PubMed Health⌕ Search

Biomedical subjects

C M Fuller

Publications and source records attributed to C M Fuller.

67 records · Page 4Linked to original sources
PubMed1992

CFTR!

Cystic fibrosis (CF) is a fatal genetic disease primarily affecting Caucasians, although cases have been reported from other ethnic groups. CF has a complex etiology, but it is chiefly a disease of electrolyte transport and is characterized by defects in fluid secretion by several epithelia, including the sweat duct, exocrine pancreas, and the pulmonary airways. The link between CF and a defect in cAMP-mediated Cl- transport in secretory epithelia was established in the early 1980s. Since then, numerous electrophysiological studies have focused on the characterization and regulation of individual Cl- channels underlying the macroscopic Cl- currents of secretory epithelia in the airways, sweat ducts, and gut. In this review the results of these studies in the light of current knowledge of the function of the CF gene product, the CF transmembrane conductance regulator (CFTR) protein, will be analyzed. The CFTR protein is a member of a family of ATP-binding proteins that act as unidirectional solute pumps. These proteins are membrane spanning, are found in both prokaryotic and eukaryotic cells, and have two ATP-binding domains. The family includes the p-glycoproteins that are involved with the expression of multidrug resistance in certain tumor cells. The majority of CF chromosomes (70%) have a single codon deletion that translates to a missing phenylalanine residue at position 508 (delta F508) of the protein. Unique for this family of proteins, the CFTR protein possesses an additional highly charged domain (the R domain) containing several consensus polypeptide sequences for kinase phosphorylation. Although CFTR bears structural resemblance to this family of ATP-dependent pumps, overexpression of the protein in a variety of different cell types is associated with the appearence of a cAMP-sensitive Cl- channel. We critically examine current information concerning the structure-function relationships of the CFTR protein obtained from both electrophysiological and biochemical approaches. We also summarize recent evidence suggesting that the CFTR protein may act as a pump and a channel, a hypothesis in keeping with the multifaceted nature of the disease.

Adenosine Triphosphate↗
PubMed1989

Secretagogue and second messenger-activated Cl- permeabilities in isolated pancreatic zymogen granules.

Previous studies of enzyme secretion from isolated pancreatic acinar cells and of isolated zymogen granules (ZG) have reported that both a Cl- and a K+ permeability are present on the ZG membrane. It has been suggested that ion influx via these permeability pathways, followed by water movement is required for granular swelling which appears to be intimately related to exocytosis. However, little is known about the regulation of these pathways by secretagogues. Evidence suggests that cAMP-protein kinase A and diacylglycerol-protein kinase C are second messengers in stimulation of exocytosis. In the present study we have examined ion permeability pathways in ZG isolated from control cells and from cells pretreated with the acetylcholine analog carbachol (Cch), with the peptide hormone cholecystokinin (CCK) and with second messengers of hormone action such as cAMP and the diacylglycerol analog 12-O-tetradecanoyl phorbol-13-acetate (TPA). Ion and water influx rates in ZG and consequent swelling and lysis of granules was monitored by measuring changes in optical densities of ZG suspensions at 540 nm following additions of the electrogenic or electroneutral ionophores valinomycin and nigericin, respectively. The data show that both a Cl- conductance and an anion exchange pathway are present in the granule membrane. Both pathways are activated by pretreatment of isolated cells with CCK or of isolated permeabilised cells with cAMP, whereas only the Cl- conductance is increased by pretreatment with Cch or with TPA.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1989

Ionic and osmotic dependence of secretion from permeabilised acini of the rat pancreas.

