Effects of sodium nitroprusside, isosorbide dinitrate, isoproterenol, phentolamine and prazosin on hepatic venous responses to sympathetic nerve stimulation in the cat.

Hepatic blood volume was recorded by a plethysmographic technique in cats anesthetized with pentobarbital. The effects of three doses of each vasodilator drug were measured on arterial and portal pressures, hepatic blood volume in the denervated liver and on the portal pressure and hepatic venous responses to sympathetic nerve stimulation. Isosorbide dinitrate caused a small reduction in basal hepatic venous tone increasing hepatic blood volume by up to 15%; it had no effect on the responses to sympathetic nerve stimulation. Isoproterenol increased hepatic venous tone perhaps by stimulation of angiotensin formation and the responses to stimulation of the hepatic nerves were reduced because of this increased basal tone. Sodium nitroprusside produced a small decrease in basal venous tone and only large doses produced any reduction in the venous responses to hepatic nerve stimulation. The evidence that nitroprusside is a venodilator requires reexamination. Phentolamine had no effect on basal venous tone but markedly reduced the responses to sympathetic nerve stimulatiqn. When compared to phentolamine, prazosin produced comparable effects on arterial pressure but much less reduction in the hepatic venous responses to sympathetic stimulation. It is suggested that the alpha receptor blocking action of prazosin is selective for arterioles and this may explain the minor incidence of postural hypotension during clinical use.     

Enhanced sympathetic nervous activity after intravenous propranolol in ischaemic heart disease: plasma noradrenaline splanchnic blood flow and mixed venous oxygen saturation at rest and during exercise

To study the mechanisms by which acute beta-adrenergic blockade may change the activity of the sympathetic nervous system we have measured haemodynamic responses including splanchnic blood flow in twenty-three patients with ischaemic heart disease at rest and during supine exercise before and after i.v. injection of 0.039 mmol (10 mg) dl-propranolol. After propranolol both at rest and on exercise blood pressure, cardiac output and heart rate decreased, while splanchnic vascular resistance increased; mixed venous oxygen saturation decreased whilst arterial oxygen saturation and oxygen uptake were unchanged. Plasma noradrenaline increased after propranolol, values correlating with mixed venous oxygen saturation and splanchnic vascular resistance, both at rest and during exercise before and after propranolol, only at rest was there any correlation with arterial blood pressure. The increase in sympathetic nervous activity after propranolol may be due to a reduction in cardiac output and thereby alteration of the metabolic state (oxygen or related factors) in tissues. Afferent neural signals from the tissues may play a significant role in the regulation of sympathetic nervous activity.     

Autonomic control of the venous system in health and disease: effects of drugs

The venous system contains 70% of the blood volume. The sympathetic nervous system is by far the most important vasopressor system in the control of venous capacitance. The baroreflex system responds to acute hypotension by concurrently increasing sympathetic tone to resistance, as well as capacitance vessels, to increase blood pressure and venous return, respectively. Studies in experimental animals have shown that interference of sympathetic activity by an ₁- or ₂-adrenoceptor antagonist or a ganglionic blocker reduces mean circulatory filling pressure and venous resistance and increases unstressed volume. An ₁- or ₂-adrenoceptor agonist, on the other hand, increases mean circulatory filling pressure and venous resistance and reduces unstressed volume. In humans, drugs that interfere with sympathetic tone can cause the pooling of blood in limb as well as splanchnic veins; the reduction of cardiac output; and orthostatic intolerance. Other perturbations that can cause postural hypotension include autonomic failure, as in dysautonomia, diabetes mellitus, and vasovagal syncope; increased venous compliance, as in hemodialysis; and reduced blood volume, as with space flight and prolonged bed rest. Several -adrenoceptor agonists are used to increase venous return in orthostatic intolerance; however, there is insufficient data to show that these drugs are more efficacious than placebo. Clearly, more basic science and clinical studies are needed to increase our knowledge and understanding of the venous system.     

