Potentiated adrenomedullin-induced vasorelaxation during hypoxia in organ cultured porcine coronary arteries.

This study describes the effect of variable oxygen supply on relaxing responses induced by α-calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) on isolated pig coronary arteries in vitro. Organ culture during normoxia (21% of O2) and hypoxia (5% of O2) induced a significant leftward shift of the AM concentration-response curves compared with fresh vessels altering the pEC50 values from 6.9 ± 0.04 to 8.0 ± 0.04, whereas the potency (pEC50) of αCGRP was attenuated from 8.8 ± 0.04 to 7.6 ± 0.04. AM22₋52 exerted significant antagonistic effect on AM-induced vasorelaxation in hypoxic and normoxic conditions (apparent pK(B) = 6.8-7.2), whereas no antagonistic effect was observed in fresh and hyperoxic (95%) organ cultured vessels. The antagonistic effect exerted by αCGRP8₋37 (10⁻6·5-10⁻5·5 M) on αCGRP-induced vasodilatation in fresh vessels (derived from Schild plot pA2 = 7.4 ± 0.1) was unaltered during organ culture. The antagonistic effect exerted by αCGRP8₋37 (10⁻6 M) on AM-induced vasorelaxation in fresh vessels (apparent pK(B) = 7.4 ± 0.1) was absent during hypoxic organ culture. The receptor activity-modifying proteins 1 (RAMP1)/calcitonin-like receptor (CLR) messenger RNA ratio was reduced and RAMP2/CLR messenger RNA ratio was increased during hypoxic and normoxic organ culture compared with fresh vessels. Hypoxic organ culture for 24-72 hours potentiated the AM-induced vasorelaxation through an AM22₋52-sensitive receptor but attenuated the vasorelaxant effect of CGRP through the CGRP receptors. This could possibly be explained by relatively decreased levels of RAMP1, thus favoring RAMP2 + CLR complex (=AM receptor) formation during hypoxic organ culture.

Head-to-Head Comparison of Tc-99m-sestamibi SPECT/CT and C-11-L-Methionin PET/CT in Parathyroid Scanning Before Operation for Primary Hyperparathyroidism.

PURPOSE: The preferred nuclear medicine method for identification of hyperfunctioning parathyroid glands in hyperparathyroidism (HPT) develops continuously in relation to the technological progress. Diagnostic methods based on PET/CT have during recent years evolved with new tracer possibilities competing with traditional scintigraphic methods. This investigation is a head-to-head comparison of Tc-99m-sestamibi SPECT/CT gamma camera scintigraphy (sestamibi SPECT/CT) and C-11-L-methionin PET/CT imaging (methionine PET/CT) for preoperative identification of hyperfunctioning parathyroid glands. PROCEDURES: The study is a prospective cohort study including 27 patients diagnosed with primary hyperparathyroidism (PHPT). Two nuclear medicine physicians assessed all examinations independently and blinded. All scanning assessments were matched to the final surgical diagnosis as confirmed by histopathology. Biochemical monitoring of the therapeutical effects was performed preoperatively by PTH-measurements and followed postoperatively for up to 12 months. Comparisons were made for differences in sensitivity and positive predictive value (PPV). RESULTS: Twenty-seven patients (18 females, 9 males; mean age (range): 58.9 years (34.1-79)) were enrolled into the study. The 27 patients had a total of 33 identified sites of lesions of which 28 (85%) turned out to be histopathological verified hyperfunctioning parathyroid glands. The sensitivity and PPV for sestamibi SPECT/CT were 0.71 and 0.95; that of methionine PET/CT was 0.82 and 1, respectively. Both sensitivity and PPV were slightly lower for sestamibi SPECT/CT than for methionine PET PET/CT (-0.11, 95% confidence interval (95% CI): -0.29 to 0.08; -0.05, 95% CI: -0.14 to 0.04, respectively), but not to a statistically significant extent (p=0.38 and p=0.31). The sensitivity and PPV for diagnostic CT were 0.64 (95% CI: 0.44 to 0.81) and 1 (95% CI: 0.81 to 1). CONCLUSIONS: Methionine PET/CT performed comparable to sestamibi SPECT/CT with respect to identification and localization of hyperfunctioning parathyroid glands prior to surgery.

Increased alphaCGRP potency and CGRP-receptor antagonist affinity in isolated hypoxic porcine intramyocardial arteries.

