Min Of Administration Research Articles

Gallstone extracorporeal shock-wave lithotripsy: time and treatment considerations.

We evaluated 30 gallstone lithotripsy procedures performed on 27 patients with the Dornier MPL-9000 Lithotripter to determine how time was spent in the lithotripsy suite and to evaluate the various technical reasons for interrupting the administration of shock waves during the treatment. The procedure averaged 98 +/- 32 min total time in the lithotripsy suite. This included an average of 22 +/- 6 min before the treatment, 70 +/- 28 min for administration of shock waves, and 6 +/- 2 min after the treatment. The time required to deliver the shock waves did not correlate with patient age, sex, or weight; the number of gallstones; or the number or date of the treatment. However, a trend was seen toward an association between shorter treatment times and larger stone volumes. On the average, the administration of shock waves was interrupted every 48 shock waves for various reasons. Electronically changing the imaging plane of the in-line sonographic transducer to retarget the stone in the focal zone was by far ...

Effect of Acetazolamide on Cerebral Blood Flow Velocity and CO<sub>2</sub> Elimination in Normotensive and Hypotensive Newborn Piglets

The objectives of this study were to measure the effect of acetazolamide on cerebral circulation, pulmonary elimination of CO2, and cerebrovascular response to hypotension in newborn piglets. Eighteen anaesthetized newborn piglets were studied. A fontanelle was surgically created and the cerebral blood flow velocity (CBFV) in an intracranial artery measured by a computerized Doppler system. In 8 piglets, 30 ml/kg of blood was removed to produce hypotension before the administration of acetazolamide. Acetazolamide (50 mg/kg i.v.) given to normotensive piglets consistently produced a large increase in CBFV (median 45% by 5 min) with no change in mean arterial blood pressure or heart rate. The rise in CBFV was negatively correlated with the starting partial pressure of CO2 in arterial blood. Within 1 min of administration of acetazolamide, the end-expiratory CO2 pressure started to fall (mean fall 1.4 kPa), and the partial pressure of CO2 in the arterial blood started to rise (mean rise 2.0 kPa), despite the controlled ventilation being unchanged. Acetazolamide had no effect on CBFV in the hypotensive piglet. It seems likely that acetazolamide produces cerebral vasodilatation by inhibiting the elimination of CO2. In hypotension, there is maximal cerebral vasodilatation, and acetazolamide cannot increase CBFV further. The interference of acetazolamide with CO2 elimination could seriously limit its use in the treatment of hydrocephalus in preterm infants.

Comparison of the Acute Hypotensive Effects of Renin Inhibition, Converting Enzyme Inhibition, and Angiotensin II Antagonism in Rats

The purpose of this study was to compare the acute hypotensive efficacy of different types of inhibitor of the renin-angiotensin system. A renin inhibitor (RI), CGP 44,099 A, a converting enzyme inhibitor (CEI), enalaprilat, a peptidic angiotensin II (Ang II) antagonist, [Sar1, Ile8]Ang II (P-Ang IIA), and a nonpeptidic Ang II antagonist devoid of agonistic properties, 2-butyl-4-chloro-1- ([2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl)-5- (hydroxymethyl)imidazol (NP-Ang IIA), were administered intravenously to sodium-depleted rats (SDRs), renal hypertensive rats (two-kidney, one-clip) (RHRs), and spontaneously hypertensive rats (SHRs). The four compounds were all effective in lowering blood pressure (BP) in SDRs and RHRs. The maximum hypotensive response observed within 30 min of administration was similar for all four compounds (approximately 30 mm Hg in SDRs and 60 mm Hg in RHRs). In SHRs, the P-Ang IIA induced a pressor response whereas the RI, CEI, and NP-Ang IIA lowered BP to a similar extent (approximately 15 mm Hg). Pretreatment with the CEI completely prevented the hypotensive response to RI in SHRs, and vice versa. These observations indicate that the principal mechanism by which converting enzyme inhibitors lower BP after acute administration in these rat models is by inhibition of the formation of Ang II. The pressor response to the P-Ang IIA in SHRs is probably a consequence of its partial agonistic properties. Renin inhibitors and nonpeptidic Ang II antagonists, devoid of agonistic properties, promise to be effective antihypertensive agents similar to the CEIs.

