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Biomedical subjects

W T Manders

Publications and source records attributed to W T Manders.

33 records · Page 2Linked to original sources
PubMed1981

Cellular mechanisms of impaired adrenergic responsiveness in neonatal dogs.

The myocardial responsiveness of conscious, instrumental dogs to exogenously administered isoproterenol and norepinephrine was investigated in neonatal, 6-wk-old, and adult animals. Comparable base-line values for peak left ventricular derivative of pressure with respect to time were observed in all age categories. However, when compared with adult responses, the sympathomimetic amine-induced increases in neonatal left ventricular dP/dt were significantly blunted at each concentration of adrenergic agonist examined, whereas the 6-wk-old puppies displayed an intermediate inotropic response. To investigate the cellular mechanisms of this blunted neonatal response, we correlated physiologic and biochemical measurements of the myocardial responses to catecholamines in each age category. When compared with adult myocardial membrane preparations, neonatal cardiac membranes were characterized in vitro by an increased density of beta-adrenergic binding sites, comparable affinity for adrenergic agonists and antagonists, and an enhanced coupling of adenylate cyclase activation to receptor occupancy. Simultaneous changes in either the serum catecholamine concentration or the membrane content of other intrinsic proteins failed to account for the observed neonatal increase in beta-adrenergic receptor density. These findings are most consistent with a compensatory mechanism of the cardiac cell membrane, whereby an inherent depression in the adrenergic responsiveness of the immature myocardium appears to induce the increase in receptor density and activation of adenylate cyclase.

Adenylyl Cyclases↗
PubMed1980

Sympathetic regulation of the cerebral circulation by the carotid chemoreceptor reflex.

The effects of carotid chemoreceptor reflex stimulation (intracarotid injection of nicotine 0.2 microgram/kg) were examined in conscious dogs on the cerebral circulation, using the radioactive microsphere technique to measure cerebral blood flow. In intact dogs (n = 18) with ventilation controlled, carotid chemoreceptor reflex stimulation increased (P less than 0.01) mean arterial pressure by 36 +/- 5% (SE) and calculated cerebral vascular resistance by 58 +/- 13%, whereas cerebral blood flow fell by 7 +/- 6% (NS). After bilateral cervical sympathectomy (n = 9), carotid chemoreceptor reflex stimulation induced significantly different (P less than 0.01) effects on cerebral blood flow, which rose by 42 +/- 8%, and cerebral vascular resistance, which did not change. To determine whether the difference in effect was due to the sympathectomy or merely to the repetition of the stimulus, another group of dogs (sham; n = 6) that had intact sympathetic nerves were studied a second time. In "sham" dogs, the repeat response to carotid chemoreceptor stimulation also induced significantly different effects from those in dogs with sympathectomy. After general anesthesia with sodium pentobarbital, or after section of the ipsilateral carotid sinus nerve, carotid chemoreceptor stimulation with nicotine, 0.2 microgram/kg, failed to induce a detectable hemodynamic effect. Thus, in the conscious dog, stimulation of the carotid chemoreceptor reflex elicits significant sympathetically mediated vasoconstriction in cerebral vessels.

Animals↗
PubMed1980

Alpha adrenergic vasoconstriction and nitroglycerin vasodilation of large coronary arteries in the conscious dog.

