Apnoeic responses to intracarotid nicotine challenge in anaesthetized cats.

To determine the effects of an intraarterial administration of nicotine on the occurrence of apnoea and the activity of rib cage respiratory muscles, we studied 31 anaesthetized, spontaneously breathing cats. Phrenic activity was used as an index of neural inspiratory drive. Activity of parasternal intercostal (PIM) and triangularis sterni (TS) muscles was recorded. Nicotine in a dose of 65 microg/kg was injected into the left common carotid artery prior to and after midcervical vagotomy, preceded by section of the superior laryngeal nerves (SLNs). In eight additional cats, initially neurotomized as mentioned, nicotine was injected after bilateral disruption of the carotid sinus nerves (CSNs). Nicotine induced prompt expiratory apnoea of mean duration of 5.4+/-0.3s in 19 non-vagotomized and of 5.92+/-0.51 s (mean+/-S.E.M.) in 13 vagotomized cats. The occurrence and duration of the temporary arrest of breathing were reduced by midcervical vagotomy but not by subsequent CSNs neurotomy, which abolished post-apnoeic acceleration of breathing.In post-nicotine breathing of increased tidal volume and respiratory rate, peak activity of the parasternal intercostal muscles increased from baseline of 3.2+/-1.2 to 9.5+/-2.0 arbitrary units (p<0.001). The peak height of the phrenic nerve elevated from 7.9+/-0.9 to 14.5+/-1.7 arbitrary units (p<0.001). That of the triangularis sterni showed no change.The response of the respiratory effectors elicited by nicotine was independent of the vagal integrity and may be attributed to activation of nicotine receptors within the brainstem respiratory neurones.     

Supranodose vagotomy precludes reflex respiratory responses to serotonin in cats

Mediation of the respiratory reflex effects of an exogenous serotonin challenge goes beyond the lung vagi and is suggested to involve the nodose ganglia. In the present experiments the effects of an intravenous serotonin challenge on breathing pattern were studied in 8 pentobarbitone-chloralose anaesthetised cats. Bolus injection of serotonin oxalate (50 µg/kg) into the right femoral vein evoked prompt apnoea of 19.2 (±2.4)-second duration in all 8 cats while intact; the apnoea was much shorter after midcervical vagal section (8.1±0.9 s, p<0.001), and was abolished by supranodose vagotomy. In post-apnoeic breaths, the tidal volume was reduced from a baseline of 34.1±4.0 to 13.5±1.1 ml (p<0.001) prior to, and from a baseline of 43.9±5.4 to 33.8±6.6 ml (p<0.01) after midcervical vagotomy; the serotonin challenge did not affect tidal volume following supranodose vagal section (p=0.4). The increase in respiratory rate found in intact (p<0.001) and midcervically vagotomised cats (p<0.01) was eliminated by the neurotomy above the nodose ganglia. Supranodose vagotomy altered cardiovascular response to serotonin by replacing the fall in blood pressure with an increase. These data suggest that the sequelae of serotonin-induced pulmonary chemoreflex, i.e. respiratory arrest, cardiovascular changes and post-apnoeic pattern of breathing require intact nodose ganglia.     

Influence of pregnancy on ventilatory and carotid body neural output responsiveness to hypoxia in cats

Pregnancy increases ventilation and ventilatory sensitivity to hypoxia and hypercapnia. To determine the role of the carotid body in the increased hypoxic ventilatory response, we measured ventilation and carotid body neural output (CBNO) during progressive isocapnic hypoxia in 15 anesthetized near-term pregnant cats and 15 nonpregnant females. The pregnant compared with nonpregnant cats had greater room-air ventilation [1.48 +/- 0.24 vs. 0.45 +/- 0.05 (SE) l/min BTPS, P less than 0.01], O2 consumption (29 +/- 2 vs. 19 +/- 1 ml/min STPD, P less than 0.01), and lower end-tidal PCO2 (30 +/- 1 vs. 35 +/- 1 Torr, P less than 0.01). Lower end-tidal CO2 tensions were also observed in seven awake pregnant compared with seven awake nonpregnant cats (28 +/- 1 vs. 31 +/- 1 Torr, P less than 0.05). The ventilatory response to hypoxia as measured by the shape of parameter A was twofold greater (38 +/- 5 vs. 17 +/- 3, P less than 0.01) in the anesthetized pregnant compared with nonpregnant cats, and the CBNO response to hypoxia was also increased twofold (58 +/- 11 vs. 29 +/- 5, P less than 0.05). The increased CBNO response to hypoxia in the pregnant compared with the nonpregnant cats persisted after cutting the carotid sinus nerve while recording from the distal end, indicating that the increased hypoxic sensitivity was not due to descending central neural influences. We concluded that greater carotid body sensitivity to hypoxia contributed to the increased hypoxic ventilatory responsiveness observed in pregnant cats.     

