No abstract

Ergotamine has been used in clinical practice for the acute treatment of migraine for over 50 years, but there has been little agreement on its place in clinical practice. An expert group from Europe reviewed the pre-clinical and clinical data on ergotamine as it relates to the treatment of migraine. From this review, specific suggestions for the patient groups and appropriate use of ergotamine have been agreed. In essence, ergotamine, from a medical perspective, is the drug of choice in a limited number of migraine sufferers who have infrequent or long duration headaches and are likely to comply with dosing restrictions. For most migraine sufferers requiring a specific anti-migraine treatment, a triptan is generally a better option from both an efficacy and side-effect perspective.

Background —The antimigraine drugs ergotamine and sumatriptan may cause angina-like symptoms, possibly resulting from coronary artery constriction. We compared the coronary vasoconstrictor potential of a number of current and prospective antimigraine drugs (ergotamine, dihydroergotamine, methysergide and its metabolite methylergometrine, sumatriptan, naratriptan, zolmitriptan, rizatriptan, avitriptan). Methods and Results —Concentration-response curves to the antimigraine drugs were constructed in human isolated coronary artery segments to obtain the maximum contractile response (E max ) and the concentration eliciting 50% of E max (EC 50 ). The EC 50 values were related to maximum plasma concentrations (C max ) reported in patients, obtaining C max /EC 50 ratios as an index of coronary vasoconstriction occurring in the clinical setting. Furthermore, we studied the duration of contractile responses after washout of the acutely acting antimigraine drugs to assess their disappearance from the receptor biophase. Compared with sumatriptan, all drugs were more potent (lower EC 50 values) in contracting the coronary artery but had similar efficacies (E max <25% of K + -induced contraction). The C max of avitriptan was 7- to 11-fold higher than its EC 50 value, whereas those of the other drugs were <40% of their respective EC 50 values. The contractile responses to ergotamine and dihydroergotamine persisted even after repeated washings, but those to the other drugs declined rapidly after washing. Conclusions —All current and prospective antimigraine drugs contract the human coronary artery in vitro, but in view of low efficacy, these drugs are unlikely to cause myocardial ischemia at therapeutic plasma concentrations in healthy subjects. In patients with coronary artery disease, however, these drugs must remain contraindicated. The sustained contraction by ergotamine and dihydroergotamine seems to be an important disadvantage compared with sumatriptan-like drugs.

Cardiac ACE activity is highest in subjects with the DD genotype. Elevated cardiac ACE activity in these subjects may result in increased cardiac angiotensin II levels, and this may be a mechanism underlying the reported association between the ACE deletion polymorphism and the increased risk for several cardiovascular disorders.

The existence of a cardiac renin-angiotensin system, independent of the circulating renin-angiotensin system, is still controversial. We compared the tissue levels of reninangiotensin 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=ll) 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=ll) in cardiac tissue were 10% to 25% of the A ngiotensin I (Ang I) is produced in the circulating / \ blood by the action of renin from the kidney on -Z A . angiotensinogen produced by the liver. Ang I is converted to Ang II, a potent vasoconstrictor, by angiotensin-converting enzyme (ACE) located on the luminal surface of the vascular endothelium. It is now well established that Ang I and II are not only produced in the blood compartment but also locally in tissues. Recent evidence suggests that complete local reninangiotensin systems (RAS) are present in a number of organs, for instance, kidney, adrenal gland, and ovary. 13In such local RAS, the production of Ang I and II is thought to depend on in situ synthesized renin rather than plasma-derived renin.A local cardiac RAS has also been postulated. 4 ' 5 However, direct evidence for Ang I and II production in the heart by in situ synthesized renin is still lacking. Renin mRNA levels in the heart are usually low and can be detected only by polymerase chain reaction. 68 Early studies showed Ang I-generating activity in left ventric-

Migraine patients have chronically low systemic 5-HT, predisposing them to develop migrainous headache once an attack has been initiated. Changes in platelet 5-HT content are not causally related, but reflect similar changes at a neuronal level. Stimulation of vascular 5-HT1 receptors, probably located in the vessel wall within the dural vascular bed, may alleviate the headache and associated symptoms, but does not interact with earlier mechanisms within the pathophysiological cascade. These receptors are of an as yet unidentified 5-HT1 subtype, closely resembling, but not identical to 5-HT1D receptors. Activation of these receptors results in vasoconstriction, inhibiting depolarization of sensory perivascular afferents within the trigemino-vascular system and thus stopping the headache. Additional inhibition of the release of vasoactive neuropeptides may be involved, but seems to be of only secondary clinical importance.