The effects of methoxamine and nitroglycerin on measurements of large vessel (left circumflex) coronary dimensions were examined in eight conscious dogs using an ultrasonic dimension gauge, and total coronary resistance was calculated from measurements of arterial pressure and coronary blood flow. Methoxamine (50 mug/kg per min), after transiently increasing left circumflex coronary dimensions, induced sustained reductions in left circumflex diameter (9+/-2%) and external (18+/-4%) and internal (27+/-5%) cross-sectional areas, at a time when mean arterial pressure rose by 65+/-5%, left ventricular dP/dt had decreased only slightly, and heart rate and mean coronary blood flow remained at control levels. Calculated large vessel and total coronary resistances rose similarly, i.e., by 108+/-29 and 92+/-14%, respectively. Methoxamine reduced coronary arterial wall stiffness from control at comparable stress levels, although at any common radius, wall stiffness was augmented substantially. Nitroglycerin (25 mug/kg) induced an initial decrease in coronary dimensions along with the fall in arterial pressure. However, left circumflex coronary dimensions then rose, reaching a maximum 5 min later at a time when left circumflex coronary blood flow was reduced and heart rate and left ventricular dP/dt were at control levels. At this time, significantly different effects were observed on large vessel coronary resistance, which fell by 18+/-2%, and on total coronary resistance, which rose by 11+/-4%. Thus, in the conscious dog, large coronary vessels not only react passively to changes in aortic pressure but also undergo substantial active changes. Alpha adrenergic stimulation is sufficiently powerful to reduce cross-sectional area, despite the opposing elevation of distending pressure.

Animals↗
PubMed1980

Cardio-selective beta adrenergic stimulation with prenalterol in the conscious dog.

The effects of cardioselective beta-1 adrenergic agonist, 1-(4-hydroxyphenoxy)-isopropylamino-2-propanol), i.e., prenalterol, were examined on direct and continuous measurements of left ventricular (LV) pressure, diameter, dP/dt, velocity of shortening, arterial pressure, iliac blood flow and heart rate in 10 conscious dogs. Prenalterol was infused on 3 separate days in doses of 1, 2 and 4 micrograms/kg/min for 15 min. The largest dose of the drug increased LV/dP/dt by 70 +/- 7% from 3581 +/- 130, velocity of LV shortening by 27 +/- 4% from 86 +/- 7 mm/sec, heart rate by 51 +/- 9% from 80 +/- 5 beats/min and iliac blood flow by 40 +/- 4% from 134 +/- 15 ml/min and decreased LV end-diastolic diameter by 8 +/- 2% from 35 +/- 2 mm and LV end-systolic diameter by 15 +/- 2% from 24 +/- 2 mm. All these responses were significant, P < .01. Mean arterial pressure did not change. The positive inotropic effects persisted for 1 hr. The lowest dose of the drug studied increased LV dP/dt and velocity but not heart rate. Practolol, a beta-1 adrenergic receptor blocker, prevented the positive inotropic effects and the increases in iliac blood flow indicating that prenalterol exerts its cardiovascular actions primarily by stimulation of beta-1 adrenergic receptors.

Adrenergic beta-Agonists↗
PubMed1979

Depressed responsiveness of the carotid sinus reflex in conscious newborn animals.

The responsiveness of the carotid sinus reflex was evaluated by comparing the effects of bilateral carotid occlusion (BCO) in conscious adult dogs and puppies on measurements of arterial pressure, cardiac output, heart rate, and calculations of total peripheral resistance (TPR). In eight adult dogs, BCO increased mean arterial pressure by 57 +/- 6%, TPR by 48 +/- 5%, and heart rate by 45 +/- 15%. In puppies, BCO induced smaller increases (P less than 0.05) in mean arterial pressure (30 +/- 5%) and TPR (29 +/- 4%), while heart rate did not change. After elimination of opposing vagal and aortic baroreceptor reflexes, the differences in responses to BCO of mean arterial pressure and TPR between adults and newborns were even greater. Thus, the carotid baroreceptor reflex appears to be depressed in the newborn when compared with the fully developed reflex in the normal, conscious adult.

Animals↗
PubMed1979

Depressed responsiveness to vasoconstrictor and dilator agents and baroreflex sensitivity in conscious, newborn lambs.

