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C Rosendorff

Publications and source records attributed to C Rosendorff.

At least 127 records · Page 7Linked to original sources
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Independent mechanisms for the chronotropic and inotropic responses in hyperthyroidism.

We established a hyperthyroid rat model and compared the hemodynamic responses of the hypertrophied rat heart in vivo and in vitro. Heart rate (557 +/- 26 beats/min), systolic blood pressure (162 +/- 5 mmHg) and dry heart mass (230 +/- 11 mg) in hyperthyroid rats were significantly greater than in control animals (408 +/- 12 beats/min, 140 +/- 5 mmHg and 193 +/- 4 mg respectively). In vitro studies were performed in order to eliminate neurohumoral and peripheral circulatory factors which are present in vivo. In the in vitro "working" heart preparation, there was no significant difference between the heart rates of L-thyroxine-treated (263 +/- 9 beats/min) and control (258 +/- 10 beats/min) animals, implying that the tachycardia of hyperthyroidism is partly mediated by in vivo factors. Consistent with this hypothesis was the observation that the hyperthyroid heart was more sensitive to the chronotropic effects of physiological concentrations of the synthetic catecholamine, isoproterenol (10(-8) M, 10(-7) M) than the control heart. The maximum rate of left ventricular pressure rise (dP/dtmax) was used as an index of myocardial contractility. In vitro values for dP/dtmax were significantly greater in hearts from hyperthyroid rats (5338 +/- 228 mmHg/s) than in control hearts (4583 +/- 158 mmHg/s), suggesting that the increased contractile response of hyperthyroidism is intrinsic to the heart itself. Although persistence of the inotropic response of the hyperthyroid heart in vitro was associated with an increase in heart mass, this factor alone did not account entirely for the enhanced contractility. It appears that intrinsic functional changes also contribute to the inotropic response of the hyperthyroid heart.

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Enhanced myocardial contractility but not tachycardia persists in isolated working hyperthyroid rat hearts.

It is generally believed that the increased contractility and tachycardia of the hyperthyroid heart are a result of thyroid hormone-induced alterations of the mechanical and electrical properties of the heart, respectively. We compared the contractility (dP/dtmax) and the spontaneous beating rate of hyperthyroid and euthyroid hearts perfused in vitro in either a non-working or a working mode. The dP/dtmax (4196 +/- 74 mm Hg s-1) and beating rate (322 +/- 8 beats/min) of the non-working hyperthyroid hearts were significantly higher (p less than 0.001) than those of the euthyroid hearts (3267 +/- 115 mm Hg s-1 and 260 +/- 6 beats/min at an external Ca2+ of 2.5 mM). At 2.5 mM Ca2+, the working hyperthyroid hearts again displayed enhanced contractility (5636 +/- 179 mm Hg s-1 vs 4508 +/- 172 mm Hg s-1; p less than 0.001) but the spontaneous beating rate (275 +/- 7 beats/min) was not significantly different from euthyroid (261 +/- 8 beats/min). When hearts were subjected to periods of alternate non-working and working perfusion, the beating rate of the hyperthyroid hearts was significantly higher than euthyroid during non-working (p less than 0.02) but not during working perfusion. Increasing the afterload on the non-working preparations in a stepwise fashion from 75 cm H2O to 120 cm H2O caused significant changes in left ventricular pressure and dP/dtmax in both heart types but the tachycardia in the hyperthyroid hearts persisted (at 120 cm H2O; hyperthyroid, 294 +/- 9 beats/min; euthyroid, 224 +/- 10 beats/min; p less than 0.001). Alteration of the preload (10 to 25 cm H2O) and afterload (75 to 105 cm H2O) on working hyperthyroid and euthyroid hearts caused changes in both left ventricular pressure and dP/dtmax but the beating rates of both heart types were never significantly different. We conclude from our results that (i) the increased contractility of the hyperthyroid rat heart is due to thyroid hormone-induced alteration of the mechanical properties of the heart; (ii) the tachycardia of hyperthyroidism is not due to thyroid hormone-induced changes in the electrical properties of the heart, but probably involves some as yet unidentified chronotropic agent.

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The role of calcium in the enhanced myocardial contractility of the hyperthyroid rat heart.

