Isoprenyl phosphinylformates: new inhibitors of squalene synthetase.
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Animals↗
Biomedical subjects
C Forster
Publications and source records attributed to C Forster.
Discharge patterns of human C-fibers induced by itching and burning stimuli.
1. The aim of this investigation was to study the peripheral neural mechanisms of the C-fiber-mediated modalities of burning pain and itch by the use of microneurography of human unmyelinated afferents. 2. Sixteen stable recordings of single C-fibers and 6 multiunit recordings were obtained from the superficial radial nerves of volunteers. All units were excited by stimulating their receptive fields with von Frey bristles (range 10-600 mN), and all but four units were also driven by radiant heat stimulation. 3. Histamine was iontophoretically applied to the receptive fields of these units for 20 or 30 s and was found to provoke itching sensations lasting several minutes, together with wheal and flare responses. Subsequently a solution containing 20 or 30% mustard oil was applied to the receptive field of the respective unit, which provoked a sensation of burning pain. 4. One-half of the units were excited by histamine, and the median discharge rates derived from interspike intervals ranged from approximately 0.1 to 0.8 Hz. Mustard oil-induced activity was observed in all histamine-sensitive units and also in three single units and in one multiunit recording that revealed no histamine response. Median interval-derived discharge rates ranged from 0.2 to 1.2 Hz. 5. Analysis of the interspike interval distribution and of the autocorrelation function derived from the chemically induced discharges of single units provided no evidence for an encoding of itch and burning pain in different discharge patterns of units responding to histamine and to mustard oil.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Inhibitory role of the coronary arterial endothelium to alpha-adrenergic stimulation in experimental heart failure.
The role of the endothelium in regulating coronary alpha-adrenergic tone was evaluated in isolated coronary arterial rings from dogs with and without pacing-induced congestive heart failure (CHF). The maximal contractile response to methoxamine was attenuated approximately 43% (p less than 0.05) in both intact and denuded CHF rings compared with control. Conversely, norepinephrine-induced contractions were diminished 58% in intact CHF vessels and 39% in denuded CHF vessels (p less than 0.05). Denudation did not alter responses to methoxamine but significantly (p less than 0.05) augmented the tension generated by norepinephrine in both control (1.7-fold) and CHF (2.4-fold) arteries. In both intact control and CHF coronary arteries, norepinephrine elicited rapid, transient relaxations that preceded slow, sustained contractions; the initial relaxation phase was endothelium dependent, because denudation eliminated the response. Relaxations to the selective alpha 2-adrenoceptor agonist BHT 920 were also dependent on the presence of an endothelium. At peak CHF, endothelium-dependent relaxations to norepinephrine and BHT 920 were enhanced, whereas relaxations to nitroglycerin and acetylcholine were unaltered. The data suggest that alpha-adrenergic tone in canine coronary arteries is diminished by pacing-induced CHF because of a decrease in alpha 1-adrenoceptor-mediated constriction and an enhanced capacity of the endothelium to antagonize the direct vascular smooth muscle response of norepinephrine through endothelium-dependent, alpha 2-adrenoceptor-mediated relaxations.
Acetylcholine↗
[The rating box--a new instrument for ambulatory detection of subjective variables].
For the acquisition of subjective variables in outpatients and inpatients, a new device--the Rating Box--has been designed. The Rating Box provides a standardized, date- and time-logged documentation of symptoms by the patient and rapid transfer of data to a personal computer. The simultaneous acquisition of several symptoms using different types of scales is possible. The acoustic alarm of the Rating Box reminds the patient to enter data at preselected times. The device is easy to handle, even by older patients, and has been successfully tested in the acquisition of pain variables in patients with a variety of painful conditions.
Data Collection↗
Automatic classification and analysis of microneurographic spike data using a PC/AT.
Using a standard PC-AT with a commercial analog data interface a system was designed which supports microneurographic experiments and which may also be used for other types of extracellular spike recordings. The signal is sampled on-line at 25 kHz and a spike is detected if the signal passes a certain threshold. The spikes are displayed on the screen and stored on disk. A second on-line mode records the responses of the examined unit to electrical stimulations, which are used to identify the type of fibre and to test the subsequent spike classification. The spikes are classified off-line using a template matching algorithm, which has unsupervised learning and discrimination phases. The results are displayed in a time-frequency plot and may be checked with the responses to electrical stimulations. Artifacts from EMG and other electrical fields are reliably sorted out. In recordings, which include more than one unit, their spikes are discriminated with a low error rate.
