Mean Maximum Response Research Articles

The Effect of Stimulus Size on the Reliable Stimulus Range of Perimetry.

Automated perimetry uses a 3.5 log unit (35dB) range of stimulus contrasts to assess function within the visual field. Using 'Size III' stimuli (0.43°), presenting stimuli within the highest 15dB of available contrast may not increase the response probability at locations damaged by glaucoma, due to retinal ganglion cell response saturation. This experiment examines the effect of instead using 'Size V' (1.72°) stimuli. Luminance increment thresholds for circular spot stimuli of each stimulus size were measured in 35 participants (mean deviation -20.9 to -3.4 dB, ages 52-87) using the method of constant stimuli, at four locations per participant. Frequency-of-seeing curves were fit at each size and location, with three free parameters: mean, standard deviation, and asymptotic maximum response probability. These were used to estimate the contrasts to which each participant would respond on 25% of presentations (c25). Using segmented orthogonal regression, the maximum observed response probabilities for size III stimuli began to decline at c25 = 25.2 dB (95% confidence interval 23.3-29.0 dB from bootstrap resampling). This decline started at similar contrast for the size V stimulus: c25 = 25.0dB (22.0-26.8 dB). Among locations at which the sensitivity was above these split-points for both stimulus sizes, c25 averaged 5.6 dB higher for size V than size III stimuli. The lower limit of the reliable stimulus range did not differ significantly between stimulus sizes. However, more locations remained within the reliable stimulus range when using the size V stimulus. Size V stimuli enable reliable clinical testing later into the glaucomatous disease process.

Beta 2-adrenoceptors in guinea-pig atria.

The occurrence of beta 2-adrenoceptors in the isolated, spontaneously beating right atrium and the electrically driven left atrium of the guinea-pig was studied. Isoprenaline was used as reference compound and procaterol as selective beta 2-agonist. Cumulative concentration response (C/R) curves were obtained with the agonists. The C/R curve of procaterol was biphasic in both preparations. Compared with isoprenaline, procaterol was a partial agonist, with a mean maximum response of 0.78 +/- 0.04 in the right atrium and 0.29 +/- 0.05 in the left atrium. The beta 2-selective antagonist ICI 118,551, 10(-7) mol litre-1, caused a small but significant shift of the C/R curve of isoprenaline to a higher concentration range in both preparations. The same concentration of the beta 2-blocker changed the shape of the C/R curve of procaterol from biphasic to monophasic by blocking the responses to low concentrations of procaterol. Practolol, a beta 1-selective antagonist, 10(-6) mol litre-1, gave a highly significant shift of the C/R curve of isoprenaline to a higher concentration range in both preparations but had no effect on the responses to low concentrations of procaterol. The effect of practolol on the responses to high concentrations of procaterol is discussed. We conclude that the guinea-pig atria may contain beta 2-adrenoceptors mediating positive chronotropic and inotropic effects.

Constitutive basal and stimulated human small bowel contractility is enhanced in obesity

Small bowel contractility may be more prominent in obese subjects, such that there is enhanced nutrient absorption and hunger stimulation. However, there is little evidence to support this. This study examined in vitro small bowel contractility in obese patients versus non-obese patients.Samples of histologically normal small bowel were obtained at laparoscopic Roux-en-Y gastric bypass from obese patients. Control specimens were taken from non-obese patients undergoing small bowel resection for benign disease or formation of an ileal pouch-anal anastamosis. Samples were transported in a pre-oxygenated Krebs solution. Microdissected circular smooth muscle strips were suspended under 1 g of tension in organ baths containing Krebs solution oxygenated with 95% O2/5% CO2 at 37°C. Contractile activity was recorded using isometric transducers at baseline and in response to receptor-mediated contractility using prostaglandin F2a, a nitric oxide donor and substance P under both equivocal and non-adreneregic, non-cholinergic conditions (guanethidine and atropine).Following equilibration, the initial response to the cholinergic agonist carbachol (0.1 mmol/L) was significantly increased in the obese group (n = 63) versus the lean group (n = 61) with a mean maximum response: weight ratio of 4.58 ± 0.89 vs 3.53 ± 0.74; (p = 0.032). Following washout and re-calibration, cumulative application of substance P and prostaglandin F2a produced concentration-dependent contractions of human small bowel smooth muscle strips. Contractile responses of obese small bowel under equivocal conditions were significantly increased compared with non-obese small bowel (p < 0.05 for all agonists). However, no significant differences were shown between the groups when the experiments were performed under NANC conditions. There were no significant differences found between the groups when challenged with nitric oxide, under either equivocal or NANC conditions.Stimulated human small bowel contractility is increased in obese patients suggesting faster enteric emptying and more rapid intestinal transit. This may translate into enhanced appetite and reduced satiety.

