Role of glucagon as a contributor to glucose intolerance in acute and chronic uremia

It has been suggested that increased sensitivity to glucagon may contribute to glucose intolerance in uremia. In order to evaluate this possibility systematically, we have assessed the effect of glucagon on hepatic glucose outflow, formation of cAMP, and activation of adenylate cyclase by livers obtained from acutely and chronically uremic rats and their respective sham operated controls. Glucagon infused at rates of 6 ng/min/kg rat resulted in minimal and equivalent increases in hepatic glucose outflow and cAMP accumulation when livers from acutely uremic and control rats were perfused for 30 min. However, at glucagon infusion rates of 18 ng/min/kg, glucose efflux from perfused livers of acutely uremic rats was significantly reduced (p < 0.001) compared to perfused livers of control rats (4.64 ± .9 vs 12.7 ± 2.4 μmol/g liver) and cAMP accumulation was also significantly lower (p < 0.01) (1352 ± 222 vs 3100 ± 348 pmol/g liver). Basal adenylate cyclase activity of hepatic membranes obtained from uremic and control rats was similar, and was stimulated by glucagon concentrations ranging from 10^?8 to 10^?6 at equivalent rates in both groups. In livers from chronically uremic rats, glucagon infused at rates of 6 ng/kg/min significantly increased hepatic glucose outflow (32.5 ± 6.9 μmolg liver). However this was not greater than that of control animals (37.6 ± 9.2). Furthermore, cAMP accumulation was significantly lower (p < .02) in chronically uremic rats than in controls, and activation of adenylate cyclase by glucagon was similar in both groups. These findings indicate that glucagon does not increase glucose efflux, cAMP accumulation or enhance activation of adenylate cyclase by isolated perfused livers from either acutely or chronically uremic rats. Thus, glucose intolerance in uremic rats does not appear to be due to increase hepatic glucose output resulting from increased sensitivity to glucagon.     

Cardiocirculatory and myocardial energetic effects of prostaglandin E1 in severe left ventricular failure due to chronic coronary heart disease

The cardiocirculatory actions of brief (69 ± 5 minutes) infusions of prostaglandin E₁ were evaluated in nine chronic coronary heart disease patients with severe left ventricular (LV) failure caused by previous myocardial infarction. Prostaglandin E₁ infusion did not alter heart rate (HR) and produced modest declines in mean systemic blood pressure (BP) (85 ± 6 to 76 ± 5 mm Hg, p < 0.025) and LV filling pressure (19 ± 3 to 15 ± 2 mm Hg, p < 0.01). Simultaneously, prostaglandin E₁ augmented LV pump function raising cardiac index from 1.9 ± 0.2 to 2.5 ± 0.2 L/min/m² (p < 0.005), elevating stroke index from 28 ± 2.4 to 35 ± 2.9 ml/beat/m² (p < 0.01), and increasing stroke work index from 26 ± 4.3 to 30 ± 4.4 gm·m/m² (p < 0.02). Additionally, total systemic vascular resistance decreased from 1862 ± 192 to 1282 ± 100 dynes-sec-cm^?5 (p < 0.02) and double product LV aerobic index of HR · systolic BP diminished from 9492 ± 666 to 8278 ± 493 (p < 0.02). Concomitantly, in the forearm, vascular resistance fell, blood flow rose, and venous tone remained unchanged. These results indicate that prostaglandin E₁ is a potent systemic arteriolar dilator with markedly beneficial effects on cardiac function in chronic coronary patients having severe ischemic LV failure refractory to conventional therapy.     

Mechanism of action of hyaluronidase in decreasing myocardial ischemia post coronary occlusion in the isolated perfused rabbit heart

