Regulation of binding properties of the nicotinic receptor protein by cholinergic ligands in membrane fragments from Torpedo marmorata.
Exposure of receptor-rich membrane fragments from Torpedo marmorata to carbamylcholine causes a slow (half-time of 5--10 min) and reversible change of properties of the cholinergic receptor protein manifested by a decrease of the initial rate of Naja nigricollis alpha-[3H]toxin binding in the presence of carbamylcholine. This change corresponds to a 5- to 20-fold increase of affinity for carbamylcholine. Other agonists, acetylcholine, phenyltrimethylammonium, show the same effect but not the antagonists d-tubocurarine and flaxedil. Decamethonium and hexamethonium show little, if any, agonistic effect in vitro on the same membrane fragments but cause the affinity change. This regulatory property can be lost after aging of the preparation of membrane fragments. Since the affinity increase progresses with a similar time course as the decrease of amplitude of the permeability response consecutive to agonist preincubation, it is proposed that, in the membrane at rest, the receptor protein is present under a state of low affinity for agonists and that the reversible stabilization by the agonists of a high affinity state corresponds to the "pharmacological desensitization" of the system as predicted by one of the models of Katz and Thesleff. (+info)
Calcium and stimulus-secretion coupling in the adrenal medulla: contrasting stimulating effects of the ionophores X-537A and A23187 on catecholamine output.
1. The ionophores X-537A and A23187, which are known to transfer calcuim across cell membranes, stimulated catecholamine release from perfused cat adrenal glands. 2. These stimulant effects persisted in the presence of hexamethonium and atropine and are therefore attributable to direct actions of the ionophores on the adrenal chromaffin cells. 3. Perfusion with calcium-free Locke abolished responses to A23187 and reduced those to X-537A. 4. Responses to X-537A were consistently large and comparable with those produced by 56 mM potassium. By contrast, responses to A23177, over the wide range of concentrations tested, were variable and much smaller. 5. That the two ionophores can stimulate through calcium-dependent mechanisms is considered fresh support for the calcium hypothesis of stimulus-secretion coupling. That they differ in effectiveness may mean that factors besides calcium are important. The greater potency of the less specific ionophore, X-537A, may be attributable to its ability to depolarize as well as carry calcuim, while the relatively small effects of A23187, a generally more effective ionophore for calcuim, may indicate that inward movement of calcium without a background of membrane perturbation such as may be produced by depolarization, is insufficient to elicit strong secretory responses. (+info)
Static pressure-flow relation in the total systemic vascular bed of the dog and its modification by the baroreceptor reflex.
To evaluate arterial baroreceptor reflex control of total systemic vascular resistance, we studied the relation between mean arterial blood pressure (P) and mean aortic flow (Q) before and after the reflex was abrogated. In 12 dogs with a perfusion pump interposed at the vena-caval-right atrial junction, Q was kept at 60, 80, 100, 120, and 140 ml/min kg-1 for up to 20 minutes. There was little time-dependent change in P at any of these flows. When the reflex was intact, the mean P-Q curve was only slightly convex to the pressure axis; its linearized slope was 0.55 mm Hg-min-kg/ml and its pressure axis intercept was 44 mm Hg. After section of the sinovagal nerves, administration of hexamethonium (30 mg/kg, iv) and norepinephrine (3-5 mug/kg min-1, iv), or both, the slope became 0.96 mm Hg-min-kg/ml and the pressure axis intercept was about 3 mm Hg. Similar findings were obtained in 3 closed-chest dogs in which P was servocontrolled and Q was measured. Therefore, we think that the conventional practice of calculating total peripheral resistance as P/Q and evaluating reflex control of it in terms of the changes in that value involves only a small error in the moderately sub -and supranormal flow range. (+info)
Neural mechanisms underlying migrating motor complex formation in mouse isolated colon.
1. Little is known about the intrinsic enteric reflex pathways associated with migrating motor complex (MMC) formation. Acetylcholine (ACh) mediates the rapid component of the MMC, however a non-cholinergic component also exists. The present study investigated the possible role of endogenous tachykinins (TKs) in the formation of colonic MMCs and the relative roles of excitatory and inhibitory pathways. 2. MMCs were recorded from the circular muscle at four sites (proximal, proximal-mid, mid-distal and distal) along the mouse colon using force transducers. 3. The tachykinin (NK(1) and NK(2)) receptor antagonists SR-140 333 (250 nM) and SR-48 968 (250 nM) reduced the amplitude of MMCs at all recording sites, preferentially abolishing the long duration contraction. Residual MMCs were abolished by the subsequent addition of atropine (1 microM). 4. The neuronal nitric oxide synthase inhibitor, N(omega)nitro-L-arginine (L-NOARG, 100 microM), increased MMC amplitude in the distal region, whilst reducing the amplitude in the proximal region. In preparations where MMCs did not migrate to the distal colon, addition of L-NOARG resulted in the formation of MMCs. Subsequent addition of apamin (250 nM) or suramin (100 microM) further increased MMC amplitude in the distal region, whilst suramin increased MMC amplitude in the mid-distal region. Apamin but not suramin reduced MMC amplitude in the proximal region. Subsequent addition of SR-140 333 and SR-48 968 reduced MMC amplitude at all sites. Residual MMCs were abolished by atropine (1 microM). 5. In conclusion, TKs, ACh, nitric oxide (NO) and ATP are involved in the neural mechanisms underlying the formation of MMCs in the mouse colon. Tachykinins mediate the long duration component of the MMC via NK(1) and NK(2) receptors. Inhibitory pathways may be involved in determining whether MMCs are formed. (+info)
Porphyria in relation to surgery and anaesthesia.
