Teresa Hentosz

Recombinant Glucagon-Like Peptide-1 Increases Myocardial Glucose Uptake and Improves Left Ventricular Performance in Conscious Dogs With Pacing-Induced Dilated Cardiomyopathy

Background—The failing heart demonstrates a preference for glucose as its metabolic substrate. Whether enhancing myocardial glucose uptake favorably influences left ventricular (LV) contractile performance in heart failure remains uncertain. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with potent insulinotropic effects the action of which is attenuated when glucose levels fall below 4 mmol. We examined the impact of recombinant GLP-1 (rGLP-1) on LV and systemic hemodynamics and myocardial substrate uptake in conscious dogs with advanced dilated cardiomyopathy (DCM) as a mechanism for overcoming myocardial insulin resistance and enhancing myocardial glucose uptake. Methods and Results—Thirty-five dogs were instrumented and studied in the fully conscious state. Advanced DCM was induced by 28 days of rapid pacing. Sixteen dogs with advanced DCM received a 48-hour infusion of rGLP-1 (1.5 pmol · kg−1 · min−1). Eight dogs with DCM served as controls and received 48 hours of a saline infusion (3 mL/d). Infusion of rGLP-1 was associated with significant (P<0.02) increases in LV dP/dt (98%), stroke volume (102%), and cardiac output (57%) and significant decreases in LV end-diastolic pressure, heart rate, and systemic vascular resistance. rGLP-1 increased myocardial insulin sensitivity and myocardial glucose uptake. There were no significant changes in the saline control group. Conclusions—rGLP-1 dramatically improved LV and systemic hemodynamics in conscious dogs with advanced DCM induced by rapid pacing. rGLP-1 has insulinomimetic and glucagonostatic properties, with resultant increases in myocardial glucose uptake. rGLP-1 may be a useful metabolic adjuvant in decompensated heart failure.

Photothrombotic brain infarction results in seizure activity in aging Fischer 344 and Sprague Dawley rats

This study was designed to determine whether photothrombotic brain infarction could result in epileptic seizures in adult animals. Male Fischer 344 (F344) rats at 2, 6, 12, 24, and 30 months of age and male Sprague Dawley (SD) rats at 2 and 6 months of age underwent photothrombotic brain infarction with the photosensitive dye rose bengal by focusing a wide (6 mm) or narrow (3 mm) diameter white light beam on the skull overlying left hemisphere anterior frontal, midfrontal, frontoparietal, or parietal areas. Animals were monitored with video and EEG recordings. Morphological analysis of infarct size was performed with a computer-assisted image analysis system. The primary finding of this study was that epileptic seizures were recorded in post-mature rats 2 months after lesioning the frontoparietal cortex with large photothrombotic infarcts that extended to the cortical-subcortical interface. These seizures were characterized behaviorally by motor arrest, appeared to originate in the periinfarct area, and could be distinguished from inherited spontaneous bilateral cortical discharges by the morphology, frequency, duration, and laterality of the ictal discharges. Small cortical lesions were ineffective in producing seizures except for one animal that demonstrated recurrent prolonged focal discharges unaccompanied by behavioral change. Stage 3 seizures were observed in a small number of mid-aged and aged animals lesioned with large infarcts in anterior frontal and frontoparietal areas. These results suggest that the technique of photothrombosis can be used to produce neocortical infarction as a means to study mechanisms of secondary epileptogenesis.

Angiotensin-Converting Enzyme Inhibitors Improve Coronary Flow Reserve in Dilated Cardiomyopathy by a Bradykinin-Mediated, Nitric Oxide-Dependent Mechanism

Background—ACE inhibitors have been used extensively in heart failure, where they induce systemic vasodilatation. ACE inhibitors have also been shown to reduce ischemic events after myocardial infarction, although their mechanisms of action on the coronary circulation are less well understood. The purpose of the present study was to determine the effects and the mechanism of action of the ACE inhibitor enalaprilat and the AT1 antagonist losartan on regional myocardial perfusion and coronary flow and vasodilator reserve in conscious dogs with pacing-induced dilated cardiomyopathy (DCM). Methods and Results—Twenty-seven conscious, chronically instrumented dogs were studied during advanced stages of dilated cardiomyopathy, which was induced by rapid pacing. Enalaprilat (1.25 mg IV) improved transmural distribution (endocardial/epicardial ratio) at rest (baseline, 0.91±0.11; enalaprilat, 1.02±0.07 mL/min per g;P <0.05) and during atrial pacing (baseline, 0.82±0.11; enalaprilat, 0.98±0.07;P <0.05). Enalaprilat also restored subendocardial coronary flow reserve (CFR) (baseline CFR, 1.89±0.11; enalaprilat CFR, 2.74±0.33;P <0.05) in DCM. These effects were abolished by pretreatment with the NO synthase inhibitor nitro-l-arginine. The effects were recapitulated by the bradykinin2 receptor agonist cereport but not by the AT1 antagonist losartan. Conclusions—The ACE inhibitor enalaprilat improves transmural myocardial perfusion at rest and after chronotropic stress and restores impaired subendocardial coronary flow and vasodilator reserve in DCM. The effects of enalaprilat were bradykinin mediated and NO dependent and were not recapitulated by losartan. These data suggest beneficial effects of ACE inhibitors on the coronary circulation in DCM that are not shared by AT1 receptor antagonists.

