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Biomedical subjects

L J Hirsch

Publications and source records attributed to L J Hirsch.

At least 55 records · Page 3Linked to original sources
PubMed1991

Skeletal muscle blood flow and O2 uptake during intravenous nicotine with and without hypertension.

The mechanism by which nicotine causes peripheral vasoconstriction and its relationship to the increased risk of peripheral vascular disease in smokers are unknown. To study the peripheral vascular effects of nicotine, we measured hemodynamic responses and oxygen consumption of the in situ gracilis muscle during intravenous (i.v.) nicotine infusions in anesthetized dogs. Nicotine 36.0 micrograms/kg/min increased gracilis artery pressure (Pga) 91 +/- 17% and muscle vascular resistance (MVR) 96 +/- 18% whereas muscle blood flow (MBF) and oxygen consumption (MVO2) were unchanged from baseline. In dogs with extracorporeal-controlled normotension during nicotine infusion, however, Pga was held at baseline levels but similar increases in MVR were observed (95 +/- 11%) as flows decreased 52 +/- 9%. Oxygen consumption decreased in direct proportion (53 +/- 5%) to MBF, indicating complete impairment of oxygen extraction (A-VO2). Thus impaired oxygen extraction was masked in dogs in which Pga was allowed to increase because of sustained pressure-dependent flows. Phenoxybenzamine block of muscle alpha-adrenoceptors increased MBF and MVO2 in both normotensive and hypertensive dogs. Combined alpha- and beta-blockade effectively neutralized all sympathoadrenal responses in the muscle. All the above results occurred regardless of innervation. Plasma levels of norepinephrine (NE) and epinephrine (EPI) increased greater than 1,000% during nicotine infusion. Apparently, these levels were high enough to (a) override dilator effects of plasma EPI and (b) cause vasoconstriction in muscle independent of nerve supply. Infusion of nicotine in the gracilis artery had no effect on muscle hemodynamics. Nicotine-induced increase in plasma catecholamines resulted in a powerful constriction of both resistance and oxygen-exchange vessels of skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Norepinephrine and phenylephrine effects on right ventricular function in experimental canine pulmonary embolism.

In a canine model of pulmonary embolism (PE) produced by infusion of autologous blood clots, mean arterial blood pressure (MAP) decreased to 73 +/- 4 mm Hg while cardiac output (CO) decreased to less than 50 percent of baseline. Intravenous infusion of phenylephrine (PHEN) and norepinephrine (NE) restored MAP to somewhat above baseline values. However, only NE restored CO to control levels. The right ventricular myocardial blood flow increased 15 percent in the PE group with PHEN and 229 percent with NE at equipressor concentrations. The right ventricular myocardial oxygen consumption (RVMVo2) was not significantly different between PE and PE + PHEN while PE + NE increased RVMVO2 by 144 percent to 20.2 +/- 1.8 ml/min/100 g. The RV output was not adequately restored with PE, but when RV contractility was augmented with NE, RV output was restored to baseline. Right ventricular minute work increased 100 percent with NE and was maintained with a 100 percent increase in oxygen consumption. Calculated pulmonary vascular resistance (PVR) was decreased during PE by 36 percent with PE + PHEN while PVR in NE-treated dogs decreased by 59 percent. In NE-treated animals, systemic vascular resistance (SVR) was restored to control levels while in PHEN-treated animals SVR increased about 75 percent from baseline. We conclude that the salutary effects of NE on RV output are due to both alpha and beta receptor stimulation, which increased contractility, RVMBF, and RVMVo2, and decreased both PVR and SVR. In the PHEN-treated dogs, our indices of minute-work, RVMBF, and RVMVo2 suggest that coronary autoregulation was intact; however, there was no apparent benefit to RV output. This study suggests that in the clinical setting of acute PE, the judicious use of NE, rather than PHEN, may be more beneficial in restoring RV function and systemic hemodynamics.

Animals↗
PubMed1988

Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus.