Cardioacceleration provoked by intrathecal administration of vasoactive intestinal peptide (VIP): Mediation by a non-central nervous system mechanism

Intrathecal administration of VIP to the thoracic spinal cord in the urethane anaesthetized rat provoked a dose-dependent increase in heart rate without any change in aterial pressure. The cardioacceleration observed following administration of 6.5 nmol of VIP at the T9 level (n = 8) occurred within 1–2 min of administration, with a peak effect of 70–85 bpm, 10–30 min after administration. The magnitude of the maximum change when this dose was given at the T2 level (n = 8) was approximately 100 beats per min, 7–8 min after administration. However, the differences between T2 and T9 administration were not statistically significant. Intravenous administration of 6.5 nmol of VIP (n = 6) mimicked the cardioacceleratory effect of intrathecal administration, and also decreased systolic and diastolic arterial pressure by 9–13 mmHg 6–13 min after administration. The cardioacceleration observed following intrathecal administration at T9 was not blocked by prior sytemic administration of the autonomic ganglion blocker hexamethonium (5 mg/kg) or by bilateral vagotomy. Nor was the effect blocked by prior intrathecal administration of the local anaesthetic lidocaine (250 μg), although lidocaine did block the tachycardia and hypertension resulting from intrathecal administration of substance P. Considered collectively, the findings that the cardioacceleration observed following intrathecal VIP injection is mimicked by i.v. administration, is not reversed by blockade of nicotinic transmission of autonomic ganglia or by bilateral vagotomy, and is not blocked by lidocaine suggest that VIP's tachycardic effect does not result from a direct action on spinal mechanisms mediating autonomic control of the cardiovascular system, but occurs via diffusion to a site of action outside the central nervous system.

Renal metabolism of formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl]-hydrazide.

Formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl]-hydrazide (FNT) is a potent renal carcinogen in the rat. This study assessed the metabolism of FNT by the isolated perfused rat kidney and whole rat. The glomerular filtration rate and the fractional excretion of sodium for the isolated perfused kidney indicated that under the conditions of these experiments FNT did not alter these renal parameters. The half-life (t1/2) for FNT in the isolated perfused kidney was 67 +/- 8 min. Using HPLC, a metabolite of FNT was observed in urine from the isolated perfused kidney. This metabolite had absorbance at 385 nm but not 254 nm and could not be detected electrochemically at +500 mV. While the excretion of FNT decreased with time of perfusion, the metabolite excretion increased. Whole animal studies demonstrated that FNT is rapidly cleared from blood within the first 5 min of administration. The FNT metabolite was excreted at approximately the same rate from 0-30 and 30-60 min after FNT administration. The metabolite was not observed in media from FNT perfused kidneys or plasma from animals administered FNT. Analysis of purified metabolite by liquid chromatography/mass spectrometry (LC/MS) and gas chromatography/mass spectrometry (GC/MS) determined the structure to be 5-nitro-2-furonitrile. This structure assignment was verified by chemical synthesis. Results demonstrate target organ metabolism of carcinogen.

Effect of the long-acting somatostatin analogue SMS 201-995 on small-intestinal interdigestive motility in the dog.

