C. Rosendorff

Pyrogen and prostaglandin fever in the rabbit-I: Effects of salicylate and the role of cyclic AMP.

Abstract Intrahypothalamic injections of dibutyryl cyclic AMP into the rabbit produce a dose-dependent rise in rectal temperature with a short latency of onset. The fevers produced by intravenous administration of a bacterial pyrogen and intrahypothalamic injections of prostaglandin E 1 were both significantly potentiated by the simultaneous administration of theophylline, a nucleotide phosphodiesterase inhibitor. This suggests the possibility that both pyrogen and prostaglandin E 1 produce fevers via cyclic AMP. Sodium salicylate infused intravenously produced a marked attenuation of the pyrogen fever but was without effect on the prostaglandin E 1 fever. Since salicylate inhibits prostaglandin biosynthesis, this result is consistent with the idea that pyrogen fever is mediated via a prostaglandlin.

Effects of prostaglandin antagonism on sodium arachidonate fever in rabbits.

1. Sodium arachidonate, the prostaglandin precursor substance, when injected intraventricularly into rabbits, results in dose‐dependent hyperthermia, which is rapid in onset and of several hours duration. 2. Arachidonate fever was inhibited by intraventricular injection of indomethacin, but not by the simultaneous intraventricular injection of either of the two prostaglandin antagonists SC 19220 or HR 546. 3. Both antagonists effectively inhibited the fever induced by the intraventricular injection of an equipotent dose of PGE1. 4. Our results show that a derivative of arachidonic acid other than prostaglandin is pyrogenic.

Pyrogen and prostaglandin fever in the rabbit—II: Effects of noradrenaline depletion and adrenergic receptor blockade

Abstract Experiments were carried out to investigate a possible role for noradrenaline in the febrile response induced by intravenous injection of a purified bacterial pyrogen (0.02 μg) and by intrahypothalamic injection of prostaglandin E 1 (PGE 1 , 500 ng). Pretreatment of the hypothalamus of rabbits with 6-hydroxydopamine, which causes degeneration of noradrenergic nerve terminals, significantly reduced the febrile response to intravenous pyrogen injection. 6-Hydroxydopamine also caused a decrease in the febrile response to PGE 1 injected into the hypothalamus. In another series of experiments an intrahypothalamic injection of 50 μg of the alpha-adrenergic antagonist, phenoxybenzamine, significantly reduced pyrogen fever. Also, addition of 50 μg phenoxybenzamine to the PGE 1 injection, resulted in a significant reduction of the febrile response. Propranolol, a beta-adrenergic blocking agent, when injected in the same dose and in the same manner as phenoxybenzamine, had no significant effect on either the pyrogen- or the PGE 1 -induced fevers. It has previously been suggested that pyrogen acts by release of PGE 1 in the hypothalamus and results from our laboratory support this idea. In addition, our results suggest alpha-receptor activation in the genesis of both pyrogen- and PGE 1 -fever.

The measurement of local cerebral blood flow and the effect of amines.

Publisher Summary A method for measuring local cerebral blood flow in the conscious animal is described in this chapter. The method depends on the rate at which the physiologically inert, but freely diffusible isotope 133 Xenon, is cleared from its injection site in the brain tissue. A small volume (2.5 to 10 μl) of a 133 Xenon in saline solution is injected to the brain at the desired stereotoxic coordinate, via a fine stainless steel cannula. The rate of clearance is measured using an external scintillation counter, and the local flow (F) is calculated. Blood flow in the hypothalamus, a subcortical region of grey matter, is homogeneous within the area of diffusion of the tracer and within the limits of the technique. Pentobarbitone anaesthesia halves cortical flow; hypothalamic flow was unchanged. Autoregulation of local flow in the hypothalamus could be demonstrated within the mean arterial blood pressure range of 41-140 mm Hg. A great advantage of this method is that it enables drugs to be added to the 133 Xenon-saline injectate, and therefore allows for an assessment of the effects of small doses applied locally to small vessels via their adventitial surface. Noradrenaline injected into the hypothalamus as 1 μg per injection causes an increase in local flow, while larger doses (10-200 μg per injection) are vasoconstrictor. The vasodilator effect of NA 1 μg, is blocked by propranalol, and the vasoconstrictor effect of NA 40 μg, is blocked by phenoxybenzamine. 5-Hydroxytryptamine is vasodilator at all doses studied. The implications of these findings in terms of the possible neurogenic control of local cerebrosvascular tone are discussed.

Renal blood flow in obstructive jaundice: an experimental study in baboons.

1. The distribution of intrarenal blood flow has been measured using the 133Xe‐washout technique in thirteen baboons 2 weeks after ligation of the common bile duct.

