Effects of catecholamines on the coronary circulation in the Langendorff-type transplanted dog heart.

Intracoronary administration of isoprenaline, adrenaline, and the noradrenaline in the Langendorff-type transplanted dog heart transiently decreased coronary blood flow measured from the inflow vessel; flow then increased. The reduction in coronary flow coincided with increased myocardial contractility and was prevented by keeping the left ventricle empty. Propranolol prevented changes in flow and contractility. It is concluded that positive inotropic changes result in the ejection of accumulated Thesbesian flow from the ventricle and affect coronary flow measurements and that the interpretation of flow changes requires a steady state.

Potentiation of vasoconstrictor responses by 3- and 4-aminopyridine.

1. In concentrations that are known to reduce potassium conductance in many excitable membranes, 3 and 4-aminopyridine (3-AP, 4-AP) potentiate vasoconstrictor responses of the isolated ear artery of the rabbit to noradrenaline and histamine. 2. 3- and 4-AP have no effect on the responses of potassium-depolarized arteries to noradrenaline, histamine or calcium. 3. The results suggest that the aminopyridines have no direct effect on the contractile machinery or on pharmacomechanical coupling, but cause potentiation by influencing electrical events at the cell membrane. 4. 4-AP causes a greater potentiation of the response te electrical stimulation than of the response to noradrenaline. This suggests that the aminopyridines may also cause an increase in the amount of noradrenaline released in response to sympathetic nerve stimulation.

Modification of cardiovascular responses to histamine by dithiothreitol.

1 Histamine produced dose-dependent contractile responses on both isolated perfused ear arteries and aortic strips of the rabbit. These responses were blocked by mepyramine and potentiated by both metiamide and dithiothreitol. 2 In the presence of maximum potentiation by metiamide, dithiothreitol still potentiated the contractile response to histamine of both preparations. 3 In the presence of mepyramine, histamine produced dose-dependent reductions in the contractile response to noradrenaline. This vasodilator action of histamine was abolished by metiamide but was unaffected by dithiothreitol. 4 The vasodilator action of histamine on the human isolated perfused temporal artery and the positive inotropic effect of histamine on the isolated spontaneously beating atria of the rabbit were blocked by metiamide but unaffected by dithiothreitol. 5 It is concluded that the rabbit aorta, like the ear artery, contains both H1 and H2 histamine receptors and that dithiothreitol potentiates cardiovascular responses mediated by H1-receptors but not by H2-receptors.

Histamine H2-receptors in the human peripheral circulation.

Histamine (10 mug/min for 3 min) infused into the brachial artery caused an increase in forearm blood flow which was reduced by mepyramine (25 mg). This effect was most marked in the first minute of the infusion. Metiamide (25 mg) had no effect on the dilatation during the infusion but caused a quicker return of flow to the resting level. The response was abolished when both drugs were given in combination. It is concluded that the response is initiated mainly by stimulation of H1-receptors and maintained by H1- and H2-receptors; continued activity of H2-receptors may account for the slow return of flow to the pre-infusional level.

Measurement of capillary pressure in humans using a venous occlusion method.

The venous occlusion technique was used to measure capillary pressure in the forearm and foot of man over a wide range of venous pressures. In six recumbent subjects venous pressure (Pv) in the forearm (mean +/- SE) was 9.3 +/- 1.4 mmHg and the venous occlusion estimate of capillary pressure (Pc) was 17.0 +/- 1.6 mmHg, whereas in another six subjects Pv in the foot was 17.1 +/- 1.2 mmHg and Pc was 23.4 +/- 2.5 mmHg. Venous pressure in the limbs was increased either by changes in posture or by venous congestion with a sphygmomanometer cuff. On standing Pv in the foot increased to 95.2 +/- 1.5 mmHg and Pc rose to 112.8 +/- 3.1 mmHg. The relationship established between venous pressure and capillary pressure in the forearm is Pc = 1.16 Pv + 8.1, whereas in the foot the relationship is Pc = 1.2 Pv + 1.6. The magnitude and duration of the changes in capillary pressure were also recorded during reactive hyperemia. The venous occlusion method of measuring capillary pressure is simple and easily applied to studies in humans.

Cholinergic effect of 4-aminopyridine and adrenergic effect of 4-methyl-2-aminopyridine in cardiac muscle.