Increased carotid body hypoxic sensitivity during acclimatization to hypobaric hypoxia

Mechanisms of ventilatory acclimatization to chronic hypoxia remain unclear. To determine whether the sensitivity of peripheral chemoreceptors to hypoxia increases during acclimatization, we measured ventilatory and carotid sinus nerve responses to isocapnic hypoxia in seven cats exposed to simulated altitude of 15,000 ft (barometric pressure = 440 Torr) for 48 h. A control group (n = 7) was selected for hypoxic ventilatory responses matched to the preacclimatized measurements of the experimental group. Exposure to 48 h of hypobaric hypoxia produced acclimatization manifested as decrease in end-tidal PCO2 (PETCO2) in normoxia (34.5 +/- 0.9 Torr before, 28.9 +/- 1.2 after the exposure) as well as in hypoxia (28.1 +/- 1.9 Torr before, 21.8 +/- 1.9 after). Acclimatization produced an increase in hypoxic ventilatory response, measured as the shape parameter A (24.9 +/- 2.6 before, 35.2 +/- 5.6 after; P less than 0.05), whereas values in controls remained unchanged (25.7 +/- 3.2 and 23.1 +/- 2.7; NS). Hypoxic exposure was associated with an increase in the carotid body response to hypoxia, similarly measured as the shape parameter A (24.2 +/- 4.7 in control, 44.5 +/- 8.2 in acclimatized cats). We also found an increased dependency of ventilation on carotid body function (PETCO2 increased after unilateral section of carotid sinus nerve in acclimatized but not in control animals). These results suggest that acclimatization is associated with increased hypoxic ventilatory response accompanied by enhanced peripheral chemoreceptor responsiveness, which may contribute to the attendant rise in ventilation.     

Attenuated carotid body hypoxic sensitivity after prolonged hypoxic exposure

Prolonged exposure to hypoxia is accompanied by decreased hypoxic ventilatory response (HVR), but the relative importance of peripheral and central mechanisms of this hypoxic desensitization remain unclear. To determine whether the hypoxic sensitivity of peripheral chemoreceptors decreases during chronic hypoxia, we measured ventilatory and carotid sinus nerve (CSN) responses to isocapnic hypoxia in five cats exposed to simulated altitude of 5,500 m (barometric pressure 375 Torr) for 3-4 wk. Exposure to 3-4 wk of hypobaric hypoxia produced a decrease in HVR, measured as the shape parameter A in cats both awake (from 53.9 +/- 10.1 to 14.8 +/- 1.8; P less than 0.05) and anesthetized (from 50.2 +/- 8.2 to 8.5 +/- 1.8; P less than 0.05). Sustained hypoxic exposure decreased end-tidal CO2 tension (PETCO2, 33.3 +/- 1.2 to 28.1 +/- 1.3 Torr) during room-air breathing in awake cats. To determine whether hypocapnia contributed to the observed depression in HVR, we also measured eucapnic HVR (PETCO2 33.3 +/- 0.9 Torr) and found that HVR after hypoxic exposure remained lower than preexposed value (A = 17.4 +/- 4.2 vs. 53.9 +/- 10.1 in awake cats; P less than 0.05). A control group (n = 5) was selected for hypoxic ventilatory response matched to the baseline measurements of the experimental group. The decreased HVR after hypoxic exposure was associated with a parallel decrease in the carotid body response to hypoxia (A = 20.6 +/- 4.8) compared with that of control cats (A = 46.9 +/- 6.3; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cervical preganglionic sympathetic nerve activity and chemoreflexes in the cat