The long-acting somatostatin analogue SMS 201-995, also called Sandostatin, is used in the treatment of acromegaly and peptide-secreting tumors. Little is known about its effect on gut motility, although such an effect might be expected considering the spectrum of activities of its parent molecule, somatostatin. We have studied the effect on the interdigestive motility of intravenous boluses of 0, 0.1, 0.5, 1.5, and 5.0 micrograms/kg of this analogue in 10 dogs with bipolar electrodes implanted along the entire small bowel. All doses induced, within 5 min of administration, premature phase-3 activity that was isolated to one segment, normally progressive, or simultaneous (stationary) in all channels. Only low doses induced isolated phase 3, whereas the frequency of the induction of stationary phase 3 increased with higher doses. In the next cycle of the migrating motor complex the duration of phase 1 was increased, although the duration of the whole cycle was not changed. This cycle ended with mostly ectopic phase-3 activity. During phase 2 of the following cycle ultra-rapid rushes of spiking activity progressing at a speed of 25 +/- 3 cm/sec in the upper jejunum were regularly observed. Although this pattern occurs very rarely under control conditions, it was present in 20%, 80%, and 100% of the experiments after doses of 0.5, 1.5, and 5.0 micrograms/kg, respectively. We conclude that gastrointestinal side effects observed during administration of SMS 201-995 might be related to these motility effects, which warrant further investigation. SMS 201-995 may be a tool to study the mechanism of the induction of ultra-rapid rushes and of stationary phase 3.

Substance P given intrathecally at the spinal T 9 level increases arterial pressure and heart rate in the rat

Administration of 10 μg of substance P intrathecally at the spinal T 9 level of the unanaesthetized and the anaesthetized rat provoked an increase in arterial pressure and an increase in heart rate. Both cardiovascular responses began within 1–2 min of administration, and the peak of each occurred at 4–10 min. In the anaesthetized rat, which gave rise to the bulk of the responses reported, peak arterial pressure was ca 20 mm Hg greater than pre-administration levels, and peak heart rate was greater by ca 50 beats per min. Similar administration of vehicle failed to alter either parameter. Arterial pressure and heart rate in substance P-treated rats were significantly different from those in vehicle-treated rats up to 15–20 min after administration. Pretreatment with the sympathetic ganglion blocker, hexamethonium (10 mg/kg, i.v.), prevented the responses to intrathecal administration of substance P. Pretreatment with [ d-Pro 2, d-Phe 7, d-Trp 9]-substance P, an analogue with antagonist properties in the central nervous system, blocked both responses to substance P but failed to alter similar responses provoked by intrathecal administration of angiotensin II. Pretreatment with vehicle had no effect on responses to substance P or to angiotensin II. The antagonist also had partial agonistic effects. Both arterial pressure and heart rate were transiently increased, but this effect was reversed within 6 min; in the case of heart rate, values returned to the pre-application level but arterial pressure fell to ca 15 mm Hg below this level. These results demonstrate a pharmacologically specific excitatory effect of substance P on spinal mechanisms controlling sympathetic output to the vessels and the heart; this output can be either via the adrenal medullae or via nerve pathways to the vessels and the heart. Our results also support the possibility that dysfunction of substance P systems at the spinal level may underly some models of hypertension and may be involved in some cases of essential hypertension in man, as well as in autonomic dysfunction associated with some neurological disorders.

Corticotropin-releasing factor acts on the brain to reduce gastric contractility.

Various stressors (cold restraint, electric shock, etc.) applied to rats increase gastric contractility and are associated with gastric erosions. Intracisternal (i.c.) thyrotropin-releasing hormone (TRH) increases contractility, gastric acid secretion and the incidence of erosion formation. Corticotropin-releasing hormone (CRF) is released by stress, and acting centrally produces autonomic and endocrine changes. We have studied the role of i.c. CRF on gastric contractility in anesthetized rats (n = 6). Contractility was measured by extraluminal force transducers sutured to the gastric corpus. Frequency, amplitude of contractions and a motility index were analyzed by computer. Baseline measures, after recovery from surgery were obtained in 24-hour fasted rats. Contractility was stimulated by intravenous carbachol (100 mg/kg/h) or i.c. injection of the TRH analog, RX 77368. Contractility thus induced was inhibited by intravenous atropine (1 mg/kg). CRF (30-1,000 ng i.c.) produced a dose-dependent suppression of RX 77368 (p less than 0.05) but had no effect on that induced by intravenous carbachol; saline i.c. had none either. Intravenous CRF was 1/10th as potent in suppressing contractions produced by i.c. RX 77368. Diminution of gastric contractions after i.c. CRF (1 mg) occurred within 5 min of administration, and lasted for at least 60 min. These data show that i.c. CRF injection acts centrally to inhibit gastric contractions stimulated centrally (i.e. by i.c. RX 77368) but not peripherally (i.e. by carbachol), and by inference reduces the risk of erosion formation induced by some stressors.

