Browsing by Subject "dogs"
Now showing 1 - 8 of 8
- Results Per Page
- Sort Options
Item Cardiac Parasympathetic Dysfunction in Morphine Addiction(1997-12-01) Napier, Leslie D.; Caffrey, James L.; Raven, Peter B.; Gwirtz, Patricia A.Napier, Leslie D., Cardiac Parasympathetic Dysfunction in Morphine Addiction. Doctor of Philosophy (Biomedical Sciences), December, 1997, 137 pp., 9 tables, 22 figures, references, 163 titles. The effects of chronic morphine treatment on parasympathetic control of the heart and associated cellular mechanisms were examined using a canine model. Vagal bradycardia was significantly blunted in dogs treated for one week with subcutaneous morphine pellets. In a separate group of dogs, heart rate and high frequency fluctuations in heart rate declined during the first three hours of subcutaneous morphine infusion consistent with the vagatonic action of acute morphine. Heart rate remained below baseline on Day 2 of the morphine infusion but had returned to normal by Day 10. Ambient sympathetic tone was increased on Days 2 and 10, and plasma catecholamines were elevated on Day 2. The intrinsic heart rates on Days 2 (160 bpm) and 10 (162 bpm) of morphine treatment were lower than the pre-treatment rate (182 bpm). Suggested mechanisms include a fundamental change in sinoatrial nodal cell function or attenuated tachycardia induced by vasoactive intestinal peptide co-released with acetylcholine from post-ganglionic parasympathetic neurons. The time to 50% maximal bradycardia during vagal nerve stimulation was increased with chronic and acute morphine suggesting an effect on the rate of acetylcholine synthesis, release or degradation. Muscarinic receptor density in left ventricular and right atrial sarcolemmal membranes from dogs treated chronically with morphine were 34% and 17% higher, respectively, than in control animals. Chronic morphine had no effect on basal or MnCl2-stimulated cyclase activity in either region. Similarly, maximal β-adrenergic and muscarinic receptor/G-protein coupling to adenylate cyclase were not altered by chronic morphine. Atrial norepinephrine content was higher than that in the ventricles and was unaltered by morphine. Ventricular norepinephrine was decreased with chronic but not acute morphine treatment. Epinephrine was evenly distributed throughout the myocardium and was reduced in both the atria and the ventricles by either acute or chronic morphine. This pattern suggests that morphine may reduce extraneuronal uptake of catecholamines. Collectively these studies show that chronic morphine treatment and the accompanying persistent vagal activity may reduce parasympathetic function. This attenuated function, however, is short-lived since sympathetic systems adapt with compensatory responses masking, or perhaps reversing, initial parasympathetic deficits.Item Coronary Perfusion Pressure-Induced Changes in Coronary Vascular Volume in the Canine Right Ventricle(1997-12-01) Yu, Ying; H. Fred Downey; Robert T. Mallet; Michael L. SmithYu, Ying, Coronary Perfusion Pressure-induced Changes in Coronary Vascular Volume in the Canine Right Ventricle. Master of Science (Biomedical Sciences), December 1997; 33 pp; 4 tables; 5 figures; bibliography, 24 titles. Changes in coronary perfusion pressure cause changes in myocardial contractile function and oxygen consumption (MVO2), particularly in the right ventricle (RV). This study determined the effects of right coronary (RC) perfusion pressure (RCP) on RC vascular volume (RCB) and its relationship to MVO2 of in situ, working canine hearts, and also investigated whether changes in MVO2 are due primarily to altered RCP or RC blood flow (RCF). In 15 open chest, anesthetized dogs, the RC artery was cannulated and perfused with arterial blood diverted from a femoral artery. To blunt RCP-induced changes in RCF, vasopressin was infused into the RC perfusion line in seven dogs. RCV was measured by an indicator dilution method as RCP was varied without vasopressin (RCP=60, 100, 140, and 180 mmHg) and with vasopressin (RCP=60 and 100 mmHg). Without vasopressin, changes in RCP induced changes in MVO2 which were associated with changes in RCV and RCF. With vasopressin, increasing RCP from 60 mmHg to 100 mmHg produced no changes in RCF, RCV, or MVO2. These results indicate that RCP-induced changes in RV MVO2 are mediated by RCV and/or RCF, but not by RCP per se.Item Dysfunctional Control of Coronary Blood Flow in Renovascular Hypertension(1999-06-01) Kline, Geoffrey Philip; Gwirtz, Patricia A.; Shi, Xiangrong; Raven, Peter B.Kline, Geoffrey Philip, Dysfunctional Control of Coronary Blood Flow in Renovascular Hypertension Doctor of Philosophy (Biomedical Sciences), June 1999, 98 pp, 2 tables, 10 figures, references, 142 