Effect of IL-1beta microinjection into the posterior hypothalamic area on trigeminal nociception in the rat.

The hypothalamus has been implicated in the pathophysiology of the most disabling forms of primary headache, namely migraine and cluster headache. Interleukin-1beta (IL-1beta) is highly expressed in the hypothalamus. We recorded from the trigeminal nucleus caudalis of rats using extracellular electrophysiological methods from neurons responding to electrical stimulation of the peri-middle meningeal artery dura mater and having receptive fields in the ophthalmic division of the trigeminal nerve. Data were collected from fifteen clusters of wide-dynamic range neurons with stable baseline firing responses between 97 and 101% ( n=3 for each unit) to stimulation. Microinjection of IL-1beta into the posterior hypothalamus of 9 animals resulted in a modest inhibition of evoked trigeminal responses in three units, no effect in six and no overall effect for the entire cohort studied. The mean maximum response was a non-significant reduction in firing to 83+/-7% ( n=9) at 30 minutes post-injection of IL-1beta. There was some variation of effect dependent on site of injection with central posterior hypothalamus being the predominant area that resulted in inhibition. There was no inhibition in the six animals injected with vehicle (saline). If there is an important effect for IL-1beta in the posterior hypothalamus it is likely to be highly somatotopically restricted.

Probabilistic assessment of wind-sensitive structures with uncertain parameters

Studies of Davenport and others have provided the basis for a simple gust factor approach to evaluate the wind-induced structural responses. This approach is based on the maximum responses that can be represented by their corresponding mean maximum response. However, the uncertainty in the wind characteristics and in the material properties and geometry variables affects not only the mean maximum responses but also their variability. By considering these uncertainties, estimates of the statistics of the maximum responses can be obtained from the unconditional probability distributions of the maximum responses. Alternatively, they can be obtained directly from the uncertainty propagation analysis based on the conditional mean maximum responses. The former is accurate whereas the latter is an approximation. The adequacy of this approximation and its effect on the structural reliability are investigated. Results reported in this study seem to support that the use of the conditional maximum response equal to the mean maximum response is adequate for the uncertainty propagation analysis. Results of the reliability analyses also suggest that the consideration of the uncertainty in structural parameters such as the fundamental period of vibration and the damping ratio is very important for serviceability limit states, and that these uncertainties may be ignored for the resistance based limit states as long as the structure behaves linearly.

Abnormal contractile properties of rectal smooth muscle in chronic ulcerative colitis.

Patients with ulcerative colitis have abnormal rectal motility. To compare the contractile properties of rectal smooth muscle from patients with ulcerative colitis and controls. Rectal smooth muscle strips from patients undergoing resection for ulcerative colitis or cancer (control) were mounted in an organ bath. The effects of carbachol (receptor-mediated) and potassium (causes membrane depolarization) were studied. Acetylcholinesterase histochemistry was performed and nerve counts compared. Ulcerative colitis (n=41) and control (n=34) strips contracted in response to potassium and carbachol. Mean (S.E. M.) maximum response to potassium in the control and ulcerative colitis groups was 1.07 (0.06) g/mg and 1.02 (0.09) g/mg tissue, respectively (P=N.S.). EC50s (concentrations required to give 50% of maximal response) were 75 (1) mM and 73 (1) mM, respectively (P=N.S. ). Although maximum responses to carbachol were similar, 2.12 (0.12) g/mg and 1.95 (0.12) g/mg tissue (P=N.S.), ulcerative colitis strips exhibited an increased sensitivity to carbachol, EC50s: 5.05 x 10-6 (0.55 x 10-6) M vs. 8.36 x 10-6 (0.88 x 10-6) M, P=0.002). There was no significant difference in nerve counts between the tissues, as assessed by staining for acetylcholinesterase. Ulcerative colitis tissue has an increased sensitivity to carbachol and this is not due to denervation; it may result from increased calcium release from intracellular stores since contraction due to membrane depolarization is not altered. Modulation of this pathway could potentially be used to alter rectal motility in patients with ulcerative colitis.