The effect of steady-state increases in systemic arterial pressure on the duration of left ventricular ejection time

The effect of steady-state increases in systemic arterial pressure on the duration of left ventricular ejection time was studied in 11 normal male subjects. Methoxamine, a pressor amine of predominantly vasoconstrictor activity but lacking significant inotropic effect, was administered intravenously resulting in an average increase in mean arterial pressure of 27 mm Hg. Heart rate was held constant by high right atrial pacing, and there was no significant change in cardiac output. During methoxamine infusion, when stroke volume, heart rate, and inotropic state were held constant, left ventricular ejection time increased as mean arterial pressure increased. There was a highly significant correlation between the increase in mean systolic blood pressure and the prolongation of left ventricular ejection time (r = 0.870). In one subject, an increase in mean systolic pressure of 75 mm Hg prolonged left ventricular ejection time 55 msec, producing paradoxical splitting of the second heart sound. The prolongation of left ventricular ejection time during infusion was not blocked by the prior intravenous administration of atropine sulfate or propranolol hydrochloride, thus ruling out both vagal inhibition of the left ventricle and reflex withdrawal of sympathetic tone as its cause. In three subjects, left ventricular end diastolic pressure was measured and found to be significantly increased. This finding suggests that the normal left ventricle maintains a constant stroke volume in the presence of an increased pressure load by the Frank Starling mechanism. This study concludes that arterial pressure must be included as a prime determinant of left ventricular ejection time along with stroke volume, heart rate, and inotropic state in intact man.     

Circuit factors in the high cardiac output of sepsis

The increase of cardiac output (CO) in sepsis must be matched by an increase in venous return. Our goal was to determine which of the determinants of venous return are responsible in volume-loaded and nonvolume-loaded pigs with endotoxemia. The determinants include stressed volume, venous compliance (C_v), venous resistance (RVR) and right atrial pressure (Pra). We also tested the effect of the nitric oxide (NO) synthase inhibitor, N^ω-nitro- -arginine-methyl ester (L-NAME) after the hemodynamics with endotoxin stabilized.

Pigs were anesthetized and mechanically ventilated. We measured CO by thermodilution, mean circulatory filling pressure (MCFP) by inflating a balloon in the right atrium, blood volume by dye dilution, and C_v by rapid blood infusions. RVR was calculated from MCFP - Pra/CO). After baseline measurements, we infused 10 μg/(kg x h⁻¹) of Escherichia coli endotoxin. Eight animals also received 30 mL × kg⁻¹ of dextran over the 2 hours (volume treated), and seven did not (no volume). After 2 hours we injected 25 mg × kg⁻¹ of the NO synthase inhibitor, L-NAME, and repeated the measurements.

In volume-treated animals, CO increased from 3.9 ± 0.7 to 5.4 ± 0.8 L x min⁻¹ (P < .05), and blood pressure (BP) fell from 118 ± 9 to 76 ± 12 mmHg. MCFP rose, and there was no change in RVR or C_v, whereas capacitance increased (ie, right shift of pressure-volume curve). Cardiac function (ie, Starling curve) did not change. In no-volume animals, CO fell from 4.47 ± 0.64 to 2.50 ± 0.86 L × min⁻¹, BP from 114 ± 10 to 9 13 mmHg and MCFP fell. Systemic vascular resistance did not change. Cardiac function was markedly depressed, and the heart rate increased from 143 ± 13 to 203 ± 30 beats x min⁻¹. L-NAME restored BP in both groups but also increased RVR and depressed cardiac function.

Changes in vascular tone during endotoxemia are dependent on volume status. The increased cardiac output in volume-treated septic animals occurred because of an increase in stressed volume due to the volume given in combination with a dilated vasculature. L-NAME restored arterial tone but decreased CO because of a rise in RVR and decrease in cardiac function.     

Side-effects of L-dopa on venous tone in Parkinson's disease: a leg-weighing assessment

In the present study, the effects of L-dopa treatment on cardiovascular variables and peripheral venous tone were assessed in 13 patients with Parkinson's disease (PD) with Hoehn and Yahr stages 1-4. Patients were investigated once with their regular treatment and once after 12 h of interruption of L-dopa treatment. L-Dopa intake significantly reduced systolic and diastolic blood pressure, heart rate and plasma noradrenaline and adrenaline in both the supine and upright (60 degrees ) positions. A significant reduction in stroke volume and cardiac output was also seen with L-dopa. The vascular status of the legs was assessed through thigh compression during leg weighing, a new technique developed in our laboratory. Healthy subjects were used to demonstrate that this technique provided reproducible results, consistent with those provided by strain gauge plethysmography of the calf. When using this technique in patients with PD, L-dopa caused a significant lowering of vascular tone in the lower limbs as shown, in particular, by an increase in venous distensibility. Combined with the results of the orthostatic tilting, these findings support that the treatment-linked lowering of plasma noradrenaline in patients with PD was concomitant with a significant reduction in blood pressure, heart rate and vascular tone in the lower limbs. These pharmacological side-effects contributed to reduce venous return and arterial blood pressure which, together with a lowered heart rate, worsened the haemodynamic status.     