The effect of 4-aminopyridine (4AP) and 4-methyl-2-aminopyridine (4M2AP), 10(-3) M, was studied on isolated spontaneously beating right atria and electrically driven left atria of the rabbit and the cat. In the rabbit preparations, 4AP had a positive inotropic effect which was unaffected by propranolol or atropine, and a negative chronotropic effect which was abolished by atropine. In the cat, 4AP decreased both force and rate, and these effects were reversed when 4AP was repeated in the presence of atropine. In contrast, 4M2AP increased the rate and force of contraction in both species. These effects were reduced but not abolished when 4M2AP was repeated in the presence of propranolol. It is concluded that 4AP has a cholinergic effect presumably mediated by acetylcholine release which predominates over its direct positive inotropic effect in the rabbit but not in the cat, and which is responsible for its effect on rate in both species. 4M2AP also has a direct positive inotropic action, but its marked effects on force and rate of contraction are largely due to noradrenaline release. The selectivity of 4AP for cholinergic and 4M2AP for noradrenergic transmission suggests that there are differences in potassium channels or in calcium uptake or release mechanisms in the respective nerve terminals.

Actions of 4-methyl-2-aminopyridine on neuromuscular transmission and contractility of skeletal muscle.

4-Methyl-2-aminopyridine (4M2AP) increased responses of isolated rat diaphragm and chick biventer cervicis nerve-muscle preparations to nerve stimulation but depressed responses to direct stimulation. Responses to acetylcholine were also increased while responses to carbachol were depressed. When tested after inhibition of acetylcholinesterase activity with neostigmine the effect of 4M2AP on responses to indirect stimulation was greatly reduced and responses to acetylcholine were depressed. It is concluded that, in contrast to other aminopyridines, 4M2AP facilitates neuromuscular transmission by inhibition of cholinesterase rather than augmenting release of acetylcholine and depresses rather than enhances muscles contractility.

Effect of dithiothreitol on histamine receptors in rabbit colon and guinea-pig ileum.

1. Dithiothreitol, an agent which reduces disulphide linkages to sulphydryl groups, potentiated the contractile responses of the rabbit colon and guinea-pig ileum to histamine, but had no effect on the resting tone or on the responses of these preparations to acetylcholine. 2. The potentiation was greater than that produced by antagonism of histamine's weak inhibitory action by metiamide, and still occurred after blockade of H2-receptors with metiamide; it is concluded that DTT potentiates responses to stimulation of H1-receptors in both preparations. 3. In this respect, these H1-receptors resemble those in vascular smooth muscle in the rabbit but not in the guinea-pig; it is concluded that there is a tissue variation rather than a species variation in the response of H1-receptors in the rabbit and guinea-pig to DTT.

Increased sensitivity of rabbit ear artery to noradrenaline following perivascular nerve stimulation may be a response to neuropeptide Y released as cotransmitter.

Neuropeptide Y (NPY 10(-10)-10(-7) mol/l) had little or no effect on the perfusion pressure of rabbit isolated ear arteries but potentiated the brief contractile responses to injections of noradrenaline, histamine or brief periods of electrical stimulation (2-20 Hz for 5 s). This effect was slowly reversible. Similar potentiation was seen following long periods of electrical stimulation (2-40 Hz for 1-5 min) which produced well sustained increases in perfusion pressure. Following even longer periods of electrical stimulation (10-30 min) during which the perfusion pressure was not maintained, responses to noradrenaline and histamine were potentiated but the responses to electrical stimulation for 5 s were greatly reduced. The increase in sensitivity following prolonged electrical stimulation may be due to NPY released as a cotransmitter.

The role of sulfhydryl groups in contraction of vascular smooth muscle.

While high concentrations (50 micronmol/l) of merurial sulfhydryl (SH) reagents p-chloromercuribenzoate (PCMB) and p-chloromercuriphenyl sulfate (PCMPS) caused a nonspecific inhibition of constrictor responses in isolated rabbit ear arteries, lower concentrations had selective effects. At a concentration of 10 micronmol/l both agents abolished responses to epinephrine and reduced responses to barium and calcium, but responses to caffeine were unaffected by PCMB and potentiated by PCMPS. Responses to histamine were little affected by PCMPS, but with PCMB, histamine responses were first reduced but later potentiated. In contrast, ethacrynic acid, a nonmercurial SH inhibitor which gains access to the intracellular space, failed to show any specificity of action and inhibited contractile responses to all these agonists. The results suggest that SH inhibitors whose actions are limited to the cell membrane exert both specific and nonspecific effects. The specific effect may be at SH groups associated with the alpha adrenoceptor while nonspecific effects may involve changes in membrane permeability.