Glutamatergic transmission in the trigeminal nucleus assessed with local blood flow

Stimulation of the superior sagittal sinus in humans is pain-producing and in experimental animals leads to excitation of neurons in the caudal trigeminal nucleus and dorsal horns of the C 1/C 2 cervical spinal cord: the trigeminocervical complex. Neuronal excitation is generally associated with an increase in local blood flow due to flow/metabolism coupling and we have used local blood flow in the trigeminocervical complex to examine the role of N-methyl- d-aspartate (NMDA)-mediated transmission in these neurons. Cats were anaesthetised with α-chloralose (60 mg/kg, ip; supplements 20 mg/kg iv) after surgical preparation under halothane (0.5–3%). Animals were paralysed with gallamine triethiodide to prevent possible movement artefact distorting the laser Doppler signals. The superior sagittal sinus was isolated for electrical stimulation (150 V; 250 μsec duration; 0.5, 1, 2, 5, 10 and 20 Hz) and the dorsal surface of the spinal cord exposed at the C 2 level. Blood flow was recorded from the region over the trigeminocervical complex by careful placement of a laser Doppler flow probe. Flow was recorded continuously by an online collection programme and NMDA-mediated transmission modulated by intravenous administration of MK-801 (0.4, 1 and 4 mg/kg, iv) at the stimulation frequency of 5 Hz. Stimulation of the superior sagittal sinus produced a stimulus-locked, frequency-dependent increase in blood flow in the region of the trigeminocervical complex. The mean maximum response was 39±4% at 20 Hz. MK-801 had no effect on the resting flow signal but markedly attenuated the SSS-evoked response in a dose-dependent manner. The mean maximum response after 4 mg/kg MK-801 was 13±2%. NMDA-mediated transmission is likely to be involved in nociceptive trigeminovascular transmission within the trigeminocervical complex and offers a possible target for both acute and preventative treatment of migraine.

In vitro contractile responses of detrusor to carbachol and neurokinin A, in children with recurrent urinary tract infection or day wetting.

To investigate whether a history of recurrent urinary tract infection (UTI) and/or the presence of day-wetting/urge symptoms might influence the contractile responses to the cholinergic agonist carbachol or to the sensory neuropeptide neurokinin A (NKA) in the urinary bladder in children. Small detrusor strips were taken from the margin of the cystotomy incision of the bladder dome during surgery to correct vesico-ureteric reflux (VUR) in 62 children (aged 4 months to 12 years) or for unrelated bladder conditions in five controls (aged 3 months to 13 years). Concentration-response curves to carbachol and NKA were constructed using organ-bath techniques, and results compared for age, sex, weight of the detrusor strip, UTI history or day-wetting syndrome. The contractile responses to NKA were no different for any of the features investigated. The contractile response to carbachol and NKA in detrusor from control and VUR patients was not significantly different. The children with a history of UTI were significantly older than those without. The contractility in response to carbachol was greater in older girls (aged 4-12 years) than younger girls (< 4 years) and than in all boys (< 4 years and 4-12 years; ANOVA P = 0.013). The mean (SEM) maximum contractile response to carbachol in the group of 20 young children (4-30 months) with previous UTI was 3.0 (0.3) g, whereas the maximum response in the age-matched group of 11 without UTI was 1.8 (0.3) g (P = 0.046). There were no significant differences in maximum responses between those with day-wetting and those without (aged > 4 years), although there was a significant difference in pD2 value, at 6.19 (0.13) and 5.58 (0.14), respectively (P = 0.018). Carbachol produced a larger contractile response in detrusor from children with a history of UTI than from those without, indicating possible alterations in muscarinic receptor characteristics. An increased sensitivity to muscarinic stimulation in day-wetting children was also suggested, whereas NKA is unlikely to be involved in any of these pathophysiological conditions.