A new approach in the treatment of hypotension in human septic shock by NG-monomethyl-L-arginine,an inhibitor of the nitric oxide synthetase

N^G-monomethyl-L-arginine (L-NMMA) is an inhibitor of the enzyme nitric-oxide-synthetase. Nitric oxide (NO), produced by endothelial and vascular cells regulates physiological vascular tone, blood pressure and tissue perfusion via guanylate-cyclase and cGMP. In an advanced stage of therapy resistant septic shock in response to inflammatory mediators, NO is overproduced. This leads to vasodilatation, a fall in systemic blood pressure and an attenuated vasoconstriction-response to sympathetic-stimuli. Two episodes of severe and prolonged hypotension in a patient with sepsis were successfully treated twice by bolus therapy of L-NMMA within 4 weeks. On both occasions blood pressure was reversed to normal and the continuous use of high doses of catecholamines were stopped. In contrast to the immediate response of blood pressure, heart rate and central venous pressure remained stable. Cardiac output dropped to 68% and PaO₂ increased. These findings indicate that NO-synthetase-inhibitors may be of value in the therapy of human septic shock.     

Haemodynamics of the pressor effect of oral water in human sympathetic denervation due to autonomic failure

Oral water ingestion increases blood pressure in normal elderly subjects and in patients suffering from autonomic failure, but the time course of the haemodynamic changes is not known. We therefore studied 14 subjects with documented sympathetic denervation due to pure autonomic failure, with continuous haemodynamic recordings obtained before and after ingestion of 500 ml of distilled water at room temperature. The time course of changes in values of systolic and diastolic beat-by-beat finger blood pressure, heart rate, stroke volume, cardiac output, ejection fraction and total peripheral resistance were analysed. Systolic blood pressure rose from 115+/-8 mmHg (mean+/-S.E.M.) to 133+/-8 mmHg (P<0.001), and diastolic blood pressure from 64+/-4 to 73+/-4 mmHg (P<0.001), with the pressor response beginning a few minutes after water ingestion, plateauing between 10 and 35 min (peak at 14 min), and returning to baseline at 50 min. Heart rate fell from 71+/-2.5 to 67+/-2 beats/min (P<0.001), and total peripheral resistance increased from 1.31+/-0.19 to 1.61+/-0.24 m-units (P<0.001). There were no significant changes in ejection fraction, stroke volume or cardiac output. This study confirmed a pressor response to oral water in subjects with sympathetic denervation. The temporal profile of the response did not favour reflexly mediated sympathetic activation. As subjects with autonomic failure are prone to salt and water depletion, and since blood pressure is exquisitely sensitive to such changes, it may be that the observed response is due to repletion or restoration of intravascular and extravascular fluid volume.     

Effects of knee surgery on cardiac function in soccer players

OBJECTIVE: To evaluate the effects of knee surgery on hematocrit and hemoglobin concentration and on resting cardiac parameters as measured by echocardiography. DESIGN: Ten soccer players who underwent knee surgery were evaluated before (T1) and after (T2) hospitalization within a 7-day interval. RESULTS: After hospitalization, end diastolic volume and stroke volume were significantly reduced (P < 0.05) by 14 and 22%, respectively. Despite a significant increase in resting heart rate (T1: 68 +/- 3.3 beats/ min, T2: 72 +/- 3.1 beats/min, P < 0.05), cardiac output was significantly decreased (T1: 4.89 +/- 0.56 liters/min; 3.95 +/- 0.62 liters/min, P < 0.05). The ejection fraction was 65% at T1 and fell to 58% at T2 (P < 0.05). After hospitalization, significant decreases in hemoglobin concentration and hematocrit were observed, suggesting a fall in blood volume. CONCLUSION: In soccer players, knee surgery leads to resting cardiac deconditioning, which is characterized by a significant reduction in stroke volume.     

