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Objectives The purpose of this study was to determine if cholesterol crystals can injure the endothelial surface by their jagged edges altering vasoreactivity and contributing to no-reflow after intervention. Background After plaque rupture, cholesterol crystals are released into the circulation and flow downstream contacting the arterial wall. Methods Both carotid arteries from 22 rabbits were placed in a dual perfusion chamber and challenged with norepinephrine followed by acetylcholine and nitroprusside. Arterial diameters were measured before and after exposure to cholesterol crystals or microspheres and compared with diameters of normal control arteries. Arteries were examined by light, confocal, atomic force and scanning electron microscopy. Results Pre-exposure mean arterial diameter was 2.33 ± 0.27 mm. With baseline norepinephrine there was vasoconstriction of 0.82 ± 0.19 mm, 0.79 ± 0.18 mm, and 0.83 ± 0.16 mm in lumen diameter in the crystal, microsphere, and control groups, respectively. After cholesterol crystals or microspheres, vasoconstriction was significantly less for cholesterol crystals but not for microspheres (0.71 ± 0.28 mm and 0.81 ± 0.15 mm; p Conclusions Cholesterol crystals damaged the endothelium and reduced vasodilator response, potentially aggravating myocardial ischemia after interventions.

We recently obtained evidence that cocaine- and amphetamine-regulated transcript (CART), a potent anorectic neuropeptide, is expressed in the bovine ovary. The objectives of this study were to characterize bovine ovarian CART and determine its localization, regulation, and regulatory role during follicular development. CART mRNA was detected in stroma of adult ovaries and in large follicles, but was undetectable in several peripheral tissues, fetal ovaries, and corpora lutea. Within the ovary, CART mRNA and peptide were localized to the granulosal layer of some, but not all, antral follicles, with low, but detectable, expression in oocytes and cumulus cells. CART mRNA was undetectable in granulosal cells of dominant ovulatory follicles collected before and after the preovulatory gonadotropin surge, but was detected in the granulosal layer of adjacent subordinate follicles. In addition, amounts of CART mRNA and follicular fluid concentrations of CART peptide were greater in subordinate follicles vs. dominant follicles of the first follicular wave. Furthermore, CART treatment inhibited basal estradiol production, but not progesterone production, by granulosal cells in a dose-dependent fashion, and the effect was dependent on stage of cell differentiation. We conclude that granulosal cell CART expression is temporally regulated and potentially associated with follicle health status, and CART can inhibit granulosal cell estradiol production. Thus, CART may be a novel local regulator of follicular atresia in the bovine ovary.

Pleiotropic effects of statins have not been fully elucidated. Recently we demonstrated that cholesterol expands when crystallizing and may trigger plaque rupture. The present study evaluated the potential direct effects of statins in altering cholesterol crystallization as a possible mechanism for plaque stabilization independent of cholesterol lowering. Cholesterol powder was dissolved in oil with and without pravastatin, simvastatin, or atorvastatin (10 to 90 mg) and then allowed to crystallize to measure peak volume expansion (ΔVE) in graduated cylinders. Effect of ΔVE on fibrous membrane damage was also evaluated. Human coronary, carotid, and peripheral arterial plaques (65 plaques from 55 patients) were incubated with statin or saline solution using matched plaque segments to evaluate direct effects of statins on preformed crystals. Also, the effect of in vivo use of oral statins on crystal structure was examined by scanning electron microscopy and crystal content in plaques scored from 0 to +3. For all statins, ΔVE decreased significantly in a dose-dependent fashion (0.76 ± 0.1 vs 0 ml at 60 mg, p

Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive C-fiber and Adelta-fiber sensory nerves, has been suggested to play a beneficial role in myocardial ischemia-reperfusion (I/R) injury. Because most previous studies showing a cardioprotective role of CGRP employed pharmacological experiments, the purpose of this study was to utilize a genetic approach by using mice with a targeted deletion of the alpha-CGRP gene to determine whether this neuropeptide had a modulatory function on the severity of I/R injury. To accomplish this goal, isolated, perfused hearts from alpha-CGRP knockout (KO) and wild-type (WT) mice were subjected to 30 min of ischemia followed by 5, 15, and 30 min of reperfusion. Cardiac functional parameters, including coronary flow rates, left ventricular developed pressure, maximum rates of pressure development, and left ventricular end-diastolic pressure, were measured before and after I/R injury, as were levels of creatine kinase, to assess myocardial damage, and malonaldehyde, to assess oxidative stress. Following I/R injury, cardiac performance was significantly reduced in the hearts from the alpha-CGRP KO mice compared with their WT counterparts. The marked reduction in myocardial function in the alpha-CGRP KO hearts compared with WT hearts after I/R injury was associated with a significant elevation in creatine kinase release into the perfusates and malonaldehyde production in the cardiac tissue. Therefore, these data indicate that, in this in vitro setting, deletion of alpha-CGRP makes the heart more vulnerable to I/R injury, possibly due, at least in part, to increased oxidative stress.

Background: It is unclear if total cholesterol content contributes to the severity of cardiovascular events by affecting the amount of thrombosis. This study evaluated relationships between cholesterol levels and the amount of thrombosis in an atherosclerotic rabbit model of plaque disruption and thrombosis. Methods: Three groups of NZW rabbits were used: normal rabbits (Group I, n = 4); atherosclerotic rabbits (Group II, n = 4); and atherosclerotic rabbits with pharmacologically triggered thrombosis (Group III, n = 16). Atherosclerosis was induced by feeding a cholesterol enriched diet and balloon deendothelialization. At post-mortem, platelet-rich thrombus and arterial wall cholesterol were quantified and histology performed by light and electron microscopy. Results: Arterial wall cholesterol was strongly correlated to serum cholesterol in all groups (r = 0.94, p < 0.0001). There was a significant correlation between the thrombus surface area with arterial wall cholesterol in Group III (r = 0.71, p < 0.002). Serum cholesterol, arterial wall cholesterol, and thrombus surface area were all significantly correlated but only arterial wall cholesterol was an independent predictor of thrombosis. A threshold specific for this model was noted for serum and arterial cholesterol levels above which thrombosis consistently occurred. Conclusions: Arterial wall cholesterol was strongly correlated to serum cholesterol and thrombosis severity. Serum cholesterol, arterial wall cholesterol and thrombus surface area were all integrally related. A model of plaque disruption and thrombosis was used to demonstrate a correlation between serum and arterial wall cholesterol (r = 0.94; p < 0.0001); arterial wall cholesterol and the amount of thrombosis (surface area; r = 0.71, p < 0.002). A threshold of serum and arterial cholesterol was determined at which thrombosis occurred in this model.

Objective: Thrombin activates platelets and contributes to the occlusion of arteries following thrombolytic therapy or angioplasty. Thrombostatin (RPPGF), the angiotensin converting enzyme degradation product of bradykinin, inhibits α-thrombin induced platelet activation. We hypothesized that thrombostatin prevents platelet aggregation and adhesion after balloon angioplasty (BA). Methods: Platelet-rich plasma (PRP) was obtained from 22 Beagle dogs before sacrifice and 10% of the PRP was labeled with 111In. Carotid arteries were then removed from each dog and mounted in a dual perfusion chamber and intimal injury was performed with BA. 111In-PRP with or without thrombostatin or aspirin alone was perfused through the arteries for 60 min. During perfusion, platelet volume was measured using a Coulter counter and a laser-light scattering technique. Platelet adhesion to arteries was measured by radioactivity count. Results: Arterial injury alone compared to non-injury increased platelet volume in the circuit by 1.4 times (×) ( P

Background Calcitonin gene-related peptide (CGRP) influences vasoregulatory activities. We determined the gender-specific effects of CGRP knockout (KO) on creatine kinase (CK) activity following ischemia. Methods Ninety-six mice were studied in a Langendorff preparation using 50 mm Hg perfusion pressure. Myocardial ischemia was induced by stopping flow to the coronary arteries for 20 minutes. The perfusion buffer was collected from a small chamber that housed the heart. Perfusion buffer was collected over 2 hours and CK activity was measured. Results CK activity was significantly greater in CGRP-KO mouse hearts compared to wild-type (see graphs). Male CGRP-KO hearts released 1.5 times more CK than female CGRP-KO hearts 15 minutes after ischemia (130.4 vs 90.2 unit/mL, p