Action Potentials↗
Pacing-induced heart failure in the dog: evaluation of peripheral vascular alpha-adrenoceptor subtypes.
Postjunctional alpha-adrenoceptor characteristics were evaluated in canine dorsal pedal arterial and saphenous vein rings studied before and after development of severe pacing-induced heart failure (CHF). Before CHF, all agonists produced concentration-dependent increases in tension of both blood vessels. After development of CHF, the responsiveness and sensitivity of the vessels to the alpha 1-agonists and the mixed agonists were significantly increased as compared with control. The maximum responses to BHT 920 and BHT 933 remained unaltered after CHF, but both vessels showed decreased sensitivity to BHT 920. Before CHF, the rank order of potency with respect to norepinephrine (NE) for the dorsal pedal artery was as follows: NE greater than epinephrine greater than methoxamine greater than BHT 933 greater than BHT 920, and for the saphenous vein was epinephrine greater than NE greater than BHT 933 greater than methoxamine greater than BHT 920. At peak CHF, the rank order of potency for the artery was epinephrine greater than NE greater than methoxamine greater than BHT 933 greater than BHT 920, whereas in the vein BHT 920 was approximately 80 times less potent than NE (as compared with being only five times less potent before CHF). Prazosin was a potent, competitive antagonist (pA2 values of 9.2 and 9.0 for the artery and the vein) of methoxamine-induced contractions before development of CHF. Prazosin had a 10-fold lower potency against epinephrine-induced contractions in the dorsal pedal artery, whereas it was not competitive against epinephrine in the saphenous vein. Against the selective alpha 2-agonists, prazosin either showed no antagonism or was not competitive. After CHF, prazosin was non competitive against all agonists tested. Yohimbine was a potent, competitive antagonist against BHT 920 both before and at CHF. Yohimbine had intermediate antagonism against epinephrine and produced no antagonism of methoxamine-induced contractions. We conclude that increased reactivity and sensitivity of the peripheral vasculature to alpha 1-agonists occurs at CHF.
Animals↗
Endothelium modulation of the effects of nitroglycerin on blood vessels from dogs with pacing-induced heart failure.
1. The relaxant actions of nitroglycerin (previously considered to be an endothelium-independent relaxing agent) and acetylcholine (an endothelium-dependent relaxing agent) were compared on 4 vascular preparations (dorsal pedal artery, saphenous vein, left anterior descending coronary artery and circumflex coronary artery) from dogs with and without pacing-induced congestive heart failure (CHF). 2. Responses of the coronary arteries to acetylcholine were unaltered in endothelium-intact rings from dogs with and without heart failure. Similarly no such changes were observed in the peripheral vessels. The maximum relaxation produced by acetylcholine was always greater in the coronary vessels compared to the peripheral vessels. 3. Before heart failure, the coronary vessels were more sensitive and reactive to nitroglycerin compared to the peripheral vessels. 4. Removal of the endothelium in both the control (dogs without CHF) and experimental (dogs with CHF) rings enhanced the relaxant effects of nitroglycerin, such that the EC50 for nitroglycerin became significantly lower in all denuded rings, with the exception of the saphenous vein and the left anterior descending coronary artery, before the development of CHF. 5. When CHF was maximally developed, vascular sensitivity to nitroglycerin was increased in peripheral vessels with an intact endothelium, but not in the coronary vessels. 6. These findings indicate that relaxation produced by nitroglycerin cannot be considered as entirely endothelium-independent but should be considered endothelium-modulated.
Acetylcholine↗
Pharmacokinetics, hemodynamic, renal, and neurohormonal effects of atrial natriuretic factor in experimental heart failure.