The role of chemoreflexes originating from carotid body and central chemoreceptors in the regulation of cervical preganglionic sympathetic nerve (PSN) activity was studied in anesthetized and spontaneously breathing cats. PSN efferents which responded to hypoxia were selected for the study. The PSN activity, breath-by-breath inspiratory tidal volume, tracheal PO2 and PCO2, and arterial systemic blood pressure were recorded simultaneously. The responses of PSN efferents to transient changes in and steady-state levels of arterial PO2 and PCO2 and to graded bolus injections of intravenous sodium cyanide (50-100 micrograms), nicotine (50-100 micrograms), and dopamine hydrochloride (30-60 micrograms) were compared before and after bilateral section of carotid sinus nerves (CSN). CSN section raised the base-line PSN activity and practically eliminated the responses to brief pharmacological stimuli, but it did not eliminate the responses to transient changes in and steady-state levels of arterial PO2 and PCO2. However, CSN section diminished PSN responses and abolished ventilatory responses to hypoxia. Thus the PSN response to hypoxia was partly independent of peripheral chemoreflex and of respiratory drive. We conclude that carotid body chemoreflex elicits fast PSN responses and that a moderate decline in arterial PO2 causes an additional slow, direct excitation of sympathetic nervous system. The latter indicates O2 chemosensitivity of the system in the physiological range of arterial PO2. This O2-sensing property may allow sympathetic nervous system to initiate chemoreflex responses independent of the peripheral chemoreceptors.     

Neural responses to intravenous serotonin revealed by functional magnetic resonance imaging.

We examined the sequence of neural responses to the hypotension, bradycardia, and apnea evoked by intravenous administration of 5-hydroxytryptamine (serotonin). Functional magnetic resonance imaging signal changes were assessed in nine isoflurane-anesthetized cats during baseline and after a bolus intravenous low dose (10 microg/kg) or high dose (20-30 microg/kg) of 5-hydroxytryptamine. In all cats, high-dose challenges elicited rapid-onset, transient signal declines in the intermediate portion of the solitary tract nucleus, caudal midline and caudal and rostral ventrolateral medulla, and fastigial nucleus of the cerebellum. Slightly delayed phasic declines appeared in the dentate and interpositus nuclei and dorsolateral pons. Late-developing responses also emerged in the solitary tract nucleus, parapyramidal region, periaqueductal gray, spinal trigeminal nucleus, inferior olivary nucleus, cerebellar vermis, and fastigial nucleus. Amygdala and hypothalamic sites showed delayed and prolonged signal increases. Intravenous serotonin infusion recruits cerebellar, amygdala, and hypothalamic sites in addition to classic brain stem cardiopulmonary areas and exhibits site-specific temporal patterns.     

In vitro perfused-superfused cat carotid body for physiological and pharmacological studies

An in vitro perfused carotid body preparation was developed to study its chemosensory responses to physiological and pharmacological stimuli. The carotid bifurcation with the carotid body was vascularly isolated and excised from pentobarbital sodium-anesthetized cats. The CB was perfused in a chamber by gravity (80 Torr) with modified Tyrode's solution (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-NaOH at pH 7.40) equilibrated at a given Po2 and superfused with the same medium at (Po2 of 20 Torr). The temperature was maintained at 35.5 +/- 0.5 degrees C. The frequency of chemosensory discharges (CD) was recorded from the whole carotid sinus nerve (n = 24), and the responses were tested by repeated interruptions of perfusate flow (SF), perfusion with hypoxic medium, and injections of nicotine and cyanide (0.1 nmol to 1 mumol) and hypercapnic medium. During hyperoxic perfusion, SF resulted in a sigmoidal increase in CD, reaching a maximum that was 23.6 +/- 4.4-fold greater than the basal activity. Restoration of flow returned CD promptly to basal values. After normoxic perfusion, SF led to a similar maximal activity more rapidly, but the duration was shorter. Reduction of the perfusate PO2 (Po2 from 450 Torr to 150, 30, and less than 10 Torr) caused a nonlinear increase in CD. CO2 stimuli (PCo2 38-110 Torr) resulted in a linear increase in CD. Nicotine or cyanide increased CD in a dose-dependent manner. The preparation retained its initial responsiveness for 2-3 h, making extensive experimental studies feasible.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory effects of propofol on neuron firing activities in the rostral ventrolateral medulla

