Effect adrenergic response modulation

Other authors showed that (R)a-methylhistamine, together with the inotropic and chronotropic adrenergic response from transmurally-stimulated atrial preparations, also inhibits the release of noradrenaline, thus providing direct evidence that histamine H3-receptors negatively modulate the cardiac sympathetic activity at a presynaptic site of action (Endou et al., 1994). In addition, it was demonstrated that (R)a-methylhistamine, at concentrations greater than 1 pM, produces further antiadrenergic activity by acting at inhibitory presynaptic a.2-adrenoceptors. This result is supported by the fact that yohimbine reverses this effect. 

The modulation of the N-type Ca2+ channels has been shown for some presynaptic receptors to be the mechanistic basis for the inhibition of Ca2+ influx [29]. In 1989 Takemura et al. [30] reported on the effective inhibition of histamine release from rat hypothalamic slices by the N-type Ca2+ -channel blocker ca-conotoxin. In addition Endou et al. [23] showed that to-conotoxin greatly potentiated the modulatory effect of (R)a-methylhistamine on cardiac adrenergic responses. Yang and Hatton [31] provided direct evidence for an H3 receptor-mediated modulation of ion permeability of neurons. They showed that in magnocellular histaminergic neurons from the rat posterior hypothalamus, H3... 

Because of the possible implication of PEA as one of the adrenergic ergotropic modulators, alterations in its disposition may be responsible for the euphoric effects of A -THC in man . Acute administration of 3 mg/kg of A -THC increased l -fold the brain levels of PEA and daily administration of 0.3 mg/kg for 8 days doubles PEA brain levels. In contrast A -THC induces only relatively small changes in the brain levels of serotonin, catecholamines and acetylcholine. 

The general picture of muscle contraction in the heart resembles that of skeletal muscle. Cardiac muscle, like skeletal muscle, is striated and uses the actin-myosin-tropomyosin-troponin system described above. Unlike skeletal muscle, cardiac muscle exhibits intrinsic rhyth-micity, and individual myocytes communicate with each other because of its syncytial nature. The T tubular system is more developed in cardiac muscle, whereas the sarcoplasmic reticulum is less extensive and consequently the intracellular supply of Ca for contraction is less. Cardiac muscle thus relies on extracellular Ca for contraction if isolated cardiac muscle is deprived of Ca, it ceases to beat within approximately 1 minute, whereas skeletal muscle can continue to contract without an extraceUular source of Ca +. Cyclic AMP plays a more prominent role in cardiac than in skeletal muscle. It modulates intracellular levels of Ca through the activation of protein kinases these enzymes phosphorylate various transport proteins in the sarcolemma and sarcoplasmic reticulum and also in the troponin-tropomyosin regulatory complex, affecting intracellular levels of Ca or responses to it. There is a rough correlation between the phosphorylation of Tpl and the increased contraction of cardiac muscle induced by catecholamines. This may account for the inotropic effects (increased contractility) of P-adrenergic compounds on the heart. Some differences among skeletal, cardiac, and smooth muscle are summarized in... 

Early evidence that prejunctional histamine H3-receptors may modulate the sympathetic nerve activity on the heart was provided by Luo et al., (1991). These authors clearly stated that the selective H3-agonist (R)a-methylhistamine attenuates the inotropic response induced by transmural stimulation of the adrenergic nerve terminals in the isolated right atrium, without affecting basal contractile force of the preparation or the positive inotropic effect elicited by exogenous noradrenaline. The effect of (R)a-methylhistamine, which is not modified by Hi and H2-receptor blockade, was reversed by the specific H3-receptor antagonist thioperamide, at concentrations which do not influence the inhibitory activity mediated by other presynaptic receptors, like a2-adrenoceptors. 

Minoxidil (loniten) is efficacious in patients with the most severe and drug-resistant forms of hypertension. A small fraction of minoxidil is metabolized by hepatic sulfotransferase to the active molecule, minoxidil N-O sulfate. Minoxidil sulfate activates the ATP-modulated channel in smooth muscle, causing hyperpolarization and relaxation of arteriolar smooth muscle. Minoxidil produces arteriolar vasodilation with essentially no effect on capacitance vessels. Minoxidil preferentially increases blood flow to skin, skeletal muscle, the GI tract, and the heart. The disproportionate increase in blood flow to the heart may have a metabolic basis, in that administration of minoxidil is associated with a reflex increase in myocardial contractility and in cardiac output. The cardiac output can increase by as much as three- to fourfold, primarily due to enhanced venous return to the heart. The increased venous return probably results from enhanced flow in vascular beds with a fast response for venous return to the heart. The adrenergic increase in myocardial contractility contributes to the increased cardiac output, but is not the predominant factor. The renal effects of minoxidil are complex it dilates renal arteries, but systemic hypotension produced by the drug actually can decrease renal blood flow. Renal function usually improves in patients who take minoxidil for the treatment of hypertension, especially if renal dysfunction is secondary to hypertension. Minoxidil potently stimulates renin secretion, an effect mediated by renal sympathetic stimulation. 

Blockade of monoamine receptors (pre- and postsynaptic, or both). Some of these are presynaptic inhibitory auto/heteroreceptors (e.g. tt2 -adrenergic), which, when blocked, cause the presynaptic neurons to release more neurotransmitter to the synaptic cleft. Postsynaptic blockade of various receptors modulates cellular activities and is presumably responsible for the antidepressive effects. 

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