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Biomedical subjects

J S Karliner

Publications and source records attributed to J S Karliner.

At least 19 recordsLinked to original sources
PubMed1992

Bepridil hydrochloride compared with placebo in patients with stable angina pectoris.

Bepridil is a calcium antagonist with a unique chemical composition and a long elimination half-life (42 hours). We evaluated the efficacy of bepridil 300 mg once/day in a crossover comparison with placebo in 45 patients with angina. Patients had an average of 7.6 anginal episodes/week during the placebo baseline phase of the trial. After 4 weeks of bepridil therapy, anginal frequency decreased to 2.9 episodes/week (p less than 0.05). Likewise, mean nitroglycerin consumption declined from 7.4 tablets/week during the placebo baseline phase to 4.0 tablets/week during bepridil therapy (p less than 0.05). Statistically significant increases over the previous period (placebo baseline or double-blind placebo) were seen in total exercise time, time to angina, and total work (p less than 0.05). During bepridil therapy, 13 of 45 patients (29%) no longer experienced angina as an exercise end point despite the increase in work and exercise time. Bepridil significantly prolonged both the QT and corrected QT (QTc) intervals; the mean increases were 10.0% and 5.6%, respectively. Side effects were reported with equal frequency in the placebo and bepridil arms of the trial, and no serious side effects were reported. In an intermediate fixed dose of 300 mg/day, bepridil relieved anginal symptoms with few side effects. Bepridil appears to be a safe and effective treatment for stable angina.

Analysis of Variance↗
PubMed1991

Alpha 1 adrenoceptor mediated signal transduction in neonatal rat ventricular myocytes: effects of prolonged hypoxia and reoxygenation.

STUDY OBJECTIVE: The aim was to study the effects of prolonged hypoxia and reoxygenation on alpha 1 adrenoceptors and inositol phosphate accumulation in neonatal rat ventricular myocytes maintained in culture for 6-8 d. DESIGN: Neonatal rat ventricular myocytes were subjected to 2 h hypoxia followed by 2 h reoxygenation. Cells were harvested at various times during hypoxia and after reoxygenation and measurements of alpha 1 adrenoceptor density and affinity and determinations of basal and (-)-noradrenaline stimulated inositol phosphate accumulation were carried out. EXPERIMENTAL MATERIAL: A neonatal rat ventricular myocyte preparation almost completely free of contaminating non-myocytes was used. Cells were grown in serum containing medium for 5 d before experiments were performed. alpha 1 Adrenoceptors were measured using the radioligand 125I-HEAT and inositol phosphates were measured by anion exchange chromatography after incubation with 1 microM (-)-noradrenaline for 5 min. MEASUREMENTS AND MAIN RESULTS: Hypoxia resulted in an increase in alpha 1 adrenoceptor density which was reversed by reoxygenation. There were no changes in antagonist affinity. (-)-Noradrenaline stimulated inositol phosphate production was increased at 1 h hypoxia but declined to control levels after 2 h hypoxia, while basal levels increased significantly at this time. This pattern was similar for all inositol phosphates measured: inositol-1-phosphate, inositol bisphosphate, and the putative second messenger, inositol trisphosphate. Displacement by (-)-noradrenaline of 125I-HEAT binding was significantly shifted to the right after 2 h hypoxia. CONCLUSIONS: Prolonged hypoxia in neonatal rat ventricular myocytes increases alpha 1 adrenoceptor density without change in antagonist affinity. Inositol phosphates follow a biphasic response, increasing after 1 h and decreasing after 2 h hypoxia in response to (-)-noradrenaline stimulation. This second messenger response and the rightward shift of the (-)-noradrenaline displacement curve suggests that after 2 h hypoxia there is a decrease in agonist affinity for the alpha 1 adrenoceptor consistent with uncoupling of the alpha 1 adrenoceptor from its effector.

Animals↗
PubMed1991

Hypoxia and glucose independently regulate the beta-adrenergic receptor-adenylate cyclase system in cardiac myocytes.