The physiological effects of natural variation in growth hormone gene copy number in ram lambs

The effects of natural variation in the number of copies of the growth hormone (GH) gene on growth parameters, plasma GH profiles, and the response to GHRH challenge were compared in Coopworth ram lambs from selection lines differing in body composition and GH levels. Different genotypes at the GH locus carried two, three, or four copies of the GH gene and GH secretion was studied under ad libitum feeding conditions and in the fasted state. There were no significant effects of GH genotype on any parameters of growth or body composition. Basal serum GH concentration, GH pulse frequency, and GH pulse amplitude differed significantly with selection line and fasting, but did not differ significantly between the GH genotypes. Significant differences of subtle nature were found between the GH genotypes in their responsiveness to GHRH. For the ad libitum-fed Lean selection line animals, the first GHRH challenge resulted in a higher mean maximum response for GH1 GH1 than GH2 GH2 ( P < 0.05) . Between the first and the second challenges there was a decrease in maximum response for the GH1 GH1 genotype and an increase for the GH2 GH2 genotype (P < 0.05 for GH genotype main effect). The differences between GH genotypes in response to GHRH challenge suggest that polymorphism in the number of GH gene copies in sheep may have physiological implications for the function of the GH axis, which may be manifested in growing lambs only under specific genotype-environment combinations.

Skin vascular reaction to short durations of normal seating

The effects of duration and compliance of seating surfaces on reactive hyperemia within the skin overlying the ischial tuberosities was determined in four normal, one paraplegic and one cerebral palsy subject. Reactive hyperemia was demonstrated thermographically after short durations (ie, 5, 10, and 15 minutes) of seating on a hard surface. The magnitude of hyperemic response increased significantly ( p < .001 for 15 v 5 minutes; p = .019 for 15 v 10 minutes; p = .001 for 10 v 5 minutes) with increased duration of seating. In all six subjects studied, the maximum postseating blood flow continued to increase with up to 15-minute seating on a hard surface, and the mean maximum response was positively correlated with duration of seating (4 = 0.918, p < 0.001). Although there was good correlation between magnitudes of interface pressures measured and vascular responses within each individual, there was no such direct correlation between individuals.

Cyclosporin treatment does not impair the release of nitric oxide in human coronary arteries.

It has been hypothesised that compromised endothelial function can contribute to the toxic manifestations associated with cyclosporin therapy. In vitro animal studies have implicated inhibition of release of the endothelium derived relaxing factor, nitric oxide; however, this has not been investigated in human tissue. The present study investigated the effect of cyclosporin A on nitric oxide release in human coronary arteries. Study of in vitro organ bath preparations and in vivo angiographic measurements in the coronary circulation. For the in vitro experiments coronary arteries were harvested from the excised hearts of 10 patients requiring transplantation for reasons other than ischaemic heart disease. Three of these patients were being re-transplanted for obliterative bronchiolitis and had been receiving cyclosporin for a mean of 22 months. The in vivo study was performed on a group of 12 cardiac transplant recipients who were clinically well 1-5 years postoperatively and were not undergoing allograft rejection at the time of assessment. Isolated vessel segments in vitro relaxed in a dose dependent manner in response to substance P (10(-11)-10(-7) mol/l). The maximum response was 76.6 (7.4)% of the response to 1 microgram/ml glyceryl trinitrate. Incubation with 1000 and 2000 ng/ml cyclosporin reduced the response to 63.0 (11.5)% and 62.2 (11.1)% respectively; this was not statistically significant. In segments taken from the explanted hearts of three patients requiring re-transplantation, the mean maximum response was 78.0 (11.0)% and there was no correlation between maximum response in segments from each patient and the duration of cyclosporin therapy. The effect of intracoronary substance P in 12 cardiac transplant recipients was also examined (mean cyclosporin blood concentration 228.9 (42.8) ng/ml). The mean maximum dilatations measured as the percentage diameter change induced by substance P and isosorbide dinitrate were 22.1 (3.2)% and 26.0 (2.5)% respectively. There was no correlation between the degree of endothelium mediated vasodilatation in response to substance P and cyclosporin concentration. The nitric oxide response was preserved in the coronary arteries of patients exposed to cyclosporin. The mechanisms that initiate cyclosporin associated toxicity remain to be elucidated.

