Conscious Goats Research Articles

Cardiorespiratory Effects of Three Infusion Doses of Adenosine in Conscious Goats: A Preliminary Study

Adenosine (AD) has been implicated in human healthcare as an endogenous signaling nucleotide in both physiologic and pathologic states. The effects of AD on cardiorespiratory parameters in ruminants has not yet been studied. The objective of this study was to evaluate the cardiac and respiratory changes that resulted from an intravenous AD infusion in goats. Six clinically healthy adult goats weighing 28 ± 2 kg were randomly assigned to one of four treatments in a crossover design with a seven day washout period. The goats received a 0.9 % saline solution (SAL treatment) and three AD treatments (AD 50, 100 and 200) intravenously at a dose rate of 50, 100 and 200 μg/kg/min. Cardiorespiratory and key cardiac parameters were measured before the treatment (baseline), during the infusion (dInf) and at 1, 3, 5 and 10 min after each infusion was discontinued. The AD 100 produced a significant increase in HR (p = 0.001) and the AD 200 resulted in significant rises in HR (p = 0.006) and RR (p = 0.001) compared with the baseline. This study concluded that the AD infusion could trigger an increase in HR and RR in a dose-dependent manner in healthy goats.

Midbrain and cerebral inflammatory and glutamatergic adaptations during chronic hypercapnia in goats

Cognitive impairment is associated with multiple human diseases that have in common chronic hypercapnia. However, the mechanisms leading to chronic hypercapnia-induced cognitive decline are not known. We have previously shown chronic hypercapnia through exposure to increased inspired CO2 (6% InCO2) in conscious goats caused an immediate (within hours) and sustained decline in cognitive performance during a shape discrimination test. Herein, within the same goats, we assessed markers of neuroinflammation and glutamate receptor expression/phosphorylation within CNS regions important for cognitive function following 24 hours (h) or 30 days (d) of chronic hypercapnia. Within 24 h, chronic hypercapnia increased expression of the inflammatory cytokine IL-1β in the orbitofrontal cortex and medial prefrontal cortex, but at 30d IL-1β levels were not different relative to time-matched goats exposed to room-air. Additionally, Iba1 expression (a marker of microglial activation) was unaltered by chronic hypercapnia in all regions tested. Finally, levels of the total and phosphorylated AMPA receptor subunit GluR2 were reduced within the hippocampus at both 24 h and 30 d of hypercapnia, and reduced following 30 d within the anterior insular cortex. These data suggest that chronic hypercapnia leads to CNS site-dependent acute inflammatory responses and shifts in select glutamate receptor expression/phosphorylation in brain regions contributing to cognitive function. Such changes may be indicative of alterations in glutamatergic receptor-mediated signaling and neuronal dysfunction that contribute to declines in cognitive function associated with human diseases defined or marked by chronic CO2 retention.

Electrophysiological approach to the hypothalamic GnRH pulse generator

The hypothalamic GnRH pulse generator that regulates intermittent GnRH discharge into the pituitary portal circulation and thereby modulates pulsatile secretion of LH has been recognized as a key determinant of the reproductive function in mammals. Thus, various internal, as well as external, factors first modify the electrical activity of the GnRH pulse generator, which then alters the pulsatile pattern of gonadotrophin secretion and eventually influences reproductive function. Here, we describe a procedure that has permitted long-term recording of electrophysiological manifestation of the GnRH pulse generator activity and its application to our research which uses ovariectomized and cyclic female goats as experimental models. We have successfully recorded characteristic increases in neuronal activity associated with pulsatile LH secretion from conscious goats by means of a multiple unit activity (MUA) recording technique, which is an adaptation of that developed originally for use in rhesus monkeys. The unitary relationship between periodical increases in MUA (MUA volleys) and LH pulses is well maintained under a variety of experimental conditions, providing evidence that these MUA volleys are the consequence of GnRH pulse generator activity.

