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Biomedical subjects

D M Cooper

Publications and source records attributed to D M Cooper.

At least 145 records · Page 8Linked to original sources
PubMed1992

Inhibition of cyclic AMP accumulation in intact NCB-20 cells as a direct result of elevation of cytosolic Ca2+.

Earlier studies established that adenylyl cyclase in NCB-20 cell plasma membranes is inhibited by concentrations of Ca2+ that are achieved in intact cells. The present studies were undertaken to prove that agents such as bradykinin and ATP, which elevate the cytosolic Ca2+ concentration ([Ca2+]i) from internal stores in NCB-20 cells, could inhibit cyclic AMP (cAMP) accumulation as a result of their mobilization of [Ca2+]i and not by other mechanisms. Both bradykinin and ATP transiently inhibited [3H]cAMP accumulation in parallel with their transient mobilization of [Ca2+]i. The [Ca2+]i rise stimulated by bradykinin could be blocked by treatment with thapsigargin; this thapsigargin treatment precluded the inhibition of cAMP accumulation mediated by bradykinin (and ATP). A rapid rise in [Ca2+]i, as elicited by bradykinin, rather than the slow rise evoked by thapsigargin was required for inhibition of [3H]cAMP accumulation. Desensitization of protein kinase C did not modify the inhibitory action of bradykinin on [3H]cAMP. Effects of Ca2+ on phosphodiesterase were also excluded in the present studies. The accumulated data are consistent with the hypothesis that hormonal mobilization of [Ca2+]i leads directly to the inhibition of cAMP accumulation in these cells and presumably in other cells that express the Ca(2+)-inhibitable form of adenylyl cyclase.

Animals↗
PubMed1992

Factors affecting the components of the alveolar CO2 output-O2 uptake relationship during incremental exercise in man.

The VCO2-VO2 (alveolar CO2 output-alveolar O2 uptake) relationship (V-slope) during increasing work rate (ramp) cycle ergometer exercise has two approximately linear components: a lower component slope (S1) with a value of about 0.95 and a steeper, upper component (S2). We examined the effect of muscle glycogen depletion (protocol 1) and the rate of increase in work rate (ramp rate) without muscle glycogen depletion (protocol 2) on S1 and S2. In protocol 1, ten healthy men with a mean age of 31.4 years (S.D. 6.2) were studied on each of 3 days (days 1 and 3 were control days). They performed a ramp exercise test to maximum tolerance and steady-state tests at rest, during unloaded pedalling and at two constant work rates below their anaerobic threshold (AT). To deplete muscle glycogen before the test on day 2, the subjects performed 2 h of very heavy cycle exercise on the preceding day and fasted overnight. S1 was reduced on day 2 (0.79 compared with 0.95, P less than 0.001), as was the VCO2-VO2 slope derived from steady-state measurements (0.81 compared with 0.99, P less than 0.001), but AT and the slope difference (S2 - S1) were unchanged. In protocol 2, seven healthy men with a mean age of 20.6 years (S.D. 2.4) performed ramp tests at three different rates of increasing work rate (15, 30 and 60 W min-1), each ramp rate being performed twice in random sequence. The ramp rate did not affect S1 but S2 was steeper with the faster rates of work rate increase (1.27, 1.43 and 1.63, respectively, P less than 0.01). Our findings support the concept that the lower component of the V-slope plot (below AT) represents muscle substrate respiratory quotient (RQ) while the difference between S1 and S2 reflects 'excess CO2' derived from bicarbonate buffering of lactic acid.

Adolescent↗
PubMed1992

13CO2 washout dynamics during intermittent exercise in children and adults.

To test the hypothesis that children store less CO2 than adults during exercise, we measured breath 13CO2 washout dynamics after oral bolus of [13C]bicarbonate in nine children [8 +/- 1 (SD) yr, 4 boys] and nine (28 +/- 6 yr, 5 males) adults. Gas exchange [O2 uptake and CO2 production (Vco2)] was measured breath by breath during rest and during light (80% of the anaerobic threshold) intermittent exercise. Breath samples were obtained for subsequent analysis of 13CO2 by isotope ratio mass spectrometry. The tracer estimate of Vco2 was highly correlated to Vco2 measured by gas exchange (r = 0.97, P < 0.0001). The mean residence time was shorter in children (50 +/- 5 min) compared with adults (69 +/- 7 min, P < 0.0001) at rest and during exercise (children, 35 +/- 7 min; adults, 50 +/- 11 min, P < 0.001). The estimate of stored CO2 (using mean Vco2 measured by gas exchange and mean residence time derived from tracer washout) was not statistically different at rest between children (254 +/- 36 ml/kg) and adults (232 +/- 37 ml/kg). During exercise, CO2 stores in the adults (304 +/- 46 ml/kg) were significantly increased over rest (P < 0.001), but there was no increase in children (mean exercise value, 254 +/- 38 ml/kg). These data support the hypothesis that CO2 distribution in response to exercise changes during the growth period.