titles. This study was designed to determine the effects of renovascular hypertension (RVH) on coronary vasoreactivity in conscious, chronically instrumented dogs. Six dogs were instrumented to measure left ventricular pressure, +dP/dtmax, heart rate, mean aortic pressure, circumflex blood flow (CBF), and cardiac output. In order to examine endothelial-dependent and independent coronary vasodilation, intracoronary injections of actylcholine (Ach), bradykinin (BDK), and sodium nitroprusside (SNP) were studied before and after induction of RVH in the presence and absence of nitric oxide (NO) blockade. After RVH, resting CBF was significantly reduced (P [less than] 0.05). In the normotensive state, NO-blockade significantly reduced the coronary vasodilation to Ach and BDK (P [less than] 0.05), but not SNP. After RVH, the coronary vasodilation to Ach, BDK, and SNP were reduced (P[less than] 0.05). After RVH, NO-blockade further reduced the coronary vasodilation to BDK (P [less than] 0.05), but not Ach. Thus, RVH resulted in an impairment of both endothelial-dependent and –independent coronary vasodilation. It also appears that during RVH the endothelium retains the ability to produce/release NO to some, but not all, stimuli. In order to examine the possibility that β-adrenergic mediated coronary vasodilation is impaired after RVH, intracoronary injections of norepinephrine (NE), isoproterenol (ISO), and terbutaline (TRB) were administered. These drugs all caused dose dependent increases in CBF before and after RVH. After RVH, the coronary vasodilatory responses to NE, ISO and TRB were significantly reduced (P [less than] 0.05). β1-blockade with intracoronary atenolol (1 mg) reduced the ISO-induced increases in CBF and had no effect on TRB responses (P [less than] 0.05). β2-blockade with intracoronary ICI-118,551 (1 mg) reduced the ISO-induced coronary vasodilation and abolished TRB responses (p[less than] 0.05). During β2-blockade, ISO-induced increases in CBF were not different after RVH. Therefore, these data indicate that β1-adrenergic mediated coronary vasodilation is preserved after RVH, whereas, β2-mediated is not. We conclude that 1) RVH results in an impairment of both endothelial-dependent and –independent coronary vasodilation; 2) RVH results in an impairment of β2-adrenergic mediated coronary vasodilation.Item Effects of Nitric Oxide on Right Ventricular Metabolism and Coronary Blood Flow(2000-01-09) Setty, Srinath; H. Fred Downey; Patricia A. Gwirtz; James L. CaffreySetty, Srinath Varadaraj. Effects of Nitric Oxide on Right Ventricular Metabolism and Coronary Blood Flow Doctor of Philosophy (Biomedical Sciences), January, 9, 2001, 123 pp, 3 tables, 16 figures, references, 211 titles. Nitric oxide (NO) formed from L-arginine and released from vascular endothelium causes relaxation of vascular smooth muscle via a cGMP mechanism. However, the of NO as a regulator of coronary blood flow control is unclear. NO has been shown also to reduce oxygen consumption in various in-vitro preparations, but its effect on myocardial oxygen consumption (MVO2) in the left ventricle of the working heart is controversial. The effect of NO on MVO2 in the right ventricle (RV) is unknown. This investigation delineated the effects of NO on RV MVO2 during controlled systemic and coronary hemodynamic conditions. In open chest dogs, NO synthesis was blocked by intracoronary infusion of NO synthesis with Nω-nitro-L-arginine methyl ester (L-NAME, 150 μg/min). To avoid effects of NO synthesis blockade on right coronary blood flow (RCBF), which might have altered RV MVO2, experiments were conducted during adenosine-induced maximal right coronary vasodilation (n=12). RCBF, RV MVO2, and other variables were measured at baseline and at elevated right coronary perfusion pressures (RCP). Under these conditions, L-NAME significantly increased RV MVO2 at baseline and at elevated RCP (P [less than] 0.05 vs. untreated control condition). These results indicate that NO acts to retard RV oxidative metabolism. We further characterized the role of NO on RV MVO2 during increases in RV workload, estimated as a product of heart rate X RV peak systolic pressure X RV dP/dt. RV workload, RCBF, and RV MVO2 were increased by intracoronary norepinephrine infusions at baseline RCP (n=5). L-NAME significantly reduced RCBF (P [less than] 0.05 vs. untreated control condition), and RV MVO2 was significantly higher at any measured RV workload during L-NAME (P [less than] 0.05 vs. untreated control condition). These findings indicate that NO is an important component of RCBF control and that NO blunts norepinephrine-induced increase in RV MVO2. If NO reduced RV MVO2 it may be cardioprotective during moderate right coronary hypoperfusion. Thus, we