Influence of leg position and environmental temperature on segmental volume expansion during venous occlusion plethysmography

Blood flow determinations by venous occlusion plethysmography applying the strain-gauge technique are frequently used. A problem with the strain-gauge technique is that the relationship between venous volume and transmural pressure is not linear and, furthermore, changes with the sympathetic tone. The present study tests the hypothesis that these factors lead to a redistribution of venous blood, which may impair the accuracy of the technique. The relative volume expansion rates of four leg segments were studied with the leg in different positions and at disparate temperatures, thereby inducing varying venous pressures and sympathetic tone ( n =6). With elevated leg and relaxed veins (at 50 degrees C), the distal thigh showed a relatively low expansion rate (25.8+/-4.5 ml.min(-1).l(-1)), whereas values in the calf segments were higher (34.5-39.0 ml.min(-1).l(-1)). With lower initial transmural pressure, calf segments can increase their volume much more during occlusion compared with the distal thigh. In a higher transmural pressure region (lowered leg), the difference in compliance between limb segments is less. In this case, compliance and volume expansion rate was higher in the distal thigh (14.2, 13.5 and 22.2 ml.min(-1).l(-1) at 10, 20 and 50 degrees C respectively) than in the calf segments (for the distal calf: 6.4, 7.7 and 16.2 ml.min(-1).l(-1) respectively). There was a significant interaction ( P <0.001) between temperature and leg position, indicating a higher degree of sympathetic vasoactivity in the calf. It is concluded that blood flow determination by strain-gauge plethysmography is less accurate, due to a potential redistribution of the venous blood. Therefore possible influences of variations in sympathetic tone and venous pressure must be considered even in intra-individual comparisons, especially in interventional studies.     

Evaluation of right ventricular function by assessment of cardiac efficiency: Influence of induction of anaesthesia in coronary artery bypass grafting patients

Considering the heart as a physical pump cardiac efficiency is calculated from the ratio of cardiac work performed to the maximum level of energy of the heart. The aim of the study was to compare cardiac efficiency with cardiac output and right ventricular ejection fraction. Nine patients scheduled for coronary artery bypass grafting were investigated. A femoral arterial and a right ventricular ejection fraction pulmonary artery catheter were placed in the awake state. Anaesthesia was induced with eltanolone and fentanyl. Cardiac output, pulmonary artery and central venous pressures, and right ventricular ejection fraction were measured in the awake state (baseline), 2 min after induction of anaesthesia and 1 and 5 min after intubation. Cardiac effeciency was calculated by dividing the stroke work by the maximum energy of the heart as calculated from the pressure volume diagram. An analysis of variance was carried out for cardiac efficiency, cardiac output and right ventricular ejection fraction. Cardiac efficiency was significantly (p<0.05) reduced 1 min after intubation from 28±11 to 14±5%. In contrast the right ventricular ejection fraction (from 48±10 to 35±13%) and cardiac output (from 6.5±1.5 to 5.3±1.2L/min) did not change significantly during the induction of anaesthesia. Cardiac efficiency was found to be a more sensitive parameter to describe changes in the right ventricular function than the ejection fraction and cardiac output during induction of anaesthesia with eltanolone and fentanyl which was used as a model to vary cardiac performance and afterload.     

Variants of hemodynamic response in transesophageal pacing in patients with chronic circulatory insufficiency

Compared were hemodynamic responses to transesophageal pacing (TEP) in 86 patients with symptoms of chronic circulatory insufficiency (CCI) and 46 healthy individuals. Cardiac output was assessed by tetrapolar chest rheogram under stimulation and its discontinuation, and end diastolic pressure (EDP) in the left ventricle. Stroke volume was diminished in all the examinees. Cardiac output changed in different directions. Poststimulation recovery of cardiac output was different. Contribution of ejection period is discussed the prolongation of which indirectly indicates shorter time of diastole and, respectively, diastolic filling of cardiac chambers. EDP rose both in healthy controls and patients, being higher in the patients. The role of systolic and diastolic compensatory mechanisms in CCI development is considered.     