The hemodynamic, renal, neurohormonal effects and pharmacokinetics of synthetic atrial natriuretic factor (ANF) were studied in six conscious dogs with severe heart failure induced by right ventricular pacing at 250 beats/min for 5.0 +/- 0.6 weeks. Severe heart failure was characterized by a low cardiac output (2.1 +/- 0.1 L/min, elevated pulmonary capillary wedge pressure (26.8 +/- 2.8 mmHg) and right atrial pressure (14.5 +/- 2.2 mmHg). Synthetic ANF (human 99ser-126tyr ANF) was administered intravenously as 2 consecutive 30 min infusions (0.02 and 0.10 microgram/kg.min respectively); and each infusion was preceded by a priming dose of 1 microgram/kg. In contrast to the potent vasorelaxant, natriuretic and renin-lowering effects previously reported in normal dogs, these effects were not observed in the dogs with heart failure with either dose of ANF. The plasma half-life was 10.0 +/- 2.6 min, significantly longer than that reported previously in normal dogs. These data suggest that in this model of heart failure, the pharmacokinetics of ANF are altered and there is generalized target organ resistance to the actions of ANF.
Animals↗
Alterations in serum sodium in relation to atrial natriuretic factor and other neuroendocrine variables in experimental pacing-induced heart failure.
The pathophysiologic role of atrial natriuretic factor and other neuroendocrine variables in relation to serum sodium and renal function was evaluated in 15 conscious dogs with severe chronic ventricular pacing-induced heart failure (250 beats/min for 5.1 +/- 0.4 weeks). Six sham-operated dogs observed over an 8 week period served as controls. Development of heart failure was characterized by a progressive increase in plasma norepinephrine, renin activity and aldosterone from control values of 293 +/- 15 pg/ml, 1.4 +/- 0.4 ng/ml per h and 124 +/- 42 pg/ml, respectively, to 1,066 +/- 96 pg/ml, 10.2 +/- 2.4 ng/ml per h and 577 +/- 151 pg/ml (all p less than 0.01), respectively, at severe heart failure. In contrast to other neuroendocrine variables, plasma atrial natriuretic factor increased from a control level of 243 +/- 74 pg/ml to a peak concentration of 724 +/- 149 pg/ml (p less than 0.01) at 2 weeks, then declined and plateaued at twice the level of the control value as severe heart failure developed. At severe heart failure, serum sodium decreased from 147 +/- 0.6 to 141.8 +/- 2.1 mmol/liter (p less than 0.05), whereas urea increased from 6.0 +/- 0.5 to 7.8 +/- 0.6 mmol/liter (p less than 0.05). The change in serum sodium concentration correlated with plasma renin activity and aldosterone (r = -0.77, -0.88, respectively, both p less than 0.01), but not with norepinephrine or atrial natriuretic factor. When sinus rhythm was restored, 14 dogs were observed for 48 to 72 h and 8 dogs were followed up for another 4 weeks after cessation of pacing.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Vascular smooth muscle responsiveness to noradrenaline and phenylephrine following experimental heart failure in dogs.
Adrenergic vascular responsiveness was assessed in the dorsal pedal artery and the saphenous vein in dogs before and after the development of congestive heart failure (CHF). Following development of severe CHF, both noradrenaline and phenylephrine could produce a greater maximum tension and a shift of the resultant concentration-effect curve to the left compared to the curves seen before the development of CHF. The saphenous vein was more sensitive than the dorsal pedal artery to both agonists before CHF. After CHF, the sensitivity difference to noradrenaline increased significantly but it remained unaltered to phenylephrine. Relative to noradrenaline, phenylephrine became more potent on the artery at peak CHF, whereas the potency ratio was unchanged in the saphenous vein at peak CHF. Prazosin was a competitive antagonist only against phenylephrine prior to CHF; competitive antagonism was not seen against noradrenaline or following CHF. Prazosin was less effective in antagonising noradrenaline induced contractions, as shown by an increase in IC50 values. These results are consistent with increased tissue sensitivity to adrenergic agents during CHF. The greater potency of phenylephrine in the artery at peak CHF suggests the presence of a greater proportion of alpha 1 adrenoceptors, which is consistent with the decrease in effectiveness of prazosin after the development of CHF.
Animals↗
Alpha 1-adrenoceptor activity in arterial smooth muscle following congestive heart failure.