The effect of epithelium removal on human bronchial smooth muscle responsiveness to acetylcholine and histamine

The respiratory epithelium produces a variety of inflammatory mediators which may be influencing the bronchial hyperreactivity observed in patients with asthma. Animal studies have demonstrated that removal of the epithelium from tracheal and bronchial smooth muscle causes enhanced responses to cholinergic agonists and histamine (Hist). In this study the effect of epithelium removal on human bronchial smooth muscle response to acetylcholine (ACh) and Hist was assessed. Bronchial smooth muscle was obtained fresh from the operating theatre from 12 patients undergoing thoracotomy. Cumulative concentration effect curves (CCEC) for Hist and ACh were generated for epithelium intact and epithelium denuded muscle strips. All CCEC's were performed in duplicate and all denuded strips were obtained from the same airway immediately adjacent to the intact strip. The mean (± SEM) maximum response for Hist for the intact strip was 8.6 ± 1.1 (grams/gram wet weight) and 12.0 ± 1.4 (grams/gram wet weight) for the denuded strip (p < 0.05). For ACh the values were 9.3 ± 1.3 (g/g wet weight and 14.3 ± 1.8 (g/g wet weight), respectively (p < 0.05). The pD 2 (− log EC 50) for ACh was increased two-fold following epithelium removal (p < 0.05). For Hist there was a similar increase in pD 2 but this did not reach statistical significance. Thus removal of the epithelium from human isolated bronchial smooth muscle appears to modulate responsiveness to ACh and Hist. This enhanced responsiveness consequent to epithelium loss may prove important with respect to the development of worsening asthma.

Effects of activating spinal α-adrenoreceptors on sympathetic nerve activity in the rat

The effects of several α-adrenoreceptor agonists and antagonists administered intrathecally at T 10 level on renal sympathetic nerve activity (RSNA) were examined, in chloralose-urethane anaesthetised rats. Intrathecal noradrenaline (NA, 0.5–500 μg) produced one of 3 responses depending on dose, an inhibition of RSNA at low doses, an excitation of RSNA at high doses, or a biphasic effect. Intrathecal adrenaline (5–200 μg) was inhibitory in the main but some doses elicited poorly repeatable brief excitation followed by prolonged inhibition. Intrathecal methoxamine (ME; 2.5 ng-25 μg) caused a dose-dependent increase in RSNA (mean maximum response 27 ± 0.5%). The excitatory effects of NA and ME were blocked (72% ± 12%) by pretreatment with intrathecal prazosin (PRA, 20–200 ng) but not by yohimbine (YOH, 200 ng). Intrathecal guanabenz (GUA 3–15 μg) caused a dose-dependent inhibitory effect on RSNA (mean maximum 32% ± 5%). The inhibitory effects of NA, adrenaline and GUA were blocked by pretreatment with intrathecal YOH (200 ng-2 μg). Intrathecal PRA (200 ng) had no effect on the inhibitory effects of NA and GUA. Intravenous administration of each of the adrenoreceptor agonists (apart from adrenaline), at similar doses to those given intrathecally, in most cases had no significant effect on RSNA; in a few cases the opposite effects to those produced by intrathecal administration were seen.