Postinversion responses to inversion in normal subjects

The purpose of this study was to determine cardiac output and related cardiovascular responses during postinversion by comparing preinversion (baseline data) to postinversion data in healthy, normal subjects. Each of 20 subjects (means = 22 years) was inverted for five minutes. Cardiac output was measured noninvasively with the Beckman MMC and CO2 rebreathing program. ANOVA with repeated measures was used to determine significance of change between preinversion and postinversion values. The alpha level was set at 0.05 for statistical significance. During postinversion stand, there were (a) significant decreases in oxygen uptake (p less than 0.0008), cardiac output (p less than 0.0005), and stroke volume (p less than 0.0018); (b) significant increases in arteriovenous oxygen difference (p less than 0.0281), peripheral vascular resistance (p less than 0.0001), and diastolic blood pressure (p less than 0.0087); and (c) nonsignificant changes in heart rate, systolic blood pressure, and double product from the preinversion baseline standing position. The results demonstrate little if any need for concern for a subject's return to the upright position.     

Clinical and haemodynamic effects of ketanserin in lean and obese hypertensive patients

Systemic and central haemodynamics were evaluated in 10 lean and 10 obese hypertensive patients (World Health Organization stage I-II) after treatment for 8 weeks with a serotoninergic antagonist, such as ketanserin. Blood pressure and heart rate were recorded and first-pass radionuclide angiocardiography was performed to determine cardiac output, cardiac index and ejection fraction of the left ventricle; total peripheral resistance was also calculated. In both obese and lean patients, ketanserin significantly reduced diastolic (P less than 0.05) and mean (P less than 0.005) blood pressure but no significant changes in systolic blood pressure, cardiac output, cardiac index and ejection fraction were observed in lean and obese hypertensive patients. Total peripheral resistance was significantly (P less than 0.05) reduced in lean patients but in obese hypertensives it was only moderately reduced. It is concluded that monotherapy with ketanserin is effective in treating mild to moderate hypertension in both lean and obese hypertensive patients, without interfering with left ventricular performance.     

Heart rate variability and hemodynamic alterations in canines with normal cardiac function during exposure to pressure support, continuous positive airway pressure, and a combination of pressure support and continuous positive airway pressure

Variations in intrathoracic pressure generated by different ventilator weaning modes may significantly affect intrathoracic hemodynamics and cardiovascular stability. Although several investigators have attributed cardiovascular alterations during ventilator weaning to augmented sympathetic tone, there is limited investigation of changes in autonomic tone during ventilator weaning. Heart rate variability (HRV), the analysis of beat-to-beat changes in heart rate, is a noninvasive indicator of autonomic tone that might be useful in the identification of patients who are at risk for weaning difficulty due to underlying cardiac dysfunction. The authors describe HRV and hemodynamics in response to 3 ventilatory conditions: pressure support (PS) 10 cmH2O, continuous positive airway pressure (CPAP) 10 cmH2O, and a combination of PS 10 cmH2O and CPAP 10 cmH2O (PS + CPAP) in a group of canines with normal ventricular function. Six canines were studied in the laboratory. Continuous 3-lead electrocardiographic data were collected during baseline (controlled mechanical ventilation) and following transition to each of the ventilatory conditions (PS, CPAP, PS + CPAP) for analysis of HRV. HRV was evaluated using power spectral analysis to define the power under the curve in a very low frequency range (0.0033 to < 0.04 Hz, sympathetic tone), a low frequency range (0.04 to < 0.15 Hz, primarily sympathetic tone), and a high frequency range (0.15 to < 0.40 Hz, parasympathetic tone). A thermodilution pulmonary artery catheter measured cardiac output and right ventricular end-diastolic volume to describe global hemodynamics. There were significant increases in very low frequency power (sympathetic tone) with a concomitant significant reduction in high-frequency power (parasympathetic tone) with exposure to PS + CPAP. These alterations in HRV were associated with significantly increased heart rate and reduced right ventricular end-diastolic volume. Although there was a small but significant increase in cardiac output with exposure to PS, HRV was unchanged. These data indicate that there was a relative shift in autonomic balance to increased sympathetic and decreased parasympathetic tone with exposure to PS + CPAP. The increase in intrathoracic pressure reduced right ventricular end-diastolic volume (preload). This hemodynamic alteration generated a change in autonomic tone, so that cardiac output could be maintained. Individuals with autonomic and/or cardiovascular dysfunction may not be capable of this type of response and may fail to successfully wean from mechanical ventilation.     