Many types of secretory granule have been observed to swell as a result of cell stimulation implying a degree of osmotic control, although the regulation of granule fusion with the apical plasma membrane is not clearly understood. In the present study we have investigated the ionic and osmotic dependency of basal and stimulated 3H-protein release from rat pancreatic acini, permeabilised by either digitonin or high voltage electric discharge. Acini were stimulated with either cholecystokinin-pancreozymin octapeptide (CCK-8), carbachol (CCh), or with phorbol ester (TPA) plus cAMP. Stimulated secretion was significantly reduced when 130 mmol/l Cl- in the buffer was replaced by I-, NO3-, SCN- or cyclamate-. Secretion in Cl- buffers was inhibited by the anion transport inhibitor 4,4-diisothiocyanatostilbene-2,2-disulfonic acid (DIDS), by 40% of the control response. Neither Na+ nor N-methyl-D-glucamine+ could replace K+ in the buffer. Ba2+ and quinine, which block K+ conductance pathways, inhibited stimulated secretion by 50%. Finally, stimulated secretion from leaky cells was nearly abolished by doubling buffer osmolarity. The data suggest that when the cell is stimulated, a Cl- and a K+ permeability appear in the zymogen granule membrane and the ions enter down their electrochemical gradients. The increased intragranular osmolarity results in granular swelling which is intimately associated with secretion.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1987

Cholinergic receptors regulate a voltage-insensitive but Na+-dependent calcium influx pathway in salivary acinar cells.

The calcium-sensitive fluorescent probe, quin 2, was employed to investigate the cholinergic receptor regulation of cytosolic free calcium concentration [( Ca2+]i) in isolated rat submandibular acinar cells. Cholinergic receptor stimulation results in a marked and sustained elevation [Ca2+]i. The major component of this response is shown to be due to activation of a calcium influx pathway. There is no evidence in K+-depolarized cells of any voltage-gated calcium influx. Acetylcholine failed to activate the calcium influx pathway in cells bathed in Na+-free solutions. The cholinergic receptors thus regulate a voltage-insensitive but Na+-dependent transport system for calcium entry in submandibular acinar cells.

Acetylcholine↗
PubMed1987

Cholinergic receptor-regulation of potassium channels and potassium transport in human submandibular acinar cells.

The cholinergic receptor-regulation of K+ transport was studied in human submandibular glands. Acetylcholine stimulation 10 mumol/L results in an increase in membrane permeability (86Rb+ efflux) for, and a net efflux of, K+ ions from the glandular tissue. In the post-stimulus period, there is a net re-uptake of K+ ions into the tissue. Patch-clamp electrophysiological techniques were employed to demonstrate the presence of a large conductance K+ selective ion channel in the basolateral membranes of isolated human submandibular acinar cells. The patch-clamp results indicate that this voltage- and calcium-activated K+ channel operates to regulate the K+ permeability in both the resting and acetylcholine-stimulated acinar cells. We discuss the role of the K+ channel, K+ efflux, and K+ re-uptake in relation to stimulus-secretion coupling.

Acetylcholine↗
PubMed1986

Potassium uptake in the mouse submandibular gland is dependent on chloride and sodium and abolished by piretanide.

Nervous or hormonal stimulation of salivary secretion in vivo is associated with a pronounced efflux of K+ from the secretory, acinar cells into the blood. This K+ efflux is followed in the post-stimulus period by a reuptake of K+ into the glandular tissue. In the present study we monitor the changes in [K+] of physiological solutions perfusing a flow chamber containing isolated segments of mouse submandibular glands. Nervous stimulation or the application of exogenous acetylcholine (ACh, 10(-5) M) to the isolated glandular tissue results in characteristic changes in the [K+] of the superfusate, indicating net K+ release followed by K+ reuptake. The post-stimulus reuptake of K+ is shown to be susceptible to blockade by either ouabain (10(-3) M) or piretanide (10(-4) M). The reuptake was markedly attenuated if Cl- in the superfusate was replaced by either NO3- or SO4(2-). The K+ uptake was, however, unaffected when Br- replaced Cl- in the superfusate. Similar effects were observed in the unstimulated glandular tissues. The introduction of Cl-(-)free media containing either NO3- or SO4(2-) resulted in a loss of K+ from the tissue which was followed, upon reintroduction of Cl-, by a pronounced uptake of K+. When Br- was substituted for Cl- there was very little change in [K+] upon removal or reintroduction of Cl-. The uptake of K+ induced by reintroduction of Cl- after a period of NO3- or SO4(2-) superfusion was blocked by both ouabain and piretanide. This uptake of K+ was also dependent on the presence of extracellular Na+. Both Cl- and Na+ had to be present in the superfusing medium for K+ uptake to be fully manifest. These findings indicate that the K+ uptake observed in both the resting and stimulated submandibular gland cannot be explained as solely due to the activity of the Na+-K+-adenosine triphosphatase (Na+-K+-ATPase). The demonstrated anionic selectivity, dependence on extracellular Na+ and susceptibility to blockade by the diuretic piretanide would strongly suggest that a coupled Na+-K+-Cl- co-transport system operates in submandibular glands as it does in other transporting epithelia to achieve K+ uptake.

