Adrenergic modulation of extrarenal potassium disposal

We studied the role of catecholamines in the regulation of potassium homeostasis in nine healthy subjects given intravenous potassium chloride (0.5 meq per kilogram of body weight) in the presence and absence of propranolol. Potassium infusion elevated serum potassium 0.6 +/- 0.09 meq per liter (mean +/-S.E.M.). Addition of propranolol augmented the rise (0.9 +/- 0.05 meq per liter) and prolonged the elevation in serum potassium without decreasing urinary potassium excretion. In a separate study, the same potassium load was administered with a concomitant infusion of epinephrine in five subjects. Epinephrine markedly blunted the increment in serum potassium (0.1 +/- 0.06 meq per liter) while reducing renal potassium excretion. Plasma aldosterone was not altered by the experimental procedures. Serum insulin fell minimally in the presence of propranolol but was unaffected by epinephrine. beta-Adrenergic blockade impairs and epinephrine enhances extrarenal disposal of an acute potassium load. These findings suggest that in patients with impaired potassium disposal, the risk of hyperkalemia may be increased when sympathetic blockade is induced.     

Temperature sensitive effects of alpha-adrenergic stimulation in mouse ventricular myocardia

The effects of alpha- and beta-adrenergic stimulation on the contractile force and L-type Ca2+ channel current were studied in mouse ventricular myocardia at two different temperatures. In ventricular tissue, at 35-36 degrees C, phenylephrine, in the presence of propranolol, produced a sustained negative inotropic response with no change in the time course of contraction and relaxation. These effects were greatly reduced at 22-23 degrees C. Isoproterenol produced marked positive inotropic responses accompanied by shortening of the time required for relaxation. In isolated ventricular myocytes, phenylephrine, in the presence of propranolol, significantly increased the L-type Ca2+ channel current (I(Ca)) at 35-36 degrees C, but the effect was small at 22-23 degrees C. Isoproterenol increased I(Ca) similarly at both temperatures. These results suggest that, in mouse ventricular myocardia, alpha-adrenoceptor mediated regulation of the contractile force and I(Ca) involve temperature-dependent mechanisms different from those of beta-adrenoceptor-mediated mechanisms.     

Direct alpha-adrenergic stimulation of hepatic glucose production in human subjects

Six normal humans each underwent infusions of 1) saline; 2) propranolol; 3) somatostatin; 4) somatostatin with propranolol; and 5) somatostatin with propranolol plus phentolamine on separate occasions. Propranolol alone had no effect on glucose production or plasma glucose. Somatostatin alone produced the expected initial decrease followed by an increase in both hepatic glucose production and plasma glucose. beta-Adrenergic blockade with propranolol displaced the glucose production (MANOVA, P = 0.0220) and plasma glucose (MANOVA, P = 0.0057) somatostatin response curves to higher levels, whereas alpha-adrenergic blockade with phentolamine combined with beta-adrenergic blockade displaced the glucose production (MANOVA, P = 0.0281) and plasma glucose (MANOVA, P = 0.0134) somatostatin response curves to lower levels. Because plasma insulin, C-peptide, and glucagon were suppressed comparably under all three conditions and plasma glucose concentrations were comparable initially, this represents direct alpha-adrenergic stimulation of hepatic glucose production in postabsorptive humans demonstrable when the primary glucoregulatory hormones are withdrawn and beta-adrenergic mechanisms are blocked. It is best attributed to sympathetic neural norepinephrine release.     

Premenstrual failure of alpha-adrenergic stimulation on hypothalamus-pituitary responses in menstrual migraine

