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Biomedical subjects

B Chernow

Publications and source records attributed to B Chernow.

At least 91 records · Page 5Linked to original sources
PubMed1987

Glucagon's chronotropic action is calcium dependent.

Evidence is increasing that many anesthetics and cardiovascular agents alter cellular Ca kinetics and flux. In prior work we demonstrated that the tachycardic effects of glucagon were significantly blunted by Ca channel blockade, but not by beta adrenergic receptor blockade. Thus, the chronotropic effects of glucagon may be dependent upon extracellular Ca levels. Based upon these observations, we tested the hypothesis that changes in circulating ionized Ca concentrations may alter glucagon's ability to increase heart rate in rats. In conscious normocalcemic rats, glucagon's tachycardic actions were dose related with peak effects obtained at 1 to 2 min and persisting approximately 10 min after 1.0 mg/kg of glucagon. The effects of altered Ca levels on glucagon tachycardia were evaluated in three groups of rats: 1) rats rendered hypercalcemic by the infusion of Ca chloride (10, 50 or 100 mg/ml/hr); 2) rats rendered hypocalcemic by infusion of the Ca chelator EDTA (15 or 30 mg/ml/hr); and 3) normocalcemic rats infused with saline. Normocalcemic rats had a mean ionized Ca level of 4.73 mg/dl. In rats, increasing Ca chloride doses resulted in increasing mean serum ionized Ca levels (5.24, 8.35 and 15.2 mg/dl, respectively), whereas increasing doses of EDTA produced progressive decreases in mean ionized Ca (3.62 and 2.13 mg/dl, respectively). Severe hypo (2.13 mg/dl)- or hypercalcemia (15.2 mg/dl) significantly blunted glucagon's chronotropic action (51 and 44%, respectively). From these data, we conclude that glucagon has its maximal tachycardic action at physiologic Ca levels (being blunted by both hyper- and hypocalcemia), indicating that this effect of glucagon is Ca dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1987

Hormonal responses to graded surgical stress.

We tested the hypothesis that selected hormonal responses to surgery reflect the degree of surgical stress. Plasma norepinephrine, epinephrine, thromboxane B2, cortisol, serum angiotensin converting enzyme, thyroxine, triiodothyronine, free thyroxine, and free triiodothyronine levels were measured preoperatively, and then one hour, 24 hours, and five days postoperatively in three groups of patients. The groups were as follows: group 1, "minimal" stress, eg, inguinal hernia repair (n = 10); group 2, "moderate" stress, eg, cholecystectomy (n = 12); and group 3, "severe" stress, eg, subtotal colectomy (n = 9). Patients in group 1 showed no significant surgery-induced changes in hormonal values. The stress-induced changes in patients in groups 2 and 3 were seen at one and occasionally 24 hours; however, by five days postoperatively, circulating hormone values had returned to preoperative levels. Increases in plasma cortisol, norepinephrine, and epinephrine, and decreases in serum angiotensin converting enzyme levels characterized the surgery-induced hormonal changes. Conclusions are as follows: hormonal responses do reflect the degree of surgical stress; the hormonal changes are transient, lasting no longer than 24 hours in patients after uncomplicated surgery; hormonal responses to minimal surgical stress are negligible.

Adult↗
PubMed1986

BAY k 8644, a calcium channel agonist, reverses hypotension in endotoxin-shocked rats.

The hypotension and depressed myocardial function frequently observed in endotoxin-induced shock are difficult to overcome pharmacologically. In this paper we demonstrate that the calcium channel agonist BAY k 8644 potently elevates blood pressure in endotoxin-shocked rats. A one time dose as low as 10 micrograms/kg of BAY k 8644 significantly elevated mean arterial pressure (MAP) in endotoxin-treated hypotensive rats while having minimal effects in normal rats. The maximum BAY k-induced percentage increase in MAP was greater in endotoxin-treated rats when compared with saline-treated control (153% vs. 120% increase respectively). BAY k 8644 also caused a dose-dependent decrease in heart rate of 37% in endotoxin-treated rats and 39% in control rats (NS vs. control). No differences in the regulatory properties of [3H]nitrendipine binding sites were discerned comparing control and endotoxin-treated rats. Thus, the enhanced activity of BAY k 8644 in hypotensive rats was not due to augmented affinity for the cardiac dihydropyridine binding site. These results demonstrate that the use of calcium channel agonists might represent a unique pharmacologic approach in pathologic states characterized by hypotension and diminished cardiac function.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

Glucagon is an antagonist of morphine bradycardia and antinociception.