Sperm collection by transrectal ultrasound-guided massage of the accessory sex glands is less stressful than electroejaculation without altering sperm characteristics in conscious goat bucks

In anesthetized non-domestic ruminants transrectal ultrasound-guided massage of the accessory sex glands (TUMASG) is an alternative method to collect semen slightly less stressful than electroejaculation (EE). However, some sperm characteristics are better when semen is collected with EE than with TUMASG. As anesthesia reduces the response to stressors, the advantages of TUMASG may be reduced in anesthetized animals, and thus, TUMASG may be even more advantageous in conscious animals. Therefore, the aim of the present study was to compare the stress response and the characteristics of the sperm collected with TUMASG and EE in conscious goat bucks. Semen was collected in 10 bucks with both procedures. During each procedure, the time required for ejaculation, the number of electric pulses applied and the number of vocalizations were recorded. Rectal temperature, heart rate, serum cortisol concentration, biochemical and hematological parameters were measured before and after each procedure. Sperm characteristics [ejaculated volume, sperm concentration, sperm mass motility (scale 0–5), sperm vigor (scale 0–5), the percentages of motile and progressive motile sperm, of sperm vitality, of sperm with plasma membrane integrity, and with acrosome damage and morphological abnormalities] were also determined. Electroejaculation required more electric pulses than TUMASG (P < 0.0001), but TUMASG took more time than EE (P < 0.0001). The EE provoked more vocalizations (P = 0.02) and a greater increase of cortisol concentrations than TUMASG (P = 0.04). Heart rate also tended to be greater with EE than with TUMASG (P = 0.07). The sperm characteristics did not differ between TUMASG and EE. In conclusion, TUMASG was less stressful and probably less painful than EE without affecting the semen quality. Thus, although it required more time, TUMASG is an alternative procedure to decrease the welfare concerns raised by EE in conscious goat bucks.

Alternation of left ventricular load by a continuous-flow left ventricular assist device with a native heart load control system in a chronic heart failure model

We previously developed a native heart load control system for a continuous-flow left ventricular assist device and demonstrated that the rotational speed synchronized with the cardiac cycle can alter left ventricular preload and myocardial oxygen consumption. In the present study, we assessed this system in a conscious goat model of chronic heart failure. Chronic heart failure was induced by coronary microsphere embolization of the left ascending artery and subsequent rapid ventricular pacing in 6 goats. After 4 to 6 weeks of rapid pacing, the goats showed a decreased ejection fraction (from 89.7% ± 3.1% to 53.3% ± 5.4%) measured during sinus rhythm. The assist device was implanted by way of a left thoracotomy, and we examined the effects of the continuous, co-pulse, andcounterpulse mode on the end-diastolic volume and stroke work, determined from the left ventricular pressure-volume loops. Significant decreases were found in the end-diastolic volume and stroke work in the counterpulse mode relative to the values observed with 0% bypass (63.4% ± 15.2% and 39.1% ± 18.2%, respectively; P<.01). Furthermore, both increased in the co-pulse mode (82.1% ± 17.6% and 68.3% ± 22.2%; P<.01) compared with those in the continuous mode (69.6% ± 15.4% and 54.6% ± 21.6%) with 100% bypass. The system offers the possibility to control the left ventricular load by changing the rotational speed of a continuous-flow assist device in synchronization with the cardiac cycle. This system should provide the most favorable left ventricular loading conditions for recovery of the native heart.

Transcutaneous communication system using the human body as conductive medium: Influence of transmission data current on the heart

We developed a new transcutaneous communication system (TCS) that uses the human body as a conductive medium for monitoring and controlling artificial hearts and other artificial organs in the body.In this study, the physiological effect of data current discharged into the body during data transmission was evaluated by an animal experiment using a goat. The external and internal units of the new TCS each mainly consist of a data transmitter and a data receiver. The data transmitter has an amplitude shift keying (ASK) modulator (carrier frequencies: 4 and 10 MHz) and an electrode.The internal unit of the TCS was fixed on the pericardium and the external unit was placed on the left ear, and each transmitter discharged an ASK-modulated current of 7 mA (RMS) into the conscious goat. The TCS was able to transmit data for 4 weeks under full duplex communication with a transmission rate of 115 kbps. On the 28th postoperative day, an electrocardiogram was measured during data transmission. Cardiac rhythm and waveform of the electrocardiogram were not changed before and during bidirectional data transmission. Also, no adverse effect on the heart was observed by autopsy.

The effects of α- and β-sympathicomimetics on rumen motility and heart rate frequency in conscious goats

The effects of α- and β-sympathicomimetics on rumen motility and heart rate frequency in conscious goats

The effects of bacterial pyrogens and leucocytic pyrogen upon gastric motility and heart rate frequency in conscious goats.

The effects of bacterial pyrogens and leucocytic pyrogen upon gastric motility and heart rate frequency in conscious goats.

