microg/h) to conscious male rats will yield similar changes in CO and systemic arterial load and to determine whether higher infusion rates of rhRLX (50 microg/h) administered to nonpregnant female rats yielding serum concentrations corresponding to late pregnancy ( approximately 80 ng/ml) will further modify CO and SVR and global AC comparable to late gestation. CO and systemic arterial load, as quantified by SVR and AC, were obtained by using the same methods as in our previous studies. With respect to baseline, chronic rhRLX administration to male rats over 10 days at 4 mug/h increased both CO (20.5 +/- 4.2%) and AC (19.4 +/- 6.9%) and reduced SVR (12.7 +/- 3.9%). These results were comparable to those elicited by the hormone in nonpregnant female rats. In contrast, neither acute (over 4 h) nor chronic (over 6 days) infusion of the higher dose of rhRLX administered to conscious female rats resulted in significant changes in CO, AC, or SVR from baseline. We conclude that 1) rhRLX increases CO and AC and reduces SVR irrespective of sex, and 2) the rhRLX dose response is biphasic insofar as significant alterations in CO and systemic arterial load fail to occur at high serum concentrations.

Animals↗
PubMed1998

Disturbance of consciousness due to methamphetamine abuse. A study of 2 patients.

The present paper reports 2 cases of methamphetamine abuse. Following consecutive methamphetamine administration, the patients developed acute intoxication, during which time they showed a unique type of disturbance of consciousness: delirium and twilight state. In both cases, mental status changed, passing through three distinct stages: restlessness and insomnia, hallucinatory paranoid state, and disturbance of consciousness. A review of the literature suggests that disturbance of consciousness may occur occasionally during the course of amphetamine and methamphetamine intoxication, although these symptoms can be overlooked easily due to confounding symptomatology.

Central Nervous System Stimulants↗
PubMed1981

Eccles's physiological evidence for a self-conscious mind.

Eccles cites three items of physiological evidence for a self-conscious mind: experiments by Libet, showing that consciousness can antedate sensory experience; slow build-up of the readiness potential, showing that the mind is weak; that brain events are scattered, but consciousness is a unity. I argue that none of the three items has any significance: the first is a confusion about the experimental evidence; the second indicates weak physical forces, no mind; the third replaces visible structures by intangible influences. Thus, these physiological arguments do not support the contention that non-physical influences are at work.

Brain↗
PubMed2002

Brief increase in carbohydrate oxidation after reperfusion reverses myocardial stunning in conscious pigs.

BACKGROUND: Previous studies have examined only acute effects of enhanced glucose oxidation on postischemic myocardium. The goal of the present study was to examine prolonged functional recovery subsequent to postischemic, intracoronary pyruvate dehydrogenase kinase inhibition with dichloroacetate (DCA) of stunned myocardium in conscious pigs. METHODS AND RESULTS: Myocardial stunning was induced in conscious pigs by coronary stenosis, ie, 40% reduction of coronary blood flow for 90 minutes, followed by full reperfusion. After the initial peak, but during early reactive hyperemia (5 minutes of reperfusion), 1 hour of intracoronary infusion at 20% of measured coronary blood flow was begun using 20 mmol/L [2-(13)C]glucose without (n=4) or with (n=5) 20 mmol/L DCA. Coronary stenosis resulted in similar reduction in wall thickening in both untreated (-53+/-3% from 3.27+/-0.22 mm, n=9) and DCA (-51+/-3% from 3.08+/-0.15 mm, n=5) groups. During reperfusion, DCA increased glucose oxidation 10-fold. In the absence of DCA, myocardial stunning was observed; ie, wall thickening was reduced by 48+/-3% at 1 hour of reperfusion and did not fully recover for 48 hours. In contrast, in DCA pigs, myocardial stunning was ameliorated (P<0.05). CONCLUSIONS: Transient metabolic intervention within a clinically relevant time after ischemia eliminates myocardial stunning in conscious pigs during augmented carbohydrate oxidation and provides sustained benefits in contractile recovery.

Animals↗
PubMed2004

Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy.