The effects of vasoconstrictors and vasodilators were compared in conscious, newborn lambs and adult sheep instrumented with electromagnetic flow probes on the ascending aorta and catheters in the thoracic aorta. Methoxamine, angiotensin II, norepinephrine, nitroglycerin and isoproterenol were administered intravenously to evaluate their effects on arterial pressure, cardiac output and systemic vascular resistance (SVR). The difference in response between adults and newborns was most apparent with methoxamine. Methoxamine, 400 micrograms/kg, i.v., which increased mean arterial pressure by 57 +/- 6% and SVR by 278 +/- 27% in newborn lambs, caused greater increases (p less than 0.01) of 81 +/- 8% and 1418 +/- 141%, respectively, in the adults. Responses also differed significantly between newborn and adult animals to norepinephrine, angiotensin II, nitroglycerin and isoproterenol. In a second group of animals in which smaller amounts of methoxamine and isoproterenol were injected directly into the terminal aorta, changes in terminal aortic flow and resistance were examined. Again, both vasoconstrictor and vasodilator responses were more marked in adults than in newborns. Finally, the sensitivity of the arterial baroreceptor reflex was evaluated by comparing the regression of pulse interval (PI) on systolic arterial pressure (SAP) after an intravenous dose of methoxamine in conscious, adult and newborn animals. The PI/SAP slopes in adult sheep, 45.4 +/- 3.5 msec/mm Hg, were significantly greater (p less than 0.01) than in newborn lambs, 11.7 +/- 2.2 msec/mm Hg.

Angiotensin II↗
PubMed1978

Effects of nitroglycerin on cardiac function and regional blood flow distribution in conscious dogs.

The effects of intravenous infusion of nitroglycerin (NTG), 8 and 32 microgram/kg.min for 7 min, and of sublingual NTG, 1.2 mg, were examined on direct and continuous measurements of systemic, coronary, and regional hemodynamics, left ventricular (LV) dimensions, pressures, and myocardial contractility in conscious dogs. NTG induced sustained reductions in LV dimensions and transient increases in heart rate and dP/dt, and decreases in mean arterial pressure. Initially NTG increased cardiac output and flows to the coronary, mesenteric, renal, and iliac beds, while systemic and regional vascular resistances fell. Later, cardiac output, cardiac work, and mesenteric and iliac flows fell significantly below control, and significant vasoconstriction in the systemic as well as mesenteric, iliac, and coronary beds was observed at a time when LV end-diastolic dimensions were still significantly reduced. Peripheral vasoconstriction was not observed with systemic NTG in deafferented dogs or when NTG, 1 microgram/kg.min, was infused intra-arterially into the iliac bed. Thus, systemic NTG induces a biphasic response consisting of initial arteriolar vasodilation followed by vasoconstriction in the mesenteric, iliac, coronary and systemic beds, which is presumably due to longer lasting effects on preload and to secondary reflex responses to the drug.

Administration, Oral↗
PubMed1978

Measurement of multiple simultaneous small dimensions and study of arterial pressure-dimension relations in conscious animals.

This paper describes the development of several important modifications that were incorporated into the ultrasonic, transit-time dimension system in order to obtain multiple simultaneous, instantaneous, and continuous measurements of the external dimensions of the aorta and its major branches in conscious, unrestrained animals. At operation a pair of small piezoelectric crystals was sutured to arterial adventitia, and a miniature pressure gauge was implanted in the vessel at the same cross-sectional plane. After recovery from surgery, wall motion was not altered appreciably and scarring was minimal. This technique allows long-term monitoring of aortic pressure-dimension relations and is applicable for small (fetal and neonatal) as well as large (adult dogs and sheep) animals. When vessel wall thickness is measured, stress-radius analysis can be performed so as to compute vascular elastic stiffness as a function of stress. Moreover, the suitability for radiotelemetry of the pressure and dimension signals measured with this technique enables the study of these parameters in unrestrained animals, e.g., during spontaneous severe exercise.

Angiotensins↗
PubMed1978

Effects of a cardiac glycoside in combination with propranolol on the ischemic heart of conscious dogs.