The interactions between yohimbine (selective alpha 2-antagonist) with noradrenaline (mixed agonist) and phenylephrine (selective alpha 1-agonist) were studied in the canine dorsal pedal artery in an attempt to characterize the peripheral vascular response to adrenergic agents before and after the development of congestive heart failure in the dog. The contractile responses of the dorsal pedal artery to potassium chloride were also examined. Both noradrenaline and phenylephrine contracted the dorsal pedal artery in a concentration-dependent manner before and at peak heart failure, the responses to the agonists being enhanced at heart failure. The responses of the artery to potassium were not modified by congestive heart failure. Yohimbine caused concentration-dependent antagonism of noradrenaline, without altering the magnitude of the maximum response, providing pA2 values ranging from 8.26 to 7.06 against low and high concentrations of noradrenaline, respectively, before heart failure development. Following heart failure, the pA2 values for yohimbine against noradrenaline remained unchanged, but slopes from the Arunlakshana-Schild plots were significantly different from unity, implying a noncompetitive antagonism. The pA2 values of yohimbine against phenylephrine were at least 10 orders of magnitude lower than those against noradrenaline. After congestive heart failure, yohimbine was even less effective against high concentrations of phenylephrine. These findings suggest that enhanced vasoconstriction during heart failure results, in part, from increased alpha 1-adrenoceptor mechanisms in peripheral arterial smooth muscle.
Acetylcholine↗
Measurement of the analgesic effects of aspirin with a new experimental algesimetric procedure.
Using controlled long lasting noxious squeeze stimuli applied to the interdigital webs we have tried to develop experimental methods allowing us to measure the effects of peripherally acting analgesics. In the present double-blind cross-over study with 12 subjects we tested the effects of aspirin (1000 and 1500 mg) vs. placebo on subjective pain induced by alternately applied 12 N (Newton) and 8 N stimuli. During the sessions blood samples were taken in regular intervals to measure acetylsalicylate (ASA)- and salicylate (SA)-plasma levels. Analyses of variance were computed with several psychophysical parameters. Both the '12 N' and the '8 N' ratings discriminated between placebo and aspirin, however, only the ratings obtained from the stronger stimuli discriminated between two doses of aspirin. Subsequently we computed analyses of covariance with the ASA- and SA-plasma levels as covariates. Significant (negative) correlations of pain ratings and SA-plasma levels were found for the high dose of aspirin, but there were no significant correlations of ASA levels and ratings.
Analgesia↗
Isoprenoid (phosphinylmethyl)phosphonates as inhibitors of squalene synthetase.
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Animals↗
Physiological effects of synthetic atrial natriuretic factor in normal conscious dogs.
The objective of this study was to examine the integrative physiologic effects of atrial natriuretic factor (ANF). Synthetic 99-126 ANF was administered to 6 normal conscious dogs as two consecutive infusions (0.02 and 0.1 microgram/kg/min respectively) each over 30 min: each infusion was preceded by a priming dose of 1 microgram/kg. With the first infusion, mean arterial pressure declined from 113 +/- 2 to 103 +/- 4 mmHg, pulmonary capillary wedge pressure declined from 9.6 +/- 0.5 to 7.2 +/- 0.7 mmHg and right atrial pressure declined from 9.8 +/- 0.4 to 8.0 +/- 0.7 mmHg (all p less than 0.05). No change in heart rate was seen. Despite very high plasma ANF concentrations, no further decline in arterial or central filling pressures were seen in the second infusion. In contrast, cardiac output declined progressively from 3.8 +/- 0.2 to 2.8 +/- 0.21/min (p less than 0.01) by the end of second infusion. Plasma renin activity declined from 2.2 +/- 0.7 to 0.9 +/- 0.3 ng/ml/hr (p less than 0.05) while plasma norepinephrine remained unchanged. Urine output and sodium excretion increased in a dose dependent manner. The diverse time course of the hemodynamic, renal and neuroendocrine effects suggests these effects of ANF are mediated by different mechanisms. Furthermore, the failure of heart rate and plasma norepinephrine to increase despite a significant decline in blood pressure and cardiac output suggests ANF may have a depressant effect on the sympathetic nervous system.