The influence of hyaluronidase (H) on subacute experimental myocardial ischemia was studied in isolated perfused rabbit hearts. Changes in ischemic area were assessed by epicardial nicotinamide adenine dinucleotide (NADH) fluorescence photography, an intrinsic high-resolution display of myocardial ischemia. Computerized determination of ischemic area was made from standardized photographs. Hyaluronidase was begun 20 minutes after coronary artery occlusion at 4 units/ml perfusate. NADH fluorophotographs were taken at 10-minute intervals up to 60 minutes of ischemia. Coronary sinus oxygen tension (P_csO₂), myocardial oxygen consumption (MV?O₂), and coronary flow were determined. After 70 minutes, the hearts were perfused with rhodamine solution to identify areas of myocardial perfusion. In 13 H-treated hearts 54.3% ± 3.7% (mean ± SEM) of the nonperfused area (rhodamine stained) was ischemic (NADH fluorescent). In 14 untreated hearts 79.8% ± 3.2% of the nonperfused area was ischemic (p < 0.0001) and the ischemic areas were uniform. The distance between perfused and ischemic tissue was 952 ± 78 μm in the H hearts and 504 ± 35 μm in the untreated hearts (p < 0.0001). In the H treated hearts P_csO₂ increased to 155% of the post-ligation control while it decreased to 79% in the untreated hearts (p < 0.0001). MV?O₂ decreased in the H-treated hearts to 62%; the untreated hearts had no further change. In the H-treated hearts, coronary flow increased to 146% of the post-ligation control while it fell to 91% in the untreated group (p < 0.0001). We conclude that H increases coronary flow while decreasing MV?O₂ during subacute ischemia. In H-treated hearts, significant amounts of myocardium remain normoxic within the nonperfused areas, and may potentially be salvaged after prolonged myocardial ischemia.     

Exercise training improves lipoprotein lipid profiles in patients with coronary artery disease

The effects of endurance exercise training on plasma lipoprotein lipids were determined in 10 men, ages 46 to 62 years, with coronary artery disease (CAD). Patients maintained body weight, health-related behaviors, and stable diets throughout the program. Training was at 50% to 85% of maximal oxygen consumption (V?O₂ max) for 40 to 60 minutes, 3 to 5 days/week for 29 ± 7 weeks. Training increased V?O₂ max (31 ± 19%, p < 0.001), reduced plasma cholesterol (C) (?8 ± 4%, p < 0.01), low-density lipoprotein-C (LDL-C) (?9 ± 9%, p < 0.01), and triglyceride (TG) (?13 ± 32%, p < 0.05) concentrations, and increased high-density lipoprotein-C (HDL-C) levels (11 ± 13%, p < 0.05) and $\text{HDL-C}\text{LDL-C}$ ratios (25 ± 20%, p < 0.01). Changes in LDL-C and V?O₂ max were correlated (r = ?0.73, p ± 0.01), while the changes in LDL-C and HDL-C each correlated inversely with pretraining lipoprotein levels (^rLDL-C = ?0.77, p < 0.01; ^rHDL-C = ?0.68, p < 0.05). Thus potentially “antiatherogenic” benefits of exercise seem to be due to a training effect, since they correlate best with changes in V?O₂ max and are maximal in patients with initially low V?O₂ max, high LDL-C, and low HDL-C levels.     

Arterial-venous differences of plasma catecholamines in man

To investigate the relationship between forearm venous levels of catecholamines and systemic levels, simultaneous arterial and forearm vein blood samples were obtained from 14 subjects undergoing elective dental procedures and assayed with a sensitive and specific radioenzymatic assay. Baseline venous levels of norepinephrine were greater than arterial levels (305 ± 30 pg/ml versus 221 ± 18; ± SEM, p < .005). Conversely, arterial epinephrine levels were higher than venous (132 ± 17 pg/ml versus 80 ± 10; p < .005). There was a significant relationship between arterial and venous levels of both norepinephrine (r = .77, p < .01) and epinephrine (r = .67, p < .01). The arterial-venous epinephrine difference increased from the baseline value of 44 ± 14 pg/ml to 108 ± 16 (p < .005) by 3 min after subcutaneous injection of epinephrine (18 μg), but the arterial-venous difference returned to 65 ± 24 by 5 min after injection (p = NS versus baseline). These findings indicate that under the conditions of this study, forearm tissues produced more norepinephrine than they removed, but removed more epinephrine than they produced. Baseline venous and arterial levels were related; when epinephrine production was augmented, there was a short time lag for the venous epinephrine increase.     