In Vitro and In Vivo Effects of the Atrial Selective Antiarrhythmic Compound AVE1231

The novel compound AVE1231 was investigated in order to elucidate its potential against atrial fibrillation. In CHO cells, the current generated by hKv1.5 or hKv4.3 + KChIP2.2b channels was blocked with IC50 values of 3.6 microM and 5.9 microM, respectively. In pig left atrial myocytes, a voltage-dependent outward current was blocked with an IC50 of 1.1 microM, mainly by accelerating the time constant of decay. Carbachol-activated IKACh was blocked by AVE1231 with an IC50 of 8.4 microM. Other ionic currents, like the IKr, IKs, IKATP, ICa, and INa were only mildly affected by 10 microM AVE1231. In guinea pig papillary muscle the APD90 and the upstroke velocity were not significantly altered by 30 microM AVE1231. In anesthetized pigs, oral doses of 0.3, 1, and 3 mg/kg AVE1231 caused a dose-dependent increase in left atrial refractoriness (LAERP), associated by inhibition of left atrial vulnerability to arrhythmia. There were no effects on the ECG intervals, ventricular monophasic action potentials, or ventricular refractory periods at 3 mg/kg AVE1231 applied intravenously. In conscious goats, both AVE1231 (3 mg/kg/h iv) and dofetilide (10 microg/kg/h iv) significantly prolonged LAERP. After 72 hours of tachypacing, when LAERP was shortened significantly (electrical remodelling), the prolongation of LAERP induced by AVE1231 was even more pronounced than in sinus rhythm. In contrast, the effect of dofetilide was strongly decreased. The present data demonstrate that AVE1231 blocks early atrial K channels and prolongs atrial refractoriness with no effects on ECG intervals and ventricular repolarisation, suggesting that it is suited for the prevention of atrial fibrillation in patients.

Chronic Left Atrial Overload in the Goat: Electrophysiological Research

In the research for dilatation induced atrial fibrillation (AF), electrophysiological and hemodynamic investigation of the left atrium (LA) was effectuated in a new animal model of chronic LA overload. In 12 goats, a thoracotomy was performed to implant a vascular graft between the aorta and LA. In a control group, the graft was ligated. Overload was quantified after chronic instrumentation of the LA with ultrasonic crystals, bipolar sensing/pacing electrodes and a LA pressure catheter. Electrophysiological evolution was regularly evaluated in the conscious goats. “Continuing” AF was the ultimate purpose. After 28.6±13.9days of overload, LA length increased significantly by 43.4±18.0% and LA pressure mounted from 8.6±6.1 to 27.0±10.4mmHg (p<0.05). Three animals presented prolonged AF, 3 sustained AF (>1hour), and 6 “continuing” AF (ongoing after 1week). Compared with the control group, LA overload enhanced significantly the effective refractory period, but did not result in a significant modification in conduction time or initial cycle length. Chronic LA pressure/volume overload can induce “continuing” AF in a span of weeks. The increased vulnerability to AF cannot be explained by electrophysiological alterations of the LA.

Chronic left atrial volume and pressure overload in the goat: A new model of sustained atrial fibrillation

Purpose: The relationship between left atrium (LA) dilatation and atrial fibrillation (AF) has been extensively proved. The aim of this study was to develop an animal model of sustained AF, induced by controlled chronic left atrial overload. Methods: In 12 goats, a left thoracotomy was performed to implant a 8ram vascular graft (gore-tex ®) between the thoracic aorta and the LA. Intra operative atrial overload was monitored by volume and invasive pressure measurements. The LA was chronically instrumented with ukrasonic crystals and bipolar sensing/pacing electrodes. LA dilatation and electrophysiology were regularly evaluated in the conscious goats and compared with a control group with a non-functional shunt. Sustained AF (1 week) was the ultimate purpose. Anew invasive LA pressure was measured ahead of sacrifice. Results: Operatively there was manifest LA overload with calculated volume augmentation of 59.34-42.2% (from 42.3 to 67.4 mm 3, p<0.05) and mean pressure elevation from 9.24-6.9 mmHg to 18.04-8.5 mmHg (p<0.05). One animal was lost during follow up. At sacrifice (324-9.7 days), shunt patency was confirmed in 9 animals. In those, mean LA pressure was 204-7.8 mmHg (ns) and LA dilatation 104.0 mm 3 (p<0.05). AF duration increased significantly from 4.74-4.9 sec (day 0) to 1134-82.3 hours (p<0.05) after 16.14-6.9 days of open shunt. SIX animals presented sustained AF. In the control group, AF duration changed not