Adult↗
PubMed1992

Effect of low and high intensity exercise on circulating growth hormone in men.

We hypothesized that circulating GH would increase only if a threshold of work intensity [corresponding to the anaerobic or lactate threshold (LT)] was exceeded. Ten healthy male volunteers (18-35 yr) first performed ramp-type progressive cycle-ergometer exercise to determine the LT and the maximal oxygen uptake. On subsequent mornings after an overnight fast, each subject performed bouts of 1, 5, and 10 min constant work rate exercise of either high intensity (above LT) or low intensity (below LT). A 1-h interval separated exercise bouts. Gas exchange (breath-by-breath), GH, immunoreactive insulin, glucose, lactate, pyruvate, and epinephrine and norepinephrine were measured at regular intervals. After the 10-min bouts of high compared with low intensity exercise, lactate was 7.2 +/- 3.7 mmol/L vs. 1.4 +/- 1.3, P less than 0.05; epinephrine was 1,113 +/- 519 pmol/L vs. 496 +/- 273, P less than 0.05; and norepinephrine was 7.89 +/- 3.45 nmole/L vs. 2.83 +/- 1.34, P less than 0.05. GH did not increase significantly from preexercise baseline during low intensity exercise (e.g., GH after 10-min low intensity exercise changed from baseline values by 1.5 +/- 2.0 micrograms/L, NS). Although lactate was elevated after 5-min of high intensity exercise, peak GH was significantly elevated (mean increase above baseline of 7.7 +/- 2.4 micrograms/L, P less than 0.05) only after 10 min of high intensity exercise (increases in 9 of 10 subjects). The GH increase occurred despite simultaneous increases in both IRI and glucose. A minimum duration of 10 min, high intensity exercise consistently increased circulating GH in adult males.

Adolescent↗
PubMed1992

Purinergic receptor regulation of signal transduction in NCB-20 cells.

In the present paper, P1 and P2 purinergic receptors and their control of signal transduction pathways were investigated in NCB-20 cells. ATP elicited an increase in [Ca2+]i. The purinergic receptor subtype involved was identified by comparing the actions of a range of nucleotides. UTP was the most potent agonist in elevating [Ca2+]i, with an EC50 value of 6.2 +/- 0.5 microM. UTP, ATP (EC50, 17.3 +/- 1.5 microM), adenosine-5'-O-(3-thio)triphosphate (23 +/- 3 microM), and ITP (55 +/- 4 microM) exerted similar maximal effects. Other nucleotides tested, including beta, gamma-methylene-ATP and 2-methylthio-ATP, which are considered prototypic agonists for P2x and P2y receptors, respectively, were ineffective; in general, modifications in the ribose-triphosphate chain and substitution on the 2-position of the purines reduced the efficacy of nucleotides. This pharmacological characterization indicated that a putative P2u receptor mediates the [Ca2+]i elevation elicited by nucleotides in NCB-20 cells. The increase in [Ca2+]i originates from intracellular Ca2+ stores; blockade of Ca2+ entry does not affect the rise in [Ca2+]i. In contrast, pretreatment with the Ca(2+)-ATPase inhibitor thapsigargin or with bradykinin, a hormone that releases Ca2+ from inositol trisphosphate-sensitive stores, does preclude the increase in [Ca2+]i induced by ATP. ATP and UTP also transiently inhibit cAMP accumulation in the intact cell, presumably via a Ca(2+)-mediated mechanism. The finding of a P2u receptor in NCB-20 cells adds to a growing perception that P2 receptors are widely distributed. Besides the P2u receptor, NCB-20 cells express adenosine A2 receptors, coupled to stimulation of cAMP accumulation. The presence of both P1 and P2 purinergic receptors permits a sequential modulation of distinct second messenger levels associated with a common stimulus, ATP.

Adenine Nucleotides↗
PubMed1991

Adenosine A1 receptor-induced inhibition of Ca2+ transients linked to action potentials in clonal pituitary cells.