Effects of oral zinc loading on zinc metabolism in humans—I: Experimental studies

The effects of oral zinc on distribution, retention and excretion of orally administered ⁶⁵Zn were studied in 50 patients with taste and smell dysfunction. The study was conducted in three phases. In the first phase all patients were studied for 21 days after receiving 3–18 μCi of ⁶⁵Zn as ZnCl₂ orally after an overnight fast. In the second phase, started after 21 days and continued for 290 to 440 (mean 336) days, all 50 patients received placebo for ZnSO₄. In the third phase 14 patients continued on placebo while 36 received ZnSO₄ (100mg/day Zn⁺⁺) for 112 to 440 (mean 307) days. Phases two and three were a controlled clinical trial of the effects of zinc on retention of ⁶⁵Zn tracer. Total body retention and activity in plasma and red blood cells were measured for all patients throughout the study. Ten of the 36 patients treated with ZnSO₄ had additional measurements of ⁶⁵Zn activity in liver and thigh made using external detectors. Total body retention during the second phase placebo period was not significantly different (p > 0.25) for the 36 subjects subsequently treated with ZnSO₄ (biological half-time (T_b) 378 ± 12 days) (mean ± SEM) and the 14 who were continued on placebo through the third phase of the study (T_b = 384 ± 8 days). During the third phase patients receiving ZnSO₄ showed an accelerated loss of total body ⁶⁵Zn (T_b = 235 ± 8 days) which was significantly different (p < 0.001) from half-time values during placebo treatment. Accelerated loss of ⁶⁵Zn from the thigh was apparent immediately, while that from the liver began after a mean delay of 107 days. There was no apparent effect of zinc on loss of mean ⁶⁵Zn activity from red blood cells.     

Lack of Effect of Nitrates on Exercise Stress Test Results in Patients with Microvascular Angina

Purpose

To assess the effects of short-acting nitrates on exercise stress test (EST) results and the relation between EST results and coronary blood flow (CBF) response to nitrates in patients with microvascular angina (MVA).

Methods

We completed 2 symptom/sign limited ESTs on 2 separate days, in a random sequence and in pharmacological washout, in 29 MVA patients and in 24 patients with obstructive coronary artery disease (CAD): one EST was performed without any intervention (control EST, C-EST), and the other after sublingual isosorbide dinitrate, 5 mg (nitrate EST, N-EST). CBF response to nitroglycerin (25 μg) was assessed in the left anterior descending coronary artery by transthoracic Doppler-echocardiography.

Results

At C-EST. ST-segment depression ≥1 mm (STD) was induced in 26 (90 %) and 23 (96 %) MVA and CAD patients, respectively (p?=?0.42), whereas at N-EST, STD was induced in 25 (86 %) and 14 (56 %) MVA and CAD patients, respectively (p?=?0.01). Time and rate pressure product at 1 mm STD increased during N-EST, compared to C-EST, in CAD patients (475?±?115 vs. 365?±?146 s, p?<?0.001; and 23511?±?4352 vs. 20583?±?6234 bpm?mmHg, respectively, p?=?0.01), but not in MVA patients (308?±?160 vs. 284?±?136 s; p?=?0.19; and 21290?±?5438 vs. 20818?±?4286 bpm?mmHg, respectively, p?=?0.35). In MVA patients, a significant correlation was found between heart rate at STD during N-EST and CBF response to nitroglycerin (r?=?0.40, p?=?0.04).

Conclusions

Short-acting nitrates improve EST results in CAD, but not in MVA patients. In MVA patients a lower nitrate-dependent coronary microvascular dilation may contribute to the lack of effects of nitrates on EST results.     

Influence of oxygen on perfused capillary density and capillary red cell velocity in rabbit skeletal muscle

The pattern of capillary blood flow changes was investigated in rabbit tenuissimus muscle as a function of oxygen tension in the solution suffusing the muscle. The density of perfused capillaries decreased from 269 ± 22 (mean ± SD) to 6 ± 10 cap/mm² when ambient pO₂ was elevated progressively from 5 to 100 mm Hg. In the same pO₂ range capillary red cell velocity decreased from 0.29 ± 0.14 (mean ± SD) to 0.18 ± 0.06 mm/sec in the capillaries which were perfused. During exposure of the muscle to atmospheric oxygen tension (pO₂ = 150 mm Hg) there were no capillaries perfused and hence flow velocity was zero in all capillaries. The results demonstrate that oxygen influences capillary blood flow over an extensive range of oxygen tensions. The anatomical structures responsible for the alterations in both capillary density and capillary flow velocity are the arterioles. This site of control determines actively the total blood flow through the capillary bed, whereas passive factors seem to determine the distribution of the flow between specific capillaries. The results do not support the existence of precapillary sphincters controlling perfused capillary density.     