Effects of FiO2 on O2 Consumption and Cardiovascular and Hormonal Responses to Hemorrhage in the Goat

This study was conducted to determine whether 100% FiO2 during hemorrhage would improve maintenance of mean arterial blood pressure and to assess the cardiovascular, arginine vasopressin, and renin-angiotensin system roles in the response. This also allowed evaluation of FiO2 effects on the baroreceptor control of these hormone systems. Six conscious female goats were hemorrhaged (0.5 mL x kg(-1) x min(-1)) for 30 minutes, while breathing 11%, 21%, or 100% O2. Mean arterial blood pressure was maintained only when the goats breathed 100% O2. FiO2 did not affect O2 consumption or delivery during hemorrhage. Increases in renin and arginine vasopressin were equal or reduced with 100% FiO2 and therefore did not contribute to the improved mean arterial blood pressure maintenance. Inspiration of 100% FiO2 during hemorrhage, therefore, may improve perfusion pressure with no changes in O2 consumption or delivery. Also, 100% FiO2 eliminated the negative correlation between both hormones and right atrial pressure, suggesting altered baroreceptor control of the hormones.

Adrenergic vasoconstrictor activity in the cerebral circulation after inhibition of nitric oxide synthesis in conscious goats

The interaction between nitric oxide (NO) and adrenergic activity in the cerebral circulation was studied using conscious goats, where blood flow to one brain hemisphere (cerebral blood flow) was electromagnetically measured, and the effects of phentolamine and hexamethonium on cerebrovascular resistance were evaluated before (control) and after inhibition of NO synthesis with N W-nitro- l-arginine methyl ester ( l-NAME). l-NAME (12 goats, 40 mg kg −1 administered i.v.) reduced cerebral blood flow from 62±3 to 44±2 ml min −1, increased mean systemic arterial pressure from 100±3 to 126±4 mm Hg, decreased heart rate from 79±5 to 50±4 beats min −1, and increased cerebrovascular resistance from 1.63±0.08 to 2.91±0.016 mm Hg ml −1 min −1 (all P<0.01). These hemodynamic variables normalized 48–72 h after l-NAME administration. Phentolamine (six goats, 1 mg), injected into the cerebral circulation, increased cerebral blood flow without changing systemic arterial pressure, but its cerebrovascular effects were augmented for about 24 h after l-NAME. The decrements in cerebrovascular resistance induced by phentolamine, in mm Hg ml −1 min −1, were: under control, 0.42±0.05; immediately after l-NAME, 1.38±0.09 ( P<0.01 compared with control); by about 24 h after l-NAME, 0.71±0.09 ( P<0.05 compared with control); and by about 48 h after l-NAME, 0.40±0.07 ( P>0.05 compared with control). Hexamethonium (six goats, 0.5–1 mg kg −1 min −1 i.v.) decreased mean systemic arterial pressure to about 75 mm Hg and caused tachycardia similarly before and after l-NAME, but the decrements in cerebrovascular resistance were augmented for about 24 h after l-NAME. The decrements in cerebrovascular resistance induced by hexamethonium, in mm Hg ml −1 min −1, were: under control, 0.61±0.09; immediately after l-NAME, 1.33±0.16 ( P<0.01 compared with control); by about 24 h after l-NAME, 1.18±0.10 ( P<0.01 compared with control); and by about 48 h after l-NAME, 0.99±0.10 ( P>0.05 compared with control). Therefore, these results suggest that adrenergic vasoconstrictor tone in cerebral vasculature may be augmented after inhibition of NO synthesis, and that this increment may contribute to the reduction of cerebral blood flow after inhibition of NO formation.

Cerebral vasoconstriction produced by vasopressin in conscious goats: role of vasopressin V(1) and V(2) receptors and nitric oxide.