A new method for quantification of tremors in mice

A procedure for quantifying whole-body tremors in mice was developed. Displacement of a free-floating platform by animal movement created a change in resistance across a strain gauge. The resulting resistive changes were assessed as voltage fluctuations by a wheatstone bridge and converted into an intensity-frequency profile by a series of calculations involving Fourier transformations. Movement profiles of normal mice were characterized by high-intensity, low-frequency peaks. Administration of oxotremorine, 2.5 mg/kg, ip, produced numerous high-frequency, high-intensity peaks within 5 min of administration. The peak frequency at 5 min after oxotremorine was approximately 15 Hz, and within 30 min the intensity-frequency profile had returned to control levels. In dose-response studies, a slight decrease in exploratory activity and initiation of low-level tremors was observed after 0.5 mg/kg. The most severe tremors were detected after a dose of 1.0 mg/kg. The peak frequency remained at approximately 15 Hz at 1.0 to 5.0 mg/kg, but varied greatly in intensity. This study describes an inexpensive, quantitative, sensitive, and rapid technique for quantifying tremors in mice.

Tissue disposition of [ 3H]sarin and its metabolites in mice

The biodisposition and metabolic fate of [ 3H]sarin was investigated in mice after iv administration of a sublethal dose (80 μg/kg). Within 1 min of administration, all tissues contained substantial quantities of radioactivity of which less than 10% represented [ 3H]sarin. The major portion of radioactivity corresponded to free [ 3H]isopropyl methylphosphonic acid (IMPA), the pharmacologically inactive hydrolytic product of [ 3H]sarin. Somewhat lesser quantities were present as bound [ 3H]IMPA which resulted from phosphorylation of protein. Plasma contained high concentrations of bound [ 3H]IMPA, consistent with sarin's very reactive nature, which were sustained throughout the time course. Plasma concentrations of free [ 3H]IMPA diminished rather quickly. The high concentrations of metabolites in kidneys implied that this organ played a major role in the detoxification and excretion of [ 3H]sarin. Large quantities of free and bound [ 3H]IMPA were also found in lung which suggested an important site for toxicity. Only trace quantities of [ 3H]sarin were found in brain after 15 min. The major portion of radioactivity was present as either free and bound [ 3H]IMPA or as nonextractable material which presumably was [ 3H]methylphosphonic acid. Examination of the time course of sarin-induced motor hypoactivity and hypothermia revealed an immediate onset of action that lasted for 24 hr. However, substantial quantities of bound [ 3H]IMPA remained in brain at 24 hr which suggested that only a small portion of phosphorylation in brain accounted for these pharmacological effects.

Biodisposition of [ 3H]diisopropylfluorophosphate in mice

The disposition of [ 3H]diisopropylfluorophosphate (DFP) and its metabolites was studied in mice after iv treatment. In addition, disposition of [ 3H]DFP in selected tissues was correlated with cholinesterase activity and spontaneous activity following DFP treatment. Within 1 min of administration [ 3H]DFP had penetrated tissues and was already irreversibly bound. The tissue concentrations of [ 3H]DFP declined in a rapid fashion so that after 2 hr all concentrations were below 50 pg/mg tissue. The major portion of radioactivity was bound to tissue in the form of [ 3H]diisopropylphosphoric acid (DIP). There was a decline in [ 3H]DIP with time in all tissues except liver, kidneys, and fat, which reached a maximum at 30 min before declining. The only appreciable quantities of [ 3H]DIP remaining after 3 days were in liver and kidneys. There was also evidence that [ 3H]DFP was rapidly hydrolyzed to free [ 3H]DIP which was found in all tissues within 1 min of [ 3H]DFP administration. [ 3H]DIP concentrations were equivalent to or exceeded those of [ 3H]DFP in all tissues, except brain. Cholinesterase inhibition in plasma, diaphragm, and brain following DFP treatment (1 mg/kg, iv) was temporarily correlated with the concentrations of bound [ 3H]DIP in these same tissues between 1 hr and 3 days. Cholinesterase inhibition in brain and diaphragm did not correlate well with bound [ 3H]DIP at earlier time points which suggested the presence of noncholinesterase binding. DFP treatment (1 mg/kg) also induced motor hypoactivity which lasted up to 6 hr after iv injection. The time course of motor hypoactivity was not correlated with free [ 3H]DFP, bound [ 3H]DIP concentrations in the brain, or with cholinesterase inhibition in the brain, which suggested that noncholinesterase bound [ 3H]DIP was responsible for this CNS depression.

