Migraine involves dysfunction of brainstem pathways that normally modulate sensory input. The involvement of calcitonin gene-related peptide (CGRP) in migraine pathology is supported by both clinical and experimental evidence. The release of CGRP and other neuropeptides from trigeminal nerves is thought to mediate neurogenic inflammation within the meninges, which contributes to the generation of severe cerebral pain experienced during migraine attacks. Hence, structure-activity relationship studies have been conducted in an attempt to develop small molecules that behave as CGRP antagonists. Recently, the development of a potent, nonpeptide CGRP antagonist, BIBN-4096BS (olcegepant), represented a major breakthrough. BIBN-4096BS demonstrates very high affinity for the human CGRP receptor expressed in SK-N-MC cells and may be useful in the treatment of migraine, as well as providing new information on CGRP receptor subtypes. Copyright
Summary— The cardiovascular effects of 5‐hydroxytryptamine (5‐HT), consisting of bradycardia or tachycardia, hypotension or hypertension, and vasodilatation or vasoconstriction, are mediated by three main types of receptors called 5‐HT 1 ‐like, 5‐HT 2 , and 5‐HT 3 . In intact animals 5‐HT elicits a short‐lasting bradycardia, accompanied by hypotension, via stimulation of 5‐HT 3 receptors located on sensory vagal nerve endings in the heart (Bezold‐Jarisch reflex). The nature of 5‐HT receptors mediating tachycardiac responses is species‐dependent. Myocardial 5‐HT 1 ‐like and 5‐HT 2 receptors subserve tachycardia in the cat and rat, respectively. Tachycardia in the dog and rabbit is due to a release of catecholamines effected via the 5‐HT 2 receptors on the adrenal medulla and the 5‐HT 3 receptors on postganglionic cardiac sympathetic nerve fibres, respectively. The receptors mediating tachycardia in the pig are unique as they do not resemble any of the three 5‐HT receptors characterized so far. The blood pressure response to 5‐HT is usually triphasic: initial short‐lasting hypotension due to reflex bradycardia ( via 5‐HT 3 receptors), a middle pressor phase ( via 5‐HT 2 receptors), and a longer‐lasting hypotension ( via 5‐HT 1 ‐like receptors). Vascular contraction by 5‐HT is generally mediated by 5‐HT 2 receptors (located primarily on the large conducting vessels), though in some instances ( e.g. , dog saphenous vein, dog and human basilar artery, and porcine arteriovenous anastomoses) the contractile response is (also) mediated via 5‐HT 2 ‐like receptors. Venous dilatation and arteriolar dilatation (leading to increased capillary [‘nutrient’] blood flow) occur via 5‐HT 1 ‐like receptors located mainly on the vascular smooth muscles but also on the endothelium; the smooth muscle and endothelial 5‐HT 1 ‐like receptors seem to be heterogeneous. In addition, 5‐HT can elicit vasodilatation and hypotension as a result of decreased sympathetic nervous tone by acting within the central nervous system and by inhibiting noradrenaline release by a presynaptic action. Both these effects also involve 5‐HT 1 ‐like receptors that do not appear to be identical. Last, knowledge of the cardiovascular effects of 5‐HT and the nature of the receptors involved should be helpful in developing 5‐HT‐related compounds that may be useful in the treatment of hypertension, migraine, and peripheral vascular diseases.
The existence of a cardiac renin-angiotensin system, independent of the circulating renin-angiotensin system, is still controversial. We compared the tissue levels of renin-angiotensin system components in the heart with the levels in blood plasma in healthy pigs and 30 hours after nephrectomy. Angiotensin I (Ang I)-generating activity of cardiac tissue was identified as renin by its inhibition with a specific active site-directed renin inhibitor. We took precautions to prevent the ex vivo generation and breakdown of cardiac angiotensins and made appropriate corrections for any losses of intact Ang I and II during extraction and assay. Tissue levels of renin (n = 11) and Ang I (n = 7) and II (n = 7) in the left and right atria were higher than in the corresponding ventricles (P < .05). Cardiac renin and Ang I levels (expressed per gram wet weight) were similar to the plasma levels, and Ang II in cardiac tissue was higher than in plasma (P < .05). The presence of these renin-angiotensin system components in cardiac tissue therefore cannot be accounted for by trapped plasma or simple diffusion from plasma into the interstitial fluid. Angiotensinogen levels (n = 11) in cardiac tissue were 10% to 25% of the levels in plasma, which is compatible with its diffusion from plasma into the interstitium. Like angiotensin-converting enzyme, renin was enriched in a purified cardiac membrane fraction prepared from left ventricular tissue, as compared with crude homogenate, and 12 +/- 3% (mean +/- SD, n = 6) of renin in crude homogenate was found in the cardiac membrane fraction and could be solubilized with 1% Triton X-100. Tissue levels of renin and Ang I and II in the atria and ventricles were directly correlated with plasma levels (P < .05), and in both tissue and plasma the levels were undetectably low after nephrectomy. We conclude that most if not all renin in cardiac tissue originates from the kidney. Results support the contentions that in the healthy heart, angiotensin production depends on plasma-derived renin and that plasma-derived angiotensinogen in the interstitial fluid is a potential source of cardiac angiotensins. Binding of renin to cardiac membranes may be part of a mechanism by which renin is taken up from plasma.