Periovulatory enhancement of spontaneous prolactin secretion in normal women

The role of endogenous estrogen in the regulation of prolactin secretion in man is controversial. To study this question further, spontaneous prolactin patterns were determined over 5 hr in 10 normal women during the early follicular and again during the periovulatory phases of the menstrual cycle. Steroid determinations revealed significant elevations in mean ±1 SE E₁ (113 ± 20 versus 55 ± 5 pg/ml), E₂ (144 ± 47 versus 48 ± 9 pg/ml), and 17-OHP (1,301 ± 266 versus 639 ± 46 pg/ml) during the periovulatory compared to the early follicular phase period. Each subject demonstrated increased mean plasma prolactin concentration during the higher estrogen state. Mean prolactin concentration (calculated from the individual mean values of samples obtained at 15 min intervals for 5 hr) during the midcycle study period was 10.7 ± 1.0 ng/ml compared to the early follicular phase period of 8.1 ± 1.0 ng/ml (p < 0.0005). The mean percent increment in plasma prolactin during the periovulatory period was 39% with a range of 9 to 117%. There was no correlation between mean prolactin and serum E₁, E₂, P, or 17-OHP levels during either study period. However, the incremental change in prolactin showed a positive correlation with the incremental increase in E₂ (correlation coefficient, r = 0.66, p < 0.05). In contrast, no significant correlation was present between mean incremental change in prolactin and E₁, P, or 17-OHP. These data suggest that enhanced cyclic estrogen secretion during the periovulatory phase of the menstrual cycle is associated with significantly increased serum prolactin concentrations.     

Interrelationships between vitamin D3 and 25-Hydroxyvitamin D3 during chronic ethanol administration in the rat

Vitamin D {D} depleted female Sprague-Dawley rats were fed for a period of 4 wk a D deficient diet containing 36% of total calories as ethanol while control animals received an isocaloric regimen where ethanol was substituted for by dextrins. In conjunction with the ethanol feeding 92 I.U. of {¹⁴C}-vitamin D₃ {{¹⁴C}-D₃} were administered by intragastric gavage 3 times 1 wk for 3 $\text{2}\text{3}$ wk. At the end of the experiment, {¹⁴C}-D₃ and {¹⁴C}-25-hydroxyvitamin D₃ {{¹⁴C}-25(OH)D₃} concentrations were analyzed in plasma, liver, striated muscle and adipose tissue. Body reserves in unchanged {¹⁴C}-D₃ were significantly reduced by ethanol treatment as seen by 24%, 26%, and 59% lower plasma (p < 0.02), muscle (p < 0.001) and adipose tissue (p < 0.001) {¹⁴C}-D₃ concentrations in ethanol-treated compared to control rats. In contrast total plasma and liver {¹⁴C}-25(OH)D₃ content were increased by 30% (p < 0.05) and 55% (p < 0.001) respectively. This increased liver and plasma {¹⁴C}-25(OH)D₃ following ethanol treatment was not accompanied by a proportional {¹⁴C}-25(OH)D₃ incorporation into muscle and adipose tissue. These results suggest that during steady state conditions 25(OH)D₃ production is increased during chronic ethanol administration while the body pool in unchanged D₃ is significantly lowered. These results also point out that in the rat plasma 25(OH)D concentrations are not a reliable guide for the determination of vitamin D status during chronic ethanol administration.     

Effects of nitroprusside-induced reduction of elevated preload and afterload on global and regional ventricular function in acute myocardial infarction

To evaluate the effects of nitroprusside infusion on left and right ventricular ejection fractions and left ventricular regional wall motion, radionuclide ventriculography with simultaneous hemodynamic assessment was performed before and during nitroprusside infusion in 20 patients with acute myocardial infarction complicated by left ventricular failure and/or systemic arterial hypertension. Nitroprusside produced significant reductions in pulmonary capillary wedge pressure (21 ± 6 to 13 ± 5 mm Hg; ?38%; p < 0.001), mean arterial pressure (107 ± 19 to 90 ± 13 mm Hg; ?15.9%; p < 0.001), left ventricular end-diastolic volume index (84 ± 28 to 75 ± 23 ml/m²; ?10.7%; p < 0.001), and right ventricular end-diastolic volume index (77 ± 30 to 67 ± 27 ml/m²; ?13.0% p < 0.007), and significant increases in left ventricular ejection fraction (0.32 ± 0.12 to 0.37 ± 0.13; +15.6%; p < 0.0001), right ventricular ejection fraction (0.37 ± 0.11 to 0.45 ± 0.14; +21.6%; p < 0.001), and stroke volume index (25 ± 7 to 27 ± 7 ml/beat m²; +8.0%; p < 0.03). These beneficial changes in global ventricular performance were accompanied by no change in the regional contractile function of 90% of the abnormally contracting infarct-related left ventricular segments and improved regional wall motion of 34% of noninfarcted but abnormally contracting left ventricular segments. We conclude that nitroprusside-induced reduction of elevated preload and afterload in acute myocardial infarction results in salutary effects on global ventricular function and improved regional function of noninfarcted left ventricular segments but with less prominent effects on regional function of infarcted segments.     