The hyperthyroid rat myocardium exhibits enhanced contractility. There is evidence that altered calcium handling by the myocardium may be responsible for this enhanced state. To investigate this, isolated hyperthyroid and euthyroid hearts were perfused in the working mode and exposed to alterations in external calcium concentration. Heart rate was not significantly different in either group of hearts, nor was it altered by the change in calcium. The concentration of calcium needed to elicit half-maximal contractility (dP/dtmax) was lower in the hyperthyroid (0.81 +/- 0.07 mM) than in the euthyroid hearts (1.12 +/- 0.09 mM, p less than 0.05). This increase in calcium sensitivity was unlikely to be at the site of the sarcolemma as verapamil exerted equal negative inotropic effects on both groups of hearts. Dantrolene, which blocks calcium release from the sarcoplasmic reticulum, exerted a significantly greater (p less than 0.01) depression in dP/dtmax after 12 min in the hyperthyroid (50 +/- 7%) than in the euthyroid heart (15 +/- 2%). We conclude from our results that the enhanced contractile state of the hyperthyroid rat heart is likely to involve an altered mechanical response to calcium which is possibly at the level of enhanced calcium release from the sarcoplasmic reticulum.

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The effect of propranolol, verapamil and dantrolene treatment on cardiac hypertrophy, enhanced myocardial contractility and tachycardia in the hyperthyroid rat.

Experimentally induced hyperthyroidism is associated with cardiac hypertrophy, tachycardia and elevated myocardial contractility. To investigate the possibility of ameliorating the cardiac changes pharmacologically, hyperthyroid rats were treated with propranolol, verapamil or dantrolene. Cardiac hypertrophy was assessed from the heart mass: body mass ratio and cardiac function was measured in vitro. Both verapamil and propranolol reversed the cardiac hypertrophy of the hyperthyroid animals from 0.92 +/- 0.02 mg.g-1 to 0.70 +/- 0.01 mg.g-1 (P less than 0.001) and 0.72 +/- 0.02 mg.g-1 (P less than 0.001) respectively. Verapamil was effective in reducing the spontaneous heart rate from 331 +/- 8 beats.min-1 to 273 +/- 7 beats.min-1 (P less than 0.001) while propranolol reduced the dP/dtmax of the hyperthyroid hearts from 4089 +/- 87 mmHg.s-1 to 3497 +/- 97 mmHg.s-1 (P less than 0.001). Dantrolene had no effect on any parameter. We conclude from our results that cardiac hypertrophy of the hyperthyroid heart can be reversed by treatment with propranolol and verapamil probably via their inotropic and chronotropic properties.

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Effect of peroral administration of sotalol on the hemodynamics of the baboon.

We investigated the effect of oral administration of sotalol on coronary and renal blood flow and other hemodynamic parameters of the baboon. Measurements were made in anesthetized baboons under basal conditions and during the intravenous infusion of isoproterenol at rates of 0.5, 1.0, 2.0 microgram. min-1 in an experimental (n = 20) and a control (n = 6) group. Subsequently, sotalol (dose 1-4 mg.kg-1, mean 2.25 mg.kg-1) or placebo was administered. After 2 h the procedure was repeated. Measurements included renal (RBF) and coronary (COR BF) blood flow, cardiac output (CO), heart rate (HR), stroke volume (SV), left ventricular systolic pressure (LVSP), maximum positive dP/dt (dP/dt max), aortic diastolic (APD) and mean (APM) pressures, heart rate-left ventricular systolic pressure product (RPP), and left ventricular stroke work index (LVSWI). RBF and COR BF were determined indirectly from the rate of 133 Xe clearance. In the control group, changes before and after the administration of placebo did not differ significantly for all parameters. In the experimental group, changes after sotalol administration were significantly lower for COR BF, CO, HR, LVSP, dP/dt max, APD, APM and RPP, but were not significantly different for RBF, SV and LVSWI. Beta-blockade had no effect on RBF. The reduction in COR BF was associated with a reduction in RPP (myocardial oxygen consumption). However, the oxygen supply-demand relationship was maintained. Decrease in CO was largely due to reduction in HR since SV (and LVSWI) were unaffected by Beta-blockade.