To determine whether non-insulin-dependent diabetes is associated with specific alterations in the pattern of insulin secretion, we studied 16 patients with untreated diabetes and 14 matched controls. The rates of insulin secretion were calculated from measurements of peripheral C-peptide in blood samples taken at 15- to 20-minute intervals during a 24-hour period in which the subjects ate three mixed meals. Incremental responses of insulin secretion to meals were significantly lower in the diabetic patients (P less than 0.005), and the increases and decreases in insulin secretion after meals were more sluggish. These disruptions in secretory response were more marked after dinner than after breakfast, and a clear secretory response to dinner often could not be identified. Both the control and diabetic subjects secreted insulin in a series of discrete pulses. In the controls, a total of seven to eight pulses were identified in the period from 9 a.m. to 11 p.m., including the three post-meal periods (an average frequency of one pulse per 105 to 120 minutes), and two to four pulses were identified in the remaining 10 hours. The number of pulses in the patients and controls did not differ significantly. However, in the patients, the pulses after meals had a smaller amplitude (P less than 0.03) and were less frequently concomitant with a glucose pulse (54.7 +/- 4.9 vs. 82.2 +/- 5.0, P less than 0.001). Pulses also appeared less regularly in the patients. During glucose clamping to produce hyperglycemia (glucose level, 16.7 mmol per liter [300 mg per deciliter]), the diabetic subjects secreted, on the average, 70 percent less insulin than matched controls (P less than 0.001). These data suggest that profound alterations in the amount and temporal organization of stimulated insulin secretion may be important in the pathophysiology of beta-cell dysfunction in diabetes.

Blood Glucose↗
PubMed1986

Dexamethasone modulates lipoprotein metabolism in cultured human monocyte-derived macrophages. Stimulation of scavenger receptor activity.

Human monocyte-derived macrophages (HMM) play a key role in the formation of atherosclerotic plaques by accumulating cholesteryl ester (CE) to become foam cells. HMM have receptors for native low density lipoprotein (LDL) and acetylated-LDL (ALDL), and uptake of ALDL can promote substantial cellular CE accumulation. Furthermore, macrophages specifically and saturably bind glucocorticoids, which in turn modulate numerous macrophage functions. Preincubating HMM in dexamethasone-inhibited LDL degradation (230 +/- 12 vs. 515 +/- 21 ng/mg cell protein X 18 h, P less than 0.001) but stimulated ALDL degradation (5.3 +/- 0.5 vs. 2.5 +/- 0.3 micrograms/mg X 18 h, P less than 0.01). These effects were time- and dose-dependent, occurring maximally by 24 h and with 2.5 X 10(-8) M dexamethasone. Dexamethasone increased the maximum velocity for ALDL degradation (16.2 vs. 12.0 micrograms/mg X 18 h, P less than 0.01) without changing the apparent Michaelis constant. Progesterone, 11 alpha-epicortisol, and 17 alpha-OH progesterone (a competitive antagonist of the glucocorticoid receptor) had no effect on HMM ALDL degradation, but 17 alpha-OH progesterone abolished the stimulatory action of dexamethasone. In he presence of ALDL, incorporation of [14C]oleic acid into CE was enhanced over fourfold by dexamethasone (4015 +/- 586 vs. 943 +/- 91 cpm/mg X 2 h, P less than 0.01), and HMM incubated with ALDL and dexamethasone accumulated more free cholesterol (34.6 +/- 1.9 vs. 26.2 +/- 0.8 micrograms/mg, P less than 0.02) and CE (32.8 +/- 2.3 vs. 14.8 +/- 0.8 micrograms/mg, P less than 0.002) than did macrophages without dexamethasone. In cultured human umbilical vein endothelial cells, dexamethasone did not change ALDL degradation, but reduced LDL degradation by 30% (P less than 0.001). In summary, dexamethasone inhibits LDL receptor activity by both macrophages and endothelial cells, but stimulates ALDL receptor activity only in macrophages. These observations provide evidence for the regulation of macrophage endocytic receptors by glucocorticoid hormones.

17-alpha-Hydroxyprogesterone↗
PubMed1983

Studies on the mechanism by which exogenous glucose is converted into liver glycogen in the rat. A direct or an indirect pathway?