Effects of hypokalemia on transmural dispersion of ventricular repolarization in left ventricular myocardium

ObjectiveTo observe effects of hypokalemia on transmural heterogeneity of ventricular repolarization in left ventricular myocardium of rabbit, and explore the role of hypokalemia in malignant ventricular arrhythmia (MVA).MethodsA total of 20 rabbits were randomly divided into control group and hypokalemic group. Isolated hearts in the control group were simply perfused with modified Tyrode's solution, and were perfused with hypokalemic Tyrode's solution in hypokalemic group. Ventricular fibrillation threshold (VFT), 90% monophasic action potential repolarization duration (APD₉₀) of subepicardial, midmyocardial and subendocardial myocardium, transmural dispersion of repolarization (TDR) and C×43 protein expression in three layers of myocardium were measured in both groups.ResultsVFT in the control group and the hypokalemic group were (13.40±2.95) V, and (7.00±1.49) V, respectively. There was a significant difference between two groups (P<0.01). APD₉₀ of three myocardial layers in the hypokalemic group were significantly prolonged than those in the control group (P<0.01). ΔAPD₉₀ in the hypokalemic group and the control group were (38.10±10.29) ms and (23.70±5.68) ms, and TDR were (52.90±14.55) ms and (36.10±12.44) ms, respectively. ΔAPD₉₀ and TDR in the hypokalemic group were significantly higher than those in the control group (P<0.05), and the increase in APD₉₀ of midmyocardium was more significant in the hypokalemic group. Cx43 protein expression of all three myocardial layers were decreased significantly in the hypokalemic group (P<0.01), and ΔCx43 was significantly increased (P<0.05). Reduction of Cx43 protein expression was more significant in the midmyocardium.ConclusionsHypokalemic can increase transmural heterogeneity of C×43 expression and repolarization in left ventricular myocardium of rabbit, and decrease VFT and can induce MVA more easily.     

Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

Aims/hypothesis The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is rapidly degraded in vivo as a result of the combination of extensive enzymatic degradation and renal extraction. The GLP-1 receptor agonist, exendin-4, has a longer duration of action, and has recently been approved as a new agent for the treatment of type 2 diabetes mellitus. Exendin-4 is less prone to enzymatic degradation, but it is still unclear what other factors contribute to the increased metabolic stability. Materials and methods The overall metabolism of GLP-1 and exendin-4 was directly compared in anaesthetised pigs (n=9). Results Metabolism of GLP-1 (C-terminal RIA; t _1/2 2.0±0.2 min, metabolic clearance rate [MCR] 23.2±2.8 ml min⁻¹ kg⁻¹; N-terminal RIA; t _1/2 1.5±0.2 min, MCR 88.1±10.6 ml min⁻¹ kg⁻¹) was significantly faster than the metabolism of exendin-4 (t _1/2 22.0±2.1 min, p<0.0001; MCR 1.7±0.3 ml min⁻¹ kg⁻¹, p<0.01). Differences in arteriovenous concentrations revealed organ extraction of GLP-1 by the kidneys (C-terminal 56.6±2.6%; N-terminal 48.3±5.9%), liver (N-terminal 41.4±3.8%), and peripheral tissues (C-terminal 42.3±6.0%; N-terminal 33.0±7.8%), whereas organ extraction of exendin-4 was limited to the kidneys (21.3±4.9%). While the renal extraction of exendin-4 (6.9±2.5 pmol/min) did not differ significantly from the amount undergoing glomerular filtration (8.4±2.0 pmol/min), the renal extraction of C-terminal GLP-1 (9.0±1.1 pmol/min), exceeded the amount which could be accounted for by glomerular filtration (4.2±0.5 pmol/min, p<0.0005). Conclusions/interpretation In addition to an increased resistance to enzymatic degradation, the increased stability of exendin-4 is the result of reduced differential organ extraction compared to GLP-1. The data suggest that in the anaesthetised pig, extraction occurs only in the kidney and can be fully accounted for by glomerular filtration.     