The effects of coronary occlusion and of subsequent propranolol and ouabain administration were examined in 12 conscious dogs. Overall left ventricular (LV) function was assessed by measurement of LV pressure and dP/dt, and regional myocardial function was assessed by measurements of segment length (SL), velocity of SL shortening and regional myocardial "work," i.e., pressure-length loops in normal and moderately and severely ischemic zones. Regional intramyocardial electrograms were measured at the same sites as function along with regional myocardial blood flow as determined by the radioactive microsphere technique. Coronary occlusion resulted in graded loss of function from the normal to severely ischemic zones, along with graded flow reductions and graded elevation of the ST segment. Propranolol, 1 mg/kg, depressed overall LV function and function in the normal zone more than in ischemic zones. Propranolol reduced flow to the normal zone and increased flow to ischemic zones, while not affecting ST-segment elevation significantly. In the presence of occlusion and propranolol, ouabain, 20 microgram/kg, improved overall LV function as well as regional function in the normal, moderately ischemic and severely ischemic zones. In addition, ouabain reduced ST elevation and increased blood flow further in moderately and severely ischemic zones. Most strikingly, ouabain returned normal systolic shortening to eight severely ischemic segments which were previously akinetic.

Animals↗
PubMed1978

Effects of a cardiac glycoside on regional function, blood flow, and electrograms in conscious dogs with myocardial ischemia.

We studied the effects of coronary occlusion and of subsequent ouabain administration on regional myocardial function, flow, and electrograms in 14 conscious dogs. Coronary occlusion resulted in a graded loss of regional function as reflected by measurements of segment length (SL), velocity of SL shortening and myocardial "work" from the normal to severely ischemic zones, along with graded flow (radioactive microsphere technique) reductions and graded elevation of the regional S-T segment. Ouabain, 20 microgram/kg, improved function in the normal zone, in which stroke shortening rose by 0.23 +/- 0.07 mm (mean +/- SE) and "work" rose by 30.2 +/- 9.5 mm Hg-mm. In moderately ischemic segments, stroke shortening rose by 0.60 +/- 0.05 mm and "work" rose by 58.1 +/- 6.1 mm Hg-mm. In the majority of severely ischemic segments, stroke shortening and "work" also increased; the average effect in all severely ischemic segments was an increase in stroke shortening of 0.35 +/- 0.10 mm and in "work" of 31.5 +/- 9.9 mm Hg-mm. In addition, ouabain reduced S-T elevation by 0.90 +/- 0.20 mV in moderately ischemic zones and by 3.14 +/- 0.35 mV in severely ischemic zones, and increased flow by 28 +/- 6% and 46 +/- 9% in moderately and severely ischemic zones, respectively. All these changes were significant, P less than 0.01. Thus, ouabain caused an improvement in perfusion of ischemic tissue, which was associated with significant enhancement of stroke shortening and "work." Most strikingly, ouabain returned normal systolic shortening to 10 severely ischemic segments which previously were akinetic.

Animals↗
PubMed1978

Effects of coronary artery reperfusion on myocardial infarct size calculated from creatine kinase.

The effects of coronary artery reperfusion at 1 and 3 h after occlusion on infarct size (IS) in the conscious dog were compared with a second group of dogs that were not reperfused (24 h occlusion). Infarct size was calculated from creatine kinase (CK) appearing in blood samples (IS(s)) and myocardial CK depletion (IS(m)), and determined from gross and histological inspection of the pathological tissue (IS(p)). Under both conditions, IS(m) correlated well with IS(p). In dogs with 24-h coronary occlusions, IS(s) correlated well with IS(m) (IS(s) = 14.26 + 1.18 x IS(m), r = 0.92). In reperfused dogs, the relationship remained linear but was altered (IS(s) = 15.33 + 2.07 x IS(m), r = 0.89). The slope was significantly greater, P <0.05, than that observed for dogs that were not reperfused, suggesting that more CK appeared in serum per gram of infarct. Similarly, significantly different relationships were observed in the reperfused and nonreperfused dogs, when IS(s) was compared with IS(p). Moreover, the configuration of the serial blood CK curve was changed significantly by reperfusion. In dogs with a 24-h occlusion, CK rose gradually to a peak at 11.4+/-0.5 h. In dogs reperfused at 3 h, CK rose sharply at 3 h and reached a peak at 6.8+/-0.5 h, significantly earlier (P <0.01) than occurred in dogs reperfused at 1 h, i.e., when the peak occurred at 4.2+/-0.4 h. The rapid appearance of CK in blood after reperfusion at 1 and 3 h suggested a washout phenomena. Thus, reperfusion alters the shape of the serial blood CK curve and results in a different linear relationship between calculated and measured infarct size, resulting in greater recovery of CK in blood per unit of infarcted myocardium.