To quantify the extent to which exogenous glucose is used directly or indirectly for hepatic glycogen synthesis, fasted rats were given [U-14C,3-3H] glucose intragastrically, intravenously, or as a component of a solid diet eaten ad libitum. In all cases liver glycogen was deposited at high linear rates over a 3-h period. Portal vein glucose levels seldom exceeded 8 mM. At a time when the specific activities of 3H and 14C in circulating glucose were identical with those in the administered material their values in newly synthesized glycogen were reduced by 72-88% and 50-65%, respectively. An intragastric load of unlabeled glucose sufficient to suppress completely hepatic glucose output greatly stimulated the incorporation of intravenously infused [14C]bicarbonate, [14C]lactate, [14C]alanine, and [14C] glutamine into liver glycogen. Using an improved assay the ability of liver homogenates to phosphorylate glucose at concentrations of 5-10 mM was found to be far short of what would be needed if glucose were used directly to support hepatic glycogen synthesis in vivo. These data support the notion that in the rat a major fraction of liver glycogen deposited in response to exogenous carbohydrate is formed by a pathway involving glucose leads to C3 unit leads to glycogen, although the site of the initial steps in the sequence is not yet known. The limited capacity of the liver to utilize intact glucose for glycogen synthesis might reside in its limited capacity to phosphorylate the sugar at physiological concentrations.

Animals↗
PubMed1983

Mesenteric blood flow response to dopamine infusion during myocardial infarction in the awake dog.

This study was designed to determine the effects of dopamine on the superior mesenteric arterial circulation of conscious dogs subjected to experimental myocardial infarction. Electromagnetic blood flow transducers were implanted on the superior mesenteric artery in 10 dogs. Direct infusion into the superior mesenteric artery of dopamine (2.5 micrograms/kg/min) after induction of acute myocardial infarction (AMI) revealed a steadily decreasing ability of dopamine to produce mesenteric vasodilation; 4 hr after AMI, infusion of dopamine decreased mesenteric resistance only 14 +/- 0.05%, which was significantly less (P less than 0.001) than during the control period when it decreased resistance 41 +/- 1.0%. Isoproterenol (N = 3) produced substantial increases in flow, despite the reduction in effectiveness of dopamine. Treatment of the 10 dogs with phenoxybenzamine, 5 mg directly into the superior mesenteric artery, restored the ability of dopamine to dilate the mesenteric bed. Beta-adrenergic blockage did not affect the dopaminergic vasodilation after alpha-blockade. The results of this study question the efficacy of dopamine to produce mesenteric vasodilation in the face of increased resistance in the splanchnic circulation during the acute myocardial infarction complicated by hypotension.

Animals↗
PubMed1982

Hepatic arterial and portal flow in cardiogenic and hemorrhagic shock in awake dogs.

The changes in liver blood flow produced by experimental cardiogenic and hemorrhagic shock are relatively unexplored. Fifteen unanesthetized dogs in which electromagnetic blood flow transducers had been implanted on the common hepatic artery and portal vein were subjected to acute myocardial infarction by mercury embolization of the circumflex coronary artery. Another group of ten dogs were bled to an arterial pressure of 40 mmHg and maintained at that level for 2 hours before reinfusion. Six additional dogs in which blood flow transducers had been implanted on the superior mesenteric artery and portal vein also were subjected to hemorrhage. In three of the six, phenoxybenzamine was infused directly into the superior mesenteric artery 45 minutes prior to bleed-out. During cardiogenic shock, both hepatic arterial and protal venous flow fell. However, whereas protal flow continued to fall, eventually stabilizing at values 36 +/- 3% of control, hepatic arterial flow subsequently rose, reaching values 93 +/- 9% above control. Total liver blood flow, after an initial decline to 53 +/- 4% of control levels rose as a result of the increased hepatic arterial flow to 73 +/- 4% of control values. During hemorrhage, both hepatic arterial and protal venous flows decreased as aortic pressure fell. Within 5 minutes of reinfusion, hepatic arterial flow surpassed its control values. Portal flow also increased but, on a percentage basis, not to so great an extent. Flow in hepatic artery remained high for 40 minutes after reinfusion, whereas portal flow rapidly decreased to levels seen at the end of hemorrhage. In hemorrhage without alpha-adrenergic receptor blockade the superior mesenteric bed constricted, thereby supporting systemic pressure. With alpha-adrenergic blockade, however, mesenteric flow became pressure-dependent and no longer acted as a homeostatic mechanism.

Animals↗
PubMed1981

Cross-sectional echocardiographic visualization of abnormal systolic motion of the left ventricle in mitral valve prolapse.