We explored the effects of two components of ischemia, hypoxia and glucose deprivation, on the beta-adrenergic receptor (beta AR)-adenylate cyclase system in a model of hypoxic injury in cultured neonatal rat ventricular myocytes. After 2 h of hypoxia in the presence of 5 mM glucose, cell surface beta AR density (3H-CGP-12177) decreased from 54.8 +/- 8.4 to 39 +/- 6.3 (SE) fmol/mg protein (n = 10, P less than 0.025), while cytosolic beta AR density (125I-iodocyanopindolol [ICYP]) increased by 74% (n = 5, P less than 0.05). Upon reexposure to oxygen cell surface beta AR density returned toward control levels. Cells exposed to hypoxia and reoxygenation without glucose exhibited similar alterations in beta AR density. In hypoxic cells incubated with 5 mM glucose, the addition of 1 microM (-)-norepinephrine (NE) increased cAMP generation from 29.3 +/- 10.6 to 54.2 +/- 16.1 pmol/35 mm plate (n = 5, P less than 0.025); upon reoxygenation cAMP levels remained elevated above control (n = 5, P less than 0.05). In contrast, NE-stimulated cAMP content in glucose-deprived hypoxic myocytes fell by 31% (n = 5, P less than 0.05) and did not return to control levels with reoxygenation. beta AR-agonist affinity assessed by (-)-isoproterenol displacement curves was unaltered after 2 h of hypoxia irrespective of glucose content. Addition of forskolin (100 microM) to glucose-supplemented hypoxic cells increased cAMP generation by 60% (n = 5; P less than 0.05), but in the absence of glucose this effect was not seen. In cells incubated in glucose-containing medium, the decline in intracellular ATP levels was attenuated after 2 h of hypoxia (21 vs. 40%, P less than 0.05). Similarly, glucose supplementation prevented LDH release in hypoxic myocytes. We conclude that (a) oxygen and glucose independently regulate beta AR density and agonist-stimulated cAMP accumulation; (b) hypoxia has no effect on beta AR-agonist or antagonist affinity; (c) 5 mM glucose attenuates the rate of decline in cellular ATP levels during both hypoxia and reoxygenation; and (d) glucose prevents hypoxia-induced LDH release, a marker of cell injury.

Adenosine Triphosphate↗
PubMed1991

Concanavalin A amplifies both beta-adrenergic and muscarinic cholinergic receptor-adenylate cyclase-linked pathways in cardiac myocytes.

Concanavalin A (Con A) is a tetrameric plant lectin that disrupts plasma membrane-cytoskeletal interactions and alters plasma membrane fluidity. We used Con A as a probe to explore beta-adrenergic and muscarinic cholinergic receptor-mediated regulation of cAMP in intact neonatal rat ventricular myocytes. Preincubation with Con A, 0.5 micrograms/ml, attenuated 1 microM (-)-norepinephrine (NE)-induced downregulation of beta-adrenergic receptors and resulted in a 50% augmentation of cAMP accumulation stimulated by 1 microM NE. Con A also augmented forskolin (1-10 microM)-stimulated cAMP accumulation by an average of 37% (P less than 0.05); however, Con A preincubation had no effect on basal or cholera toxin-stimulated cAMP content. The muscarinic cholinergic agonist carbachol (1-100 microM) decreased 1 microM NE-stimulated cAMP generation by an average of 32% (n = 7, P less than 0.05); preincubation with Con A further enhanced the inhibitory effect of carbachol by 18% (n = 7, P less than 0.05). Carbachol (1 microM) for 2 h decreased muscarinic cholinergic receptor density in whole cells by 33%; preincubation with Con A prevented this receptor downregulation. Con A pretreatment did not affect (-)-isoproterenol- or forskolin-stimulated adenylate cyclase activity in cell homogenates, suggesting that an intact cytoarchitecture is necessary for Con A to augment cAMP formation. We conclude that Con A, through its modulation of beta-adrenergic and muscarinic cholinergic receptor signaling, amplifies both stimulatory and inhibitory adenylate cyclase-linked pathways in intact neonatal ventricular myocytes. These data suggest the possibility that plasma membrane-cytoskeletal interaction is an important regulator of transmembrane signaling because interference with this interaction results in alterations in cAMP accumulation mediated by both beta-adrenergic- and muscarinic cholinergic-adenylate cyclase pathways.