Animals↗
PubMed1977

Effects of propranolol on regional myocardial function, electrograms, and blood flow in conscious dogs with myocardial ischemia.

The effects of coronary occlusion and of subsequent propranolol administration were examined in 18 conscious dogs. Overall left ventricular (LV) function was assessed by measurements of LV pressure and dP/dt, and regional myocardial function was assessed by measurements of segment length (SL), velocity of SL shortening and regional myocardial "work", i.e., pressure-length loops in normal, moderately, and severely ischemic zones. Regional intra-myocardial electrograms were measured from the same sites along with regional myocardial blood flow as determined by the radioactive microsphere technique. Coronary occlusion resulted in graded loss of function from the normal to severely ischemic zones with graded flow reduction and graded elevation of the ST segment. Propranolol depressed overall LV function, function in the normal zone (work fell by 17+/-4%), and in the majority of moderately ischemic segments (work fell by 7+/-3%). In severely ischemic segments the extent of paradoxical motion and post-systolic shortening was reduced by propranolol. After propranolol regional myocardial blood flow fell in the normal zone (11+/-2%) and rose in the moderately (15+/-4%) and severely (63+/-10%) ischemic zones. Thus, in the conscious dog with regional myocardial ischemia, propranolol induces a redistribution of myocardial blood flow, with flow falling in normal zones and rising in moderately and severely ischemic zones. The improvement in perfusion of ischemic tissue was associated with slight but significant depression of shortening, velocity, and work in the moderately ischemic zones and of paradoxical bulging and post-systolic shortening in the severely ischemic zone.

Animals↗
PubMed1976

Effects of sodium pentobarbital anesthesia on left ventricular function and distribution of cardiac output in dogs, with particular reference to the mechanism for tachycardia.

Sodium pentobarbital (PB), 30 mg/kg, iv, was administered to 30 conscious dogs instrumented for measurement of cardiac output and regional blood flow distribution, left ventricular (LV) diameter, LV pressure, dP/dt, and dD/dt, i.e., velocity of myocardial fiber shortening. Ventilation was controlled during anesthesia to maintain arterial blood gases at control values for conscious dogs. The anesthetic produced an initial transient, peripheral vasodilation but the steady state effects 15-30 minutes later were characterized by slight reductions in mesenteric flow and cardiac output and increases in mesenteric and systemic resistances, whereas iliac and renal resistances were not significantly different from control. When heart rate rose, PB increased end-systolic diameter and decreased coronary resistance, LV end-diastolic diameter, dP/dt/P (42%), and shortening velocity (36%). When heart rate was controlled, PB still increased end-systolic diameter and decreased shortening velocity and dP/dt/P, as occurred during spontaneous rhythm, but end-diastolic diameter rose instead of falling and coronary resistance did not change. After recovery from bilateral cervical section of both carotid sinus and aortic nerves, PB failed to elicit tachycardia. Thus, PB affects systemic and regional hemodynamics only slightly, but depresses the myocardium markedly. The tachycardia associated with PB anesthesia in intact, trained dogs appears not to be only vagolytic, as previously thought, but is predominantly mediated through the arterial baroreceptor reflex.

Anesthesia, General↗