Acetylcholine↗
PubMed1985

Human pancreatic acinar cells: studies of stimulus-secretion coupling.

Elements of stimulus-secretion coupling were studied in human pancreatic acinar cells by using tissue samples obtained from cadaver organ donors. In pancreatic fragments, acetylcholine evoked amylase secretion as well as potassium release and increased the outflux of 45Ca and 86Rb from the prelabeled tissue. In patches of basolateral plasma membrane excised from acinar cell clusters, single-channel potassium currents were recorded. The inside of the plasma membrane faced the bath solution, allowing the effects of changes in the free ionized calcium concentration in contact with the membrane interior to be tested. Two types of calcium-activated potassium-selective channels were found with unit conductances of about 250 and 50 picosiemens (pS), respectively. In both cases channel opening was determined by the electrical potential difference across the plasma membrane and the free ionized calcium concentration in the bath solution. The probability of channel opening was markedly increased by elevation of the free ionized calcium concentration in contact with the membrane inside. The results suggest that the acetylcholine-evoked cellular potassium release occurs via selective membrane potassium channels opened by calcium released intracellularly after the action of the secretagogue.

Acetylcholine↗
PubMed1984

Beta-adrenergic receptor mechanisms in rat parotid glands: activation by nerve stimulation and 3-isobutyl-1-methylxanthine.

The technique of electrical field stimulation (e.f.s.) was employed in conjunction with selective pharmacological antagonists to specifically investigate the role of endogenous neurotransmitter(s) in the activation of beta-adrenergic receptor mechanisms in isolated parotid gland segments of the rat. The field-stimulus-induced amylase release due to beta-adrenergic receptor activation was characterized as that persisting in the presence of atropine (10(-5) M) and phentolamine (10(-5) M) and susceptible to blockade by propranolol (5 X 10(-6) M), i.e. combined beta 1- and beta 2-receptor blockade. The selective beta 1-receptor antagonist metoprolol (10(-5) M) was as effective as propranolol in blocking the beta-mediated enzyme release. The selective beta 2-receptor antagonist, H35/25 (10(-5) M) did not significantly affect the field-stimulus-induced amylase release. In the absence of any phosphodiesterase inhibitor the levels of cyclic AMP in the tissues were close to the limit of detection. Field stimulation was however associated with a fourfold increase in cyclic AMP. By comparison isoprenaline (10(-5) M) gave rise to a tenfold increase in cyclic AMP. The changes in cyclic AMP metabolism, in response to both field stimulation and isoprenaline, were greatly enhanced in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). The field-stimulus-induced increase in cyclic AMP was abolished by the beta 1-adrenergic receptor antagonist, metoprolol, but persisted in the presence of the beta 2-adrenergic antagonist, H35/25. IBMX was found to have a potent direct effect on amylase release. IBMX (10(-3) M) also gave rise to a tenfold increase in cyclic AMP. IBMX is then as effective as 10(-5) M-isoprenaline in stimulating both enzyme secretion and cyclic AMP metabolism. The secretory response to IBMX was unaffected by beta-adrenergic blockade by propranolol, was independent of extracellular calcium and did not give rise to 86Rb+ efflux. Importantly, isoprenaline (10(-5) M) failed to evoke any significant increase in amylase release if introduced during sustained superfusion of IBMX, yet it is in such protocols that the greatest changes in cyclic AMP metabolism are seen. The study clearly demonstrates that the beta-adrenergic-receptor-regulated amylase release in response to nerve stimulation is mediated predominantly, if not exclusively, by the beta 1-receptor subtype.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1983

Hemophilus endocarditis. Two patients with complications.