The effect of propofol on neuronal activity in the rostral ventrolateral medulla (RVLM) is not well established. Therefore, we performed extracellular recording on neurons of the RVLM to investigate neuronal activity before and after administration of intravenous propofol. The mean systemic arterial pressure (MSAP), heart rate and integrated neuronal firing rate (INFR) in the RVLM were continuously recorded in anesthetized cats before and after intravenous injection of 2 mg/kg propofol or supplemental injections of 1, 2 and 4 mg/kg propofol that were given respectively. Additionally, we compared the MSAP, heart rate (HR), and INFR in the RVLM following intravenous injection of 2 mg/kg propofol or 12.5 microg/kg nitroprusside. Neuronal firing was dose-dependently and reversibly inhibited after the supplemental doses of 1, 2 and 4 mg/kg propofol. The control INFR was 14.2 +/- 9.9 Hz, and this decreased to 12.1 +/- 9.4 Hz after the first dose of propofol (P = 0.085 vs. control), and further decreased to 9.3 +/- 7.7 Hz (P = 0.001 vs. control) and 7.5 +/- 7.7 Hz (P < 0.001 vs. control) after the second and third doses of propofol, respectively. Besides, SAP and HR were dose-dependently decreased by propofol as well. However, the effects of propofol and nitroprusside on neuronal activity in the RVLM differed. Propofol inhibited neuronal firing, whereas nitroprusside activated neuronal firing. In conclusion, propofol may dose-dependently inhibit spontaneous neuronal activity and the baroreflex in the RVLM.     

The effect of ACTH stimulation on cortisol and progesterone concentrations in intact and ovariohysterectomized domestic cats

The objective was to evaluate the adrenocortical capacity for cortisol and progesterone production in female cats, both while intact and after ovariohysterectomy. Five privately owned female cats, 1-3 years old, were used in two trials while intact at an inactive stage of the cycle, and again in two trials, 2 weeks after ovariohysterectomy. The four trials were: intact saline injection control trial; intact ACTH injection (0.125 mg); ovariohysterectomized saline injection control trial; and ovariohysterectomized ACTH injection. Blood samples were obtained by an indwelling cephalic vein catheter at -30 and 0 min (immediately before injections) and at 60, 90, 120 and 180 min after injection. The mean basal pre-treatment concentrations of cortisol in the intact and ovariohysterectomized cats were 33 +/- 19 and 32 +/- 19 nmol/L, respectively; the corresponding values for progesterone were 1.1 +/- 0.6 and 0.7 +/- 0.6 nmol/L, respectively. Saline did not alter the serum cortisol or progesterone concentrations. In contrast, both cortisol and progesterone were elevated after ACTH, with peak values at 90 min and returned to basal levels at approximately 180 min. There was a positive correlation between cortisol and progesterone concentrations (r = 0.8, P < 0.05). In some instances, the procedure used to restrain the cats during blood collection induced increases in cortisol and progesterone of the same magnitude as when the ACTH was administered; these effects of restraint could alter the results of assisted reproduction efforts.     

Glucose dependent insulinotropic polypeptide (GIP) infused intravenously is insulinotropic in the fasting state in type 2 (non-insulin dependent) diabetes mellitus