Plasma catecholamine concentrations in hyperthyroidism and hypothyroidism

Using a modification of the fluorometric method of Anton and Sayre,⁴ we have measured the plasma epinephrine (E) and norepinephrine (NE) concentrations in patients with thyroid dysfunction. There was no significant difference in plasma E in hyperthyroid or hypothyroid subjects, the values being similar to those observed in normal subjects. There was a striking relationship between age and plasma NE in the euthyroid individuals (r = 0.685, p < 0.001, n = 41). Observed plasma NE concentrations were similar in control subjects (21.05 ± 1.6 ng/100 ml; mean ± SEM) and hyperthyroid patients (22.33 ± 2.0 ng/100 ml). However, plasma NE was significantly increased in hypothyroidism (35.46 ± 3.9 ng/100 ml; p < 0.01) and remained statistically different when the age factor was excluded (31.31 ± 2.67 ng/100 ml; p < 0.025). There was no correlation between plasma NE and serum thyroxine (T₄), free thyroxine (FT₄), or triiodothyronine (T₃), in any of the three groups studied. These data indicate that hyperthyrodism is accompanied by normal plasma NE concentrations and that hypothyroidism is associated with significantly increased plasma NE concentrations, possibly in an attempt to compensate for the lack of thyroid hormones.     

The effect of uremia on circulating mevalonate metabolism in rats

Mevalonate, an essential intermediate in cholesterol synthesis, is metabolized either to sterols or by the shunt pathway to CO₂. Previous studies have demonstrated that the kidneys are the chief site of circulating mevalonate metabolism by both pathways. Following nephrectomy, as expected, the shunt pathway was reduced by greater than 50%. However, nephrectomy resulted in an enhancement of total body sterologenesis which was due to a marked stimulation of both liver and carcass sterol synthesis. The present study unexpectedly demonstrates that, even in the presence of intact kidneys, uremia induces marked alterations in the metabolism of circulating mevalonate that are similar to those observed following nephrectomy. In rats with normal renal mass the oxidation of mevalonate to CO₂ is reduced by 57% in acutely uremic and by 34% in chronically uremic animals. This reduction in shunt pathway activity directly correlates with the degree of impairment of renal function as measured by plasma BUN and creatinine levels. In contrast to the inhibition of the shunt pathway, acute and chronic uremia is associated with a two- to threefold increase in both hepatic and carcass cholesterol and nonsaponifiable lipid synthesis from circulating mevalonate. In the liver this enhancement of sterologenesis directly correlates with plasma BUN and creatinine concentrations. Renal sterologenesis from circulating mevalonate is not significantly altered by either acute or chronic uremia. This study demonstrates that uremia per se greatly alters circulating mevalonate metabolism resulting in a marked reduction in the shunt pathway and a large stimulation of sterol synthesis in both the liver and carcass.     

Effect of intraaortic balloon counterpulsation on regional myocardial blood flow and oxygen consumption in the presence of coronary artery stenosis: Observations in an awake animal model