Adenylyl Cyclases↗
PubMed1990

Effects of pertussis toxin on alpha 1-agonist-mediated phosphatidylinositide turnover and myocardial cell hypertrophy in neonatal rat ventricular myocytes.

In neonatal rat ventricular myocytes pretreatment with pertussis toxin did not affect 1 microM (-)-norepinephrine stimulation of inositol phosphates or myocardial cell hypertrophy as measured either by protein radiolabelling or by myocardial cell protein content. Thus guanine nucleotide protein(s) ADP-ribosylated by pertussis toxin do not play a role in two alpha 1-adrenoceptor-mediated processes, phosphatidylinositide turnover and induction of myocardial cell hypertrophy.

Adenosine Diphosphate Ribose↗
PubMed1990

Complex regulation of calcium current in cardiac cells. Dependence on a pertussis toxin-sensitive substrate, adenosine triphosphate, and an alpha 1-adrenoceptor.

We investigated regulation of the cardiac L-type calcium channel by intracellular ATP and by alpha 1-adrenergic agonism using single adult guinea pig ventricular cells and the whole-cell patch clamp method. Inclusion of 5 mM ATP in the patch clamp pipette prevented calcium current rundown but did not increase the maximal magnitude of the slow inward calcium current (ICa). During beta 1-adrenergic blockade with 10 microM (-)-propranolol, cells preincubated with 1 microgram/ml pertussis toxin for 2-5 h exhibited a rapid twofold increase in ICa after rupture of the membrane patch when 5 mM ATP was present in the patch clamp pipette. In the absence of ATP, the increase in ICa did not occur. In pertussis toxin-treated cells, 100 microM (-)-phenylephrine inhibited the augmentation of ICa. This inhibitory effect was blocked by 100 nM terazosin, a selective alpha 1-antagonist. The inhibitory effect of alpha 1-adrenergic agonism was not mediated by cAMP-dependent phosphodiesterase since incubation with 100 microM (-)-phenylephrine did not augment the activity of this enzyme. We conclude that regulation of the L-type calcium channel in cardiac cells is complex, and is dependent on a pertussis toxin-sensitive substrate, ATP, and an alpha 1-adrenergic receptor. The marked increase in ICa after pertussis toxin treatment in the presence of ATP indicates significant inhibition of ICa by a pertussis toxin substrate, presumably the guanine nucleotide inhibitory protein (Gi) in the basal state. The inhibitory action of (-)-phenylephrine in pertussis toxin-treated cells is consistent with modulation of ICa by an alpha 1-adrenergic receptor not coupled to Gi.

Adenosine Triphosphate↗
PubMed1989

Refined membrane preparations mask ischemic fall in myocardial beta-receptor density.

Most of the previous studies of ischemic myocardial beta-adrenergic receptors have employed membrane preparations in which the initial pellet from the myocardial homogenate spun at a low speed was discarded. We studied changes in beta-adrenergic receptor density ([125I]-iodocyanopindolol; Bmax) during 30 min of coronary occlusion in surgically anesthetized open-chest rabbits using just such a pellet [homogenized heart spun at 1,000 g (1,000-g pellet)], as well as a second pellet from the supernatant of the first pellet [spun at 40,000 g (40,000-g pellet)]. Bmax fell during acute ischemia in the 1,000-g pellet [46.8 +/- 6.1 vs. 21.6 +/- 2.4 (SE) fmol/mg protein; P less than 0.01; n = 7] but did not change in the 40,000-g pellet [46.8 +/- 6.5 vs. 47.9 +/- 2.6 (SE) fmol/mg protein; P = NS; n = 6]. The 1,000-g pellet contained 70.0 +/- 8.1% of the beta-adrenergic receptors measured between the two preparations (P less than 0.05; n = 8) and all of the histamine H2-receptors; therefore, to minimize receptor loss and other potential artifacts, unspun myocardial homogenate was studied. An ischemic decrease in Bmax was still observed [32.9 +/- 2.0 vs. 20.9 +/- 4.1 (SE) fmol/mg protein; P less than 0.05; n = 5]. These results support the use of data from cruder myocardial membrane preparations (e.g., 1,000-g pellet or unspun homogenate), which may be of greater pathophysiological relevance than data derived from a standard more-refined preparation (40,000-g pellet).