Dopamine-induced physical barrier to inhibit prolactin release in mammotrophs disappears during resumption of prolactin secretion.

After finding that dopamine can cause extensive changes in mammotroph ultrastructure within 2 min of administration, we further examined mammotrophs 20 and 40 min after dopamine injection when prolactin secretion had resumed. Dopamine (1,000 micrograms/kg) was injected into the right atrium of estradiol-primed male rats through indwelling cannulae. Rats were killed by decapitation 2, 20 and 40 min after dopamine treatment and their pituitaries were processed for electron microscopy. Within 2 min of administration, dopamine completely stopped prolactin release and significant changes in mammotroph ultrastructure were observed: peripheral relocation of rough endoplasmic reticulum (RER) ('dopamine barrier'); fewer secretory granules in close proximity to the cell membrane; fewer exocytoses, and increased numbers of 'intracellular bodies' associated with secretory granules (putative granule disposal system). 20 min following dopamine administration, when prolactin secretion had resumed, there appeared to be a breaking up of the 'RER barrier' in that more vesicular elements were seen and the amount of peripheral RER was reduced; more granules were adjacent to the cell membrane and exocytotic figures were more numerous. 'Intracellular bodies' decreased in number. By 40 min, mammotrophs appeared to resemble those of estradiol-primed controls with the RER stacked to one side of the cell and small numbers of 'intracellular bodies'. The correlation between ultrastructural changes in mammotrophs and prolactin release implies that the 'RER barrier' is part of a mechanism by which prolactin release is inhibited.

Epinephrine Absorption after Intratracheal Administration

Tracheal intubation during cardiopulmonary resuscitation often precedes establishment of an intravenous route for the administration of drugs. To determine the efficacy of intratracheal administration of drugs during cardiopulmonary resuscitation we measured plasma catecholamine levels and hemodynamic responses to intratracheal epinephrine (EPI) administration using a double-blind, randomized crossover design in 7 male baboons (Papio anubis), each studied twice, who received 5 ml of 1:10000 EPI on one day and 5 ml of 0.9% NaCl on another day. Arterial blood samples for measurement of plasma EPI and norepinephrine (NE) concentrations were collected, and heart rate (HR) and mean arterial blood pressure (MAP) were measured before and 1, 2, 4, 8, 16, and 30 min after intratracheal drug administration. Intratracheal EPI significantly (P less than 0.05) elevated HR to 120 +/- 6 from 105 +/- 6 beats/min, MAP to 120 +/- 4 from 112 +/- 5 mm Hg, and plasma EPI to 8882 +/- 2143 from 928 +/- 209 pg/ml within 1 min of administration, and these effects persisted for 30 min. Plasma NE levels did not change after intratracheal EPI administration. None of the four variables changed after intratracheal saline was given. We conclude that in subhuman primates, intratracheal EPI is rapidly absorbed and is an effective pressor agent when given by this route; and that these data lend support to the clinical practice of intratracheal EPI administration during cardiac arrest or in the treatment of shock.

