Anaphylaxis

Mediators of immediate hypersensitivity.

Ophthalmic drug delivery systems

Adenosine is known to regulate myocardial and coronary circulatory functions. Adenosine not only dilates coronary vessels, but attenuates beta-adrenergic receptor-mediated increases in myocardial contractility and depresses both sinoatrial and atrioventricular node activities. The effects of adenosine are mediated by two distinct receptors (i.e., A1 and A2 receptors). A1 adenosine receptors, located in atrial and ventricular myocardium and sinoatrial/atrioventricular nodes, are responsible for inhibition of adenylyl cyclase activity. A2 adenosine receptors, located in coronary endothelial and smooth muscle cells, are responsible for stimulation of this enzyme activity. During increased myocardial oxygen demand due to rapid pacing and exercise, although both coronary blood flow and adenosine concentrations in the myocardium and coronary efflux increased, there is no clear consensus explaining its cause and effect relation at present. However, ischemia/reperfusion-induced coronary hyperemia is believed to be mostly attributed to released adenosine, and it has been proven that adenosine attenuates the severity of ischemia due to its coronary vasodilatory action. The beneficial effects of adenosine during ischemia/reperfusion processes do not seem simple. This is because myocardial ischemia and reperfusion injury is caused by 1) activated leukocytes and platelets, 2) ATP depletion and calcium overload of myocardium, and 3) catecholamine release from the presynaptic nerves as well as 4) the impaired coronary circulation. Intriguingly adenosine attenuates all of these deleterious actions and thereby attenuates ischemia/reperfusion injury. Indeed, adenosine attenuates the severity of contractile dysfunction (myocardial stunning) and limits the infarct size. Thus, administration of adenosine or potentiators of adenosine production in the ischemic myocardium may be beneficial for the attenuation of ischemic and reperfusion injuries, although further clinical investigations are necessary.

Adenosine, the heart, and coronary circulation.

Modification of the cardiac rhythm by histamine has been appreciated almost since the compound's isolation from ergot by Barger and Dale in 1910. The major arrhythmogenic actions of histamine are an Hi-receptor-mediated slowing of atriovenrricular (AV) conduction and H2-receptor-mediated increases in sinus rate and ventricular automaticity. These actions were elucidated by observing the salutary effects of histamine antagonists on the arrhythmias of anaphylaxis, and by administering exogenous histamine to various cardiac preparations in the presence and absence of histamine antagonists. The ability to record transmembrane action potenrial(s) (TAP) from single cells has permitted the study of electrophysiological mechanisms underlying histamine-induced arrhythmias.

Histamine and cardiac arrhythmias.

Histamine is released into the systemic circulation during anaphylaxis, by drugs and by surgical procedures. Studies in animal models have conclusively demonstrated that released cardiac histamine is a major mediator of arrhythmias that occur during anaphylaxis and following the administration of histamine-releasing drugs. Several lines of evidence suggest a similar arrhythmogenic role for cardiac histamine in humans: (1) The human heart is rich in histamine; (2) cardiac histamine can be readily released from human heartin vitro by therapeutic concentrations of drugs; (3) histamine has potent arrhythmogenic effects on the human heartin vitro.

Dysrhythmias caused by histamine release in guinea pig and human hearts.

https://www.cell.com/trends/pharmacological-sciences/pdf/0165-6147(81)90247-9.pdf

Cardiac histamine: a mediator in search of a function

The effects of histamine and the selective agonists impromidine (H2-agonist) and 2-(2-thiazolyl ethylamine)(H1-agonist) on ventricular fibrillation threshold were tested in the isolated guinea-pig heart. All three compounds produced reversible concentration-dependent decreases in ventricular fibrillation threshold. Ventricular fibrillation threshold reduction was not secondary to the positive chronotropic effect of the three compounds. Computer analysis of the data using appropriate theoretical models suggests that the net effect of histamine on ventricular fibrillation threshold is the resultant of two components: H1 and H2. Pyrilamine inhibited the H1-mediated effects of histamine on ventricular fibrillation threshold with a Kb value of 0.449 nM. H1- and H2-receptors mediating ventricular fibrillation threshold reduction differ in their relative sensitivity to histamine (H1 greater than H2; EC50 for histamine, 53.9 nM at H1- and 311 nM at H2-receptors) and in the maximum response which they are capable of producing (H1 congruent to 1/2 that of H2). The finding that extremely low concentrations of histamine (less than 1 pg/ml) can effectively reduce ventricular fibrillation threshold reinforces the concept that histamine is highly arrhythmogenic.

Reduction of ventricular fibrillation threshold by histamine: resolution into separate H1- and H2-mediated components.

The cardiac pharmacology of tiotidine, a potent and specific antagonist of H2-receptors, was studied in isolated Langendorff-perfused guinea-pig hearts. At a concentration of 2.5 x 10(-6) M, tiotidine caused a slight prolongation of the P-R interval, but had no effect on rate, contractility or coronary function. Tiotidine competitively antagonized the positive chronotropic action of histamine with an apparent dissociation constant of 3.0 x 10(-8) M (2.3 x 10(-8)-3.8 x 10(-8) M). Tiotidine abolished H2-mediated increases in contractile force leaving H2-mediated negative inotropic responses unopposed. The actions of histamine at the A-V node, manifested by lengthening of the P-R interval and A-V block, were attenuated by 2.5 x 10(-7) M tiotidine; nevertheless, higher concentrations of the antagonist did not produce additional inhibition of the negative dromotropic response. As a function of concentration, tiotidine reduced the incidence and duration of histamine-induced idioventricular arrhythmias. Based on its high affinity and specificity for the H2-receptor and relative lack of cardio-depressant effects, tiotidine appears to be a useful new drug for investigating the role of histamine in cardiac function and dysfunction.

J P Trzeciakowski

Papers

Dysrhythmias caused by histamine release in guinea pig and human hearts.

Cardiac histamine: a mediator in search of a function

Reduction of ventricular fibrillation threshold by histamine: resolution into separate H1- and H2-mediated components.

The cardiac pharmacology of tiotidine (LCL 125, 211): a new histamine H2-receptor antagonist.

Effects of N-demethylated Carbachol on Iris and Ciliary Muscles