Glucagon and its receptors have been identified within the mammalian brain, and their anatomical distribution correlates well with the distribution of opioid peptides and their receptors. To evaluate possible physiological interactions between these two peptidergic systems, we examined the effects of glucagon on two opioid responses - bradycardia and antinociception. Glucagon administered either intravenously (iv) (100-1000 micrograms/kg) or intracerebroventricularly (icv) (5 micrograms) significantly attenuated morphine-induced (200 micrograms/kg, iv) bradycardia without producing any alterations in cardiovascular parameters when given alone. Furthermore, glucagon did not antagonize the bradycardia produced by phenyldiguanide (10 micrograms/kg, iv), a non-opioid substance. Peripheral (1 mg/kg, iv) and central (5 micrograms, icv) glucagon pretreatment antagonized morphine-induced (7.5 mg/kg, intraperitoneal) antinociception by 67% and 86%, respectively, at 30 minutes (as determined by the hot plate test). Glucagon treatment alone at these doses did not alter baseline response latencies. In both cases, central injections of glucagon were more effective than iv injections in antagonizing morphine's effects. These findings demonstrate a central action for glucagon and provide the first evidence that this neuropeptide may function as an endogenous antagonist of opioid actions.

Analgesia↗
PubMed1986

Phorbol esters inhibit alpha 1-adrenergic receptor-stimulated phosphoinositide hydrolysis and contraction in rat aorta: evidence for a link between vascular contraction and phosphoinositide turnover.

We investigated the actions of two biologically active phorbol esters, phorbol dibutyrate (PDB) and phorbol myristate acetate (PMA), on receptor-stimulated phosphoinositide hydrolysis in rat aorta. We found both PDB and PMA potently inhibited norepinephrine (NE) stimulated PI hydrolysis in rat aortic rings. The biologically inactive phorbol, 4-alpha-phorbol was ineffective. In the presence of the calcium channel antagonist nitrendipine, PDB potently inhibited both the phasic and tonic components of NE-induced contraction. These results suggest a functional coupling between receptor-stimulated PI turnover and vascular contraction. They also suggest a mode of feed-back regulation in vascular tissue involving phorbol esters in receptor-stimulated PI hydrolysis.

Animals↗
PubMed1986

Species variability in the cardiovascular and hematologic effects of zymosan-activated plasma infusion.

The anaphylatoxins have been implicated in the pathogenesis of endotoxin shock and the adult respiratory distress syndrome. Both endotoxin and zymosan activate the complement pathway. Because there are marked species differences in the cardiovascular and hematologic effects of endotoxin infusion, the purpose of this study was to compare the effects of zymosan-activated plasma (ZAP) infusion in dogs, sheep, and baboons. ZAP was infused (0.11 ml/kg/min for 60 min) into dogs (n = 5), baboons (n = 5), and sheep (n = 3). The infusion of ZAP resulted in significant changes in heart rate (HR) (P less than 0.03), mean arterial pressure (MAP) (P less than 0.002), pulmonary artery pressure (PAP) (P less than 0.004), cardiac index (CI) (P less than 0.034), and extra vascular lung water (EVLW) (P less than 0.001). A specific difference between the species' response to ZAP infusion was present when evaluating the effect of ZAP on MAP (P less than 0.02), HR (P less than 0.003). EVLW (P less than 0.001), platelet count (P less than 0.01), and white blood cell count (P less than 0.01). The main species differences in the changes in MAP, HR, and platelet count were an increase in MAP, decrease in HR, and decrease in platelet count that occurred in dogs. The species difference in the WBC count was the result of ZAP-induced neutropenia in sheep versus a leukocytosis in dogs. Unlike dogs and baboons, sheep developed an increase in EVLW. Like endotoxin, the cardiovascular and hematologic effects of ZAP infusion are species dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

The effect of propranolol on catecholamine clearance.

Normal subjects given propranolol increased their plasma t1/2 for infused isoproterenol from 2.68 to 6.25 minutes. Propranolol increased plasma norepinephrine (NE) levels only slightly. Propranolol increased the t1/2 of isoproterenol but not that of NE in men with autonomic nervous system degeneration. This suggests that propranolol acts on nonneuronal uptake-2 processes, rather than on uptake-1 mechanisms. alpha-Blockers slow uptake-1 and beta-blockers slow uptake-2 processes. When 27 subjects exercised, those who attained the highest plasma levels of the alpha- and beta-receptor agonist NE also had the briefest apparent t1/2 for NE. Adrenergic receptor blocking drugs slow catecholamine clearance. NE may stimulate its own clearance.