Inhibition of dopamine uptake by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a cause of parkinsonism

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine has been reported to cause parkinsonism in man and monkeys, producing behavioral effects within 5 min of administration. The compound reversibly and competively inhibited (IC50 = 2 μM) dopamine uptake into PC12, a clonal line of rat pheochromocytoma cells that store and secrete dopamine and acetylcholine. Uptake of choline and 2-deoxyglucose was not affected. Prolonged exposure to the compound was lethal to PC12; survivors of this treatment lost the ability to store dopamine and acetylcholine and to extend neurites upon incubation with nerve growth factor.

Dopamine creates a physical barrier to inhibit prolactin release in mammotrophs of estradiol-primed male rats.

After finding that ergocristine and somatostatin can cause extensive changes in mammotroph ultrastructure within 2 min of administration, we chose dopamine, the putative physiological prolactin-inhibiting factor, to correlate ultrastructural changes to inhibition of prolactin release. In order to choose a dose of dopamine for this study we tested the effects of 2 doses of dopamine (10 and 1,000 micrograms/kg) on inhibition of prolactin release. The higher dose of dopamine (1,000 micrograms/kg) completely inhibited prolactin release immediately (in less than 2 min) and maintained complete blockage for a period of 14 min. For the ultrastructural study we injected dopamine (1,000 micrograms/kg) in the right atrium of conscious free-moving rats through indwelling cannulae, and killed the rats by decapitation 2 min after dopamine administration. The following changes in mammotrophs were observed after the dopamine treatment: (1) increased numbers of secretory granules, (2) peripheral relocation of rough endoplasmic reticulum, and (3) increased numbers of 'intracellular bodies' (putative prolactin granule disposal system) associated with secretory granules. Because these rapid ultrastructural changes have been observed after treatment with three different compounds (dopamine, somatostatin and ergocristine), we do not believe that they are the unique effect of any one compound but the common denominator of the three compounds, i.e., inhibition of prolactin secretion being closely linked to the ultrastructural changes. We thus propose that the extensive ultrastructural changes that occurred in such a short period of time following dopamine administration are the mechanism of inhibition of prolactin release.

The penetration of misonidazole into a mature structural cartilage.

Mature cartilage may be expected to contain populations of hypoxic cells as a result of the tissues lack of direct vascularization and structure; it may therefore be at risk from possible radiosensitization. The hypoxic-cell radiosensitizing drug misonidazole Ro-07-0582 (MISO) was administered i.v. to mature New Zealand White rabbits at a dose of 100 mg/kg, and the resulting drug concentrations in both blood and ear-cartilage samples measured by HPLC. Samples were taken at regular intervals up to 4 h after administration of MISO. Blood concentrations of MISO rose rapidly to 240 microgram/ml within 5 min of administration, before falling steadily, with a t1/2 of 45 min. Cartilage levels reached a peak of 70% of the blood levels approximately 30 min after administration. The levels of MISO then fell, with a t1/2 of 44 min.

Response of Factor VIII/Von Willebrand Factor to Intranasal DDAVP in Healthy Subjects and Mild Haemophiliacs (with Observations in Patients with Combined Deficiency of Factors V and VIII)

The effect of a single standard dose of intranasal DDAVP (260 micrograms) was investigated in healthy subjects and in patients with mild deficiencies of VIII:C. Changes in FVIII/VWF activities were measured from baseline after 30, 60, 120 and 360 min of administration of the drug. Intranasal DDAVP was followed by a two-fold increase of VIII:C in both groups studied. VIIIR:AG and VIIIR:RCo increased to a lesser extent. Even though FVIII/VWF activities reached their maximum after 60-120 min, a significant increase over baseline was still observed after 360 min. The rise of VIII:C was unrelated to the body weight of the patients and was proportional to the baseline levels of this factor. In two sisters with combined deficiencies of FV/FVIII, the responses in all activities of FVIII/VWF were similar to those seen in mild hemophiliacs. Factor V did not undergo any variation. No alteration in serum osmolarity and no consistent variation in blood pressure or pulse rate were noted. It is concluded that the i.n. administration of a single high dose of DDAVP might be adopted to provide an emergency aid in bleeding patients with mild to moderate haemophilia A and to yield higher VIII:C levels in blood donors.