Growth hormone and somatomedin-C in bulimia

Somatomedin-C (SOM-C) concentrations are regulated by circulating growth hormone (GH) concentrations; however, other factors, such as nutrition, also influence SOM-C concentrations. We evaluated the GH-SOM-C axis in seven normal-weight female bulimics one day after hospital admission, and in seven age-, sex-, and weight-matched normal controls. Subjects were medication-free for at least one month. Fasting morning serum GH concentrations were higher in all bulimics (range 2.5–13.3 ng/ml) than in all controls (range <1.0–1.8 ng/ml). The mean (±SD) maximum GH response to TRH (500 μg) was greater in the bulimics (12.9±4.9 ng/ml) than in the controls (3.7±2.7 ng/ml) (p<.001). Despite this GH elevation, the mean (±SD) SOM-C concentration was comparable in the bulimics (2.0±0.6 U/ml) and the controls (1.6±0.8 U/ml). This suggests that SOM-C generation is resistant to the elevated circulating GH in bulimia and that SOM-C is not inhibiting GH secretion in the pituitary-hypothalamic axis.

Fenoterol and salbutamol actions on guinea-pig myometrium: Effects of ovarian steroids

Responses of isolated preparations of longitudinal myometrium from the guinea-pig to fenoterol, salbutamol and isoprenaline were examined. Virgin adult guinea-pigs were treated (i) with oestradiol cypionate 20 μg/kg s.c. thrice weekly for two weeks; or (ii) as in (i) plus progesterone 3 mg/animal for the last four days. Other animals (dioestrous; cycle days 6–10) were untreated. The order of potency of the agonists in inhibiting field stimulation-induced contractions of the preparations (isoprenaline ⩾ fenoterol > salbutamol) indicated interaction with β 2-adrenoceptors. Oestrogen treatment enhanced the potency of isoprenaline 5-fold. Treatment with oestrogen plus progesterone enhanced the potency of all agonists 10- to 30-fold, and increased the mean maximum response to salbutamol. The mean pK D values for displacement by fenoterol of binding of (−)-[ 125I]cyanopindolol to membrane preparations from animals in both treatment groups were 5.57–5.92. These results raise the possibility that progesterone may enhance the coupling of β 2-adrenoceptors to transduction mechanisms in the longitudinal myometrium from oestrogen-primed guinea-pigs.

Trace element nutrition of grazing ruminants. 2. Hepatic copper storage in young and adult sheep and cattle given varying quantities of oxidized copper particles and other copper supplements

Hepatic copper (Cu) storage was determined by biopsy after oxidized Cu wire was given to sucking lambs at 0-43 days of age, and to weaned Merino sheep and Hereford cattle varying in age. Cu-calcium edetate (Cu-EDTA) and soluble glass pellets were also evaluated as Cu supplements. A dose of 45 mg oxidized particles/kg liveweight was predicted to induce a mean maximum response of 84 and 179 mg Cu/kg DM in hepatic concentrations in weaned Merino sheep and Hereford cattle at 49 and 100 days from dosing respectively; these responses should not result in unacceptable hepatic concentrations in cattle, or in sheep of low Cu status, but the response is variable, and supplementation as a precautionary measure without prior indications of Cu insufficiency is not desirable. The particles were effective when given to lambs from birth, but did not increase hepatic Cu concentrations in lambs when ewes were dosed post partum. A dose of 1 g particles/lamb was as effective as a 2 g dose in increasing hepatic Cu concentration, and lambs given 2 g were lighter than those given 1 g; the dose increased hepatic Cu concentrations for at least 292 days. Cu-EDTA was given subcutaneously at the rate of 50 mg Cu for sheep and 150 mg Cu for cattle, and was as effective in increasing hepatic Cu concentration as 45 mg oxidized particle/kg liveweight; it did not produce the severe reactions frequently reported in the literature. The soluble glass pellet was less effective, but studies with a later prototype suggest that subsequent formulations may be more satisfactory.

Three‐dimensional dynamic analysis for multi‐component earthquake spectra

AbstractAt the present time, there is a need for a rational approach for the analysis and design of three‐dimensional structures subjected to multi‐component earthquake motions. In this paper, a general design criterion for multi‐component earthquake input is proposed. A new method for three‐dimensional dynamic analysis is presented which estimates maximum displacements, forces or stresses for specified points within a structure. For each maximum value calculated, the corresponding critical angle of earthquake input is evaluated. The method is readily incorporated into existing computer programs for earthquake analysis, allowing one computer run to produce mean maximum response values for all possible angles of earthquake input. Combined axial and bending stresses are calculated at the modal level. It is shown that combining modal stresses yields lower estimates than if stresses are evaluated from maximum axial forces and moments. In addition, the method can be used without modifications to perform design checks for arbitrary blast or seawave spectra.

