Differences In Receptor Sensitivity Research Articles

Attenuated Purinergic Receptor Function in Patients With Type 2 Diabetes

OBJECTIVEExtracellular nucleotides and nucleosides are involved in regulation of skeletal muscle blood flow. Diabetes induces cardiovascular dysregulation, but the extent to which the vasodilatatory capacity of nucleotides and nucleosides is affected in type 2 diabetes is unknown. The present study investigated 1) the vasodilatatory effect of ATP, uridine-triphosphate (UTP), and adenosine (ADO) and 2) the expression and distribution of P2Y2 and P2X1 receptors in skeletal muscles of diabetic subjects.RESEARCH DESIGN AND METHODSIn 10 diabetic patients and 10 age-matched control subjects, leg blood flow (LBF) was measured during intrafemoral artery infusion of ATP, UTP, and ADO, eliciting a blood flow equal to knee-extensor exercise at 12 W (∼2.6 l/min).RESULTSThe vasodilatatory effect of the purinergic system was 50% lower in the diabetic group as exemplified by an LBF increase of 274 ± 37 vs. 143 ± 26 ml/μmol ATP × kg, 494 ± 80 vs. 234 ± 39 ml/μmol UTP × kg, and 14.9 ± 2.7 vs. 7.5 ± 0.6 ml/μmol ADO × kg in control and diabetic subjects, respectively, thus making the vasodilator potency as follows: UTP control subjects (100) > ATP control subjects (55) > UTP diabetic subjects (47) > ATP diabetic subjects (29) > ADO control subjects (3) > ADO diabetic subjects (1.5). The distribution and mRNA expression of receptors were similar in the two groups.CONCLUSIONSThe vasodilatatory effect of the purinergic system is severely reduced in type 2 diabetic patients. The potency of nucleotides varies with the following rank order: UTP > ATP > ADO. This is not due to alterations in receptor distribution and mRNA expression, but may be due to differences in receptor sensitivity.

Modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor desensitization by extracellular protons.

The interstitial milieu of the brain is buffered to an average pH of 7.3, but synaptic activation produces a temporal sequence of events that can affect pH in the synaptic cleft. Furthermore, pathophysiological processes such as ischemia and seizures produce global and prolonged acidification of interstitial pH. Changes in pH, in turn, can affect neuronal excitability by modulating receptors and channels. Patch-clamp recordings were made from cultured rat hippocampal neurons to determine whether physiologically relevant changes in interstitial pH (6.5-7.8) significantly affect AMPA receptor function. Acidic pH, such as that typically associated with ischemia (pH 6.5), significantly inhibited AMPA receptor-mediated responses in neurons. The effect of pH was agonist-dependent, with 2-fold greater inhibition of responses evoked by the strongly desensitizing agonists glutamate and quisqualate than the weakly desensitizing agonist kainate. Additional experiments tested the hypothesis that protons modulate AMPA receptor desensitization. In the presence of drugs that block AMPA receptor desensitization, pH 6. 5 had no effect on glutamate-evoked responses. In neuronal macropatches, protons increased equilibrium desensitization without affecting macroscopic desensitization or deactivation kinetics. The mechanisms and molecular determinants of pH-mediated effects were further investigated using human embryonic kidney 293 cells expressing recombinant AMPA receptors. Inhibition of kainate-evoked responses varied with subunit and isoform composition, ranging from 10% to >40%. Flop isoforms, which exhibit faster and more extensive desensitization, were most strongly inhibited. These findings suggest that interstitial acidification can modulate AMPA receptor-mediated synaptic transmission and that differences in receptor sensitivity to proton modulation may underlie the selective vulnerability of certain neuronal populations to ischemia.

Differential postalightment oviposition behavior of monarch butterflies on Asclepias species.

The monarch butterfly, Danaus plexippus L., oviposits mainly on plants in the Asclepiadaceae, particularly within the genus Asclepias. We studied postalightment oviposition behavior of monarch females on three host species—Asclepias curassavica, A. incarnata , and A. tuberosa. After landing on the host, they used their forelegs, midlegs, and antennae to assess plant suitability. When these appendages were examined by scanning electron microscopy, contact chemoreceptor sensilla were found. In choice tests, A. incarnata was most preferred, while A. tuberosa was least preferred. However, the use of appendages varied for the different host species. Antennae were most frequently used during post-alightment behavior on A. curassavica, whereas forelegs were used more often on A. incarnata, and all three appendages were used extensively on A. tuberosa. Use of the midlegs was generally followed by use of the antennae. Tasting with either forelegs or antennae apparently may lead to egg laying on some host species. Rupture of the plant surface by midleg spines was also observed. The behavior and host preference of individual females varied significantly and may reflect differences in receptor sensitivity.

Opioid peptide regulation of neurons in the bed nucleus of the stria terminalis: a microiontophoretic study

Single unit activity was recorded from neurons in the bed nucleus of the stria terminalis (BNST) in response to single or combined microiontophoretic ejection of d-Ala 2-Met 5-enkephalinamide (DAME) and naloxone. BNST neurons showed predominantly excitatory responses following small iontophoretic applications of DAME, and these responses were antagonized by naloxone. In contrast, inhibitory responses that were elicited by DAME required larger ejection currents and usually failed to show naloxone antagonism. The results indicate that activation of enkephalin-sensitive BNST neurons by DAME is primarily, but not exclusively, excitatory, which suggests that these responses may reflect differences in receptor sensitivity to the applied agonist.

Anaesthetic problems associated with the treatment of cardiovascular disease: II. Beta-adrenergic antagonists.

There are a number of beta-adrenergic antagonists available for general clinical use. The pharmacological action of these agents in patients with ischaemic heart disease and hypertensive cardiovascular disease is similar to that of the prototype, propranolol. No less than three per cent of patients treated with propranolol develop life-threatening cardiac complications. Since the combined circulatory depressant effect of beta blockade and anaesthesia is a cause for concern, surgical patients, who are also treated with beta an-tagonists for their cardiovascular disease, should be properly assessed and prepared. Due to individual differences in receptor sensitivity, pharmacokinetic factors and compliance with treatment, the daily maintenance dose does not reflect the degree of beta blockade. A thorough examination of the cardiovascular system is helpful. There is no reason to withhold or reduce the maintenance dose before surgery in the optimally treated patient; but corrective measures are necessary in the patient on a toxic dose. Choice of anaesthetic agents should be made according to known interactions between these agents and beta-adrenergic antagonists. The combined circulatory depressant effect of halothane as well as morphine and beta blockade is additive, while that of enflurane and beta blockade is less predictable. There is minimal interaction between isoflurane and propranolol, but the combination of methoxyflurane and practolol seems to be unacceptable. There are both practical and theoretical disadvantages to the use of succinylcholine because of its muscarinic action and the use of d-tubocurarine because of its ganglionic blocking effect. On the other hand, no objection to the use of dimethyl-tubocurarine and pancuronium exists. To avoid adverse interaction, neostigmine should be given in small increments, and only after the administration of atropine. Since acute myocardial infarction can strike as early as twenty-four hours after abrupt withdrawal, the surgical patient treated with beta antagonists should be allowed to go back to his maintenance dose as early as possible after operation. For patients who have to abstain from oral intake postoperatively, intravenous infusion of propranolol is recommended. If life-threatening bradycardia and hypotension should develop, the use of beta agonists can overcome the competitive beta-adrenergic blockade. Atropine, aminophylline, cardiac glycosides, calcium salts and glucagon can also be used to counteract the circulatory effects of beta antagonists.