Evidence for an action of morphine and the enkephalins on sensory nerve endings in the mouse peritoneum.

1 A modification of the abdominal constriction test in mice has been developed, and used to study the antinociceptive effects of morphine and several related drugs. In most experiments, acetic acid (0.6% i.p.) was used as the nociceptive stimulus, and in a few cases, acetylcholine (3.2 mg/kg i.p.) was used. When the abdominal constriction response had reached a maximum, the drugs under test were given intraperitoneally, and their ability to decrease the number of abdominal constrictions was determined, beginning immediately after its administration. The aim of this study was to investigate the possibility that morphine and its congeners may produce an antinociceptive effect by an action within the peritoneum.2 It was found that morphine was an extremely potent antinociceptive agent in this modified test, with an ID(50) of 5.4 x 10(-9) mol/kg (1.54 mug/kg). Codeine and pentazocine were about 40 times less active and oxymorphine was about twice as potent as morphine. Met- and Leu-enkephalin were also potent but their action diminished very rapidly with time. Ketocyclazocine was the most potent substance tested, and had an ID(50) value of 1.26 x 10(-10) mol/kg (0.036 mug/kg). All the drugs tested produced their maximal effect within 1 or 2 min of administration.3 Pretreatment of the mice with naloxone caused a dose-dependent shift to the right of the dose-response curve to morphine. The pAx plot was linear over part of the range, with a slope of -1.02 and the ;apparent pA(2)' value was 6.14. Naloxone was much less effective in antagonizing Met-enkephalin, and caused a slight potentiation of ketocyclazocine and pentazocine and of cocaine, which was used for comparison.4 Pretreatment of mice with morphine, 3 h earlier, caused a marked tolerance to a subsequent dose of morphine, and a potentiation of the antagonist potency of naloxone. However, there was little cross-tolerance between morphine and Leu-enkephalin.5 It is concluded that morphine and its congeners can produce an antinociceptive effect by an action within the mouse peritoneum, presumably by interacting with one or more types of opioid receptors which may be situated on sensory nerve endings.

Effect of chicken hypothalamus on prolactin and growth hormone secretion in male chickens.

The effects of a chicken hypothalamic extract (HE) on the secretion of prolactin and growth hormone (GH) in vivo have been investigated by radioimmunoassay in the domestic fowl. Different i.v. doses of HE (0.25--25 HE equivalents/kg body weight) had no effect on GH secretion in conscious or anaesthetized cockerels. In both groups of birds the concentration of plasma prolactin was significantly increased within 10 min of administration of the extract. Extracts of other brain tissues (cerebral cortex, cerebellum and medulla oblongata) had no stimulatory effect on prolactin or GH secretion. Release of both prolactin and GH by dispersed pituitary cells and by hemipituitary glands in vitro was enhanced following incubation with HE (5 hypothalami equivalents/ml) or with single whole hypothalami respectively. Other brain tissues (cerebellum, optic lobes and medulla oblongata) had no effect on the concentration of prolactin or GH released by incubated hemipituitary glands.

Influence of dietary sodium on renin activity and arterial pressure during anesthesia

The effect of pentobarbital anesthesia on plasma renin activity (PRA) and mean arterial pressure (MAP) was studied in chronically catheterized dogs maintained on normal or low-sodium intake. Within 1 min of administration, pentobarbital caused a rapid fall in MAP which was followed by a restoration of MAP toward control within 5 min. Thirty minutes after induction of anesthesia, PRA was unchanged in sodium-replete dogs and elevated two-fold in sodium-depleted dogs. MAP was significantly lowered (20 mmHg) in normal salt dogs and only slightly decreased in low-salt dogs 30 min after pentobarbital. MAP returned to preanesthetic control value in dogs given converting enzyme inhibitor before anesthesia. Surgical stress or cutaneous electrical stimulation causey hexamethonium. These results indicate that change in PRA and MAP of pentobarbital-anesthetized dogs is significantly influenced by the sodium intake of the animal and by the degree of surgical stress.