Adenylyl Cyclases↗
PubMed1989

Effects of acute ischemia in the dog on myocardial blood flow, beta receptors, and adenylate cyclase activity with and without chronic beta blockade.

We ligated the left anterior descending coronary artery for 1 or 2 h in 31 purebred beagles. We did not detect any changes in beta-adrenergic receptor density or affinity when normal and ischemic zones were compared, either in the subendocardium or in the subepicardium. In the ischemic zones, there was a significant decline in all measures of adenylate cyclase activity, including activity mediated by the beta-adrenergic receptor. By contrast, after chronic beta-adrenergic blockade (1.5 mg/kg propranolol i.v. twice daily for 7 d), there was an increase in adenylate cyclase activity stimulated by (-)-isoproterenol relative to adenylate cyclase activity stimulated by guanyl-5'imidodiphosphate (GppNHp) in both normal and ischemic tissue, suggesting that one effect of chronic beta blockade may be to enhance coupling between the stimulatory guanine nucleotide regulatory protein (Gs) and the beta-adrenergic receptor, despite a reduction in the number or function of Gs units. Chronic beta blockade also led to up regulation of beta-adrenergic receptor density in subepicardial regions. After 20 min of reperfusion following 2 h of ischemia, adenylate cyclase activity tended to return to control levels, particularly in the subepicardium, where (-)-isoproterenol-stimulated adenylate cyclase activity was not different from normal myocardium. We conclude that chronic beta-adrenergic blockade may have beneficial effects during prolonged episodes of myocardial ischemia by preserving signal transduction mediated by the beta-adrenergic receptor.

Adenylyl Cyclases↗
PubMed1989

Effects of beta-blockade on beta-adrenergic receptors and signal transduction.

Recent work on the effects of beta-blockers on the beta-adrenergic receptor-adenylate cyclase pathway has led to an increased understanding of the influence of chronic beta-blockade on signal transduction mediated by the beta-adrenergic receptor. In chronic congestive cardiac failure the beta-adrenergic receptor is downregulated, and small doses of beta-blockers have reversed this trend. Since adrenergic receptor density during beta-blockade tends to return toward normal levels, it has been hypothesized that the adrenergic system could then participate in inotropic support during periodic increases in local neurotransmitter release or elevation of circulating catecholamines produced by exercise or other activities, despite the presence of a competitive beta-blocking agent. Preliminary clinical results appear to support this hypothesis. In addition, the role of guanine nucleotide regulatory proteins in chronic congestive heart failure has recently been examined, but the results are conflicting. Whether an increase in the quantity or function of the guanine nucleotide inhibitory protein (Gi) is responsible at least in part for the decline in catecholamine-stimulated adenylate cyclase activity in chronic congestive heart failure remains controversial. Recent evidence also suggests that chronic beta-blockade may enhance coupling of the beta-receptor to the guanine nucleotide stimulatory protein. This could be an additional benefit of chronic beta-blockade in patients with congestive heart failure.

Adenylyl Cyclase Inhibitors↗
PubMed1988

Relation of left ventricular shape to volume and mass in patients with minimally symptomatic chronic aortic regurgitation.

In 19 male patients with significant but minimally symptomatic or asymptomatic chronic aortic regurgitation, measurements of left ventricular shape, volume, and mass were assessed by cross-sectional echocardiography. End-diastolic volume and mass were significantly larger than normal values. There was a significant negative correlation between the volume-to-mass ratio (V/M) and both the end-diastolic (r = -0.70, p less than 0.01) and end-systolic (r = -0.73, p less than 0.001) long axis-to-minor diameter ratios (L/D), suggesting that maintenance of the normal geometry of the left ventricle is in part dependent on the adequacy of hypertrophy, as expressed by a normal V/M. Since preoperative volume-to-mass indices have been shown to be important predictors of postoperative course, the L/D ratio should be a useful and simple parameter to follow in asymptomatic patients.

Adult↗
PubMed1987

Left ventricular functional recovery from exercise in normals and patients with coronary heart disease.