Background-Angiotensin (Ang) II type 2 (AT 2 ) receptor stimulation results in coronary vasodilation in the rat heart. In contrast, AT 2 receptor-mediated vasodilation could not be observed in large human coronary arteries. We studied Ang II-induced vasodilation of human coronary microarteries (HCMAs). Methods and Results-HCMAs (diameter, 160 to 500 m) were obtained from 49 heart valve donors (age, 3 to 65 years).Ang II constricted HCMAs, mounted in Mulvany myographs, in a concentration-dependent manner (pEC 50 , 8.6Ϯ0.2; maximal effect [E max ], 79Ϯ13% of the contraction to 100 mmol/L K ϩ ). The Ang II type 1 receptor antagonist irbesartan prevented this vasoconstriction, whereas the AT 2 receptor antagonist PD123319 increased E max to 97Ϯ14% (PϽ0.05). The increase in E max was larger in older donors (correlation ⌬E max versus age, rϭ0.47, PϽ0.05). The PD123319-induced potentiation was not observed in the presence of the NO synthase inhibitor L-NAME, the bradykinin type 2 (B 2 ) receptor antagonist Hoe140, or after removal of the endothelium. Ang II relaxed U46619-preconstricted HCMAs in the presence of irbesartan by maximally 49Ϯ16%, and PD123319 prevented this relaxation. Finally, radioligand binding studies and reverse transcription-polymerase chain reaction confirmed the expression of AT 2 receptors in HCMAs. Conclusions-AT 2 receptor-mediated vasodilation in the human heart appears to be limited to coronary microarteries and is mediated by B 2 receptors and NO. Most likely, AT 2 receptors are located on endothelial cells, and their contribution increases with age.

We used a modification of the isolated perfused rat heart, in which coronary effluent and interstitial transudate were separately collected, to investigate the uptake and clearance of exogenous renin, angiotensinogen, and angiotensin I (Ang I) as well as the cardiac production of Ang I. The levels of these compounds in interstitial transudate were considered to be representative of the levels in the cardiac interstitial fluid. During perfusion with renin or angiotensinogen, the steady-state levels (mean +/- SD) in interstitial transudate were 64 +/- 34% (P < .05 for difference from the arterial level, n = 8) and 108 +/- 42% (n = 6) of the arterial level, respectively; the levels in coronary effluent were not significantly different from those in interstitial transudate. Ang I was not detectable in interstitial transudate during perfusion with Tyrode's buffer or angiotensinogen. It was very low in interstitial transudate during perfusion with renin and rose to much higher levels during combined renin and angiotensinogen perfusion. The total production rate of Ang I present in interstitial fluid could be largely explained by the renin-angiotensinogen reaction in the fluid phase of the interstitial compartment. In contrast, the total production rate of Ang I present in coronary effluent and the net ejection rate of Ang I via coronary effluent were, respectively, 4.6 +/- 2.2 and 2.8 +/- 1.3 (P < .01 and P < .05 for difference from 1.0, n = 6) times higher than could be explained by Ang I formation in the fluid phase of the intravascular compartment. Ang I from the interstitial fluid contributed little to the Ang I in the intravascular fluid and vice versa. These data reveal two tissue sites of Ang I production, ie, the interstitial fluid and a site closer to the blood compartment, possibly vascular surface-bound renin. There was no evidence that the release of locally produced Ang I into coronary effluent and interstitial transudate occurred independently of blood-derived renin or angiotensinogen.