sought to determine if in fact the RV MVO2 was reduced by NO during moderate right coronary hypoperfusion (n=9). RCP was reduced to 60 (n=5) and 40 mmHg (n=4), and RCBF and RV MVO2 fell as RCP was reduced. L-NAME significantly increased RV MVO2 at RCP of 60 and 40 mmHg (P [less than] 0.05 vs. untreated control condition), although RV workload was not altered. Since NO reduced RV MVO2 without compromising RV mechanical performance, RV oxygen utilization efficiency was enhanced. Taken together, these findings demonstrate that NO has a significant dampening effect on RV MVO2.Item Regulation and Characterization of Cardiac Phosphoinositide-Specific Phospholipase C (PLC) Isoenzymes(1997-12-01) Wang, Juan; Eugene E. Quist; Thomas Yorio; Ming-Chi WuWang, Juan, Regulation and Characterization of Cardiac Phosphoinositide-Specific Phospholipase C Isoenzymes. Master of Biomedical Science, Dec., 1997, 79 pp., 20 illustration, bibliography, 62 titles. It is hypothesized that myocardial phosphoinositide-specific phospholipase C (PLC) isoenzymes are regulated by physiological intracellular Ca2+ and by cytosol-membrane translocation. The regulation and identification of PLC isoenzymes in rat and dog ventricular subcellular fractions were studied. PLC-β1, PLC-β3 and PLC-δ1 were identified in rat and dog cytosol and microsomal membranes by chromatographic separation, enzyme assays and western blotting. Truncated PLC-β isoforms with molecular weights of 69 kDa and 114 kDa were isolated from rat and dog cytosol, respectively. Species differences in the relative distribution of PLC isoenzymes were evident as PLC-δ dominant in rat whereas PLC-β isoenzymes were dominant in dog. A 91 kDa cytosolic protein which did not contain PLC activity alone markedly led to PLC activation when combined with microsomes. The activator protein was immunoprecipitated with an anti-PLC-δ identifying this activator as an inactive PLC-δ isoenzyme. These studies indicate that cytosolic PLC-δ may be activated by translocating to membranes. In addition, proteolysis may be involved in long term activation of cytosolic PLC isoenzymes. Further studies will be required to resolve the physiological significance of these modes of cardiac PLC activation.Item Regulation of Myocardial Blood Flow and Function During Exercise in Dogs(1995-06-01) Kim, Song-Jung; Patricia A. Gwirtz; Peter B. Raven; James L. CaffreyIntroduction. Background. Coronary circulation during exercise. Coronary blood flow is regulated primarily by local metabolic mechanisms according to the oxygen and nutrient needs of the heart (2, 4, 19). The local “metabolic signal” involves vasoactive metabolites, such as adenosine, released from myocytes in direct proportion to myocardial work (Figure 1). However, other external factors are superimposed on local regulatory mechanisms and can substantially modulate coronary blood flow. One of these modulatory factors is the sympathetic nervous system. Sympathetic vasoconstriction mediated by α-adrenergic receptors in the coronary circulation has been shown to oppose metabolic vasodilation and limit oxygen supply to the myocardium during physiologic and pathophysiological cardiac stresses, such as exercise and myocardial hypoperfusion (1, 6, 7, 8, 10-14, 17, 18, 21). This limitation on myocardial oxygenation appears to impose a restriction on the increase in regional left ventricular subendocardial contractile function during submaximal exercise (7). In this regard, studies have shown that removing this α1-constrictor tone leads to an increase in coronary blood flow and, as a result, regional contractile function (8). This adrenergic coronary constriction during exercise is mediated by neutrally released norepinephrine, not by circulating catecholamines (8). Endothelial-mediated control of coronary vascular tone. Recent investigations indicate that another factor involved in modulating coronary blood flow is the vascular endothelium. The endothelium exerts an influence on vascular smooth muscle vasomotor tone by releasing an endothelium-derived relaxing factor (EDRF) or nitric oxide (NO), which is derived from the amino acid L-arginine by nitric oxide synthase (5, 22). Synthesized NO diffuses into the underlying vascular smooth muscle to activate cytosolic guanylate cyclase (GC), thereby stimulating the intracellular accumulation of cyclic GMP (cGMP). This is illustrated in Figure 2. NO is released by the stimulation of muscarinic receptors on endothelial cells by acetylcholine, as well as by other agonists or physical stimuli (e.g., shear stress) at the interface between blood and endothelial cell surface (15). During exercise, for example, the work output of the normal heart may increase several-fold by the stimulation of