The mechanism by which intraaortic balloon pumping ameliorates myocardial ischemia in patients with unstable angina pectoris is uncertain. Accordingly, the following study was performed to determine the effect of intraaortic balloon pumping on regional myocardial blood flow and myocardial oxygen consumption (MVO₂) distal to severe coronary artery stenosis. Nine closed chest conscious pigs were instrumented with a 7.5 mm long plastic stenosis which reduced vessel diameter by 82%. Measurements of hemodynamics, regional myocardial blood flow (microsphere technique) and MVO₂ were made (1) before intraaortic balloon pumping, (2) at the end of 15 to 20 minutes of intraaortic balloon pumping, and (3) 20 minutes after its discontinuation.Control endocardial blood flow (ml · min^{? 1} · g^{? 1}) distal to the stenosis (1.04 ± 0.20, mean ± 1 standard deviation [SD]) was less than endocardial flow in myocardium perfused by the unobstructed circumflex coronary artery (1.67 ± 0 0.77, p < 0.01). Likewise, control distal zone epicardial flow (1.16 ± 0.36) was reduced in comparison with control circumflex zone epicardial flow (1.48 ± 0.60, p < 0.01In response to intraaortic balloon pumping rate-pressure product declined versus control (10,300 ± 2,090 [SD] mm Hg · min^{? 1} to 9,110 ± 2,010, p < 0.005), whereas aortic mean diastolic pressure (mm Hg) increased versus control (109.0 ± 9.9 to 121.0 ± 13.8, p < 0.01). Distal coronary mean diastolic pressure did not change in response to intraaortic balloon pumping (61.9 ± 13.0 to 68.7 ± 16.5, p = NS). Likewise, endocardial blood flow (ml · min^{? 1} · ^{? 1}) distal to the stenosis did not change during intraaortic balloon pumping (1.00 ± 0.24) versus control (1.04 ± 0.20). In contrast, during intraaortic balloon pumping epicardial blood flow distal to the stenosis declined versus control (1.16 ± 0.36 to 1.01 ± 0.27, p < 0.05). Regional MVO₂ (ml · min^{? 1} · 100 g^{? 1}) distal to the stenosis also decreased versus control in response to intraaortic balloon pumping (12.90 ± 3.55 to 10.30 ± 2.52, p < 0.05). Furthermore, regional MVO₂ correlated well (r = 0.74, p < 0.002) with rate-pressure product.Thus, intraaortic balloon pumping reduces myocardial oxygen demand but does not improve blood flow distal to a severe coronary stenosis; (2) blood flow distal to a severe stenosis may fail to increase with intraaortic balloon pumping because (A) distal coronary mean diastolic pressure may not increase, and (B) blood vessels distal to the stenosis tend to autoregulate in response to a decline in myocardial oxygen demand; and (3) intraaortic balloon pumping ameliorates myocardial ischemia in patients with unstable angina pectoris primarily by reducing oxygen demand rather than by increasing oxygen supply.     

Effect of coronary vasodilation on ventricular fibrillation threshold: Role of exogenous vasodilators and perfusion conditions

Even without myocardial ischemia, coronary blood flow (CBF) constitutes a major determinant of ventricular fibrillation threshold (VFT). To clarify whether abnormal distribution of normal or increased CBF plays any additional role, 14 open-chest chloralose-anesthetized dogs with fixednormalized heart rate, cardiac output, and systemic arterial pressure and separate servocontrolled left main coronary artery perfusion were studied as follows: VFT was determined first with coronary perfusion pressure (CPP) set at systemic level (80 mm Hg). Then CBF index was fixed at control levels (134.0 ± 9.5 ml/min · 100 gm^?1 LV) and coronary vasodilation was induced by intracoronary infusion of adenosine until CPP decreased to 49.0 ± 2.0 mm Hg. Myocardial O₂ consumption, LV pressure, LV $\text{dp}\text{dt}$, and surface ECG remained unchanged. However, VFT decreased in all trials by about 45% (p < 0.001). When CPP was reset to 80 mm Hg while maintaining vasodilation, CBF index increased by 90% to 255.4 ± 15.4 ml/min · 100 gm^?1 LV and VFT by 26% (p < 0.005) from control. Yet these VFT increases in response to intraluminal pharmacologic vasodilation were about 19% (p < 0.002) lower than expected for similar CBF index increases occurring physiologically. We conclude that intraluminal coronary vasodilation not matched by appropriate CBF increase results in substantial decrease of VFT. Moreover, at comparable increase of CBF, spontaneous physiologic vasodilation is more effective than intraluminal pharmacologic coronary vasodilation in increasing VFT.     

Effects of perfusate viscosity on the perfused rat kidney

Elevation of blood hematocrit has been shown to result in little effect upon renal blood flow despite the resulting elevation in whole blood viscosity (L. Share, Amer. J. Physiol.171, 159–163, 1952). Perfused rat kidneys were used to study the effects of doubling the perfusate viscosity from 0.858 to 1.768 cP. A portion of the bovine serum albumin (BSA) that was present in the low viscosity perfusate (5 g% BSA) was replaced by a high molecular weight dextran (4 g% BSA + 1.4 g% dextran) so as to double the perfusate viscosity but keep the colloid osmotic pressure constant. [¹⁴C]Inulin was used to measure glomerular filtration rate (GFR) and absolute filtrate reabsorption (T_H2O). Perusion with the high viscosity perfusate reduced the arterial flow by 50% and doubled the total renal flow resistance from 4.5 ± 0.4 (SD) to 9.1 ± 0.8 mm Hg·gKw (gram kidney weight)·min·g^?1. Thus, the kidney was not capable of autoregulating the perfusate flow in response to a viscosity alteration. Both GFR and T_H2O were reduced with increased viscosity (GFR, 1.18 ± 0.16 (SD) to 0.96 ± 0.200 g/min/gKw (P < 0.05) and T_H2O, 0.75 ± 0.07 to 0.59 ± 0.09 g/min/gKw, P < 0.005); however, these reductions were accompanied by a fall in ATP content of the kidneys from 1.43 ± 0.15 (SD) to 1.15 ± 0.11 μmoles ATP/gKw. This indicates that a reduction in metabolic rate due to lower O₂ delivery (lower flow) may have been responsible for these latter results.     