Animals↗
[Psychosocial adaptation with an artificial intestinal outlet].
A total of 1625 patients with colostomy, ileostomy or urostomy, including all members of the Swiss ILCO Association, received a questionnaire concerning their medical, social, family and personal situation. 948 questionnaires were analyzed. The mean age was 64 and the time since operation 6 years. 60% regarded their postoperative instruction in stoma care as adequate, but 32% were unhappy with the preoperative information. The transstomal colonic irrigation technique was still unknown to 21% of the colostomy patients and was utilized by only 32%. One year after the operation 69% of the patients with colostomy, 83% with ileostomy and 59% with urostomy in the under-62 age group were fully reintegrated in their professions. Acceptance of the stoma by family and friends was good and there were no major difficulties in practising sports and other hobbies. Sexuality proved to be the most seriously affected aspect of their personal lives, as 33% male and 13% female patients reported major problems.
Adaptation, Psychological↗
Rotational behaviour elicited by intracerebral injections of apomorphine and pergolide in 6-hydroxy-dopamine-lesioned rats. I: Comparison between systemic and intrastriatal injections.
Rotational behaviour in unilaterally 6-hydroxy-dopamine-denervated rats has been attributed to stimulation of dopamine receptors on striatal as well as limbic areas. In the present study the rotational behaviour elicited by local intrastriatal injections of apomorphine or pergolide was compared to the rotation elicited by systemic injections of the drugs. We found that intrastriatal injections induced rotational behaviour almost identical to the behaviour occurring after systemic treatment. Furthermore, studies of the spread of [3H]apomorphine in brain tissue showed that at the peak of rotation the radioactivity was confined within the limits of the striatum. Non-significant amounts of radioactivity was found in the nucleus accumbens. On the basis of these data we conclude that rotational behaviour elicited by systemic injections of apomorphine or pergolide originates from stimulation of striatal sites. The difference in rotational patterns elicited by these drugs is more likely to relate to differences in receptor stimulation within the striatum than differences in, for example, relative distribution between limbic and striatal areas.
Animals↗
Rotational behaviour elicited by intracerebral injections of apomorphine and pergolide in 6-hydroxy-dopamine-lesioned rats. II: The striatum of the rat is heterogeneously organized for rotational behaviour.
The present study compares the role of the nucleus accumbens and the striatum, as well as various regions of the striatum, in the ability of intracerebral injections of the dopamine agonists apomorphine and pergolide to elicit rotational behaviour in 6-hydroxy-dopamine-lesioned rats. We found that apomorphine and pergolide elicit rotational behaviour when injected into the denervated striatum, but not when injected into the ipsilateral nucleus accumbens. The striatum seems heterogeneously organized as regards rotational behaviour since maximal-apomorphine rotation was elicited from the corpus of the striatum as compared to the effects produced by injections into the head and the tail of the striatum. This topographical distribution is similar to the distribution of dopamine-stimulated cyclic AMP. The pergolide response is more evenly distributed in the striatum. It is suggested that the difference in the topographical distribution of the ability of apomorphine and pergolide to elicit rotational behaviour reflects a regional distribution of dopamine receptors in the striatum of the rat.
Animals↗
Neuroleptic drugs and their action on different neuronal pathways.
The occurrence of tardive dyskinesia has been related to treatment with most typical neuroleptic drugs. It has been hypothesized that risk of the disorder may be less with some atypical antipsychotic agents. Other contributing risk factors may include an underlying vulnerability of the nervous system. Understanding of these features of tardive dyskinesia should be enhanced through more information on functional differences between dopamine receptors and on how different types of antipsychotic drugs affect such receptors. In our animal studies, we have found evidence that dopamine D-1 and D-2 receptors are functionally linked to different behavioral phenomena in the rat, that they are differently affected by dopamine agonist and antagonist drugs, and that they may be selectively localized to different postsynaptic neuronal systems. We suggest that the development of antipsychotic drugs with a low risk of inducing tardive dyskinesia or of novel treatments for this condition may arise from improved understanding of the functions of various dopamine receptors in the brain.
Animals↗