Blood Pressure↗
PubMed1986

Insulin stimulates glucose transport in isolated human adipose cells through a translocation of intracellular glucose transporters to the plasma membrane: a preliminary report.

Insulin's effect on glucose transport activity and the subcellular distribution of glucose transporters have been examined in isolated human abdominal adipose cells, by measuring 3-O-methylglucose transport and specific D-glucose-inhibitable cytochalasin B binding to plasma membranes and low-density microsomes, respectively. Insulin appears to stimulate glucose transport in isolated human adipose cell through the translocation of glucose transporters from a large intracellular pool to the plasma membrane as initially postulated for rat adipose and muscle cells.

Adipose Tissue↗
PubMed1986

Hemorrhagic hypotension increases plasma beta-endorphin concentrations in the nonhuman primate.

The role which beta-endorphin plays in the pathogenesis of hemorrhagic hypotension is controversial. In the present experiment, 20 ml/kg of blood was bled from ten healthy male baboons (Papio anubis) over 60 min and then retransfused over the next 30 min. We found that the mean plasma beta-endorphin level increased 109% above baseline (p less than .05) within 15 min after starting hemorrhage, and rapidly returned to a baseline concentration with retransfusion. We conclude that in a primate species, circulating endogenous opioid peptide concentrations increase rapidly in response to sublethal hemorrhagic hypotension and normalize with restoration of the baseline intravascular volume. These findings support the concept that endogenous opioid peptides may mediate the hypotension of shock states.

Animals↗
PubMed1986

Positive end-expiratory pressure increases plasma catecholamine levels in non-volume loaded dogs.

UNLABELLED: Positive end-expiratory pressure (PEEP) is commonly used in the treatment of critically ill patients whose sympathetic nervous system is stressed; however, PEEP's actions on sympathetic nervous system activity are unknown. We therefore measured the plasma noradrenaline response (an index of sympathetic nervous system activity) to graded doses of PEEP in nine mongrel dogs. After 30 minutes at each level of PEEP, plasma noradrenaline concentrations increased from baseline mean values of 300 (SD 108) pg/ml to 388 (SD 225) pg/ml (P less than 0.05) at 5 cm, 433 (SD 255) pg/ml (P less than 0.01) at 10 cm and 1194 (SD 882) pg/ml (P less than 0.01) at 20 cm water pressure of PEEP. The increases in plasma noradrenaline concentrations correlated inversely (r = -0.43, P less than 0.01) with PEEP-induced changes in cardiac output. Plasma adrenaline levels did not change significantly in response to 5 or 10 cm of PEEP; however, plasma adrenaline increased, while heart rate and mean arterial blood pressure fell, at 20 cm water pressure of PEEP (P less than 0.05). Within 15 minutes after discontinuation of PEEP, the plasma catecholamine concentrations returned to baseline levels. CONCLUSIONS: 1. PEEP significantly increases sympathetic nervous system activity in a rapid, dose-dependent, reversible manner; 2. the PEEP-induced increases in sympathetic activity may explain the reductions in organ blood flow which others have observed following the initiation of PEEP; 3. PEEP-related changes in sympathetic nervous system activity are a consequence of PEEP-induced reductions in cardiac output.

Animals↗
PubMed1986

Glucagon: endocrine effects and calcium involvement in cardiovascular actions in dogs.