To examine the role of vasopressin V(1) and V(2) receptors, nitric oxide and prostanoids in the cerebrovascular effects of arginine vasopressin, cerebral blood flow was electromagnetically measured in awake goats. In 16 animals, vasopressin (0.03 - 1 microg), injected into the cerebral circulation, caused increments of resting cerebrovascular resistance which ranged from 18% (0.03 microg, P<0.01) to 79% (1 microg, P<0.01). Desmopressin (0.03 - 1 microg, four goats) did not affect significantly cerebrovascular resistance. The cerebrovascular resistance increases by vasopressin were reduced significantly by the antagonist for vasopressin V(1) receptors d(CH(2))(5)Tyr(Me)-AVP in a rate depending way (five (six goats) and 15 (four goats) microg min(-1)), and by the mixed antagonist for vasopressin V(1) and V(2) receptors desGly-d(CH(2))(5)-D-Tyr(Et)Val-AVP (5 microg min(-1), four goats), and they were not significantly affected by the antagonist for vasopressin V(2) receptors d(CH(2))(5), D-Ile(2), Ile(4)-AVP (5 microg min(-1), four goats). The inhibitor of nitric oxide synthesis N(w)-nitro-L-arginine methyl ester (L-NAME, 47 mg kg(-1) i.v., five goats) augmented cerebrovascular resistance by 130% (P<0.01), and for 24 h after this treatment the cerebrovascular effects of vasopressin were potentiated. The inhibitor of cyclo-oxygenase meclofenamate (6 mg kg(-1) i.v., five goats) did not modify significantly resting haemodynamic variables measured or the cerebrovascular effects of vasopressin. Therefore, the vasopressin-induced cerebral vasoconstriction may be mediated by vasopressin V(1) receptors, without involvement of vasopressin V(2) receptors, and may be modulated by nitric oxide but not by prostanoids.

Spatial Correlation Analysis of the Pharmacological Conversion of Sustained Atrial Fibrillation in Conscious Goats by Cibenzoline

The nonlinear spatial redundancy and the linear spatial correlation function were used to investigate to what extent non-linearity was involved in the coupling of atrial regions and how organization in activation patterns of sustained atrial fibrillation (AF) had been modified by administration of the class IC agent cibenzoline in the experimental model of sustained AF in instrumented conscious goats. Electrograms were measured in five goats during sustained AF and when the fibrillation interval had been prolonged to about 25%, 50% and 85% (CIB25, CIB50, CIB85) with respect to control. The nonlinear association length and linear correlation length were estimated along the principal axes of two-dimensional correlation maps estimated from the spatial redundancy and the spatial correlation function, respectively. The estimated short axis association length in the right atrium increased already shortly after the start of infusion (CIB25, +61%), and remained significantly different from control during the experiment, including the effects of non-simultaneous interaction. At CIB85 the association length had almost become twice as long with respect to control (increase from 16 to 29 mm, 89%), while in the left atrium changes were less pronounced (increase from 9 to 12 mm, +32%). The linearized association length which was estimated using multivariate surrogate data increased more gradually and was less sensitive to changes in spatial organization. The results of the spatial correlation analysis suggest that the drug-induced nonlinearity in the spatio-temporal dynamics of sustained AF is related to activation patterns which are characterized by extended uniformly propagating fibrillation wavefronts (AF type I). We conclude that cibenzoline enhanced the spatial organization of sustained AF associated with a transition from type II to type I AF activation patterns. This may destabilize the perpetuation of AF since an increase in association length is equivalent to a reduction of atrial tissue mass available to support reentrant circuits. The results are consistent with the hypothesis that larger association lengths result from fewer and larger reentrant circuits. It is argued that effects of diminished curvature of fibrillation wavefronts are anti-arrhythmic under conditions of suppressed excitability imposed by cibenzoline. Termination of AF may be mediated by a mechanism resembling a bifurcation of the dynamics which sets in when the ends of fractionated wavefronts cannot sufficiently curve anymore to maintain a positive balance of newly generated wavelets needed to sustain AF.

Spatial Correlation Analysis of Atrial Activation Patterns during Sustained Atrial Fibrillation in Conscious Goats