In nine women suffering from menstrual migraine (MM), and in six healthy asymptomatic volunteers, plasma beta-endorphin (beta-EP), growth hormone (GH), norepinephrine (NE), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) concentrations were measured in response to clonidine (0.075 mg, i.v.) stimulation. In MM patients clonidine testing was performed in both the early and the late luteal phases of the menstrual cycle. Premenstrual symptoms were prospectively evaluated in the actual cycle using the Moos Menstrual Distress Questionnaire. beta-EP (after gel chromatography) and GH were measured using radioimmunoassay. NE and MHPG were evaluated by HPLC using electrochemical detection. In both phases of the menstrual cycle clonidine significantly reduced NE and MHPG levels in MM patients and controls in a similar way. In MM patients beta-EP and GH plasma levels were stimulated by clonidine only in the early luteal phase, whereas they remained unchanged when they were stimulated in the premenstrual period. In controls the response of both hormones was not affected by the menstrual cycle. The lack of hormonal response to clonidine in MM may suggest a postsynaptic alpha 2-adrenoreceptor hyposensitivity during the premenstrual period. This demonstrates a transient vulnerability of the neuroendocrine/neurovegetative systems, and could thus be a factor facilitating the precipitation of both behavioral changes and migraine attacks.     

Effects of caffeine on gluconeogenesis and urea synthesis induced by alpha-adrenergic stimulation in suspensions of rat hepatocytes

Effects of caffeine on gluconeogenesis and urea synthesis of rat isolated hepatocytes were investigated in the presence of hormonal agonists. Phenylephrine at 10 microM stimulated 1.7-fold gluconeogenesis and 1.9-fold (compared to control) urea synthesis from 4 mM glutamine. Stimulative effects of caffeine in the range from 0.1 to 10 mM were biphasic depending on its concentration, and it showed maxima at about 1 mM. Caffeine at 1 mM stimulated 2.1-fold gluconeogenesis and 2.4-fold urea synthesis. Caffeine without phenylephrine did not stimulate both syntheses. These effects of caffeine and phenylephrine diminished in the absence of extracellular Ca2+. Results on uptake of 45Ca2+ into hepatocytes and change in quin-2 fluorescence indicated that phenylephrine induced Ca2+ influx into the cell and consequently increased the intracellular Ca2+ concentration, [Ca2+], and that the addition of caffeine did not further stimulate the effect of phenylephrine on [Ca2+]. Therefore, we suggest that stimulation of gluconeogenesis and urea synthesis by phenylephrine is due to increase in [Ca2+]. Since caffeine is known to inhibit phosphodiesterase, the additional stimulation of both syntheses by caffeine plus phenylephrine may be due to the synergistic effect of increases in cAMP and [Ca2+]. The increase in the rates of gluconeogenesis and urea synthesis similarly depended on the caffeine concentration. Furthermore, the ratio of [acetoacetate]/[3-OH-butyrate] which shows intramitochondrial redox state, also depended on the caffeine concentration, indicating a possible coupling of the redox function of mitochondria with [Ca2+].     

Ultrastructural responses by Golgi apparatus of rat submandibular gland to beta-adrenergic, alpha-adrenergic, and cholinergic stimulation

Rat submandibular gland tissue pieces were stimulated in vitro for 30 min with a beta-adrenergic agent or a cyclic AMP analog to stimulate protein secretion, or with alpha-adrenergic or cholinergic agents or a Ca2+ ionophore to stimulate fluid secretion. Acinar cells were examined by transmission electron microscopy. In control tissue, acinar cells showed little evidence of secretory activity. The Golgi apparatus was sparse and was associated with a few small, immature secretory granules with fine fibrillar contents. Following secretory granule discharge stimulated by isoproterenol or dibutyryl cyclic AMP, acinar cells were constricted, and had extensive basolateral membrane folding and tightly packed rough endoplasmic reticulum. Golgi complexes were prominent and had multiple small granules with filamentous contents. After stimulation of fluid secretion by alpha-adrenergic agents (epinephrine, phenylephrine), or cholinergic agents (acetylcholine, carbachol, pilocarpine), or a Ca2+ ionophore (A23187), the Golgi apparatus had compact concave cisternae enclosing aggregates of tubulovesicles. Acinar cells were distended, basolateral membranes were expanded, and rough endoplasmic reticulum was dilated and vesiculated.     

Influence of alpha-adrenergic receptor stimulation on splanchnic intravascular volume in conscious humans.

