Objective: Increased vascular stiffness is central to the pathophysiology of aging, hypertension, diabetes mellitus, and atherosclerosis. However, relatively few studies have examined vascular stiffness in both the thoracic and the abdominal aorta with aging, despite major differences in anatomy, embryological origin, and relation to aortic aneurysm.
Approach And Results: The 2 other unique features of this study were (1) to study young (9±1 years) and old (26±1 years) male monkeys and (2) to study direct and continuous measurements of aortic pressure and thoracic and abdominal aortic diameters in conscious monkeys.
Background: We previously demonstrated that older beagles have impaired whole body and myocardial insulin responsiveness (MIR), and that glucagon-like peptide-1 (GLP-1 [7-36] amide) improves MIR in young beagles with dilated cardiomyopathy (DCM). Here, we sought to determine if aging alone predisposes to an accelerated course of DCM, and if GLP-1 [7-36] amide would restore MIR and impact the course of DCM in older beagles.
Methods: Eight young beagles (Young-Control) and sixteen old beagles underwent chronic left ventricle (LV) instrumentation.
Objective: Pulmonary hypertension remains a major clinical problem despite current therapies. In this study, we examine for the first time a novel pharmacological target, smooth muscle myosin, and determine if the smooth muscle myosin inhibitor, CK-2019165 (CK-165) ameliorates pulmonary hypertension.
Materials And Methods: Six domestic female pigs were surgically instrumented to measure pulmonary blood flow and systemic and pulmonary vascular dynamics.
Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin.
View Article and Find Full Text PDFThe second window of ischemic preconditioning (SWOP) provides maximal protection against ischemia through regulation of the inducible nitric oxide synthase (iNOS), yet its application is limited by the inconvenience of the preliminary ischemic stimulus required for prophylaxis. Overexpression of H11 kinase/Hsp22 (Hsp22) in a transgenic mouse model provides cardioprotection against ischemia that is equivalent to that conferred by SWOP. We hypothesized that short-term, prophylactic overexpression of Hsp22 would offer an alternative to SWOP in reducing ischemic damage through a nitric oxide (NO)-dependent mechanism.
View Article and Find Full Text PDFCurr Opin Investig Drugs
September 2010
One of the primary impediments to successful drug R&D is the frequent failure of successfully translating positive results obtained in animal models to human disease. To a large degree, this discrepancy is secondary to the substantial biological differences between species. Non-human primate models have the advantage of significant physiological, metabolic, biochemical and genetic similarity to humans.
View Article and Find Full Text PDFAm J Physiol Heart Circ Physiol
September 2010
A major difference between experimental ischemic preconditioning (IPC), induced by brief ischemic episodes, and the clinical situation is that patients generally have repetitive episodes of ischemia. We used a swine model to examine differences in genes regulated by classical second-window IPC (SWOP) [two 10-min episodes of coronary artery occlusion (CAO) followed by 24 h reperfusion] compared with repetitive CAO/reperfusion (RCO), i.e.
View Article and Find Full Text PDFBackground: Therapy for chronic systolic heart failure (sHF) has improved over the past 2 decades, but the armamentarium of drugs is limited and consequently sHF remains a leading cause of death and disability. In this investigation, we examined the effects of a novel cardiac myosin activator, omecamtiv mecarbil (formerly CK-1827452) in 2 different models of heart failure.
Methods And Results: Two different models of sHF were used: (1) pacing-induced sHF after myocardial infarction (MI-sHF) and (2) pacing-induced sHF after 1 year of chronic pressure overload left ventricular hypertrophy (LVH-sHF).
Background: We have shown that glucagon-like peptide-1 (GLP-1[7-36] amide) stimulates myocardial glucose uptake in dilated cardiomyopathy (DCM) independent of an insulinotropic effect. The cellular mechanisms of GLP-1-induced myocardial glucose uptake are unknown.
Methods And Results: Myocardial substrates and glucoregulatory hormones were measured in conscious, chronically instrumented dogs at control (n=6), DCM (n=9) and DCM after treatment with a 48-hour infusion of GLP-1 (7-36) amide (n=9) or vehicle (n=6).
The triptans, serotonin 5-HT(1B/1D) receptor agonists exemplified by sumatriptan, are a mainstay migraine therapy but have class labeling contraindicating their use in patients with coronary artery disease. Triptans constrict human coronary artery in vitro, and there are case reports of myocardial infarction in patients using sumatriptan. However, preclinical studies with sumatriptan in normal dogs have failed to demonstrate effects on resting coronary flow.
View Article and Find Full Text PDFAm J Physiol Cell Physiol
October 2009
Cytochrome c oxidase (COX) is composed of 13 subunits, of which COX I, II, and III are encoded by a mitochondrial gene. COX I and II function as the main catalytic components, but the function of COX III is unclear. Because myocardial ischemia affects mitochondrial oxidative metabolism, we hypothesized that COX activity and expression would be affected during postischemic cardiomyopathy.
View Article and Find Full Text PDFThe goal of this investigation was to determine the distribution of myocardial apoptosis in myocytes and nonmyocytes in primates and patients with heart failure (HF). Almost all clinical cardiologists and cardiovascular investigators believe that myocyte apoptosis is considered to be a cardinal sign of HF and a major factor in its pathogenesis. However, with the knowledge that 75% of the number of cells in the heart are nonmyocytes, it is important to determine whether the apoptosis in HF is occurring in myocytes or in nonmyocytes.
View Article and Find Full Text PDFBackground: The hypothesis of the present study was that molecular mechanisms differ markedly when mediating ischemic preconditioning induced by repetitive episodes of ischemia versus classic first- or second-window preconditioning.