Little information is available regarding left ventricular (LV) functional recovery from treadmill exercise. Accordingly, we used a recently described ultrasound index of LV function, the isovolumic index (IVI), to assess LV performance before and after exercise in 9 normal middle-aged men and 12 male patients with coronary artery disease (CAD). The IVI was measured at rest and at each minute for at least 10 min after completion of the Bruce protocol; normals had maximal tests and CAD patients had symptom limited studies. At rest the IVI value for normals was 26.2 +/- 2.1 (SD) and it was 43.5 +/- 8.2 for CAD patients (p less than 0.001); isovolumic times were longer in CAD patients (137 +/- 26 vs. 89 +/- 8 ms, p less than 0.001). The rate of recovery from exercise did not differ between normals and CAD patients. We conclude that despite depression of resting LV performance in CAD patients, the time course of functional recovery of the left ventricle from exercise is not different from normal subjects.

Adult↗
PubMed1986

Beta-adrenergic receptor properties of canine myocardium: effects of chronic myocardial infarction.

To determine the effects of chronic myocardial infarction on beta-adrenergic properties of canine myocardium, the hearts of nine mongrel dogs were studied 3 weeks after acute myocardial infarction. Infarction was produced by ligating the left anterior descending coronary artery in five dogs and the circumflex artery in four dogs. The heart was divided into normal and infarct zones (either anterior or posterior, depending on the vessel ligated) and marginal zones (septal and lateral), each zone being subdivided into epicardial and endocardial portions. Myocardial blood flow (microsphere technique) was markedly reduced in the infarct zone. In eight endocardial infarct samples after left anterior descending ligation, the maximal number (+/- SD) of binding sites assessed by 125I-iodocyanopindolol was 3.9 +/- 1.9 pmol/mg deoxyribonucleic acid (DNA) and was reduced from normal endocardial values (9.7 +/- 9.4 pmol/mg DNA, p less than 0.05). The dissociation constant (Kd), which is a measure of the affinity of the iodinated antagonist for the receptor, did not differ (304 +/- 222 versus 338 +/- 219 pM, p = NS). In the epicardium, the maximal number of beta-adrenergic receptors was also reduced (p less than 0.05), without a change in Kd. In the lateral and septal zones neither the maximal number of binding sites nor Kd values differed from those of normal endocardium. In nine endocardial infarct zones, (-)-isoproterenol-stimulated adenylate cyclase activity was reduced compared with control (34,870 +/- 29,430 versus 88,660 +/- 63,640 pmol/mg DNA/30 minutes, p less than 0.01), but the ratio of (-)-isoproterenol-stimulated to maximal (sodium fluoride-stimulated) adenylate cyclase activity was unchanged between normal and infarct zones.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1986

Mechanisms and time course of beta 1 adrenoceptor desensitisation in mammalian cardiac myocytes.

To study the mechanisms and time course of beta1 adrenoceptor desensitisation in mammalian heart tissue neonatal rat cardiac myocytes (greater than 90% pure) were cultured in serum free medium. Cells were exposed to 1 mumol X litre-1 (-)-isoprenaline for 30 min, 4 h, and 16 h. In myocyte membranes mean(SEM)) 125I-iodocyanopindolol binding was 167(46) pmol X litre-1 (n = 5) and did not differ at 30 min, 4 h, or 16 h in control compared with (-)-isoprenaline treated cells. The maximum number of binding sites was 84(32) fmol X mg protein-1 and was unchanged at 30 min, but (-)-isoprenaline stimulated adenylate cyclase activity significantly decreased from 221(62) to 103(37) pmol X mg protein-1 30 min-1. (-)-Isoprenaline competition curves at 30 min showed a significant increase in the proportion of low affinity binding sites from 46% to 62% (n = 5). By 4 h the maximum number of binding sites was significantly decreased by 54%, adenylate cyclase activity remained depressed, and agonist affinity decreased threefold in the (-)-isoprenaline treated cells. At 16 h (-)-isoprenaline treated cells showed alterations similar to the 4 h values in the maximum number of binding sites, adenylate cyclase activity, and affinity for (-)-isoprenaline. (-)-Isoprenaline stimulated adenylate cyclase activity took 72 h to recover after desensitisation. Overnight ultracentrifugation of the cytosol showed a significant 40% increase in beta adrenoceptor density in cells exposed to (-)-isoprenaline for 4 h (n = 5), suggesting receptor internalisation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