BACKGROUND: The failing heart demonstrates a preference for glucose as its metabolic substrate. Whether enhancing myocardial glucose uptake favorably influences left ventricular (LV) contractile performance in heart failure remains uncertain. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with potent insulinotropic effects the action of which is attenuated when glucose levels fall below 4 mmol. We examined the impact of recombinant GLP-1 (rGLP-1) on LV and systemic hemodynamics and myocardial substrate uptake in conscious dogs with advanced dilated cardiomyopathy (DCM) as a mechanism for overcoming myocardial insulin resistance and enhancing myocardial glucose uptake. METHODS AND RESULTS: Thirty-five dogs were instrumented and studied in the fully conscious state. Advanced DCM was induced by 28 days of rapid pacing. Sixteen dogs with advanced DCM received a 48-hour infusion of rGLP-1 (1.5 pmol x kg(-1) x min(-1)). Eight dogs with DCM served as controls and received 48 hours of a saline infusion (3 mL/d). Infusion of rGLP-1 was associated with significant (P<0.02) increases in LV dP/dt (98%), stroke volume (102%), and cardiac output (57%) and significant decreases in LV end-diastolic pressure, heart rate, and systemic vascular resistance. rGLP-1 increased myocardial insulin sensitivity and myocardial glucose uptake. There were no significant changes in the saline control group. CONCLUSIONS: rGLP-1 dramatically improved LV and systemic hemodynamics in conscious dogs with advanced DCM induced by rapid pacing. rGLP-1 has insulinomimetic and glucagonostatic properties, with resultant increases in myocardial glucose uptake. rGLP-1 may be a useful metabolic adjuvant in decompensated heart failure.

Animals↗
PubMed1987

The end-systolic pressure-volume relationship in conscious dogs.

The end-systolic pressure-volume relationship (ESPVR) has been shown to be an afterload-insensitive descriptor of ventricular inotropic state in the isolated heart. The purpose of this study was to examine the effects of changes in afterload, heart rate, intravascular volume, autonomic tone, and inotropic state on the ESPVR in conscious dogs. In 30 dogs, left ventricular and pleural pressures were measured with micromanometers, and left ventricular volume was assessed with global ultrasonic crystals. The ESPVR was obtained during vena caval occlusions in each dog during pharmacologic afterload interventions at control and after autonomic blockade. Analysis of variance techniques were used to compare the slopes (Emax) and intercepts (Vd) of ESPVR regression lines in a given study. All estimates of the ESPVR in conscious dogs involved large extrapolations to obtain estimates of Vd. Repeat determinations of Emax at control in the unblocked state were significantly different in six of eight dogs (p less than .05). After autonomic blockade, these differences were significant in only one of eight dogs. Changes in heart rate and volume loading had minimal effects on the ESPVR. In the absence of autonomic blockade, increases in inotropic state with either calcium or dobutamine tended to cause parallel shifts in the ESPVR. After autonomic blockade, Emax increased with augmentation of inotropic state, while Vd was unchanged. ESPVRs obtained at different afterloads showed statistically significant differences in Emax and in Vd in 12 of 14 dogs. However, no statistically significant relationship of Emax to afterload was observed. Thus, the ESPVR is probably valid in conscious dogs, but measurement with an intact cardiovascular system is hampered by statistically significant variability in Emax and Vd with changes in afterload. Baseline variability is magnified by the autonomic nervous system, probably mediated through sympathetic reflexes.

Analysis of Variance↗
PubMed1988

Response of the left ventricular end-systolic pressure-volume relation in conscious dogs to a wide range of contractile states.

