Experimental Physiology

The present study evaluated whether catechol-O-methyltransferase inhibition in pregnant rats results in increased blood pressure and vascular endothelial dysfunction as a consequence of decreased nitric oxide bioavailability. Pregnant Sprague–Dawley rats were given entacapone (a catechol-O-methyltransferase inhibitor) by gavage from the 10th to the 20th day of pregnancy. Blood pressure was measured by plethysmography in the tail artery. Vascular endothelial function and NO release were assessed both in the absence and in the presence of tempol. Systolic blood pressure increased significantly in pregnant rats treated with entacapone compared with untreated pregnant rats on days 14 (143 ± 4 versus 122 ± 3 mmHg) and 19 of gestation (129 ± 4 versus 115 ± 5 mmHg). Both conductance (aortic rings) and resistance vessels (mesenteric small arterial vessels) from entacapone-treated pregnant rats showed diminished relaxation in response to acetylcholine compared with vessels from vehicle-treated pregnant and virgin rats. In mesenteric arterioles, this endothelial dysfunction was abolished in the presence of l-NAME, indicating that it was caused by reduced NO availability, and it also improved in the presence of tempol, suggesting increased oxidative stress in hypertensive pregnant rats. Endothelial release of nitric oxide induced by calcium ionophore (A23187) was significantly greater in aortas from vehicle-treated pregnant rats than in aortas from pregnant rats given entacapone. This endothelial dysfunction seen in hypertensive rats was prevented by addition of tempol. The present study provides evidence that catechol-O-methyltransferase inhibition in pregnant rats produces arterial hypertension and endothelial dysfunction due to reduced nitric oxide bioavailability.

The energetic requirements of the heart are, weight for weight, higher than for any other organ. The heart provides non-stop function for a lifetime, while maintaining energy in reserve in order to respond to increased demand. This demand is met by continuously recycling a relatively small pool of ATP, with the creatine kinase (CK) system acting as a spatial and temporal buffer. In the failing heart, key components of this system are downregulated, but whether these energetic changes are biomarkers or drivers of dysfunction and whether they represent therapeutic targets are the subjects of ongoing research. Key methodologies are now becoming available in vivo to help address these questions in mouse models, such as 31P magnetic resonance spectroscopy to detect high-energy phosphates and 1H magnetic resonance spectroscopy to detect total creatine. This report briefly discusses the challenges involved in using these technologies, the application and pitfalls of murine surgical models of heart failure, and how this has contributed to our understanding of pathophysiology in recent years.

Improved understanding of the processes involved in infarct healing is required for identification of novel therapeutic targets to limit infarct expansion and consequent long-term ventricular remodelling after myocardial infarction. Infarct healing can be modelled effectively in murine models of coronary artery ligation. While imaging the murine heart is challenging due to its size and high rate of contraction, advances in preclinical imaging now permit accurate assessment of myocardial structure and function in vivo after myocardial infarction. Furthermore, rapid development of a range of molecular probes for use in a number of imaging modalities allows more detailed in vivo analysis of processes, including inflammation, fibrosis and angiogenesis. Here we consider the practical application of in vivo imaging by magnetic resonance imaging, ultrasound and fluorescence molecular tomography for assessment of infarct healing in the mouse.

Microconductance catheters have been successfully applied to measure left ventricular (LV) function in the mouse to assess cardiac or pharmacological interventions for a number of years. New complex admittance methods produce an estimate of the parallel admittance of cardiac muscle that can be used to correct the measurement in real time. This contrasts with existing conductance technologies that require in vivo calibration using a bolus of hypertonic saline. Here, we report the application of this emerging technology in the context of myocardial infarction and LV remodelling. Using a combination of high-resolution ultrasound and LV conductance catheters, we compared measures of LV function using an admittance system and a traditional conductance-derived pressure–volume (PV) system. We subjected C57BL/6 mice to focal myocardial ischaemia–reperfusion by transient ligation of the left anterior descending coronary artery and assessed cardiac function with different systems to determine the reliability and accuracy of these methods to distinguish between normal and dysfunctional ventricle. We demonstrate that the admittance PV system, in our hands, provides a straightforward solution for assessing LV function in mice. Using this technique in combination with other established methods, we measured LV dysfunction following coronary artery occlusion and reperfusion, which can be ameliorated using a known preconditioning agent (CORM-3), and found that functional read-outs are representative of other methods. We have found that, especially in diseased tissue, LV pressure–volume loops derived from complex admittance provide a reproducible and reliable method of determining LV function without the need for technically challenging calibration. Our data suggest that admittance records accurate/physiological LV cavity volumes when compared with other invasive methods in the same animal. This emerging technology is both effective and reproducible for measuring LV function and dysfunction in the mouse, without the need for complicated interventions to calibrate the measurements or training in a new technology. This may mark the way towards a fast and accurate assessment of murine cardiac function in normal animals and disease models.