The effects of an intravenous infusion of porcine GIP on beta-cell secretion in patients with untreated type 2 diabetes mellitus have been studied. The subjects were studied on two separate days. After a 10 h overnight fast and a further 120 min basal period they were given an intravenous infusion of porcine GIP (2 pmol.kg-1.min-1) or control solution in random order from 120-140 min. Frequent plasma glucose, insulin, C-peptide and GIP measurements were made throughout and the study was continued until 200 min. Plasma glucose levels were similar throughout both tests. During the GIP infusion there was an early significant rise in insulin concentration from 0.058 +/- 0.006 nmol/l to 0.106 +/- 0.007 nmol/l (P less than 0.01) within 6 min of commencing the GIP infusion and insulin levels reached a peak of 0.131 +/- 0.011 nmol/l at 10 min (P less than 0.01). Insulin levels remained significantly elevated during the rest of the GIP infusion (P less than 0.01-0.001) and returned to basal values 20 min post infusion. No change in basal insulin values was seen during the control infusion. C-peptide levels were similarly raised during the GIP infusion and the increase was significant just 4 min after commencing the GIP infusion (P less than 0.05). GIP levels increased from 16 +/- 3 pmol/l prior to the infusion to a peak of 286 +/- 24 pmol/l 20 min later. At 4 min when a significant beta-cell response was observed GIP levels were well within the physiological range.(ABSTRACT TRUNCATED AT 250 WORDS)     

内皮素对麻醉大鼠动脉压力感受器反射的调制作用

在27只隔离灌流颈动脉窦区的麻醉大鼠,观察了内皮素（ET-1）对动脉压力感受器反射的调制作用。结果如下：（1）在颈动脉窦区灌流1nmol／L的ET-1时,压力感受器机能曲线向左下方移位,曲线的最大斜率（PS）由0.40±0.02增至0.51±0.02kPa／kPa（P＜0.01）,压力感受器反射性血压下降幅度（RD）由5.66±0.23增至6.76±0.22kPa（P＜0.01）。由此提示,这一剂量的FT-1对压力感受器反射有易化作用。（2）用10nmol／L的ET-1灌流时,压力感受器机能曲线则向右上方移位,PS降至0.28±0.01kPa／kPa（P＜0.01）,RD降至4．16±0.19kPa（P＜0.01）;100nmol／L的ET-1可使压力感受器机能曲线向右上方移位更为明显,PS降至0.19±0.03kPa（P＜0.001）,RD进一步降至3.33±0.38kPa（P＜0.001）。这些结果表明,上述两种剂量的ET-1对压力感受器反射有抑制作用。（3）ETA受体选择性阻断剂BQ123（0.15μmol／L）可以阻断ET-1（10nmol／L）对压力感受器反射的抑制效应。（4）预先灌流KATP通道阻断剂格列苯脲（10μmol／L）,也可阻断ET-1的效应。综上所述,ET-1对压力感受器反射有双重效应,低剂量时有易化作用,而较高剂量时则有抑制作用,后一作用由ET-1型受体介导并有KATP通道的参与。     

Plasma molybdenum reflects dietary molybdenum intake

The relationship between plasma molybdenum (Mo) and dietary intake has not been investigated in humans. We developed an isotope dilution method to determine molybdenum in 0.5 mL blood plasma by ICP-MS and conducted a study to determine the effect of dietary intake on plasma molybdenum. Twelve young men consumed a very low Mo diet (22 microg/day) for 24 days while confined to the WHNRC metabolic research unit and plasma molybdenum was monitored. (97)Mo was infused in four of the subjects (Group 1) to follow its clearance from the blood. The other eight remained in unit for 120 days (an additional 96 days). Four consumed the 22 microg/day molybdenum diet for 102 days followed by 467 microg/day for 18 days (Group 2). and four consumed five levels of dietary molybdenum for 24 days each (Group 3). (100)Mo was added to the diet one or more times at each dietary level. Total plasma molybdenum and (100)Mo were monitored throughout the study. Plasma molybdenum in the 12 subjects decreased from 8.2 +/- 0.5 to 6.1 +/- 0.5 nmol/L after 13 days of low molybdenum intake and was 5.1 +/- 0.5 nmol/L after 24 days. In Group 2, average plasma molybdenum was 7.8 +/- 0.9 nmol/L at the beginning of the study, 5.4 +/- 0.4 nmol/L during the 102 days low molybdenum period, and 16.5 +/- 0.6 nmol/L during the high molybdenum period. Plasma molybdenum in Group 3 was 4.2 +/- 2.1 nmol/L at 22 microg/day; 5.8 +/- 2.5 nmol/L at 72 microg/day; 6.6 +/- 2.3 nmol/L at 121 microg/day; 19.7 nmol/L +/-2.1 at 467 microg/day; and 43.9 +/- 2.1 nmol/L at 1490 microg/day. The results demonstrate that, in contrast to most other essential minerals, plasma molybdenum reflects low and high dietary molybdenum intakes within 14 days and may a useful indicator of low and high dietary intakes.     