In this study we applied both linear and nonlinear spatial correlation measures to characterize epicardial activation patterns of sustained atrial fibrillation in instrumented conscious goats. It was investigated if nonlinearity was involved in the spatial coupling of atrial regions and to what extent fibrillation was organized in the experimental model of sustained atrial fibrillation (AF) in instrumented goats. Data were collected in five goats during experiments to convert AF by continuous infusion of cibenzoline. Spatial organization during AF was quantified with the linear spatial cross correlation function and the nonlinear spatial cross redundancy which was calculated using the Grassberger-Procaccia correlation integral. Two different types of correlation were evaluated to distinguish simultaneous interaction from non-simultaneous interaction, for instance resulting from propagation of fibrillation waves. The nonlinear association length and the linear correlation length were estimated along the principal axes of iso-correlation contours in two-dimensional correlation maps of the nonlinear spatial redundancy and the linear spatial correlation function, respectively. To quantitatively assess the degree of nonlinearity, the association length was also estimated from the linearized spatial redundancy using multivariate surrogate data. The differences between the nonlinear and linearized association lengths indicated that a nonlinear component in the spatial organization of AF predominantly existed in the right atrium. The degree of organization characterized by association length along the short principal axis was higher in the right atrium (15 ± 7 mm) than in the left atrium (8 ± 4 mm). The spatial extension of coherent atrial patches was estimated from a surface of association equal to the area spanned by the principal axes of iso-correlation contours from the redundancy, including the effects from non-simultaneous interaction. Interpreting this area as the spatial domain of a fibrillation wavelet, the results suggest that the mapped region was activated on average by two wavelets in the left atrium and by one wavelet in the right atrium. Therefore, the activation pattern of sustained AF in goats was relatively organized, consistent with type II of AF. It is suggested that the surface of association is a measure of the number of independent wavelets present in the atria during sustained AF, and that larger association lengths result from fewer and larger reentrant circuits.

Role of nitric oxide in the cerebral circulation during hypotension after hemorrhage, ganglionic blockade and diazoxide in awake goats

The role of nitric oxide in cerebrovascular response to hypotension was analyzed by evaluating the changes in cerebrovascular resistance after inhibition of nitric oxide synthesis with N w-nitro- l-arginine methyl ester ( l-NAME) during three types of hypotension in conscious goats. Blood flow to one brain hemisphere was electromagnetically measured, hypotension was induced by controlled bleeding, and by i.v. administration of hexametonium (ganglionic blocker) or of diazoxide (vasodilator drug), and l-NAME was injected by i.v. route (35 mg kg −1). Under control conditions (13 goats), l-NAME increased arterial pressure from 98±3 to 123±4 mmHg and decreased cerebral blood flow from 65±3 to 40±3 ml min −1 (all P<0.001); cerebrovascular resistance increased from 1.52±0.04 to 3.09±0.013 mmHg ml −1 min −1 ( P<0.01) ( Δ=1.59±0.12 mmHg ml −1 min −1). After bleeding (five goats), mean arterial pressure decreased to 60±4 mmHg and cerebral blood flow decreased to 37±4 ml min −1 (all P<0.01); cerebrovascular resistance did not change (1.56±0.14 vs. 1.54±0.12 mmHg ml −1 min −1, P>0.05). During this hypotension, l-NAME increased arterial pressure to reach the normotensive values and did not affect the hypotensive values for cerebral blood flow; cerebrovascular resistance increased from the hypotensive values to 2.91±0.19 mmHg ml −1 min −1 ( P<0.01) ( Δ=1.37±0.16 mmHg ml −1 min −1), and this increment is comparable to that under control conditions ( P>0.05). Ganglionic blockade (six goats) decreased arterial pressure to 67±2 mmHg) and did not affect significantly cerebral blood flow; cerebrovascular resistance decreased from 1.71±0.11 to 1.05±0.09 mmHg ml −1 min −1 ( P<0.01). During this hypotension, l-NAME increased arterial pressure to 103±6 mmHg ( P<0.001), and did not affect cerebral blood flow; cerebrovascular resistance increased from the hypotensive values to 1.68±0.18 mmHg ml −1 min −1 ( P<0.01) ( Δ=0.63±0.10 mmHg ml −1 min −1), and this increment was lower than under control conditions ( P<0.01). Diazoxide (six goats) decreased arterial pressure to 69±5 mmHg ( P<0.01) without changing cerebral blood flow; cerebrovascular resistance decreased from 1.89±0.11 to 1.16±0.14 mmHg ml −1 min −1 ( P<0.01). During this hypotension, l-NAME increased arterial pressure to 87±6 mmHg ( P<0.05) and did not affect the hypotensive values for cerebral blood flow ( P>0.05); cerebrovascular resistance increased from the hypotensive values to 1.53±0.13 mmHg ml −1 min −1 ( P<0.05) ( Δ=0.36±0.06 mmHg −1 ml −1 min −1), and this increment was lower than under control conditions ( P<0.01). Therefore, the role of nitric oxide in cerebrovascular response to hypotension may differ in each type of hypotension, as this role during hemorrhagic hypotension may not change and during hypotension by ganglionic blockade or diazoxide may decrease. These differences may be related to changes in nitric oxide release as stimuli on the endothelium (shear stress and sympathetic activity) may vary in each type of hypotension.