Heart failure (HF) is a complex disease syndrome, which affects physiology at all levels, from the molecule to the whole organism. Following a causative insult, a maladaptive response occurs, which sustains cardiac remodelling and leads to a final common pathway of debilitating HF symptoms. In terms of mechanisms, distinct defects of excitation–contraction coupling compartments and organelles have been identified in cardiac samples of patients and animal models, which include changes in Ca2+ transport proteins and T-tubules. From a physiological standpoint, the source of regulatory intracellular Ca2+ is defined by ~20,000 Ca2+ release units per cardiac myocyte, which jointly modulate contractile force production. We and others have characterized key changes in protein and membrane components of Ca2+ release units during HF in patient samples and transgenic models to gain insight into complex disease mechanisms. While earlier HF studies identified intracellular Ca2+ release as a major cause of contractile dysfunction, electrical dysfunction has gained attention as an important mechanism of HF mortality. In parallel, high-resolution imaging techniques have become instrumental to understand HF mechanisms in the intact cell and tissue environment, supporting translation of novel diagnostic strategies. Indeed, the increased spatial and temporal resolution of different experimental imaging techniques addresses the vastly different scales of HF pathophysiology, to correlate experimental with clinical surrogate markers, and to extend mechanisms to early, often subtle changes in HF. This last goal, in particular, will be essential to translate novel pathophysiological insight back to the growing number of asymptomatic individuals at increased risk for HF development, who may benefit most from early therapeutic interventions.

The high temporal and spatial resolution of echocardiography makes it a powerful and reliable tool for the non-invasive study of cardiac phenotype and disease in both adult and embryonic preclinical models. This overview of the use of high-resolution ultrasound for echocardiography highlights the present and potential applications of the technique.

Different animal models have been used to reproduce coronary heart disease, but in recent years mice have become the animals of choice, because of their short life cycle and the possibility of genetic manipulation. Various techniques are currently used for cardiovascular imaging in mice, including high-resolution ultrasound, X-ray computed tomography (CT), magnetic resonance imaging and nuclear medicine procedures. In particular, molecular imaging with cardiac positron emission tomography (PET) allows non-invasive evaluation of changes in myocardial perfusion, metabolism, apoptosis, inflammation and gene expression or measurement of changes in left ventricular functional parameters. With technological advances, dedicated small laboratory PET/CT imaging has emerged in cardiovascular research, providing in vivo a non-invasive, serial and quantitative assessment of left ventricular function, myocardial perfusion and metabolism at a molecular level. This non-invasive methodology might be useful in longitudinal studies to monitor cardiac biochemical parameters and might facilitate studies to assess the effect of different interventions after acute myocardial ischaemia.

The gut and kidney command >50% of cardiac output postprandially, highlighting the importance of these vascular beds in cardiovascular homeostasis. The gastrointestinal peptide cholecystokinin (CCK) induces vagally mediated splanchnic sympathoinhibition that is attenuated in animals fed a medium high-fat diet (MHFD); therefore, our aim was to determine whether renal sympathetic nerve discharge (RSND) responses to CCK are also affected by this diet, and whether these changes are associated with obesity and hypertension. Another aim was to determine whether regional vasodilator responses to CCK are affected in obesity-related hypertension. In two separate studies, Sprague–Dawley rats were fed either a low-fat diet (LFD; control) or a MHFD for 13 weeks, after which MHFD animals were classified as obesity prone (OP) or obesity resistant (OR) based on their weight gain falling into the upper or lower tertile, respectively. Arterial pressure and heart rate were monitored in isoflurane-anaesthetized, artificially ventilated animals, and either RSND or regional vascular responses to CCK (0.1–8 μg kg–1) were evaluated. The OP rats had higher baseline arterial pressure compared with control/OR rats (P < 0.05). Administration of CCK inhibited RSND and increased renal vascular conductance in control/OR rats, and these responses were significantly blunted in OP rats (P < 0.05 for all). Baseline arterial pressure was positively correlated with weight gain and inversely correlated with CCK-induced vasodilatation (P < 0.05 for both). We hypothesize that in obesity-related hypertension, disruption of the sympathoinhibitory signals elicited by CCK reduces vasodilatation in the splanchnic/renal regions, leading to increased postprandial vascular resistance.