Acute hemodynamic effects of combined therapy with digoxin and nifedipine in patients with chronic heart failure

The acute hemodynamic effects of combining administration of digoxin (DIG) (0.01 mg/kg intravenously) with nifedipine (NFP) (10 mg sublingually) were compared with those of DIG and NFP considered alone in 12 patients with chronic congestive heart failure due to coronary artery disease (CAD, seven patients) or primary congestive cardiomyopathy (CCM, five patients); four patients also had mitral regurgitation (MR). NFP significantly reduced systolic and diastolic blood pressure (BP), systemic vascular resistance (SVR) from 1925 ± 400 (mean ± SD) to 1333 ± 256 dyne · sec · cm^?5 after 30 minutes (p < 0.00001), and left ventricular filling pressure (LVFP) from 19 ± 7.5 to 15.6 ± 4.2 mm Hg (p < 0.005). The cardiac index (CI) increased from 2.16 ± 0.47 to 2.81 ± 0.63 L/min/m² (p < 0.00001). DIG induced a significant reduction in LVFP from 18.1 ± 7.7 to 14.3 ± 5.4 mm Hg after 90 minutes (p < 0.005) and a slight increase in stroke volume index; no significant change in BP, Cl, and SVR was seen. The combination of DIG and NFP produced a significant increase in Cl from control value of 2.2 ± 0.48 to 2.95 ± 0.44 L/min/m² (p < 0.00001), and a significant reduction in LVFP from 18.1 ± 7.7 to 13 ± 4.7 mm Hg (p < 0.00001), and in SVR. Simultaneous administration of DIG and NFP resulted in an augmentation in cardiac performance greater than that achieved with either agent considered alone. The combination produced a greater output increase and a greater LVFP reduction, indicating a shift upwards and to the left to a more improved left ventricular function curve. No significant difference was seen between the hemodynamic response to the three drug regimens in patients with CAD versus patients with CCM. NFP produced a greater improvement in cardiac performance in patients with MR when compared with those without MR.     

Glucose utilization by edematous rat lungs

Edema was produced in the isolated perfused rat lung by raising left atrial pressure. Eleven control lungs consumed 18±3.9 µmoles glucose/lung · hr⁻¹ and released 17.1±4.2 µmoles lactate/lung · hr⁻¹. During pulmonary edema in 13 isolated perfused lungs, glucose consumption was 35.5±8.8 µmoles/lung · hr⁻¹ (P<.05) and lactate production was 37±5.9 µmoles/lung · hr⁻¹ (P<.05). Separation of radiolabeled glucose and lactate indicated that all lactate was derived from glucose in control and edematous lungs. We found no important difference in¹⁴CO₂ production from 1-¹⁴C, 6-¹⁴C, or¹⁴C(U)-glucose. Tissue slices of lungs made edematous in vivo had differences in glucose consumption and lactate production which were similar to those observed in the isolated lungs. Oxygen consumption by 1 mm thick lung slices was 224±9.7 µl O₂/mg DNA · hr⁻¹ in control and 218±18 µl O₂/mg DNA · hr⁻¹ in edematous lungs. When dinitrophenol was added to the medium, the QO₂ was greater in the control than in the edematous lung slices (391±22 µl O₂/mg DNA · hr⁻¹ control vs. 334±33 µl O₂/mg DNA · hr⁻¹ edema,P<.05). We concluded that pulmonary edema in the isolated rat lung is accompanied by: 1) greater glucose consumption; 2) greater lactate production; 3) no important difference in¹⁴CO₂ production from pentose pathway or tricarboxylic cycle activity; and 4) lower response of edematous tissue slices to dinitrophenol stimulation.