Methods And Results: To test this, chronically instrumented conscious pigs were subjected to either repetitive coronary stenosis (RCS) or a traditional protocol of second-window ischemic preconditioning (SWIPC). Lethal ischemia, induced by 60 minutes of coronary artery occlusion followed by reperfusion, resulted in an infarct size/area at risk of 6+/-3% after RCS and 16+/-3% after SWIPC (both groups P<0.
Am J Physiol Heart Circ Physiol
August 2008
The objective of this study was to test the hypothesis that the mechanism mediating left ventricular (LV) dysfunction in the aging rat heart involves, in part, changes in cardiac cytoskeletal components. Our results show that there were no significant differences in heart rate, LV pressure, or LV diameter between conscious, instrumented young [5.9 +/- 0.
View Article and Find Full Text PDFAm J Physiol Heart Circ Physiol
November 2007
Aging is associated with insulin resistance, often attributable to obesity and inactivity. Recent evidence suggests that skeletal muscle insulin resistance in aging is associated with mitochondrial alterations. Whether this is true of the senescent myocardium is unknown.
View Article and Find Full Text PDFWe studied gender-specific changes in aging cardiomyopathy in a primate model, Macaca fascicularis, free of the major human diseases, complicating the interpretation of data specific to aging in humans. Left ventricular (LV) weight/body weight decreased, p<0.05, in old males but did not change in old females.
View Article and Find Full Text PDFBackground: Our hypothesis was that the changes in vascular properties responsible for aortic stiffness with aging would be greater in old male monkeys than old female monkeys.
Methods And Results: We analyzed the effects of gender differences in aging on in vivo measurements of aortic pressure and diameter and on extracellular matrix of the thoracic aorta in young adult (age, 6.6+/-0.
Although increased vascular stiffness is more prominent in aging males than females, and males are more prone to vascular disease with aging, no study has investigated the genes potentially responsible for sex differences in vascular aging. We tested the hypothesis that the transcriptional adaptation to aging differs in males and females using a monkey model, which is not only physiologically and phylogenetically closer to humans than the more commonly studied rodent models but also is not afflicted with the most common forms of vascular disease that accompany the aging process in humans, e.g.
View Article and Find Full Text PDFAm J Physiol Heart Circ Physiol
February 2007
Both enhanced sympathetic drive and altered autonomic control are involved in the pathogenesis of heart failure. The goal of the present study was to determine the extent to which chronically enhanced sympathetic drive, in the absence of heart failure, alters reflex autonomic control in conscious, transgenic (TG) rabbits with overexpressed cardiac Gsalpha. Nine TG rabbits and seven wild-type (WT) littermates were instrumented with a left ventricular (LV) pressure micromanometer and arterial catheters and studied in the conscious state.
View Article and Find Full Text PDFWe tested the hypothesis that cardiac nerves may mediate ischemic preconditioning. Pigs were chronically instrumented to measure aortic, left atrial and left ventricular pressures, and regional myocardial function (wall thickening). Hemodynamic variables, area at risk, and tissue blood flows (radioactive microspheres) were similar among groups.
View Article and Find Full Text PDFObjectives: Given that adverse effects of chronic sympathetic activation are mediated by all three adrenergic receptor subtypes (beta1, beta2, alpha1), we examined the effects of standard doses of carvedilol and metoprolol succinate (metoprolol controlled release/extended release [CR/XL]) on hemodynamics, myocardial metabolism, and regional organ perfusion.
Background: Both beta1 selective and combined adrenergic blockade reduce morbidity and mortality in heart failure. Whether there are advantages of one class over the other remains controversial, even in the wake of the Carvedilol Or Metoprolol European Trial (COMET).
We overexpressed cardiac Gsalpha in rabbits using the beta-myosin heavy chain promoter. Gsalpha protein levels in the heart were increased 3-fold by Western blotting in both juvenile (3-4 months), adult (8-10 months), and older (11-16 months) rabbits, compared with wild type (WT) littermates. In transgenic (TG) rabbits, baseline levels of heart rate were elevated, P<0.
View Article and Find Full Text PDFRecent evidence suggests that glucagon-like peptide-1 (GLP-1) enhances recovery of left ventricular (LV) function after transient coronary artery occlusion. However, it is uncertain whether GLP-1 has direct effects on normal or ischemic myocardium and whether the mechanism involves increased myocardial glucose uptake. LV function and myocardial glucose uptake and lactate production were measured under basal conditions and after 30 min of low-flow ischemia and 30 min of reperfusion in the presence and absence of GLP-1-(7-36) amide.
View Article and Find Full Text PDFDespite extensive study, the extent to which cocaine use predisposes to cardiac injury remains unknown. We hypothesized that chronic cocaine binging would increase susceptibility to a subsequent cardiac insult, even in the absence of demonstrable effects on baseline hemodynamics. We studied progression of dilated cardiomyopathy (DCM) induced by rapid ventricular pacing (240 beats per minute) in five conscious, chronically instrumented dogs, after exposure to repetitive cocaine binging (COC) in the form of four consecutive 1 mg/kg i.
View Article and Find Full Text PDFWe have shown previously that the glucagon-like peptide-1 (GLP-1)-(7-36) amide increases myocardial glucose uptake and improves left ventricular (LV) and systemic hemodynamics in both conscious dogs with pacing-induced dilated cardiomyopathy (DCM) and humans with LV systolic dysfunction after acute myocardial infarction. However, GLP-1-(7-36) is rapidly degraded in the plasma to GLP-1-(9-36) by dipeptidyl peptidase IV (DPP IV), raising the issue of which peptide is the active moiety. By way of methodology, we compared the efficacy of a 48-h continuous intravenous infusion of GLP-1-(7-36) (1.
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