THE EFFECTS OF HYPERCHOLESTEROLAEMIC PLASMA ON VASCULAR SENSITIVITY TO NORADRENALINE

1 The pressor responses to injected noradrenaline (NA) of 42 isolated perfused femoral arteries of the rabbit were studied. 2 Potentiation of the responses was found when hypercholesterolaemic plasma was perfused through the arteries. No change was found with normal plasma. 3 Potentiation of the responses was found when isolated β‐lipoprotein in Krebs solution was perfused. No change was found with similar amounts of bovine albumen. 4 Pure cholesterol dissolved directly into normal plasma, and dissolved via propanol into Krebs solution or plasma caused no potentiation. Propanol alone in Krebs or plasma had no effect. 5 Potentiation was caused by a decreased equilibrium coefficient (Keq) for the NA‐adrenoceptor interaction and an increased maximal pressor response (Rmax). 6 It is concluded that cholesterol carried on its apoprotein is capable of potentiating the pressor effects of noradrenaline.

The effect of an inhibitor of adenylate cyclase on the development of pyrogen, prostaglandin and cyclic AMP fevers in the rabbit

SummaryAn exotoxin of Bacillus thuringiensis known to inhibit adenylate cyclase in vitro has been used to investigate the role of cyclic AMP in the pathogenesis of fever in the rabbit. Intra-hypothalamic microinjections of the exotoxin are non-pyrogenic and significantly attenuate the hyperthermia caused by intrahypothalamic microinjections of both bacterial pyrogen (endotoxin) and prostaglandin E1. The hyperthermia produced by dibutyryl cyclic AMP is not affected by the exotoxin. These results support the idea that adenylate cyclase is activated during the development of fever in the rabbit.

A dissociation between temperature regulation and fever in the rabbit.

1. The role of 5‐hydroxytryptamine (5‐HT) in temperature regulation and in fever in the rabbit has been investigated. 2. Intrahypothalamic microinjections of 5‐HT in the conscious rabbit alters body temperature in a dose‐dependent manner. 3. Low doses (5‐5nmol) of 5‐Ht and control saline injections produced a small, non‐significant increase in temperature, with a long latency. 4. Doses of 14 nmol 5‐HT produce a hyperthermia with a 45 min delay; while microinjections of 28 nmol result in a biphasic response; an initial short hypothermia is followed later by a hyperthermia. 5. Depleting the rabbits brain of 5‐HT by pretreatment with p‐chlorophenylalanine (PCPA) fails to affect its body temperature at thermoneutral temperatures but significantly impairs the ability to thermoregulate against a cold stress. 6. PCPA pretreatment did not, however, impair the febrile response to bacterial pyrogen and prostaglandin E1. 7. These results reveal a dissociation between the effects of 5‐HT depletion on temperature regulation, and on fever. The site of action of 5‐HT in temperature regulation must be proximal to the fever input, but distal to the convengence of peripheral and hypothalamic temperature inputs.

Beta-blocking agents with vasodilator activity

Use of non-selective beta-blockers: Non-selective beta-blockers reduce blood pressure by reducing cardiac output. They have a proven record of efficacy, alone or in combination with other drug classes, in the treatment of hypertension, ischemic heart disease and some tachyarrhythmias. They have also proved effective in the primary and secondary prevention of myocardial infarction. However, adverse effects include increased peripheral resistance, limitation of exercise tolerance, and bradyarrhythmia, cold extremities and bronchoconstriction in susceptible patients. Effects of beta 1-selective blockers: beta 1-Selective antagonists cause less vasoconstriction and less bronchoconstriction than non-selective beta-blockers, but the reduction in cardiac output may still activate a sympathetically mediated increase in peripheral resistance. beta 1-blockers with beta 2 agonist activity are vasodilatory because they activate postsynaptic beta 2 receptors on vascular smooth muscle cell membranes, via the formation of cyclic AMP. Non-selective beta-blockers with alpha 2-adrenoceptor blocking activity: Non-selective beta-adrenoceptor blockers with alpha 1-adrenoceptor blocking activity, such as carvedilol, labetalol, medroxalol and bucindolol, combine the advantages of beta- and alpha 1-blockade, including peripheral vasodilation. As an example of this class of agent, carvedilol has been shown to be effective in the treatment of hypertension by reducing peripheral resistance. There are some indications, still to be confirmed, that it improves left ventricular diastolic function and causes regression of left ventricular hypertrophy, and that it may be useful in the treatment of some patients with congestive heart failure or arrhythmia. In animal models of myocardial ischemia, carvedilol has proved to be cardioprotective.

THE EFFECT OF PHENOXYBENZAMINE AND SARALASIN ON THE ALTERED RENAL BLOOD FLOW DISTRIBUTION IN BABOONS WITH OBSTRUCTIVE JAUNDICE

1. Using the 133xenon (133Xe) washout technique, renal cortical perfusion was measured in fourteen baboons before and 1 and 2 weeks after ligation of the common bile duct.