Blocking the CGRP Receptor:Differences across Human Vascular Beds

Multiple drugs targeting the calcitonin gene-related peptide (CGRP) receptor have been developed for the treatment of migraine. Here, the effect of the small-molecule CGRP receptor antagonist zavegepant (0.1 nM–1 µM) on CGRP-induced relaxation in isolated human coronary arteries (HCAs) was investigated. A Schild plot was constructed and a pA2 value was calculated to determine the potency of zavegepant. The potency and Schild plot slopes of atogepant, olcegepant, rimegepant, telcagepant, ubrogepant and zavegepant in HCAs and human middle meningeal arteries (HMMAs), obtained from our earlier studies, were compared. Zavegepant shifted the concentration–response curve to CGRP in HCAs. The corresponding Schild plot slope was not different from unity, resulting in a pA2 value of 9.92 ± 0.24. No potency difference between HCAs and HMMAs was observed. Interestingly, olcegepant, atogepant and rimegepant, with a Schild plot slope &lt; 1 in HCAs, were all &gt;1 log unit more potent in HMMAs than in HCAs, while telcagepant, ubrogepant and zavegepant, with a Schild plot slope not different from unity, showed similar (&lt;1 log difference) potency across both tissues. As a Schild plot slope &lt; 1 may point to the involvement of multiple receptors, it is important to further identify the receptors involved in the relaxation to CGRP in HCAs, which may be used to improve the cardiovascular safety of future antimigraine drugs.</p

Histological evaluation disqualifies IMT and calcification scores as surrogates for grading coronary and aortic atherosclerosis

__Background/objectives__ Carotid intimal media thickness (IMT) and coronary calcium scores (CCS) are thought to reflect atherosclerotic burden. The validity of this assumption for IMT is challenged by recent meta-analyses; for CCS by absence of a relationship between negative scores, and freedom of future events. As such, we considered evaluation of the relationship between tissue IMT and CCS, and extend of atherosclerotic disease relevant. __Methods__ Analyses were performed on donor aortas obtained during renal graft procurement, and on coronary arteries collected during heart valve procurement for tissue donation. Movat pentachrome and Hematoxylin staining was performed, and the degree of atherosclerosis histologically graded. IMT and presence of calcium deposits were quantified on graded tissue sections. __Results__ 304 aortas and 185 coronary arteries covering the full atherosclerotic spectrum were evaluated. Aortas and coronaries showed similar relationships between tissue IMT and degree of atherosclerosis, with gradual increase in tissue IMT during earlier phases of atherosclerosis (r = 0.68 and r = 0.30, P < 0.00001 for aorta and coronaries respectively), followed by plateauing of the curve in intermediate and advanced stages. Results for tissue IMT reveal high variability, resulting in wide confidence intervals. Results for CCS are similar for aorta and coronaries, with calcium depositions limited to advanced lesions. __Conclusions__ Histological IMT measurements for the aorta and coronaries show large variations around the trend and plateauing of, and possibly reductions in IMT in late stage atherosclerotic disease. These observations for the aorta and coronaries may (partly) explain the limited benefit of including carotid IMT in risk prediction algorithms

Analyse der Tätigkeiten kardiovaskulärer Gewebebanken in Deutschland in den Jahren 2007 bis 2010

__Background:__ Especially in complicated aortic valve endocarditis, infections of the aorta by mycotic aortic aneurysms and prosthetic infections, or as part of the Ross procedure, the use of allogeneic heart valve transplants remains important. The production of such allografts in Germany is the task of cardiovascular tissue banks (CVTB). __Materials and methods:__ During an analysis of the years 2007-2010, basic data on donor numbers, production, and distribution as well as the technical conditions of not only the four participating CVTB (Bad Oeynhausen, Berlin, Kiel, Munich) but also data from the CVTB Rotterdam as an external reference were recorded. __Results:__ The German CVTB delivered an average of 44 aortic and 95 pulmonary allografts per year to clinical users. By incorporating the annually imported valve allografts, the demand in Germany approximately averages 220 heart valve allografts per year. The heart tissue was harvested from approximately 100 multiorgan donors, 45 cardiovascular deaths, and 80 domino donors annually. __Discussion:__ The participating cardiovascular tissue banks have comparable technical and administrative requirements and are able to produce tissue preparations according to the rules of Good Professional Practice in accordance with § 3 (3) AMWHV to assess their quality, whereby harmonization of microbiological monitoring and antibiotic treatment is still necessary

Angiotensin IIaldosterone interaction in human coronary microarteries involves GPR30, EGFR, and endothelial NO synthase

The aim of this study was to investigate the aldosteroneangiotensin (Ang) II interaction in human coronary microarteries (HCMAs). HCMAs, obtained from 75 heart-beating organ donors, were mounted in myographs and exposed to Ang II, either directly or following a 30-min pre-incubation with aldosterone, 17-oestradiol, hydrocortisone, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, the extracellular regulated kinase 1/2 (ERK1/2) inhibitor PD98059, the GPR30 antagonist G15, or the epidermal growth factor receptor (EGFR) antagonist AG1478. Ang II constricted HCMAs in a concentration-dependent manner. All ster Steroids including aldosterone affect Ang II-induced vasoconstriction in a biphasic manner. Potentiation occurs at nanomolar steroid levels and depends on GPR30 and EGFR transactivation. At micromolar steroid levels, this potentiation either disappears (aldosterone and hydrocortisone) or is reversed into an inhibition (17-oestradiol), and this is due to the endothelial NOS activation that occurs at such concentrations