Administration, Oral↗
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Sotalol and infarct size after coronary ligation in the baboon.

We investigated the hemodynamic effects and myocardial salvage actions of sotalol during experimental myocardial infarction in the baboon. Ten baboons received placebo and six were given sotalol. In anesthetized open-chest baboons base-line determinations included heart rate (HR), rate-pressure product (RPP), left ventricular dP/dt, aortic pressures, serum creatine kinase MB isoenzyme (CK-MB) activity, and a 16-point epicardial ST segment map. The left anterior descending coronary artery was then ligated and the measurements were repeated at 15-min and at 2-h intervals up to 12 h after occlusion. At 12 h, coronary blood flow and myocardial CK activity were also measured. Twenty minutes after ligation, either sotalol (3 mumol . kg-1 followed by 2 nmol . kg-1 . min-1) or placebo (saline) was administered intravenously. Sotalol reduced HR but not dP/dt or the degree of afterload. The reduction in HR resulted in a significant decrease in RPP (myocardial O2 consumption). Sotalol administration also resulted in a decrease in coronary blood flow (myocardial O2 supply). There were no significant differences between the two groups in serum CK-MB activity or in the extent of myocardial damage, as predicted by the 15-min ST-segment deviations and myocardial CK activity at 12 h. The reduction in myocardial oxygen demand caused by sotalol was accompanied by a decrease in oxygen supply. As a consequence, no significant reduction in myocardial ischemic damage was found in the group given sotalol.

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Renal blood flow in obstructive jaundice: an experimental study in baboons.

1. The distribution of intrarenal blood flow has been measured using the 133Xe-washout technique in thirteen baboons 2 weeks after ligation of the common bile duct. 2. In comparison with eight sham-operated baboons, there was a signifigant decrease in the percentage distribution of blood to the cortex, although the rate of flow was unchanged. These changes were accompanied by a significantly increased flow rate and percentage distribution of flow through the juxtameduallary circulation. 3. In a further five baboons treated in the same way, various doses of noradrenaline were infused into the renal artery. In these animals there was an enhanced pressor response to noradrenaline, and this effect was completely abolished by an alpha-adrenoreceptor blocking agent (phenoxybenzamine). The beta-adrenoceptor blocking drug (propranolol) had no such effect. 4. This enhanced response was not seen when noradrenaline was infused into three sham-operated baboons. 5. These observations suggest that the alterations in renal perfusion in obstructive jaundice may be due to an increase renovascular sensitivity to circulating catecholamines and an enhanced alpha-adrenoceptor activity.

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Renovascular hypersensitivity to noradrenaline in dietary-induced hypercholesterolaemia in baboons.

1. Using the xenon-133 washout technique, the renovascular response to intrarenal infusions of 3 and 30 mumol/min noradrenaline in four baboons with dietary-induced hypercholesterolaemia was measured. 2. The degree of reduction in cortical blood flow rate during an intrarenal infusion of 3 mumol/min noradrenaline in the four hypercholesterolaemic baboons was not significantly different from that in normocholesterolaemic baboons. However, a significant difference in the degree of reduction in cortical blood flow rate was found with the 30 mumol/min noradrenaline infusion (P less than 0.05). 3. The mean arterial blood pressure of the four animals was significantly higher (P less than 0.001) than the mean blood pressure in baboons used in this laboratory for other experiments. 4. These results have shown that baboons with dietary-induced hypercholesterolaemia have an enhanced renovascular sensitivity to exogenous noradrenaline. However, the possibility that this enhanced sensitivity was due to the associated hypertension cannot be excluded.

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Role of catecholamine degradative enzymes and the adrenergic innervation in determining the cerebrovascular response to infused norepinephrine.

Cerebral blood flow responses to intra-arterial infusion of norepinephrine (NE) at 0.55 microgram/kg/min and 1.1 microgram/kg/min were studied in 3 groups of baboons. The flow was measured by the intracarotid 133xenon clearance technique using a computer program to calculate flow (height over area--H/A) flow (initial slope--is) and cerebral metabolic utilization of oxygen (CMRO2). The normal response to NE was to increase flow without significant changes in CMRO2. Blockade of catechol-o-methyl transferase (COMT) produced vasoconstrictor responses to these same NE doses. Monoamine oxidase blockade abolished the normal vasodilation. Denervation of the cerebral circulation with intracisternal 6-hydroxydopamine produced vasoconstrictor responses with flow (H/A) but not with flow (is). It is concluded that the extra-neuronal COMT enzyme is important in limiting the access of blood-borne NE to cerebrovascular constrictor receptors.