1. We studied the effects of four doses of nimodipine (0.5, 1, 2 and 4 micrograms kg-1 min-1) on systemic haemodynamics and on regional vascular beds, in particular the cerebral circulation, in conscious pigs. 2. Nimodipine caused dose-dependent, probably reflex-mediated, increases in heart rate (42% with the highest dose) and cardiac output (54%), while arterial blood pressure was only minimally affected. Left ventricular end-diastolic pressure and systemic vascular resistance decreased dose-dependently (35-40% at the highest dose) while stroke volume remained unchanged. 3. Total brain blood flow was not affected by the drug. Furthermore, we could not demonstrate any regional cerebral differences, as blood flows to both cerebral hemispheres as well as the diencephalon, cerebellum and brain stem remained unchanged. 4. Blood flow to the kidneys, liver, small intestine and skin also did not change. Nimodipine caused dose-dependent increases in blood flow to the stomach (95%), myocardium (97%) and adrenal glands (102%), while blood flow to skeletal muscles (267%) increased most. 5. It is concluded that in the conscious pig, nimodipine is an arterial vasodilator which shows some selectivity for the skeletal muscle vasculature but does not increase total or regional cerebral blood flow.
The role of platelet activating factor (PAF) in endotoxic shock was investigated in anaesthetized pigs receiving 5 micrograms/kg E. coli endotoxin (LPS) into the superior mesenteric artery over a 60 min period. Concentrations of PAF and tumor necrosis factor (TNF) were measured in blood obtained from the superior mesenteric vein and aorta before, during and 60 min after the LPS infusion. The effect of 4 mg/kg of BN 52021, a PAF receptor antagonist, given as a bolus injection 5 min prior to LPS infusion and/or PAF administration into the superior mesenteric vein was studied on systemic and regional hemodynamic variables. Eight of the 17 animals infused with LPS died within 30 min after start of LPS, while the other 9 survived the experimental period of 3 h, though in a shock state. In survivors, PAF concentration in both superior mesenteric vein and aorta increased twenty-fold at 30 min of endotoxaemia, but rapidly returned back towards normal values. No changes in PAF release, but a marked rise in TNF production were measured in non-survivors. Exogenous administration of PAF (0.01 micrograms/kg) produced similar hemodynamic effects as observed in survivors. BN 52021 markedly reduced the effects of PAF on arterial blood pressure for over 1 h. Treatment with BN 52021 (4 mg/kg), injected 5 min prior to LPS infusion, failed to exert any effect on the surviving rate. However, in survivors all circulatory and laboratory parameters studied were improved after treatment with BN 52021. PAF release observed during LPS infusion in survivors may play a role in the development of shock; however, its role in the rapid death seems to be negligible. Present results clearly demonstrate that endotoxin shock is not crucially dependent on one class of mediators.
The systemic and regional hemodynamic effects of the centrally acting putative 5-HT1A receptor agonist flesinoxan (3, 10, 30, and 100 micrograms/kg) were investigated in the anesthetized cat and compared with those of 8-hydroxy-2(di-n-prophylamino) tetralin (8-OH-DPAT 3, 10, 30, and 100 micrograms/kg) and clonidine (0.3, 1, 3, and 10 micrograms/kg). Cardiac output (CO) was measured with a precalibrated electromagnetic flow probe placed on the ascending aorta, and regional blood flows and conductances were measured with radioactive microspheres. Flesinoxan and 8-OH-DPAT caused a decrease in blood pressure (BP 44 and 37%, respectively, at 100 micrograms/kg) mainly resulting from an increased peripheral vascular conductance; in the case of 8-OH-DPAT, however, a reduction in CO (34%) also contributed. Clonidine decreased BP (12% at 10 micrograms/kg) by reducing CO (31%). All three drugs decreased heart rate (HR). Flesinoxan and 8-OH-DPAT decreased tissue perfusion in the heart, lungs, gastrointestinal tract, eyes, and skin, but both renal and cerebral blood flows were preserved as a result of increased vascular conductances. These two drugs also redistributed intrarenal blood flow from the outer cortex toward the inner cortex and medulla. Low doses of clonidine tended to increase but higher doses decreased organ blood flows, especially to the heart, lungs, liver, and eyes. Clonidine did not redistribute intrarenal blood flows. These results establish that the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT elicited a systemic and regional hemodynamic profile that differs from that of the alpha 2-adrenoceptor agonist clonidine.