1. This study describes the effects of hypoxia on relaxing responses and cAMP production induced by the known vasodilator peptides: alphaCGRP, amylin (AMY) and adrenomedullin (AM) on isolated pig coronary arteries in vitro. 2. Hypoxic incubation increased the vasorelaxant effect of alphaCGRP (four-fold; P<0.05), AMY (3.2-fold; P<0.05), but not significantly for AM (two-fold; NS). 3. Whereas hypoxia had no effect on arterial cAMP levels, it significantly potentiated the production of cAMP stimulated of alphaCGRP and AMY, but not of AM. 4. The antagonist alphaCGRP(8-37) also exerted an increased effect in hypoxia. The Schild plot-derived pK(B) values revealed an increase in the apparent affinity of the antagonist for the CGRP(1) receptor from 7.0 to 7.2 under control conditions versus 8.0 in hypoxia. 5. Removal of endothelium, peptidase inhibitors, preincubation with the adenosine A(2A) receptor antagonist CSC (10(-3) M), the ATP-sensitive K-channel inhibitor glibenclamide (10(-5) M), the cyclooxygenase inhibitor indomethacin (10(-3) M) or NG-monomethyl-L-arginine (10(-4) M) had no effect on the alphaCGRP-induced vasorelaxation in hypoxia; neither did hypoxia influence the levels of CGRP and AM receptor mRNA. 6. We conclude that hypoxic incubation increases the relaxation and cAMP production induced by alphaCGRP and AMY in rings of porcine coronary arteries in vitro. A concomitant release of adenosine, a cyclooxygenase product, an endothelium-derived substance, activation of vascular ATP-sensitive K-channels, peptidase inhibitors or changes in CGRP and AM receptor mRNA cannot account for the changes observed in hypoxia. Moreover, alphaCGRP(8-37) showed increased affinity at the CGRP(1) receptor during hypoxia, possibly due to a conformational change at the CGRP(1) receptor site.

Reference Ranges in [(99m)Tc]Mercaptoacetyltriglycerine Renography: Comparison of a Semi-automated (Xeleris, GE) and Manual (Picker, Odyssey) Processing Software.

PURPOSE: The purpose of the study was to define reference ranges for quantitative parameters in [(99m)Tc]mercaptoacetyltriglycerine ([(99m)Tc]MAG3) renography to assist interpretation in a semi-automated (Xeleris, GE) compared to a manual (Picker, Odyssey) software package. PROCEDURES: Forty-eight subjects approved for renal donation were evaluated with [(99m)Tc]MAG3 renography using both the Xeleris and the Picker software. RESULTS: Reference ranges for the two software were comparable regarding the relative function of the two kidneys (the split function, SF) and the residual activities (RA). The time to peak whole-kidney activities (T max whole-kidney) was more dependent on the type of software. Using Bland-Altman limits, we found good and acceptable agreement between the two methods. CONCLUSIONS: We found good correlation between renography results using the Xeleris and Picker software packages. However, software-specific reference ranges are needed.

Cost-effectiveness of PET and PET/computed tomography: a systematic review.

The development of clinical diagnostic procedures comprises early-phase and late-phase studies to elucidate diagnostic accuracy and patient outcome. Economic assessments of new diagnostic procedures compared with established work-ups indicate additional cost for 1 additional unit of effectiveness measure by means of incremental cost-effectiveness ratios when considering the replacement of the standard regimen by a new diagnostic procedure. This article discusses economic assessments of PET and PET/computed tomography reported until mid-July 2014. Forty-seven studies on cancer and noncancer indications were identified but, because of the widely varying scope of the analyses, a substantial amount of work remains to be done.

Calcitonin gene-related peptide and adrenomedullin release in humans: effects of exercise and hypoxia.

Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are potent vasorelaxant peptides. This study examined exercise-induced changes in CGRP and AM levels in 12 healthy sea level natives at sea level (SL) and subsequently after 24 h (HA1) and 5 days (HA5) in high altitude hypoxia (4559 m). Plasma values of CGRP, AM, calcitonin, noradrenaline, adrenaline, lactate and heart rate were measured at rest and during maximal exercise (W(max)). On each study day, the dopamine D(2)-receptor antagonist, domperidone (30 mg; n=6), or no medication (n=6) was given 1 h before exercise. W(max) at SL, HA1 and HA5 increased CGRP and AM along with heart rate, lactate and catecholamines, whereas, calcitonin remained unchanged. The maximal CGRP levels at W(max) were significantly decreased at HA1 (74.3+/-6.1 pmol/l; p=0.002) and HA5 (69.6+/-6.0 pmol/l; p<0.001) compared to maximal CGRP at SL (85.1+/-4.9 pmol/l). A similar pattern was observed for lactate and the relation between CGRP and lactate release showed a close linear correlation (r(2)=0.63, P<0.0001). Domperidone produced a marked increase in noradrenaline at W(max), but had no affect on CGRP or AM. In conclusion, CGRP release during hypoxic exercise does not respond to domperidone-induced changes in circulating levels of noradrenaline, rather the release may be directly related to the production of lactate.

Vasoactive modulators during and after craniotomy: relation to postoperative hypertension.

Hypertension after craniotomy is frequent. To establish an association between vasoactive modulators and postoperative hypertension, we followed the arterial blood pressure and plasma concentrations of selected substances in patients undergoing craniotomy. Twelve consecutive patients scheduled for operation of a supratentorial brain tumor were anesthetized with thiopental, fentanyl, isoflurane, and pancuronium. None of the patients had a history of arterial hypertension or were hypertensive before the operation. Arterial blood pressure and heart rate measurements were obtained preoperatively, after incision, during closure, and four times in the 50-minute interval after stopping isoflurane. At the same time, plasma concentrations of norepinephrine, epinephrine, renin, aldosterone, atrial natriuretic peptide, endothelin, and cortisol were measured. Data are given as mean +/- SD (range). The postoperative concentrations of these substances were significantly higher than the baseline concentrations measured preoperatively. Six of the patients developed postoperative hypertension defined as a mean arterial pressure (MAP) > 20% more than the baseline MAP (group H), and six had normal blood pressure postoperatively (group N). The mean value of the maximal postoperative MAPs measured in groups H and N, respectively, was 118 +/- 16 mm Hg (range: 96-132) and 103 +/- 9 mm Hg (range: 92-115) (P =.01). Only renin levels were higher intraoperatively in group H when compared to group N. However, postoperative levels of catecholamines, aldosterone, renin, and endothelin levels were higher in group H patients. The results suggest that in addition to an increased discharge of the sympathetic system, activation of the renin-angiotensin aldosterone system may also play an important role in the development of postoperative hypertension after craniotomy.

[Giant cell arteritis diagnosed by PET-CT scan].

Giant cell arteritis (GCA) is easily diagnosed in case of typical symptoms such as headache and jaw claudication. We present an 82-year-old man who was admitted due to symptoms of pneumonia, weight loss and fever. He did not respond to antibiotic treatment. An 18F-fluordeoxyglucose PET-CT scan showed increased uptake of the thoracic branches of aorta, raising the suspicion of GCA. The result from a subsequent temporal artery biopsy supported the diagnosis. Based on the clinical symptoms, the results from the PET-CT scan and the biopsy, and the response to high dose of prednisolone, the patient was diagnosed with GCA.

18F-FDG-PET/CT in fever of unknown origin: clinical value.

OBJECTIVE: Fever of unknown origin continues to be a diagnostic challenge for clinicians. The aim of this study was to confirm whether (18)F-fluorodeoxyglucose ((18)F-FDG)-PET/computed tomography (CT) is a helpful tool in patients suffering from this condition. PATIENTS AND METHODS: Fifty-seven patients with fever of unknown origin were examined with (18)F-FDG-PET/CT as part of their diagnostic workup at the clinicians' discretion. The medical records were read retrospectively to establish the final diagnosis and evaluate the degree to which PET/CT contributed to the diagnosis. RESULTS: The examination was considered helpful if it corresponded to the final diagnosis by showing uptake in an organ considered responsible for the condition, or if it was without focal findings, thereby excluding the patient from having focal infection or malignancy. It was perceived false positive if it pointed towards an organ not regarded by the clinicians as being related to the final diagnosis. It was perceived not helpful if the cause of fever was not visible on (18)F-FDG-PET/CT. We found (18)F-FDG-PET/CT helpful in 75% of patients, not helpful in 4%, and false positive in 21% of patients. CONCLUSION: (18)F-FDG-PET/CT is a useful tool in the investigation of fever of unknown origin; it can reduce patient inconvenience and possibly costs to society if used earlier in the diagnostic process.