We assessed the linearity and slope of the left ventricular end-systolic pressure (PES)-volume (VES) relation over a wide range of contractile states in conscious dogs. The animals were instrumented to determine left ventricular volume from ultrasonic left ventricular internal dimensions and measure left ventricular pressure with a micromanometer. Studies were performed 1-2 weeks after instrumentation while the animals were conscious. Contractile state was increased by incremental infusion of dobutamine (0, 2, 4, 6, and 8 micrograms/kg/min i.v.) and decreased by verapamil (10 mg i.v.) given after autonomic blockade. The 44 +/- 11 mm Hg (mean +/- SD) portion of the PES-VES relation generated by bicaval occlusion demonstrated a slight but consistent nonlinearity, apparent as a concavity toward the volume axis. This nonlinearity, present at all inotropic states, did not prevent the PES-VES relation from being well approximated by a straight line (r = 0.984 +/- 0.020, SEE = 2.1 +/- 1.4 mm Hg); furthermore, the slope of the PES-VES line provided a sensitive index of contractile state, progressively increasing with incremental doses of dobutamine and decreasing in response to verapamil. The volume-axis intercept of the linear approximation of the PES-VES relation was 2.9 +/- 3.3 ml less (p less than 0.05) than the volume-axis intercept of the nonlinear quadratic fit. Thus, the linear PES-VES relation, whose slope is sensitive to a wide variety of inotropic states, is a reasonable and useful description of the left ventricle in the range of PES-VES points that can be produced by bicaval occlusion in the conscious dog. However, linear extrapolation of the relation beyond the range of data points may not be accurate.

Animals↗
PubMed1989

Superoxide dismutase reduces reperfusion arrhythmias but fails to salvage regional function or myocardium at risk in conscious dogs.

To determine if oxygen free radical scavengers administered before coronary artery reperfusion can limit reperfusion arrhythmias, increase the return of regional function in ischemic myocardium, and reduce tissue necrosis at 1 week after 90-minute coronary artery occlusion and reperfusion, conscious dogs were treated with superoxide dismutase (SOD) and catalase before and for 1 hour after coronary artery reperfusion. Another group was treated with recombinant SOD (rSOD) because the commercially available SOD and catalase contained endotoxin. The conscious dogs were studied 3-4 weeks after implanting left ventricular pressure gauges, ultrasonic wall thickness gauges in the posterior left ventricular wall, left atrial catheters, and arterial catheters, Doppler flow transducers, and hydraulic occluders on the left circumflex coronary artery. The only beneficial effect observed was that the number of arrhythmic beats per minute in the rSOD-treated group was significantly lower (p less than 0.05) when compared with a control group after coronary artery reperfusion. Treatment neither increased the amount of recovery of wall thickening in the ischemic zone nor reduced infarct size when expressed either as a percentage of the area at risk or as a function of collateral blood flow in the ischemic zone. For example, infarct size as a percentage of the area at risk was 32.6 +/- 5.8%, 37.4 +/- 6.4%, 28.3 +/- 5.1% in the control, SOD and catalase-, and rSOD-treated groups, respectively. Thus, although treatment with oxygen free radical scavengers invoked a transient reduction in the number of reperfusion arrhythmias, this treatment in conscious dogs failed to improve regional myocardial dysfunction or reduce the amount of necrosis when compared with a control group. The lack of a sustained salutary effect may indicate that longer periods of treatment with free radical scavengers are required in chronic preparations.

Animals↗
PubMed1992

Enhancement of the force-frequency effect on myocardial contractility by adrenergic stimulation in conscious dogs.

BACKGROUND: The influence of changes in heart rate on myocardial contractility (the force-frequency effect) differs under various experimental conditions, including the anesthetized versus the conscious state. METHODS AND RESULTS: To assess the influence of beta-adrenergic stimulation on force-frequency effects on myocardial contraction and relaxation, seven instrumented conscious dogs were studied in which heart rate could be controlled by atrial pacing after the intrinsic rate was slowed with a bradycardiac agent (UL-FS 49 0.5-0.75 mg/kg). Left ventricular (LV) pressure was measured with a micromanometer under resting conditions and during dobutamine infusion at low, intermediate, and high doses (2.7, 5.4, and 10.7 micrograms/kg/min). At each dose, heart rate was progressively increased from 100 to 210 beats per minute. In the absence of dobutamine (control), no significant positive force-frequency effect was detected on LV dP/dtmax; this was probably due to the known effect of the observed decrease in preload to reduce LV dP/dtmax, thereby offsetting an effect of the force-frequency response to increased dP/dt. However, during dobutamine infusions, the force-frequency effect was observed to increase significantly in a dose-dependent manner with increases in heart rate. An increase in heart rate from 100 to 210 beats per minute increased LV dP/dtmax by 12.4 +/- 12.5% with low-dose, 22.7 +/- 13.1% with intermediate-dose, and 27.5 +/- 8.9% with high-dose dobutamine. Changes in preload and aortic pressure were within the same ranges under control conditions and at each of the three dobutamine doses. The time constant of LV pressure fall (tau) was significantly shorter with increases in heart rate during control, but only the highest dobutamine dose caused further significant shortening in tau with increased heart rate. CONCLUSIONS: These data indicate that there is a pronounced dose-dependent action of beta-adrenergic stimulation to enhance force-frequency-induced contractile responses in normal conscious dogs.