The influence of selective alpha-adrenergic receptor stimulation on total splanchnic intravascular volume and blood volume in individual splanchnic organs in humans has not been previously examined. The present study employed a previously validated quantitative radionuclide imaging technique, involving a gamma camera and Tc-99m labeled erythrocytes, to measure changes in total splanchnic, hepatic, splenic, and extrahepatosplenic volume during a 20-minute phenylephrine infusion (30-120 micrograms min-1 iv). Changes in total splanchnic volume were estimated from changes in total splanchnic radioactivity, blood radioactivity, and estimated in vivo tissue attenuation. Radionuclide-estimated total splanchnic volume increased 477 +/- 96 ml (P less than 0.0003) at the end of phenylephrine infusion. Hepatic volume increased 25 +/- 5% (P less than 0.0003), splenic volume decreased 46 +/- 7% (P less than 0.0003), and extrahepatosplenic volume decreased 15 +/- 2% (P less than 0.0003). Systolic and diastolic arterial pressures increased from 119 +/- 4 to 138 +/- 5 mmHg (P less than 0.0003) and from 83 +/- 1 to 96 +/- 2 mmHg (P less than 0.0003), respectively. Heart rate decreased from 62 +/- 2 to 51 +/- 3 bpm (P less than 0.0003). Thus, in man, selective alpha-adrenergic receptor stimulation is associated with an increase in splanchnic intravascular volume that is due to an increase in hepatic volume and occurs despite decreases in splenic and extrahepatosplenic volumes. This increase in total splanchnic volume would be associated with a decrease in venous return from the splanchnic vasculature to the right heart which would act to decrease cardiac output.     

Enhancement of ATP-sensitive potassium current in cat ventricular myocytes by beta-adrenoreceptor stimulation.

1. To address the questions of whether beta-adrenoreceptor stimulation can augment ATP-sensitive potassium current (IK(ATP)), and what the mechanism of such an effect might be, action potentials and whole-cell ionic currents were recorded from adult cat cardiac ventricular myocytes using a conventional whole-cell patch technique. 2. An outwardly directed, ohmic, non-inactivating, glyburide (10 microM)-sensitive current reversing near the reversal potential for potassium (EK) developed slowly (10-25 min) in cells dialysed with an ATP-free pipette (intracellular) solution. During this time, action potential duration markedly decreased while the resting membrane potential hyperpolarized closer to EK. Extended (> 30 min) periods of internal dialysis with ATP-free solution eventually resulted in run-down of the outward current. 3. Externally applied isoprenaline (1 microM) caused a rapidly developing (< or = 60 s), sustained enhancement of a glyburide (10 microM)-sensitive IK(ATP) in cells internally dialysed with ATP-free solution. IK(ATP) remained elevated even after the isoprenaline was removed, and subsequent applications of the beta-agonist failed to increase IK(ATP) further. Half-maximal isoprenaline stimulation of IK(ATP) occurred at a concentration of approximate of 1.5 nM. 4. Pretreatment with propranolol (1 microM) prevented the enhancement of IK(ATP) by a beta-agonist. 5. Isoprenaline-induced IK(ATP) could be blocked by either internal application of GDP-beta-S (2-5 mM) or pretreatment with cholera toxin (1-10 microgram ml-1, > 18 h). Pretreatment with pertussis toxin (1-2 microgram ml-1, > 18 h) did not attenuate the isoprenaline response, whereas internally applied GTP-gamma-S (100 microM) or F- (20 mM) caused IK(ATP) to increase rapidly in the absence of the beta-agonist. 6. Although externally applied forskolin (10 microM) also stimulated IK(ATP), neither 1,9-dideoxyforskolin (10 microM) nor 8-(4-chlorophenylthio)-cAMP (200 microM) had any effect on the current. Internal application of the adenylate cyclase inhibitor 2'-deoxyadenosine-3'-monophosphate (100 microM) resulted in a reduction in the response to isoprenaline, while internal application of a protein kinase A inhibitor (PKI5-24, 22.5 microM) did not attenuate the response to the beta-agonist. 7. IK(ATP) developed slowly during internal dialysis with ATP-free solution.(ABSTRACT TRUNCATED AT 400 WORDS)     

Release of noradrenaline from the cat spleen by nerve stimulation and potassium.