Although the cardiovascular effects of glucagon are understood, its mechanism(s) of action remains unclear. We studied the effects of increasing doses of glucagon (0.001, 0.01, 0.1 mg/kg) on cardiovascular responses in dogs relative to concurrent measurements of circulating glucagon, cyclic AMP, glucose, norepinephrine, epinephrine, triiodothyronine, thyroxine, and cortisol levels. Glucagon-induced increases in plasma cyclic AMP, glucose, and catecholamine concentrations paralleled the heart rate response to glucagon administration. Further studies were conducted to evaluate the role of beta-adrenergic function as well as calcium in mediating glucagon's actions. The tachycardic effects of glucagon (0.01 mg/kg) were unaltered by prior beta-adrenergic receptor blockade with propranolol (3.5 mg/kg total dose). The calcium antagonist verapamil (0.2 mg/kg bolus then 7.5 micrograms/kg/min/infusion) prevented glucagon-induced increases in heart rate. However, the coadministration of glucagon (0.01 mg/kg) with calcium (1.0, 5.0, 10.0, or 50.0 mg/kg) did not alter glucagon's cardiovascular effects. These data indicate that glucagon is a potent tachycardiac agent that also elevates circulating endocrine-related substances. The antagonism of glucagon's tachycardiac effects by verapamil suggests that glucagon's action may be via glucagon-induced calcium movement through calcium channels, although extracellular calcium changes do not alter glucagon's effect. Furthermore, the persistence of glucagon's cardiovascular actions following beta-adrenergic blockade indicates the potential clinical utility of glucagon in reversing the adverse effects of beta-blocker overdoses, and its potential usefulness in treating circulatory shock in "beta-blocked" patients.

Animals↗
PubMed1986

Pharmacologic manipulation of the peripheral vasculature in shock: clinical and experimental approaches.

An improved understanding of the patho-physiological and biochemical changes that occur in shock states has led to new and innovative pharmacologic approaches to shock reversal. In this article, we review the actions of several pharmaceutical agents on the peripheral vasculature in shock states. Agents with known efficacy, probable utility, and possible usefulness are each discussed. A model of factors modulating alpha-1 adrenergic receptor action is presented.

Adrenal Cortex Hormones↗
PubMed1986

Hepatic alpha 1-adrenergic receptor alteration in a rat model of chronic sepsis.

Catecholamine therapy is often ineffective in reversing the peripheral vasodilatation and hypotension of septic shock. This suggests that catecholamines might not be able to activate alpha 1-adrenergic receptors to cause vasoconstriction. Despite elevations in endogenous catecholamines, hypoglycemia is also a complication of human sepsis, suggesting that among many other causes, hepatic alpha 1-receptors might be altered. To better understand the pathophysiologic basis for this pharmacologic dilemma, we studied the effect of experimental sepsis on alpha 1-adrenergic receptors in hepatic tissue, a rich source of alpha 1-receptors, from septic and control Sprague-Dawley rats. alpha 1-adrenergic receptors were measured with [3H]-prazosin and data analyzed by a computerized nonlinear least-square regression algorithm. Twenty-four hours following cecal ligation with puncture, a decreased number of alpha 1-adrenergic receptors was noted in crude and purified plasma membrane fractions (23 and 40% reductions respectively) from septic animals. No changes in either agonist or antagonist affinity for receptors from septic animals were noted. These data indicate that the catecholamine refractoriness seen in septic shock may be a result of alterations in alpha 1-adrenergic receptor number or receptor-effector coupling.

Animals↗
PubMed1986

Vascular endothelium contributes to decreased aortic contractility in experimental sepsis.

In this study, we compared responses to norepinephrine (NE) by thoracic aortic rings isolated from rats made septic by cecal ligation with puncture, and aortic tissue from sham-operated control rats. We also examined the responses of septic and sham-operated rat aortas after removal of the vascular endothelium. Acetylcholine caused relaxation of NE-induced contractions in septic and sham tissue with an intact endothelium but had no effect on tissue with the endothelium removed experimentally. In preparations with intact endothelium, septic tissue manifests a significantly diminished maximal contractile response to NE (424 +/- 62 (SE) mg tension/mg tissue) in comparison to sham tissue (747 + 30). Tissues with the endothelium removed show no significant maximal contractile difference between septic (688 +/- 23) and sham (669 +/- 32) preparations, or the equivalent sham tissue with an intact endothelium. No difference in the log ED50 for sham tissue (-7.33 +/- 0.12 M) and septic tissue (-7.53 +/- 0.15) with intact endothelium existed. Removal of the endothelium from both septic and sham tissue shifted the dose response curves to the left, disclosing a significant difference in the ED50 between sham (-8.88 +/- 0.14) and septic (-8.18 +/- 0.20) tissue. In conclusion, a significant impairment of vascular contractility in response to NE, with no change in ED50, persists in septic vascular tissue in vitro, and the sepsis-induced defect in contractility is mediated, at least in part, by vascular endothelium, since removal of the endothelium partially restores the NE-stimulated contraction to normal.

Acetylcholine↗