A review is presented of the more recent biochemical findings in the hepatic porphyrias. The clinical aspects of acute porphyria are re-emphasized and illustrated with a case history. In particular the differentiation between porphyria and surgical causes of abdominal pain is stressed. The anaesthetic management is discussed and details of diagnostic and screening tests are given. (+info)
Excitatory, inhibitory and biphasic synaptic potentials mediated by an identified dopamine-containing neurone.
1. A giant dopamine-containing cell, situated in the left pedal ganglion of the water snail Planorbis corneus, was identified in isolated living preparations of the central nervous system. Spectrophotofluorimetric analysis confirms that the cell contains dopamine, whereas noradrenaline appears to be absent. The cell is unique in being a repeatedly identifiable dopamine-containing neurone. 2. Stimulation of the giant dopamine-containing cell resulted in excitatory, inhibitory or biphasic (depolarizing-hyperpolarizing) synaptic potentials in a number of follower neurones. The duration of the e.p.s.p.s and i.p.s.p.s was 0-3-5 sec; they ranged from barely detectable responses to ones 7 mV in amplitude in different cells. The depolarizing phase of a biphasic synaptic potential (b.p.s.p.) was usually less than 1 mV in amplitude (max. 3mV) and lasted 40-400 msec. The latency of i.p.s.p.s was long (70-120 msec) compared with that of e.p.s.p.s and b.p.s.p.s (20 msec). Abolition of the depolarizing phase of b.p.s.ps. by tubocurarine left a long-latency (70-120 msec) i.p.s.p. All responses showed summation and marked facilitation. 3. Evidence is presented that the post-synaptic potentials are produced by direct connections from the giant cell and result from a release of dopamine. Of eight putative transmitter substances tested on these different groups of neurones, only dopamine produced a potential change which in each case was of the same polarity as the post-synaptic potential when this was monophasic. However, generally applied dopamine produced only a hyperpolarization in follower cells showing b.p.s.p.s. This result is probably partly due to rapid desensitization of the receptors mediating the depolarization and also to a masking of the depolarization by the more effective hyperpolarizing response. 4. Erogometrine and 6-hydroxydopamine specifically antagonized the i.p.s.p.s and dopamine receptors mediating inhibition. Neither the e.p.s.p.s nor the excitatory dopamine response were blocked by high concentrations of hexamethonium. Hexamethonium was also ineffective in blocking the depolarizing phase of a b.p.s.p., which was, however, selectively eliminated by tubocurarine. 5. It is suggested that dopamine is the transmitter released from the giant cell and that it can mediate excitatory, inhibitory or biphasic responses in different follower neurones. (+info)
Drinking behaviour in the cat induced by renin, angiotensin I, II and isoprenaline.
1. Angiotensin I, II and hog renin, infused into the lateral cerebral ventricles (I.C.V.) of water replete cats, each induced water drinking behaviour. 2. Intravenous infusion of high doses of angiotensin I or II also elicited a drinking response. The dipsogenic effect of I.V. renin was not marked. 3. Drinking in response to I.C.V. angiotensin II was abolished after autonomic ganglion blockade with I.V. hexamethonium or pempidine and was significantly reduced after I.V. atropine methonitrate. 4. The dipsogenic response to I.C.V. angiotensin II was unaffected by either peripheral adrenergic neurone blockade with I.V. bethanidine, alpha-adrenoceptor blockade with phentolamine or beta-adrenoceptor blockade with sotalol. 5. Atropine, atropine methonitrate, hexamethonium and pempidine given I.C.V did not inhibit the diposgenic response to I.C.V. angiotensin II. 6. Bethanidine I.C.V. produced a dose related reduction in the dipsogenic response to I.C.V. angiotensin II. 7. The alpha-adrenoceptor blocking agents tolazoline and phenoxybenzamine given I.C.V did not affect angiotensin induced drinking but the response was regularly inhibited by phentolamine I.C.V. 8. The beta-adrenoceptor blocking agents propranolol and practolol given I.C.V. each inhibited angiotensin induced drinking. The L-isomer of propranolol was a more effective blocker than the D-isomer. 9. Isoprenaline given I.C.V induced drinking in ten of sixteen cats. Subcutaneous administration of isoprenaline also elicited drinking but the onset of the response was delayed and the amount consumed slightly less than after I.C.V infusion. (+info)
The intrinsic innervation of the human alimentary tract and its relation to function.
The intrinsic innervation of the human gut has been studied in strips of circular and longitudinal muscle removed at operation. Electrical stimulation of the nerves at a wide range of frequencies (0-1 to 128 Hz) can evoke a variety of responses due to activation of four types of nerves. There is evidence for cholinergic, adrenergic, non-adrenergic inhibitory, and non-cholinergic excitatory fibres, which may be stimulated at different frequencies. The various regions of the alimentary tract, and even the muscle layers within a region, may respond differently to nerve stimulation. This is most marked at 4 Hz and the observed differences correlate with the function of each part and its dependence on extrinsic innervation. The stomach is relatively insensitive to electrical stimulation, and this is consistent with its reliance on vagal innervation. The dominant excitatory responses in the longitudinal muscle of the oesophagus and ileum correlate with their high motility and propulsive function, whereas the dominant inhibitory responses in the colon correlate with its lower motility and storage function. (+info)