Bezold-Jarisch reflex attenuates dynamic gain of baroreflex neural arc

Although acute myocardial ischemia or infarction may induce the Bezold-Jarisch (BJ) reflex through the activation of serotonin receptors on vagal afferent nerves, the mechanism by which the BJ reflex modulates the dynamic characteristics of arterial pressure (AP) regulation is unknown. The purpose of this study was to examine the effects of the BJ reflex induced by intravenous phenylbiguanide (PBG) on the dynamic characteristics of the arterial baroreflex. In seven anesthetized rabbits, we perturbed intracarotid sinus pressure (CSP) according to a white noise sequence while renal sympathetic nerve activity (RSNA), AP, and heart rate (HR) were recorded. We estimated the transfer function from CSP to RSNA (neural arc) and from RSNA to AP (peripheral arc) before and after 10 min of intravenous administration of PBG (100 microg. kg-1. min-1). The intravenous PBG decreased mean AP from 84.5 +/- 4.0 to 68.2 +/- 4.7 mmHg (P < 0.01), mean RSNA to 76.2 +/- 7.0% (P < 0.05), and mean HR from 301.6 +/- 7.7 to 288.4 +/- 9.0 beats/min (P < 0.01). The intravenous PBG significantly decreased neural arc dynamic gain at 0.01 Hz (1.06 +/- 0.08 vs. 0.59 +/- 0.17, P < 0.05), whereas it did not affect that of the peripheral arc (1.20 +/- 0.12 vs. 1.18 +/- 0.41). In six different rabbits without intravenous PBG, the neural arc transfer function did not change between two experimental runs with intervening interval of 10 min, excluding the possibility that the cumulative effects of anesthetics had altered the neural arc transfer function. In conclusion, excessive activation of the BJ reflex during acute myocardial ischemia may exert an adverse effect on AP regulation, not only by sympathetic suppression, but also by attenuating baroreflex dynamic gain.     

Lowering of interstitial fluid pressure after neurogenic inflammation is inhibited by mystixin-7 peptide

Soft tissue injury is accompanied by lowering of interstitial fluid pressure (P(if)), plasma protein extravasation, and edema. Inflammation was produced by electrical stimulation (ES) of the vagus and the effects of the synthetic peptide mystixin-7 (p-anisoyl-Arg-Lys-Leu-Leu-D-Thi-Ile-D-Leu-NH(2)) on P(if) were examined. Micropuncture measurement of P(if) in submucosa, without opening the trachea, was conducted on rats anesthetized with pentobarbital sodium (50 mg/kg) and euthanized with intravenous KCl. P(if) in control (intravenous saline) was -1.2 +/- 0.7 mmHg before ES and decreased to -4.7 +/- 1.0 mmHg (P < 0.01, n = 8) after ES. Mystixin-7 (10 and 20 microg/kg iv) blocked the fall in P(if) after ES (-1.1 +/- 0.3 and -0.8 +/- 0.2 mmHg, P < 0.01, n = 8 and n = 4). The 1 microg/kg dose was without effect. When trachea from animals pretreated with mystixin-7 (20 microg/kg iv) were soaked in phosphate-buffered saline (0.15 M, pH 7.4), the rate of fluid accumulation was significantly reduced. This study suggests that mystixin peptides, which have structural similarity to a fragment from laminin-alpha1 chain, may be useful tools for studying cell adhesion and factors that maintain the structural integrity of connective tissue after injury.     

