Effect of alpha-1 adrenoceptor blockade on plasma levels of atrial natriuretic peptide during dynamic exercise in normal man.
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Biomedical subjects
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Graded exercise was performed in three healthy volunteers. Plasma levels of immunoreactive atrial natriuretic peptide (iANP) were determined at different workloads. Unchanged or slightly decreased plasma levels of iANP were observed during light exercise, whereas at medium to high workloads a considerable increase in plasma levels of iANP was found. Factors responsible for the increase in plasma levels of iANP might include elevated right atrial pressure and increased plasma levels of epinephrine and norepinephrine.
A 25-year-old man was admitted with severe chest pain and an electrocardiogram suggestive of anterior myocardial infarction. Echocardiogram was normal, but chest X-ray showed left-sided pneumothorax. The electrocardiogram showed increasing R-wave amplitude in the days after correction of pneumothorax. Taken in the supine position the electrocardiogram can be misleading in case of pneumothorax or mediastinal emphysema, but the electrocardiogram should be normal if taken in the erect position.
Increased plasma levels of atrial natriuretic peptide (ANP) during exercise have been reported. To investigate the role of tachycardia as a stimulus for release of ANP during exercise the following study was undertaken. Graded exercise was performed in six healthy volunteers before and after beta 1-adrenoceptor blockade. Plasma levels of ANP were determined at different workloads in both cases. At rest and at all workloads during exercise plasma levels of ANP were higher after beta 1-adrenoceptor blockade than without. Therefore, it is unlikely that tachycardia is a major stimulus for secretion of ANP during exercise. It is suggested that increased right atrial pressure and/or pulmonary arterial blood pressure and increased plasma levels of catecholamines are important secretory stimuli for ANP during exercise.
The Proteus anguinus L. is a blind cave perennibranch amphibian whose visual system undergoes an important morphogenetic degeneration in adulthood. The eyeball becomes atrophied and disappears under the fat tissue of the head. However, a retina can still be identified and a photophobic behavior of the animal indicates a remaining photosensitivity. In the oldest animal observed, some photoreceptor cells are still present as well as other types of retinal neurons. Characteristic synapses are observed in both the inner and outer plexiform layers. Dopaminergic amacrine cells, with processes in the inner plexiform layer, can be identified by their tyrosine-hydroxylase immunoreactivity. Taken together, these results indicate a possible functional role of the remaining retina. Since dopamine is especially involved in light adaptation from darkness, the residual retina could act in triggering the turning behavior of Proteus in response to lightening.
A highly sensitive and accurate radio-immunoassay for measurement of atrial natriuretic peptide in human plasma has been established. All reagents are commercially available. The sensitivity of the method is 1 pmol/l. The 50% intercept of the standard curve was at 22 fmol/tube and inter- and intra-assay precision were 10.9 and 5.3%, respectively. Plasma immunoreactive atrial natriuretic peptide levels measured in healthy subjects, during pregnancy, and in congestive cardiac failure were within the limits reported in the literature.
Arachidonic acid induced a reversible breakdown of the blood-aqueous barrier in the iridial processes of the rabbit ciliary body, whereas the ciliary processes were not affected under the conditions of this study. The focal passage of horseradish peroxidase through the tight junctions was demonstrated. In freeze-fracture images, this breakdown of the barrier function was associated with focal changes: an alteration in the geometry of the tight junctional network; an increase in the number of discontinuities of the P-face ridges and particles and short bars in the E-face furrows; an increase in the density of intramembranous particles within the junctional area. The significance of the ultrastructural alterations of the tight junctions as a structural counterpart of the physiological changes is discussed.
The tight junctions of the ciliary epithelium act as a barrier preventing the passage of blood borne macromolecules into the posterior chamber. The use of the freeze-fracture technique has led to a good knowledge of their morphological pattern in various species. However, in order to attempt a correlation of the morphology of the tight junctions with their physiological properties, their intimate substructure must be considered. As in other glutaraldehyde-fixed epithelia, the tight junctions appear as networks (variable in their apico-basal thickness) of more or less discontinuous P-face ridges and as complementary E-face furrows in which some particles or short bars are found. The significance of the discontinuities of ridges has been analysed. The continuity of the junctional fibrils was evident as assessed both by quantitative measurements as well as morphological examination of complementary fracture faces. In addition, the absence of loss of junctional material showed that the integrity of the junction was preserved during the freeze-fracture process, even in conditions where an increase in "transfer" of junctional elements was experimentally induced. Most of all, a "pore system" due to visualizable gaps in the fibrils is not tenable for the ciliary epithelium. Furthermore, the analysis of transition steps at the level of membrane "fusion" showed that the tight junctions of the ciliary epithelium must now be considered as formed by two slightly offset fibrils, one per adjacent plasma membrane.