No increase of calcitonin gene-related peptide in jugular blood during migraine.

Increased calcitonin gene-related peptide (CGRP) in external jugular venous blood during migraine attack is one of the most cited findings in the headache literature. The finding has not been convincingly reproduced and is based on comparison with historic control subjects. The validity of this finding is important for the understanding of migraine. We therefore investigated the issue using an intrapatient comparison design and two different CGRP assays. We sampled blood from the external jugular and cubital vein during, as well as outside of, an attack of migraine without aura. We succeeded in 17 patients, whereas only cubital fossa blood could be sampled in an additional 4 patients. CGRP was measured with the same assay as most previous studies (assay I) and furthermore with a more sensitive and validated assay (assay II). For assay I, mean CGRP concentration in external jugular venous blood during attack was 17.18 pmol/L compared with 15.88 pmol/L outside of attack. Mean difference was 1.81 pmol/L (95% confidence interval [CI]: -2.88, 6.41; p = 0.44). In peripheral blood during attack, CGRP was 16.86 pmol/L compared with 17.57 pmol/L outside of attack. Mean difference was -0.79 pmol/L (95% CI: -4.64, 3.06; p = 0.69). For assay II, external jugular venous blood concentration of CGRP during attack was 32.59 pmol/L compared with 30.59 pmol/L outside of attack; mean difference was 2.00 pmol/L (standard error, 2.39; 95% CI: -3.07, 7.07; p = 0.416). In peripheral blood during attack, CGRP was 33.37 pmol/L compared with 31.84 pmol/L outside of attack; mean difference was 1.53 pmol/L (standard error, 1.90; 95% CI: -2.46, 5.51; p = 0.431). Thus, no difference between CGRP level in external jugular or cubital fossa blood during and outside of attack was found. No difference was found between external jugular and peripheral venous blood. Thus, previous findings of increased CGRP level in external jugular or cubital fossa venous blood could not be confirmed. Our finding strongly suggests that CGRP is not increased in jugular venous blood during migraine without aura. CGRP cannot be used as a biomarker to validate human or animal models of migraine.

Investigation of CGRP receptors and peptide pharmacology in human coronary arteries. Characterization with a nonpeptide antagonist.

Calcitonin gene-related peptide (CGRP), adrenomedullin (AM), and amylin are structurally related peptides mediating vasorelaxation in the coronary circulation possibly via CGRP receptors (subtypes 1 or 2). Functional CGRP1 receptors appear to consist of at least three different kinds of proteins: the calcitonin receptor-like receptor (CRLR), receptor-activity-modifying proteins (RAMPs) and the receptor component protein (RCP). No CGRP2 receptor has yet been cloned. Using reverse transcriptase - polymerase chain reaction, the presence of mRNA sequences encoding CRLR, RCP and RAMPs was demonstrated in human coronary arteries. Relaxant responses were studied on isolated segments of coronary arteries after precontraction with U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F(2alpha)). The human peptides alphaCGRP, AM, and amylin induced relaxation with mean pEC50 values of 8.6, 6.8, and 6.3 M, respectively. Preincubation with alphaCGRP(8-37) (10(-7) -10(-5) M) and a novel nonpeptide CGRP antagonist "Compound 1" (WO98/11128) (10(-7)-10(-5) M) caused a dose-dependent rightward shift of the concentration-response curves for alphaCGRP with pA(2) values of 7.0 and 7.1, respectively. Preincubation with alphaCGRP(8-37) (10(-6) M) and Compound 1 (10(-6) M) caused significant rightward shift of the concentration-response curves for AM and amylin as well with pK B values between 6.6 and 7.5. Preincubation with AM(22-52) had no antagonistic effect on the AM and amylin response, neither did diacetoamidomethyl cysteine CGRP cause any concentration dependent (10(-11)-10(-6) M) dilatation. In conclusion, mRNA for the components forming CGRP1 and AM receptors was detected in the human left anterior descending coronary arteries. alphaCGRP, AM, and amylin mediated vasorelaxation via the CGRP1 receptor. Compound 1 acted as a nonpeptide antagonist at the CGRP1 receptor and could thus become a tool for the study of CGRP-mediated functional responses in human tissue.