Angiotensin II type 1 (AT1)-receptor blocker prevents impairment of endothelium-dependent cerebral vasodilation by acute cigarette smoking in rats

Our aim was to test for smoking-induced endothelial dysfunction in rat cerebral vessels, then to evaluate the effect of valsartan [angiotensin II type I (AT1)-receptor blocker] on that impairment. In pentobarbital-anesthetized, mechanically ventilated Sprague-Dawley rats, we used a cranial window preparation to measure changes in pial vessel diameters following topical applications of acetylcholine (Ach) (before and after smoking or intravenous nicotine infusion; n = 6 in each group), and adenosine (n = 6 for before and after smoking). Then, after intravenous valsartan pretreatment we reexamined the pial vasodilator response to topical Ach (before and after cigarette smoking). Under control conditions, cerebral arterioles were dilated by 6.9 +/- 4.2% and 13.6 +/- 4.8% by topical Ach (10(-6) M and 10(-5) M, respectively) and by 6.4 +/- 2.5% and 12.2 +/- 3.1% by topical adenosine (10(-5) M and 10(-4) M, respectively). One hour after a 1-min inhalation of mainstream smoke (1-mg nicotine cigarette), 10(-5) M Ach constricted cerebral arterioles (-4.4 +/- 4.1%), while 10(-4) M adenosine dilated them by 13.4 +/- 3.4%. One hour after a 1-min nicotine infusion (0.05 mg), 10(-5) M Ach dilated cerebral arterioles by 9.9 +/- 2.4%. Thus, vasodilator response to topical Ach was impaired after smoking, whereas that to adenosine was unaffected. However, the vasodilator response to Ach was unaffected by intravenous nicotine. Valsartan prevented smoking from impairing Ach-induced vasodilation. In conclusion, acute single-cigarette smoking causes a dysfunction of endothelium-dependent, but not endothelium-independent, vasodilation of rat cerebral vessels in vivo, and the effect was not mimicked by intravenous nicotine. AT1-receptor blockade prevented the above smoking-induced impairment of endothelium-dependent vasodilation.     

Peptidase modulation of noncholinergic vagal bronchoconstriction and airway microvascular leakage

We investigated whether inhibition of neutral endopeptidase 24.11 (NEP) and/or angiotensin-converting enzyme (ACE) modifies vagally induced nonadrenergic noncholinergic (NANC) airflow obstruction and airway microvascular leakage as measured by extravasation of Evans blue dye (intravenous) in anesthetized guinea pigs. We gave phosphoramidon to inhibit NEP and enalapril maleate or captopril to inhibit ACE. Animals pretreated with inhaled phosphoramidon (7.5 or 75 nmol), enalapril maleate (87 or 870 nmol), or captopril (350 nmol) reached higher peak lung resistance (RL) values (14.3 +/- 2.7, 15.7 +/- 3.8, 16.7 +/- 3.8, 11.4 +/- 1.6, and 24.6 +/- 3.5 cmH2O.ml-1.s, respectively) than saline-treated animals (5.9 +/- 1.1; P less than 0.05) after bilateral vagus nerve stimulation (5 Hz, 10 V, 10 ms, 150 s). Intravenous phosphoramidon (1 mg/kg), but not intravenous captopril (6 mg/kg), potentiated peak RL (22.9 +/- 6.9 and 7.1 +/- 1.5 cmH2O.ml-1.s, respectively). Vagal nerve stimulation (1 and 5 Hz) increased the extravasation of Evans blue dye in tracheobronchial tissues compared with sham-stimulated animals, but this was not potentiated by inhaled enzyme inhibitors or intravenous captopril. However, intravenous phosphoramidon significantly augmented the extravasation of Evans blue dye in main bronchi and intrapulmonary airways. We conclude that degradative enzymes regulate both NANC-induced airflow obstruction and airway microvascular leakage.     