Prolactin response to metoclopramide in the castrated male rat.

The effect of castration on the prolacrin (PRL) response to the dopaminergic antagonist metoclopramide (MET) has been examined in the male rat. The mean ± SD PRL Content in pituitaries of intact rats (1802 ± 293 ng/mg) was significantly higher (P<0.00l) than that of rats 10 days after caStration (1170 ± 157 ng/mg). Basal plasma PRL levels, however, were unaffected by castration. In intact animals, the maximum PRL response to metoclopramide (0.25 mg/kg) was 144.2 ± 49.6 nglml, and increasing doses of MET (0.5, 1.0, and 2.5 mg/kg) did not augment the response. In the castrated rat, the mean maximum PRL response to MET (0.25 mg/kg) was only 59.8 ± 21.8 ng/ml (P<0.01 compared with intact animals.) Higher doses of MET (0.5, 1.0, and 2.5 mg/kg) increased the maximum PRL response, but this was still less (P<0.05) than the peak response in intact animals. With a larger dose of MET (10 mg/kg), a further increase in the peak PRL response was not observed in the castrated rats. These experiments demonstrate that castration can depress pituitary PRL concentration as well as the PRL response to the dopaminergic antagonist metoclopramide without altering basal PRL levels.

Direct vascular effects of agents used in the pharmacotherapy of cerebrovascular disease on isolated cerebral vessels.

The direct vasomotor effects of a number of agents used in the therapy of cerebral circulatory and metabolic disease were studied in isolated segments of cat pial vessels in vitro. Studies were repeated eight times generally, thus permitting the calculation of the mean maximum response—termed EAm (in dynes)—and of the molar agonist concentration required to effect the half-maximal response, termed EC50. The results obtained with various agonists were compared to a well-documented vasodilator, acetylcholine ( EAm = −780 dyn; EC50 = 0,029 μm) and a known vasoconstrictor, 5-hydroxytryptamine ( EAm = + 1630 dyn; EC50 = 0.036 μm). Papaverine and its derivatives effected a relaxation of the pial arteries with the following order of potency: YC-93 &gt; papaverine &gt; naftidrofuryl &gt; viquidil. The EC50 for papaverine was 1,5 μm. Methyl xanthine derivatives (aminophylline, pentoxifylline, and theophylline) were essentially inactive, In contrast, drugs that are known to be capable of decreasing the volume of an experimental infarction, many of which are described as α-adrenolytic agents, contracted the isolated cerebrovascular smooth muscle, Their order of efficacy, based on the mean EAm values, was ifenprodil &gt; vincamine &gt; nicergoline &gt; dihydroergotoxine &gt; raubasine, In addition, it was considered worthwhile to determine whether the ifenprodil-induced vasoconstriction occurred when human, rather than cat, pial vessels were studied, Ifenprodil and vincamine contracted the human vessels in a biphasic manner; the EC50 was calculated to be 2,0 and 30 μm. Based on the above observations, the following comments would appear justified, Firstly, an increase in cerebral blood flow does not necessarily mean a compound is a direct vasodilator. Secondly, the vasoconstrictory actions of some agents correlate well with their anti-ischaemic properties (e.g., ifenprodil, vincamine, and nicergoline), Lastly, one action of effective anti-ischaemic agents might be to reduce flow, by vasoconstriction, in hyperaemic tissue: the inverse “steal” effect.

Age and beta adrenoceptor-mediated function.

Beta adrenoceptor-mediated responsiveness to isoproterenol was compared in young and old subjects using the production of cyclic adenosine monophosphate (cyclic AMP) by lymphocytes as an index. The mean log dose-response curve for the elderly group was displaced to the right and the mean maximum response was less than that for the young subjects. The results corroborate evidence of a decreased response to isoproterenol-induced increases in heart rate in the elderly and raise the possibility of a generalized decrease in beta adrenoceptor-mediated functions in old age.