Effect of alterations of pleural pressure on cardiac output

Cardiac output is determined by the interaction of cardiac pump function and the mechanical properties of the peripheral circulation that govern venous return. Increasing pleural pressure impedes peripheral venous return but aids cardiac ejection; on the other hand, decreasing pleural pressure can augment venous return but impedes the emptying of the left ventricle, creating an increase in aortic pressure. Whether a fall in pleural pressure leads to an increase or decrease in cardiac output depends upon the functional state of the heart and its sensitivity to changes in afterload. Understanding the effect of pleural pressure on cardiac output may lead to the development of therapeutic or diagnostic techniques using altered pleural pressure.     

Combined left and right ventricular volume determination by radionuclide angiocardiography using double bolus and equilibrium technique

Summary. Eighteen patients with ischaemic heart disease were studied. Left and right ventricular volumes including cardiac output (forward flow) were determined by radionuclide angiocardiography using a double bolus and equilibrium technique. As reference, cardiac output was simultaneously measured by indicator dilution. The radionuclide technique comprised four steps:

• 1 a first-pass study of right ventricle;
• 2 a bolus study of left ventricle;
• 3 an equilibrium study of left ventricle;
• 4 determination of the distribution volume of red blood cells.

Absolute volumes of left ventricle were determined from steps 2+3+4. Absolute volumes of right ventricle were calculated from stroke volume and right ventricular ejection fraction (EF) which in turn was determined from step 1 by creating composite systolic and composite diastolic images. There was an acceptable agreement between stroke volume determinations by radionuclide angiocardiography and indicator dilution (r= 0.74; P<0.001). Stroke volume determination by radionuclide was 83±20 ml (mean±SD) and by indicator dilution 84±20 ml with a difference of -1±15 ml (NS). Cardiac output determination by radionuclide was 5.24±1.37 1 min^-1 and by indicator dilution 5.28±1.23 1 min^-1 with a difference of -0.04±0.95 1 min^-1 (NS). Left ventricular EF was 0.44 ±0.14 and right ventricular EF 0.57 ±0.10. The intra-observer coefficient of variation for duplicate calculations of the radionuclide determinations was 5.5% for stroke volume, 2.5% for left ventricular EF and 4–8% for right ventricular EF.     

Obesity and hypertension: epidemiology, mechanisms, treatment

There is a close epidemiological association between obesity and elevated blood pressure for all age groups, although not every obese individual becomes hypertensive. In populations without age-related increases in body weight, an elevation of blood pressure with age is not seen. Mechanisms included in the development of hypertension in obesity are hyperinsulinemia, insulin induced sodium retention and increased sympathetic tone. Overnutrition with over intake of sodium and lack of physical exercise contribute to the metabolic syndrome of obesity. Thus, weight reduction by decreased energy uptake and increased physical exercise is recommended in the treatment of hypertension in obese patients. The resulting fall in insulin levels may lead to decreased sodium absorption in the kidney. Although treatment of obesity by weight loss decreases blood pressure substantially, a minority of patients do not respond to the weight loss. Blood pressure generally decreases before normal weight is achieved. Salt intake reduction does not appear to explain why weight reduction lowers blood pressure. Reduced levels of plasma renin activity, serum aldosterone levels, catecholamine levels and serum insulin levels may be involved in the blood pressure lowering associated with weight loss. Since the risk of cardiovascular disease in the hypertensive patient is not only determined by the blood pressure, an overall treatment which aims at reduction of other risk factors such as glucose intolerance and hyperlipoproteinemia is advocated. Thus, in any obese hypertensive patient normalization of excess body weight and increased physical activity appears to be the first and most important step of any rational therapeutic strategy.     

Digitalis-Induced Increase in Aortic Regurgitation and the Contrasting Effects of Glucagon in the Sedated Dog