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The ocular hypotensive efficacy of continuously delivered epinephrine is compared to that of pulsed doses provided by eyedrops in both normotensive and hypertensive rabbit eyes. In normotensive eyes, 2 microgram/hr and 4 microgram/hr epinephrine delivered into the tear film continuously for 12 hours reduces intraocular pressure as well as eyedrop pulses of 0.5% epinephrine hydrochloride or 2% epinephrine bitartrate (doses of 500 and 1100 microgram, respectively). Ocular hypertension induced by an intragastric water load in rabbits is significantly inhibited by continuous delivery of epinephrine at the rates of 3 or 6 microgram/hr, or by 2% epinephrine bitartrate (1% free base) eyedrops. Epinephrine delivered continuously at rates of 2-6 microgram/hr for 6 to 12 hours (12-72 microgram total) has hypotensive efficacy equivalent to 15 to 40 times as much epinephrine applied once in eyedrops. Epinephrine bitartrate eyedrops reduce tear film pH well below normal. Continuous delivery of epinephrine bitartrate does not reduce tear film pH below normal levels.
The development of techniques for the continuous administration of drugs to the eye raises the question of whether a conjunctivitis can be controlled by continuous low rates of steroid release, or whether large, intermittent doses of steroid, as provided by eyedrops, are necessary. Efficacy of the two modes of drug administration was evaluated in a conjunctivitis model produced in immunized rabbits by daily topical ocular challenge with antigen. The acetates of hydrocortisone and prednisolone were released from a drug delivery system inserted in the cul-de-sac of the eye or were provided in eyedrops. The model was sufficiently sensitive to differentiate between the effectiveness of hydrocortisone and prednisolone. The continuous delivery of either steroid from the drug delivery system was as efficacious, or more so, than the corresponding steroid dose given as eyedrops.
Changes in tear film pH were observed during the 1st hr after instillation of pilocarpine in various dosage forms to the rabbit eye. In anesthetized rabbits, with periodic blinking induced electrically, commercial formulations of pilocarpine salts applied as drops or a spray acutely lowered tear film pH by 1.1-1.6 pH units. The pH remained below pretreatment levels for 45-greater than 60 min after instillation. Pilocarpine base, administered continuously at the rates of 20 or 80 mug/hr from ocular therapeutic systems, had little or no effect on tear film pH in this same animal preparation. The reduction in tear film pH produced by pilocarpine eyedrops or spray solution is attributable to the acid pH and buffer capacity of these solutions. Delivery of pilocarpine base without pH change was achieved with ocular therapeutic systems, because the drug (pKa = 7.07) was delivered free, or virtually so, of excipients. These observed differences in tear film pH after application may partially explain the four- to eightfold reduction in total effective pilocarpine dose with ocular therapeutic systems compared to eyedrops or spray, since the cornea is less permeable to ionized than to unionized molecules.
Hydrocortisone acetate was administered to rabbit eyes intermittently in 250mug doses (given twice daily or once hourly) or continuously at 10mug/hr from an experimental ocular therapeutic system. Tissue drug distribution was measured over a 1 to 4 day period in experimental conjunctivitis. Anti-inflammatory efficacy was evaluated over a 4 day period in the same model. Statistically significant improvement in inflammation was observed 48 hours after initiation of continuous delivery treatment and after 4 days of the twice daily eyedrop regimen. Drug uptake by ocular tissues correlated with drug efficacy. Continuous delivery at 10mug/hr produced conjunctival steriod concentrations exceeding 1mug/g during 8 through 24 hours of treatment, and average levels of 1mug/g from days 2 through 4. Conjunctival steroid concentations generally did not exceed 1mug/g in eyedrop treated eyes until the fourth treatment day, when their clinical improvement matched that observed in the continuously treated eyes.
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