Digoxin delays recovery from tachycardia-induced electrical remodeling of the atria.

Atrial fibrillation (AF) induces electrical remodeling, which is thought to be responsible for the low success rate of antiarrhythmic treatment in AF of longer duration. Electrical remodeling seems to be related to tachycardia-induced intracellular calcium overload. Due to its vagomimetic action, digoxin is widely used to control the ventricular rate during AF, but it also increases intracellular calcium. On the basis of these characteristics, we hypothesized that digoxin would aggravate tachycardia-induced electrical remodeling. We analyzed the atrial effective refractory period (AERP) at cycle lengths of 430, 300, and 200 ms during 24 hours of rapid atrio/ventricular (300/150 bpm) pacing in 7 chronically instrumented conscious goats treated with digoxin or saline. Digoxin decreased the spontaneous heart rate but had no other effects on baseline electrophysiological characteristics. In addition to a moderate increase in the rate of electrical remodeling during rapid pacing, digoxin significantly delayed the recovery from electrical remodeling after cessation of pacing (at 430, 300, and 200 ms: P=0. 001, P=0.0015, and P=0.007, respectively). This was paralleled by an increased inducibility and duration of AF during digoxin. Multivariate analysis revealed that both a short AERP and treatment with digoxin were independent predictors of inducibility (P=0.001 and P=0.03, respectively) and duration (P=0.001 for both) of AF. Dioxin aggravates tachycardia-induced atrial electrical remodeling and delays recovery from electrical remodeling in the goat, which increases the inducibility and duration of AF.

Adrenergic reactivity after inhibition of nitric oxide synthesis in the cerebral circulation of awake goats

The interaction between nitric oxide (NO) and adrenergic reactivity in the cerebral circulation was studied using in vivo and in vitro preparations. Blood flow to one brain hemisphere (cerebral blood flow) was electromagnetically measured in conscious goats, and the effects of norepinephrine, tyramine and cervical sympathetic nerve stimulation were recorded before (control) and after inhibition of NO formation with N w-nitro- l-arginine methyl ester ( l-NAME). The responses to norepinephrine, tyramine and electrical field stimulation were also recorded in segments, 4 mm in length, from the goat's middle cerebral artery under control conditions and after l-NAME. In vivo, l-NAME (10 goats, 47 mg kg −1 administered i.v.) reduced resting cerebral blood flow by 37±2%, increased mean systemic arterial pressure by 24±3%, reduced heart rate by 35±2%, and decreased cerebrovascular conductance by 52±2% (all P<0.01). Norepinephrine (0.3–9 μg), tyramine (50–500 μg), and supramaximal electrical sympathetic cervical nerve stimulation (1.5–6 Hz) decreased cerebrovascular conductance, and these decreases were significantly higher after l-NAME than under control conditions, remaining higher for about 48 h after this treatment. Norepinephrine (10 −8–10 −3 M), tyramine (10 −6–10 −3 M) and electrical field stimulation (1.5–6 Hz) contracted isolated cerebral arteries, and the maximal contraction, but not the sensitivity, was significantly higher in the arteries treated than in non-treated with l-NAME (10 −4 M). Therefore, the reactivity of cerebral vasculature to exogenous and endogenous norepinephrine may be increased after inhibition of NO synthesis. This increase might be related, at least in part, to changes at postjunctional level in the adrenergic innervation of the vessel wall, and it might contribute to the observed decreases in resting cerebral blood flow after inhibition of NO synthesis.

Acute hyperinsulinemia fails to change GLUT-4 content in crude membranes from goat skeletal muscles and adipose tissue

The effect of insulin on GLUT-4 protein level in samples of adipose tissue and skeletal muscles from goats was studied in vivo using an euglycemic hyperinsulinemic clamp. The clamp was maintained in conscious goats for 6 h in the presence of amino acids to prevent insulin-induced hypoaminoacidemia. GLUT-4 protein was assessed in crude membrane preparations from adipose tissue and four skeletal muscles (longissimus dorsi, tensor fasciae latae, anconeus and diaphragm) by Western blot analysis. No changes of GLUT-4 protein content were detected after 6 h of hyperinsulinemia in either adipose tissue or skeletal muscles from goats. These results suggest that insulin is not the prime factor involved in the short-term regulation of GLUT-4 protein transporter content in insulin-sensitive tissues from goats.