Adrenergic beta-Agonists↗
PubMed1989

Hemodynamic and renal responses to physiological levels of atrial natriuretic factor in conscious dogs.

The effects of increases in plasma atrial natriuretic factor (ANF) similar to those encountered after rapid volume expansion were examined in conscious dogs. Hemodynamics and renal function were continuously monitored during 30 minutes of human ANF infusion (10 ng/kg.min) and throughout a 30-minute recovery period. Ten minutes into the infusion period, plasma levels of ANF were elevated (p less than 0.01) by 34 +/- 9 from 36 +/- 5 pg/ml and sodium excretion increased (p less than 0.05) by 34 +/- 7 from 67 +/- 9 mueq/min. At that time, urine flow did not differ from baseline (0.25 +/- 0.03 ml/min). Renal blood flow velocity fell (p less than 0.01) by 5.0 +/- 0.5 from 42.3 +/- 3.7 cm/sec. Thirty minutes into the infusion period, plasma ANF levels were increased (p less than 0.01) by 61 +/- 9 pg/ml, similar to levels found after rapid volume expansion in conscious dogs. Urine flow and sodium excretion were elevated (p less than 0.01) by 0.35 +/- 0.06 ml/min and by 65 +/- 12 mueq/min, respectively. Renal blood flow velocity was reduced (p less than 0.05) by 4.4 +/- 1.5 cm/sec. Neither right atrial pressure, left ventricular end-diastolic pressure, mean arterial pressure, the first derivative of left ventricular pressure over time (dP/dt), nor heart rate were influenced by the elevated ANF plasma levels. Circulating levels of vasopressin and aldosterone were unaltered by these increases in plasma ANF. Thirty minutes into the recovery period, all variables were similar to the preinfusion baseline. Thus, in conscious dogs, physiologically relevant increases in plasma levels of ANF reached diuretic and natriuretic thresholds.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

The early and late phases of ischemic preconditioning: a comparative analysis of their effects on infarct size, myocardial stunning, and arrhythmias in conscious pigs undergoing a 40-minute coronary occlusion.