sympathetic nerves to heart. The increased work output of the heart increases myocardial oxygen demand. Consequently, the coronary circulation undergoes vasodilation due to local metabolic mechanisms. The elevation in shear stress caused by increases in coronary blood flow triggers release of NO from the endothelium because of the extremely pulsatile nature of the flow. Therefore, it is likely that during exercise, release of NO by shear stress and by neurohormonal stimuli, concomitant with local release of metabolites, contributes to coronary dilation. These vasodilatory influences counteract a sympathetic α-adrenergic coronary constriction, which limits the increase in coronary blood flow and cardiac performance. Accordingly, coronary vascular smooth muscle tone during exercise is modulated by the endothelium, which responds to the increased shear stress and adrenergic stimulation, which provides the major extrinsic input.Item The Effects of Hyperlipidemia and Hypoglycemia on Myocardial Contractile Function and Oxygen Utilization During Coronary Hypoperfusion(1998-08-01) Hart, Bradley Joe; Downey, H. Fred; Mallet, Robert T.; Smith, Michael B.Hart, Bradley Joe, The Effects of Hyperlipidemia and Hypoglycemia on Myocardial Contractile Function and Oxygen Utilization During Coronary Hypoperfusion Master of Science (Biomedical Sciences), August, 1998, 85 pp., 1 table, 5 figures, references, 51 titles. This study was designed to determine the effects of elevated fatty acid and lowered glucose concentrations on myocardial contractile function and substrate selection during hypoperfusion. Coronary perfusion pressure (CPP) was lowered in the left anterior descending coronary artery of open-chest anesthetized dogs. Glucose uptake, fatty acid uptake, and percent segment shortening (%SS) were determined with normal arterial FFA concentrations (Group 1) or with elevated concentrations (Groups 2 and 3). When glucose was removed by dialysis in Group 3, FFA uptake increased and glucose uptake decreased relative to Group 1 at 40 mmHg CPP (p [less than] 0.05). Oxygen consumption significantly increased (p [less than] 0.05); however, %SS was unchanged. Thus, although the myocardium switches from fatty acid to glucose metabolism to increase oxygen utilization efficiency during hypoperfusion, blocking this switch does not contribute to a further decrease in myocardial contractile function.Item The Effects of Insulin on Myocardial Glucose Metabolism and Contractile Function During Moderate Coronary Hypoperfusion(1997-08-01) Tune, Johnathan D.; Downey, H. Fred; Mallet, Robert T.; Caffrey, James L.Tune, Jonathan David, The Effects on Insulin on Myocardial Glucose Metabolism and Contractile Function during Moderate Coronary Hypoperfusion Doctor of Philosophy (Biomedical Sciences), August, 1997, 98 pp, 3 tables, 11 figures, references, 117 titles. This study was designed to determine the effects of insulin on myocardial metabolism and contractile function during moderate coronary hypoperfusion. Coronary perfusion pressure (CPP) was lowered from 100 to 60, 50, and 40 mmHg in the left anterior descending coronary artery of anesthetized, open chest dogs. Regional glucose uptake, lactate uptake, oxygen consumption (MVO2), and percent segment shortening were determined without (n=12) or with either intravenous insulin (4 U/min, n=12) or intracoronary insulin (4 U/min, n=6). Glucose metabolites, high energy phosphates, and the phosphorylation state of creatine phosphate were determine in freeze clamped biopsies of control (n=6), and of intravenous insulin (n=6) treated hearts at the completion of the protocol (CPP = 40 mmHg). Glucose uptake increased with both intravenous and intracoronary insulin treatments (P0.05). Thus, insulin treatment improved contractile function while myocardial oxygen demand was unchanged, i.e. oxygen utilization efficiency increased. Myocardial glycogen, alanine, lactate, and pyruvate contents were not significantly different in untreated and intravenous insulin treated hearts. Reducing CPP to 40 mmHg produced similar changes in both untreated and insulin treated hearts: ATP content was unchanged, creatine phosphate content decreased 17%, creatine content and inorganic phosphate concentration increased 27% and 124%, respectively, and the phosphorylation potential decreased 80%. We conclude that 1) when the potentially detrimental effects on insulin stimulated glucose metabolism are avoided during moderate ischemia, insulin treatment increases contractile function without significantly elevating myocardial oxygen demand; 2) during moderate ischemia, insulin stimulated glucose metabolism increases oxygen utilization efficiency and prevents a further decline in the energy state of the myocardium.