Stimuli of Sensory-Motor Nerves Terminate Arterial Contractile Effects of Endothelin-1 by CGRP and Dissociation of ET-1/ETA-Receptor Complexes

Endothelin-1 (ET-1), a long-acting paracrine mediator, is implicated in cardiovascular diseases but clinical trials with ET-receptor antagonists were not successful in some areas. We tested whether the quasi-irreversible receptor-binding of ET-1 (i) limits reversing effects of the antagonists and (ii) can be selectively dissociated by an endogenous counterbalancing mechanism.-receptor complexes.-receptors by ET-1 (i) occur at an antagonist-insensitive site of the receptor and (ii) are selectively terminated by endogenously released CGRP. Hence, natural stimuli of sensory-motor nerves that stimulate release of endogenous CGRP can be considered for therapy of diseases involving ET-1

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

<p>Abstract</p> <p>Background</p> <p>Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics.</p> <p>Discussion</p> <p>In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.</p> <p>As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy.</p> <p>Summary</p> <p>Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.</p

Muscarinic receptors and drugs in cardiovascular medicine

The parasympathetic system and its associated muscarinic receptors have been the subject of a renaissance of interest for the following two main reasons: (1) the association of endothelial muscarinic receptors and the nitric oxide (NO) pathway; (2) the discovery of several muscarinic receptor subtypes and drugs interacting with them. In the present survey modern insights into the subdivision of muscarinic receptors have been dealt with as the basis for a description of the muscarinic receptor agonists and antagonists thus far known. There are at least four pharmacologically defined M receptors (M1, M2, M3, M4) in primary tissues, and five muscarinic receptors have been cloned (m1, m2, m3, m4, m5). Selective agonists for M-receptor subtypes hardly exist, and all classical agonists (acetylcholine, carbachol, etc.) are clearly nonselective. A few selective antagonists for M1 (pirenzepine) and M2 receptors (AF-DX 116) have been introduced, although selective M3 receptors are hardly available. Finally, the potential therapeutic use of M-receptor agonists (myocardial ischemia, hypertension) and muscarinic antagonists (certain forms of bradycardia, coronary spasm) has been critically discussed. Although only in a preliminary stage, this development appears to be promising and at least of great fundamental interes

Effects of calcitonin gene-related peptide and BIBN4096BS on myocardial ischemia in anesthetized rats

The cardioprotective effect of calcitonin gene-related peptide (CGRP) was investigated in an ischemia rat model. Ischemia-reperfusion injury was provoked by 60 min left main coronary artery occlusion followed by 60 min of reperfusion in anesthetized rats. The transverse slices of ventricles were stained by 2,3,5-triphenyltetrazolium chloride to determine the infarct area. Plasma creatine phosphokinase levels were determined by means of a creatine phosphokinase (CPK) kit. A radioimmunoassay was used to determine plasma CGRP levels. Intravenous infusion of CGRP (1 nmol . kg-1 . h-1) 10 min before occlusion until the end of reperfusion reduced infarct size by 89 %+/- 5 %. The reduction in infarct size was accompanied by a decrease in circulating levels of creatine phosphokinase. Infusion of the same dose of CGRP commencing from the start of reperfusion until its end induced a 40 % +/- 3 % reduction of the infarct size. The cardioprotective effects of CGRP were blocked by the novel CG RP antagonist BIBN4096BS (20 nmol . kg-1 . h-1). Although cardiac ischemia resulted in an almost 50 % increase in plasma CGRP levels in blood sampled from right cardiac ventricle, intravenous infusion of the CGRP antagonist BIBN4096BS before occlusion until the end of reperfusion had no statistically significant effect on the infarct size. The present study demonstrates that CGRP is a potent myocardial protective substanc