Two cases of Hemophilus endocarditis were diagnosed in our hospital during a six-month period. Although both patients were in good health until the onset of their endocarditis, both had brain emboli and required emergency heart-valve surgery. Falsely low incidences of this disease have been reported, since Hemophilus sp are difficult to isolate. Additionally, these organisms are consistently associated with large vegetations and have a greater than 50% incidence of embolization. It is this higher incidence of embolization that leads us to conclude that prophylactic surgery should be considered in selected patients.

Anti-Bacterial Agents↗
PubMed1981

Early post-myocardial infarction treadmill stress testing. An accurate predictor of multivessel coronary disease and subsequent cardiac events.

Limited (heart rate to less than or equal to 120 beats/min) standardized treadmill stress testing was done before hospital discharge in 40 survivors of uncomplicated acute myocardial infarction. Each patient had subsequent coronary arteriography. Twenty-one had inferior, 10, anterior, and nine, nontransmural infarctions; in 30 patients this was their first infarction. A positive electrocardiographic response or angina, or both, occurred in 15 patients and correctly detected most patients with multivessel disease (sensitivity 67%, predictive value 87%) and patients at risk for coronary events: 35% of positive responders admitted for angina in the first month after discharge versus 4% of patients with a negative test (p less than 0.05). During a 7-month follow-up period, 73% of patients with a positive test result developed angina versus 16% of those with negative test results (p less than 0.001). Thus, predischarge post-myocardial infarction limited stress testing correctly identifies the high-risk subset of patients with multivessel coronary disease and thereby allows intelligent selection of patients for early coronary arteriography.

Adult↗
PubMed1980

Exercise-induced coronary arterial spasm: angiographic demonstration, documentation of ischemia by myocardial scintigraphy and results of pharmacologic intervention.

Exercise-induced coronary arterial spasm is an infrequently recognized phemonemon whose mechanism and management are not well established. In two patients with reproducible exercise-induced S-T segment elevation and angina pectoris thallium-201 scintigraphy showed areas of reversible anteroapical hypoperfusion, and gated radionuclide ventriculography revealed anteroapical hypokinesia with a decrease in left ventricular ejection fraction at peak exercise. During coronary arteriography supine exercise provoked occlusive spasm of the left anterior descending coronary artery, which at rest had only minimal plaques. Consequently, treadmill testing was performed with five different pharmacologically provoked interventions: direct vasodilatation (nitrates), alpha adrenergic blockade (phenmoxybenzamine), beta adrenergic blockade (propranolol), calcium flux blockade (verapamil), and prostaglandin inhibition (indomethacin). Exercise-induced coronary arterial spasm, manifested as S-T segment elevation and angina, was prevented by nitrates, but was not eliminated by short-term oral administration of an alpha or beta blocking agent, a calcium antagonist or a prostaglandin inhibitor. Further, beta adrenergic blockade appeared to be detrimental. Thus, this study demonstrates (1) that coronary arterial spasm may be the underlying mechanism of at least some cases of exertional angina associated with transient perfusion deficits and left ventricular dysfunction, and (2) that it may be prevented by oral nitrates.

Angina Pectoris, Variant↗
PubMedDate not supplied

Bear meat trichinosis with a concomitant serologic response to Toxoplasma gondii.

A severe case of trichinosis occurred following the ingestion of raw meat from a common black bear, Ursus americanus, that was shot in Butte County, California. Examination of steaks cut from the bear revealed heavy infection with T. spiralis. A good clinical response was obtained following treatment with prednisone (1 mg/kg body weight per day) and thiabendazole (50 mg/kg body weight per day); no toxic effects were observed. In comparison with the pre-treatment biopsy, a more intense inflammatory response was seen following the administration of thiabendazole. Nevertheless, a muscle biopsy taken several months after discharge still showed well-encapsulated, morphologically intact larvae. In addition to the expected immunological responses to T spiralis, a marked rise in titer of antibodies to Toxoplasms gondii was observed by the fluorescent antibody and Sabin-Feldman dye test methods. Since toxoplasma infection of muscle is widespread in man, it is possible that an unrelated disease of muscle could result in stimulation of anti-toxoplasma antibodies similar to the findings in polymyositis and dermatomyositis. Alternatively, the possibility that a dual infection was acquired from the bear meat cannot be excluded.

Adult↗