In 11 of 34 patients with typical mitral valve prolapse on the M-mode echocardiogram, cross-sectional echocardiography in the apical four-chamber view revealed a characteristic abnormality not previously described. In mid- to late-systole the ventricular septum contracted vigorously, forming a bend or sharp convexity toward the left ventricle, while motion of the posterolateral basal left ventricle was diminished and delayed. This finding was not encountered in 35 other patients with innocent systolic murmurs, or in 15 patients with mitral regurgitation of etiologies other than mitral valve prolapse. This abnormal pattern of left ventricular contraction on cross-sectional echocardiography occurred with equal frequency in patients with holosystolic and late-systolic prolapse; it was seen more frequently in patients with severe prolapse than in those with mild to moderate prolapse.

Adult↗
PubMed1980

Unusual echocardiographic appearances attributable to submitral calcification simulating left ventricular "masses".

Using M-mode and cross-sectional echocardiography, we visualized in five patients abnormal large echos attributable to anterior submitral calcification or sclerosis (on or near the ventricular aspect of the anterior mitral leaflet). Such abnormal echos on M-mode echocardiography could have been mistaken for a mass in the left ventricular chamber. Autopsy in two cases confirmed the presence of nonrheumatic anterior submitral calcification. Echocardiographic features of anterior submitral calcification which are helpful in differentiating it from neoplastic or thrombotic ventricular masses include (1) less diastolic mobility and more echo density; (2) continuity with the base of the anterior mitral leaflet and/or the posterior aortic root region, whereas tumors or thrombi are attached to the left ventricular wall; and (3) calcification in the region of posterior "mitral annulus." Cross-sectional long-axis views and M-mode scanning from the left ventricle to the aortic root were particularly helpful in making the differentiation.

Adult↗
PubMed1976

Direct effects of various catecholamines on liver circulation in dogs.

As measured by electromagnetic blood flow transducers, direct infusion of epinephrine, norepinephrine, and dopamine into the portal vein (PV) produced a 40-50% decrease in hepatic arterial (HA) blood flow; isoproterenol increased HA flow by about 69%. No changes in PV flow or pressure were observed. Direct HA infusion of the vasoconstrictors decreased HA flow by amounts comparable to those occurring after PV infusion. However, HA infusion of isoproterenol increased HA flow only 15% suggesting a difference in beta-receptor population in the two vessels. When infused directly into the superior mesenteric artery (SMA), epinephrine and norepinephrine reduced SMA flow by about 45% and PV flow by 20-25%; HA flow increased 6-8%. Infusion of isoproterenol and dopamine into SMA increased SMA flow by 115% and 206% and PV flow by 60% and 70%, respectively, whereas HA flow decreased by 25% and 50%. Portal vein pressure increased less than 3 mmHg. Alpha- and beta-receptor blockade of the liver did not change significantly the alterations in hepatic arterial blood flow that were secondary to changes in portal venous blood flow. It is likely that regulation of hepatic arterial flow resides in mechanisms located within the liver sinusoids.

Adrenergic beta-Antagonists↗
PubMed1975

Contrasting splenic mechanisms in the blood clearance of red blood cells and colloidal particles.

We have studied the blood clearance and organ uptake of colloidal particles and of antibody-coated and chemically treated Na2 51Cr O4-labeled erythrocytes (RBC) in mice. Hepatic and splenic uptake of both colloidal particles and autologous RBC coated with rabbit antibody were reduced significantly following pretreatment of animals with cortisone acetate. Hepatic removal of RBC previously treated in vitro with N-ethyl-maleimide (NEM) or phenylhydrazine-HCl (PHZ) was similarly depressed by pretreatment with cortisone. In contrast, the splenic uptake of NEM- and PHZ-altered erythrocytes was unaffected by cortisone. Scanning and transmission electron microscopic examination of perfused spleens from PHZ-injected animals demonstrated extensive mechanical trapping of Heinz body-containing RBC in sinus wall apertures, whereas little erythrophagocytosis was observed. These studies suggested that, while clearance of inert particulate matter and of antibody-coated RBC from the blood occurred primarily by a cortisone-suppressible, presumably phagocytic process in the spleen, chemically altered RBC were removed primarily by a cortisone-insensitive filtration process in the splenic microvasculature.

Animals↗