1. In rabbits under pentobarbitone anaesthesia stimulation of the nasal mucous membrane with ether vapour causes apnoea, bradycardia and a rise in arterial blood pressure. 2. Simultaneous measurements of femoral arterial blood pressure and of femoral arterial or venous blood flow show that vascular resistance increases in both the intact and skinned hind limb in response to nasal stimulation. Evidence is presented to show that the increase in hind-limb vascular resistance is due to vasoconstriction which is relfex in nature. 3. The change in vascular resistance in the hind limb following nasal stimulation may be divided into two distinct phases. The primary (early) phase is mediated by the efferent sympathetic nerves to the limb whereas the secondary (late) phase is mediated by adrenal gland hormones. 4. The secondary phase of the hind-limb vascular response is invariably less pronounced than the primary phase, and with regard to the time course of the appearance of the two phases of the response it appears that following stimulation of the nose there is no mutual reinforcement of sympathetic neural and humoral influences on the hind-limb blood vessels. 5. The cardiovascular response occur in the absence of changes in pulmonary ventilation.     

Impairment of the discrimination of the direction of single-whisker stimulation induced by the lemniscal pathway lesion

In the rodent somatosensory system, stimulus information received by the whiskers is relayed to the barrel cortex via two parallel pathways, the lemniscal pathway and the paralemniscal pathway. The lemniscal pathway includes the principal trigeminal nucleus (Pr5) and the ventral posteromedial thalamic nucleus (VPm). The paralemniscal pathway includes the spinal trigeminal subnucleus interpolaris (Sp5i) and the medial division of posterior thalamic nucleus (POm). The purpose of this study was to investigate the roles of those pathways in perceptions of the direction of the single-whisker stimulation in the rat. Rats were trained to perform a go/no-go task that required the discrimination of forward or backward stimulation applied to their single whisker. When a selective lesion was made in VPm or Pr5, error rate for the task performance increased significantly. In contrast, when a selective lesion was made in POm or Sp5i, we found no significant change in performance. These results suggest that the lemniscal pathway plays more important roles in a discrimination of stimulus direction applied to the single whisker.     

Renal manifestations of extrarenal neoplasms

In a study of 1270 consecutive autopsies there were 314 patients with malignant neoplasms arising in sites other than the kidney and central nervous system. In over 50 per cent of these there was significant renal damage related to cancer. Renal damage was produced by direct involvement of one or both kidneys by the neoplasm or by indirect effects. The latter included ischemic damage, metabolic injury, immunologic injury, and effects of therapy directed at the malignant tumor. In patients with cancer, tumor bulk and invasion of vital organs do not always explain the clinical deterioration and cause of death. Recognition of the indirect effects of tumors on the kidney and other organ systems is essential to the understanding of the generalized host response to malignant disease.     

Impairment of visual perception and visual short term memory scanning by transcranial magnetic stimulation of occipital cortex

Summary Transcranial magnetic stimulation (TMS) of occipital cortex was performed using a magneto-electric stimulator with a maximum output of 2 Tesla in 24 normal volunteers. The identification of trigrams, presented for 14 ms in horizontal or vertical arrays was significantly impaired when the visual stimulus preceded the occipital magnetic shock by 40 to 120 ms. The extent of impairment was related to TMS intensity. The latency of perceptual impairment was shorter for more intense TMS. No perceptual impairment was obtained by sham stimulation when TMS shocks were applied to the upper cervical region rather than the occipital region to rule out unspecific startle reactions affecting attention possibly responsible for the observed reduction in performance. Occipital TMS did not evoke systematic eye movements except for blink responses at latencies beyond 40 ms which were too late to interfere with visual input. Depending on the required serial order of readout of the trigram perceptual impairment was more marked for the second and third part of the trigram. This demonstrates that TMS interferes with the internal serial processing of visual input. To elucidate this further, TMS was used in a Sternberg short term visual memory scanning task. TMS caused a marked decrease in memory scanning rates whereas visual stimulus encoding and storage remained unaffected when tested at various TMS delays. TMS appears to be a useful method to study processes of visual perception and short term memory handling in the occipital cortex. Advantages over classical visual masking techniques especially regarding topical localisation are discussed.This work was partially supported by a grant from the Deutsche Forschungs Gemeinschaft (SFB 200/B9) to V.H.