GnRH immunocontraception of male cats

The development of nonsurgical contraceptives for cats may facilitate population control of the species. The purpose of this study was to investigate the utility of GnRH for immunocontraception of male cats. Male cats (n=12) were divided into groups of three and were immunized once with 0 (sham), 50, 200, or 400 microg synthetic GnRH coupled to keyhole limpet hemocyanin and combined with a mycobacterial adjuvant to enhance immunogenicity. GnRH antibody titer, serum testosterone concentration, and scrotal size were determined monthly. At 6 months, semen was collected by electroejaculation and testes were examined histologically. GnRH antibodies were detected in all cats receiving GnRH vaccine by 1 month post-treatment and persisted throughout the study. No dose effect of GnRH was observed; titers were not different among cats treated with 50, 200, or 400 microg GnRH (P=0.5). Six of nine treated cats were classified as responders based on high GnRH antibody titers (>32,000). By 3 months post-treatment, responder cats had undetectable testosterone concentrations and testicular atrophy. Nonresponder cats had GnRH titers of 4000-32,000 and testosterone concentrations intermediate between responder and sham-treated cats. At 6 months, total sperm counts were similar for sham-treated cats (3.1+/-1.8 x 10(6) sperm) and nonresponder cats (3.4+/-1.6 x 10(6) sperm; P=0.7). Only one of the six responder cats produced sperm, none of which were motile. Combined testicular weights of responder cats (1.3+/-0.1 g) were lower than sham-treated controls (5.3+/-1.3 g; P=0.02) and nonresponder cats (2.9+/-0.3 g; P=0.02). Histologic evaluation of the testes revealed that in responder cats, the interstitial cells that were present were pale and shrunken compared to the plump, polyhedral eosinophilic cells in sham-treated cats. GnRH responder cats had marked tubular atrophy with vacuolated Sertoli cells and a paucity of germ cells. Single-dose GnRH treatment resulted in testosterone concentrations and semen quality consistent with immunocastration in a majority of cats treated.     

Urinary selenium excretion in selenite-loaded sheep and subsequent Se dynamics in blood constituents

Renal selenium excretion in sheep was measured during intravenous infusion of sodium selenite, and the post-infusion dynamics of Se levels in whole blood, plasma and red blood cells (RBC) were investigated for the next 5 days. The plasma Se level increased almost twenty fold with the infusion of Na2SeO3 (from 0.39 +/- 0.02 to 7.83 +/- 0.33 micromol x L(-1), P < 0.001) compared with the baseline value. The selenium concentration in urine (0.07 +/- 0.02 vs. 18.53 +/- 2.56 micromol x L(-1), P < 0.001), the amount of Se excreted (0.14 +/- 0.07 vs. 21.40 +/- 2.31 nmol x min(-1), P < 0.001) and the renal clearance of Se (0.1 9 +/- 0.03 vs. 3.01 +/- 0.34 mL x min(-1), P < 0.001) were found to be highly significantly elevated during selenite loading. The clearance measurements showed no changes in the urinary flow rate or in the glomerular filtration rate. During and at the end of infusion the highest Se level was attained in plasma, followed by whole blood and RBC. The plasma Se level fell rapidly within 10 min after the end of infusion, but the concentration of Se in RBC was stable up to the fourth hour, when it started to decrease too. On day 5 the Se concentrations in plasma, RBC and whole blood were found to be only slightly but still significantly higher than before the selenite infusion. The large disproportion between the infusion rate of Se (8.76 microg x min(-1)) and its renal excretion rate (1.69 microg x min(-1)) found in clearance measurements suggests low glomerular filtration of infused selenium, which might primarily be caused by the binding of selenite metabolites to blood constituents. The presented results confirm the low bioavailability to ruminants of Se from sodium selenite.     

Baroreceptor influence on a spinal cardiovascular reflex

A stretch of the walls of the thoracic aorta, performed in vagotomized cats without obstructing aortic flow, induces increases in heart rate, myocardial contractility, and arterial pressure. These reflex responses are still present after high spinal section. Cats under chloralose-urethane anesthesia were vagotomized and one carotid sinus was isolated and perfused with arterial blood at constant flow. The contralateral carotid sinus nerve and both aortic nerves were sectioned. A stretch of the walls of the thoracic aorta between the 7th and 10th intercostal arteries induced a reflex increase in mean arterial pressure 29 +/- 2 mmHg (mean +/- SE). Stepwise increases of carotid sinus pressure (CSP) or electrical stimulation of the carotid sinus nerve induced stepwise decreases of this reflex response. At maximal baroreceptor stimulation (CSP 212 +/- 9 mmHg) the reflex response to aortic stretch was reduced by 42%. These experiments show that this spinal cardiovascular reflex is at least partially under the inhibitory control of the baroreceptor input.