Catecholamine stimulation is associated with impaired myocardial O2 utilization in heart failure

OBJECTIVES To investigate the effect of alpha,beta(1) and beta(2) adrenergic receptor (AR) stimulation on coronary hemodynamics, myocardial oxygen consumption (M(v)O(2)) and metabolic substrate preference in advanced dilated cardiomyopathy (DCM). METHODS We studied 19 conscious, instrumented dogs with pacing-induced DCM. We evaluated systemic, coronary hemodynamics and M(v)O(2) in response to norepinephrine (NOR, 0.05-0.4 microg/kg per min), dobutamine (DOB, 1-10 microg/kg per min), phenylephrine (PHE, 1-5 microg/kg per min) and isoproterenol (ISO, 0.05-0.4 microg/kg per min) alone or in the presence of metoprolol (ISO+MET). Experiments were conducted in control state and in advanced DCM, 4-5 weeks after the initiation of pacing. RESULTS Contractile responses (LV dP/dt) to catecholamines were desensitized and accompanied by a parallel decrease in heart rate-adjusted myocardial O(2) consumption (M(v)O(2/beat)), when alpha(PHE) or beta(1) (DOB) or both alpha/beta(1) (NOR) AR were stimulated in DCM. This was due to impaired transmyocardial (Ao-Cs) O(2) extraction rather than limitations in CBF responses. There was an associated shift in myocardial metabolism, evidenced by an increased preference for glycolytic substrates (Respiratory Quotient) following administration of any of these three adrenergic agonists in DCM. Combined beta(1)/beta(2) stimulation with ISO or beta(2)-AR stimulation (ISO+MET) in DCM resulted in greater M(v)O(2/beat), [(Ao-Cs) O(2)] extraction, and decreases in myocardial RQ consistent with a shift toward oxidation of FFA. CONCLUSIONS The impairment in contractile responses to dobutamine and norepinephrine in DCM is associated with impaired myocardial O(2) extraction, and a shift toward a preference for glycolysis. A different myocardial metabolic pattern suggestive of increased oxidation of FFA with increased myocardial O(2) extraction was observed in the presence of combined beta(1)/beta(2) stimulation with isoproterenol or beta(2) stimulation (ISO+MET). These data suggest that beta(2)-AR stimulation in DCM shifts substrate preference toward FFA oxidation associated with greater M(v)O(2) requirements. These findings identify a putative metabolic effect of beta(2) -AR in DCM that may be deleterious.

Alterations in hippocampal voltage-gated calcium channel α1 subunit expression patterns after kainate-induced status epilepticus in aging rats

Young adult and aged male Fisher 344 rats underwent kainate-induced convulsive status epilepticus (SE) for 4 h prior to sacrifice to determine potential aging-related differences in the effect of prolonged SE on the expression of hippocampal voltage-gated calcium channels (VGCCs). Immunohistochemistry was performed on hippocampal sections using antibodies directed against the alpha1 subunit of class A-D VGCCs. Compared to age-matched controls, SE animals showed a marked loss of alpha1A immunoreactivity (IR) in CA3 and the hilus, which was more prominent in aged animals. Alpha1B-IR was decreased selectively in the stratum lucidum of CA3. Alpha1C-IR was increased on neuronal somata in the pyramidal and granule cell layers of both age groups. In contrast, there was a marked decrease of alpha1C-IR in the neuropil of CA3 stratum pyramidale and portions of CA1, which was more pronounced in aged animals. Alpha1D-IR was decreased in CA3 and the hilus, which was more prominent in aged animals. Nissl staining demonstrated mild somal dysmorphia in the pyramidal cell layer of CA3, which was more apparent in aged animals. Fluoro-Jade B staining was prominent in the stratum pyramidale of CA3 and in the hilus of aged SE animals. These results demonstrated that expression patterns of hippocampal high-threshold VGCC alpha1 subunits were altered variably during prolonged convulsive SE and were associated with prominent early degenerative changes in aged neurons in CA3 and the hilus.