The effectiveness of the late phase of ischemic preconditioning (PC) in protecting against myocardial infarction and the concomitant contractile dysfunction after sustained ischemia remains unclear. The early and late phases of PC have not been compared using the same protocol in the same experimental model; furthermore, the late phase of PC has not been assessed in the conscious state in a large animal preparation. The goal of this study was to directly compare the effects of early and late PC on myocardial infarct size and postischemic dysfunction in chronically instrumented, conscious pigs. Four groups of pigs were subjected to a 40-minute coronary occlusion followed by 3 days of reperfusion. Group 1 (n=7) served as control. Group 2 (n=6) was subjected to ten 2-minute occlusion/2-minute reperfusion cycles 25 minutes before the 40-minute occlusion (early PC). Groups 3 (n=7) and 4 (n=4) were subjected to 10 and 25 cycles, respectively, of 2-minute occlusion/2-minute reperfusion 24 hours before the 40-minute occlusion (late PC). Infarct size averaged 45.1+/-5.9% of the region at risk in control pigs, was reduced by 79% (to 9.4+/-3.2%) in group 2, but did not differ in groups 3 (33.3+/-4.8%) and 4 (38.8+/-8.2%) versus group 1. Power analysis demonstrated that there was an 80% probability of detecting a 40% decrease in infarct size in groups 3 and 4 versus group 1. The recovery of systolic wall thickening (measured with ultrasonic crystals) after the 40-minute occlusion was poor in groups 1, 3, and 4 but markedly enhanced in group 2 throughout the 3 days of reperfusion; this beneficial effect could have been due to limitation of infarct size, alleviation of stunning, or both. Thus, a series of ten 2-minute coronary occlusions had a profound (approximately 80%) early infarct-limiting effect, which was associated with a marked functional benefit. This protection, however, disappeared 24 hours later and could not be reinstituted by increasing the number of PC coronary occlusions to 25. The incidence and duration of ventricular tachycardia after reperfusion was not changed by either early or late PC; no conclusions could be drawn regarding ventricular fibrillation or ischemia-induced ventricular tachycardia, since these arrhythmias did not occur in control animals. Taken together, the present results demonstrate striking differences between the early and late effects of PC: In conscious swine subjected to a sustained coronary occlusion, a PC protocol that induces powerful protection during the early phase of PC fails to induce any protection during the late phase, indicating either that a late protective effect of PC does not exist or that, if it exists, it must be weaker than the early protective effect.

Animals↗
PubMed1997

Evidence that late preconditioning against myocardial stunning in conscious rabbits is triggered by the generation of nitric oxide.

Recent studies in conscious pigs and rabbits have demonstrated that a series of brief coronary occlusions renders the heart relatively resistant to myocardial "stunning" 24 hours later (late preconditioning [PC] against stunning). The mechanism of this powerful cardioprotective response is unknown. The goal of the present study was to test the hypothesis that the development of late PC against stunning is triggered by increased generation of NO during the first ischemic challenge. Conscious rabbits underwent a sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles for 3 consecutive days (days 1, 2, and 3). On day 1, rabbits received either an intravenous infusion of the NO synthase inhibitor NG-nitro-L-arginine (L-NA, 13 mg/kg before the first occlusion) (group II, n = 10) or vehicle (group I [control], n = 10). In the control group, on day 1 systolic wall thickening (WTh) in the ischemic/reperfused region remained significantly depressed for 4 hours after the sixth reperfusion, indicating myocardial stunning. On days 2 and 3, however, the recovery of WTh improved markedly, so that the total deficit of WTh decreased by 60% on day 2 and 55% on day 3 compared with day 1 (P < .01). In the L-NA-treated group, the total deficit of WTh on day 1 was similar to that observed in the control group. On day 2, however, the total deficit of WTh was not significantly different from that observed on day 1 and was 132% greater than that observed in control rabbits on day 2 (P < .01). On day 3, the total deficit of WTh was 66% less than that noted on day 2 (P < .01). Thus, in L-NA-treated rabbits the sequence of six coronary occlusions and reperfusions performed on day 1 failed to precondition against stunning on day 2, but the same sequence performed on day 2 did precondition against stunning on day 3. Another group of rabbits (group III, n = 6) received L-NA on day 1 in the absence of ischemia and was subjected to the occlusion/ reperfusion sequence on days 2 and 3. In these animals, the total deficit of WTh on day 2 did not differ from that observed in control rabbits on day 1, indicating that administration of L-NA did not exacerbate the severity of myocardial stunning 24 hours later; therefore, the absence of late PC against stunning on day 2 in group II cannot be ascribed to a delayed deleterious action of L-NA on WTh. In conclusion, these results demonstrate that the NO synthase inhibitor L-NA completely blocks the development of late PC against myocardial stunning in conscious rabbits, indicating that NO generated as a result of the PC ischemia triggers the development of the cardioprotective response observed 24 hours later. NO is known to exert numerous biological actions resulting in rapid but transient physiological responses. The present observations support a novel pathophysiological paradigm in which NO also plays a key role in the delayed myocardial adaptations to ischemic stress, acting as a signaling step in the transduction pathway that leads to increased resistance to subsequent ischemic injury.

Animals↗