Staffing crisis in preclinical medicine.

The proportions of medical graduates on the staffs of the preclinical departments of Australian medical schools have declined dramatically in recent years. It is now extremely difficult to attract medically qualified applicants to positions in these departments. The present proportions of medically qualified staff now fall short of the levels regarded as "educationally desirable" by Australian preclinical departmental chairmen, at a time when the curricula of most of our medical schools are being reformed so as to include more medically relevant courses in the preclinical disciplines. The cause of the problem is that there are serious disincentives, of both salary and career prospects, to the choice of a career in preclinical medicine. Methods of removing these disincentives are discussed in this paper.

Effects of 4-methyl-2-aminopyridine on [3H]-noradrenaline overflow and contractility of isolated rabbit arteries.

1. The effects of 4-methyl-2-aminopyridine (4M2AP) and 4-aminopyridine (4AP) on spontaneous and evoked [3H]-noradrenaline overflow were compared in rabbit ear artery strips. The effects of 4M2AP on smooth muscle contractility were also investigated in isolated perfused ear arteries. 2. Both 4M2AP and 4AP enhanced spontaneous [3H] overflow from arterial strips in a concentration-dependent manner (10-1000 microM). A bell-shaped dose-response relation was obtained for evoked [3H] overflow over the same concentration range, with maximum effects occurring at 10 microM for 4M2AP (163 +/- 31% increase) and 100 microM for 4AP (154 +/- 16% increase). 3. 4M2AP did not significantly affect evoked tension in the 1-to 100-microM range but clearly depressed it at 1,000 microM (by 65 +/- 11%). In contrast, 4AP enhanced evoked tension in the 10- to 100-microM range (by 30-50%). 4. 4M2AP (10-100 microM) enhanced vasoconstrictor responses to exogenous noradrenaline injections in isolated perfused rabbit ear arteries, whereas higher concentrations (1,000 microM) caused significant depression. 5. 4M2AP (1,000 microM) markedly potentiated vasoconstrictor responses induced by perfusion with a high extracellular K+ solution. When 4M2AP was present during the reloading of noradrenaline-sensitive Ca2+ stores, it enhanced the subsequent vasoconstrictor responses to noradrenaline obtained in a Ca(2+)-free medium. 6. The results show that 4M2AP, like 4AP, enhances [3H] overflow from sympathetic nerve terminals and has complex effects on vascular smooth muscle contractility, indicating the ability of these compounds to affect the Ca2+ permeability of both extracellular and intracellular membrane systems.

Blockade by phentolamine of the potentiation of histamine-induced vasoconstriction caused by serotonin and methysergide in the rabbit ear artery.

1. In subconstrictor doses, both serotonin and methysergide potentiated the vasoconstrictor responses to histamine in the isolated artery of the rabbit ear. 2. In the presence of phentolamine (5 microgram/ml) the potentiating actions of serotonin and methysergide were significantly reduced. 3. This blocking action of phentolamine could be overcome by increasing the concentration of serotonin or by washing the preparation. 4. In arteries taken from rabbits pretreated with reserpine, serotonin still potentiated the response to histamine and phentolamine still blocked this potentiation. 5. The concentration of phentolamine required to block potentiation also blocked the direct constrictor response to serotonin. It did, however, produce a significantly greater blockade of the vasoconstrictor response to noradrenaline. 6. The results indicate that the action of phentolamine in blocking the vascular potentiation produced by serotonin and methysergide is not due to a blockade of alpha-receptors.

Funnelweb-spider venom antagonist.

It was found in a series of experiments on anaesthetized monkeys that rat plasma and rat euglobulin fractions contain a substance which could offer some protection against funnelweb-spider envenomation when administered before envenomation or simultaneously with the funnelweb-spider venom. Further work to isolate, identify, and purify this substance is needed.