The hemodynamic and phasic ascending aortic flow changes induced by acetylstrophanthidin and glucagon were studied in closed-chest sedated dogs with aortic regurgitation. While the positive inotropic effect of both agents was reflected in an increase in peak rate of rise of left ventricular pressure, acetylstrophanthidin increased aortic regurgitation, while glucagon decreased it. With the former, left ventricular end-diastolic pressure rose from 20+/-6 to 27+/-6 mm Hg (P < 0.005), but fell from 18+/-4 to 11+/-3 mm Hg (P < 0.001) with glucagon. Acetylstrophanthidin increased systemic vascular resistance, aortic diastolic pressure, and diastolic regurgitant flow rate, and, heart rate and the duration of regurgitation per beat and per minute being unchanged, regurgitant flow per beat increased 32+/-15% (P < 0.001). Glucagon decreased regurgitant flow per beat 27+/-14% (P < 0.001) because of abbreviation of diastole associated with tachycardia, and because of reduction in regurgitant flow rate. Despite tachycardia, the duration of regurgitation per minute was unchanged, and the small fall in regurgitant blood flow per minute was not significant, but this pertained in the face of 47% increase in effective cardiac output (P < 0.001). In contrast, acetylstrophanthidin increased regurgitant flow per minute 28+/-14% (P < 0.001) without change in effective cardiac output. The increase in cardiac contractility, tachycardia, and systemic vasodilatation induced by glucagon preferentially enhanced forward blood flow, which led to reduction in left ventricular volume overload, while it increased cardiac output. Contrarily, acetylstrophanthidin increased aortic regurgitation and, despite its inotropic effect, increased left ventricular volume overload without an increase in cardiac output.     

Relative rates of oxidation of glucose and free fatty acids by ischaemic and non-ischaemic myocardium after coronary artery ligation in the dog

Abstract. 1. Small regional ischaemic lesions, involving about 7 % of the volume of the whole heart, were produced in the greyhound dog by ligation of a branch of the anterior descending coronary artery. Arteriovenous differences across ischaemic tissue were studied by cannulation of a local vein visibly draining the ischaemic area, whereas arteriovenous differences across the non-ischaemic tissue were obtained by coronary sinus samples. This system permitted study of those ischaemic cells draining into the local vein and perfused by residual collateral circulation. Flow factors were common to all metabolites measured in local venous blood, thereby allowing detection of changes in substrate metabolism relative to each other. As the contribution of local venous blood to coronary sinus blood was negligible, it was possible to use coronary sinus values as non-ischaemic control data for each local venous sample.—2. The contributions of glucose, free fatty acids (FFA) and other substrates (lactate, pyruvate, ketones, triglycerides) to the residual oxidative metabolism of the ischaemic, infarcting dog myocardium were indirectly assessed by calculations of the oxygen extraction ratio (OER), and directly by the rate of ¹⁴CO₂ formation from ¹⁴C-labelled glucose or palmitic acid.—3. Within two hours of arterial ligation, the arteriovenous difference of glucose across the ischaemic tissue was increased relative to that of IT A. Whether calculated from OER or from ¹⁴CO₂ data, there was an increase in the oxidation rate of glucose relative to that of FFA. In absolute terms the oxygen uptake of ischaemic tissue fell almost as much as the flow rate, and the glucose uptake probably fell too. Nevertheless, glucose competed more favourably than did FFA for the residual oxidative metabolism of the ischaemic tissue.—4. In coronary sinus blood, draining predominantly non-ischaemic tissue, formation of ¹⁴CO₂ accounted for about half the uptake of ¹⁴C-glucose and formation of ¹⁴C-lactate was very low. In local venous blood draining predominantly ischaemic tissue, ¹⁴CO₂ formation accounted for about 30–40% and ¹⁴C-lactate for about 10% of the arteriovenous difference of ¹⁴C-glucose. The chemical oxygen extraction ratio of glucose and FFA could account for 90–100% of the residual oxygen uptake of the ischaemic myocardium 60–100 min. post-ligation, with glucose accounting for nearly twice as much oxygen as FFA. Thus an unexpected finding was that a major part of the glucose extracted by the ischaemic myocardium was oxidized, possibly because local venous blood drained the less severely ischaemic areas.—5. The major fate of labelled FFA extracted by the non-ischaemic myocardium also appeared to be oxidation. After arterial ligation, rates of FFA oxidation fell as assessed by both OER calculation and by rates of ¹⁴CO₂ formation. More ¹⁴C-label was recovered in the “mitochondrial” and less in the “microsomal” lipid fractions of the ischaemic tissue.—6. Lactate uptake by the normal myocardium was changed to lactate discharge by the ischaemic myocardium. Initially, tissue glycogen was the major source of the lactate formed, but 60–120 min. after arterial ligation there was less discharge of lactate and circulating ¹⁴C-gIucose became a major source of venous lactate.—7. It was concluded that not only was anaerobic metabolism of glucose accelerated by coronary artery ligation, but the aerobic metabolism of glucose increased relative to that of FFA.