Adrenergic Fibers↗
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Cholinergic regulation of intracerebral noradrenergic pathway-induced hypothalamic vasodilatation.

Stimulation of the intracerebral noadrenergic pathway (INP) increases hypothalamic blood flow as measured in conscious rabbits using a 133xenon washout technique. This increase is abolished by the intra-hypothalamic injection of 0.65 micrograms of the muscarinic antagonist atropine and by 5 micrograms of the nicotinic antagonist mecamylamine. Further, 1 micrograms of the cholinomimetic methacholine produces a similar vasodilation. While methacholine enhances the vasodilatation on stimulation of the INP, destruction of the pathway abolishes the entire vasodilator response to methacloline. Removal of the superior cervical sympathetic ganglia does not abolish vasodilatation. A role for endogenous acetylcholine in the INP-induced vasodilatation is thus proposed. This vasodilatation appears to act via an increase in neuronal activity with a resultant lowering of local pH, as 60 micrograms barbiturate and intra-hypothalamic bicarbonate abolish the dilatation completely. The cholinergic vasodilatation reported here is probably an excitatory effect on the INP and is not likely to be due to an inhibition of sympathetic vasoconstrictor tone.

Acetylcholine↗
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Cerebrovascular reactivity and metabolism after subarachnoid hemorrhage in baboons.

Subarachnoid hemorrhage (SAH) was induced in baboons by puncturing the middle cerebral artery. Four to seven days later cerebral blood flow (CBF) responses to changing PaCO2 and to intracarotid infusion of 1.0, 2.5 and 5.0 micrograms of 5-hydroxytryptamine (5-HT)/kg/min were studied using the intracarotid 133xenon clearance technique. Indices of cerebral metabolism were determined by measuring arterio-venous differences for oxygen, pyruvate, lactate and glucose. The results were compared with those from sham-operated baboons. In the sham-operated group normal CO2 reactivity was seen, and 5-HT infusion did not produce any significant change in CBF or cerebral metabolism. By contrast, the group in which SAH was induced showed a significant decrease in CBF and cerebral oxygen utilization, and attenuated CO2 reactivity.

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The role of the carotid body in mediating the cerebrovascular response to altered arterial carbon dioxide tension.

The role of the carotid bifurcation chemoreceptors in mediating the cerebrovascular response to altered arterial PCO2 has been suggested to be large. In the present study the cerebrovascular response to raised PCO2 was measured in a group of baboons before and after bilateral inactivation of the carotid bodies. The results suggest that these chemoreceptors do play a part in the cerebral vasodilator response to raised PCO2. The role of the carotid body, however, appears to be relatively minor as it only accounted for +/- 40% of the total response and became significant only at arterial PCO2 levels of more than 50 mm Hg. It is postulated that the peripheral chemoreceptors in the carotid bifurcation mediate part of the cerebrovascular response to altered PaCO2 but the role is quantitatively small.

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Cerebrovascular response to infused 5-hydroxytryptamine in the baboon. Part 1. 5-Hydroxytryptamine infusion.

Cerebral blood flow was measured in 17 baboons before and during infusion of 5-hydroxytryptamine (5-HT) into the internal carotid artery. The mean values for total cerebral blood flow, grey matter flow, and white matter flow before 5-HT infusion were 40.8, 59.2, and 12.7 ml/min/100 gm of tissue, respectively. There was no significant alteration in total blood flow or flow through grey matter when 5-HT was infused at dosages ranging from 0.5 to 10.0 microng/kg/min. A small but significant decrease in white matter blood flow was recorded when 5-HT was infused at a rate exceeding 2.5 microng/kg/min. The study indicates that in vivo, with the xenon clearance method, intra-arterial infusion of 5-HT does not significantly alter cerebral blood flow.

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