Adenosine is a potent paracrine/autocrine feedback inhibitor of cell activation in a variety of tissues. Adenosine action was studied in pituitary cells, in which spontaneous electrical activity causes characteristic oscillations of the cytosolic free Ca2+ concentration, [Ca2+]i. Cells of the GH3B6 rat pituitary tumor line were studied by microspectrofluorimetry using the Ca2+ probes indo-1 and fura-2, in part in combination with electrophysiological tight seal whole cell recordings, obtained with the novel approach of patch perforation. It was demonstrated that adenosine receptor activation by N6-(R-phenyl-isopropyl)-adenosine (PIA) caused a block of electrical activity and abolished the ensuing alterations in [Ca2+]i. PIA mimicked the inhibitory action of somatostatin. Adenosine effects are mediated by A1 receptors in these cells and are antagonized by IBMX, an adenosine receptor blocker. PIA also suppressed action potentials that were elicited by the activation of protein kinase C with the phorbol ester PMA, or during the second phase of TRH action. In contrast, no interference was notable on TRH-induced intracellular Ca2+ mobilization. In addition to the abolition of Ca2+ transients, PIA lowers basal [Ca2+]i in some cells. It is proposed that in addition to the inhibition of adenylate cyclase, A1 receptor action on [Ca2+]i is an important element in the control of excitable pituitary cells.

Action Potentials↗
PubMed1991

Bradykinin stimulates Ca2+ mobilization in NCB-20 cells leading to direct inhibition of adenylylcyclase. A novel mechanism for inhibition of cAMP production.

The modulation of neuronal adenylylcyclase by Ca2+, acting via calmodulin, is a long-established example of a positive interaction between the Ca2(+)-mobilizing and cAMP-generating systems. In the present study, concentrations of Ca2+ that stimulate brain adenylylcyclase inhibit the adenylylcyclase of NCB-20 plasma membranes. These inhibitory effects of Ca2+ have been characterized and seem to be exerted at the catalytic unit of the enzyme; they are independent of calmodulin, Gi, and phosphodiesterase. To determine whether this inhibition of adenylylcyclase by Ca2+ could occur in the intact cell, cAMP accumulation was measured in response to bradykinin. Bradykinin, which mobilizes Ca2+ in NCB-20 cells, as a consequence of stimulating inositol phosphate production, causes a transient inhibition of prostaglandin E1 stimulation of cAMP accumulation. The inhibitory action of bradykinin is attenuated significantly by treatment of cells with the cell-permeant Ca2+ chelator, 1,2-bis-(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid. It seems likely that the inhibition of adenylylcyclase by low concentrations of Ca2+ represents a novel means for a negative interaction between Ca2(+)-mobilizing and cAMP-generating systems.

Adenylyl Cyclase Inhibitors↗
PubMed1991

13CO2 washout kinetics in acute hypercapnia.

The redistribution of CO2 and bicarbonate throughout the body following perturbations of normal respiration is not well described. We used tracer techniques to examine CO2-bicarbonate dynamics in an animal model in which acute hypercapnia was induced by hypoventilation. Eleven rabbits were anesthetized, tracheostomized, paralyzed and ventilated. In five animals PaCO2 was kept between 30 and 35 mmHg (control, C) while in six PaCO2 was held between 65 and 70 mmHg (acute hypercapnia, AH). A bolus of [13C]bicarbonate was given intravenously. Breath samples were obtained for 13CO2 by isotope ratio mass spectrometry and CO2 output (VCO2) was measured breath-by-breath for 240 min. There was no difference in the VCO2 between C [5.6 +/- 1.8 (SD) ml/min per kg] and AH (5.3 +/- 0.8). The 13CO2 washout for both C and AH was well fit by the sum of three exponentials. Only the time constant of the third (slowest) exponential was significantly longer in AH (103 +/- 11 min) compared with C (75 +/- 15, P less than 0.01). The mean residence time in AH (82 +/- 9 min) was significantly lower than in C (57 +/- 10, P less than 0.001). The estimated mass of exchangeable CO2 and bicarbonate was significantly greater in AH (443 +/- 37 ml per kg) compared with C (312 +/- 63, P less than 0.005). Compartmental analysis indicated that the increase in CO2-bicarbonate occurred primarily in the slowly exchanging pool. The data suggest that acute hypercapnia may be accompanied by a redistribution of exchangeable CO2 and bicarbonate in the body.

Acute Disease↗
PubMed1991

Oxygen uptake dynamics during high-intensity exercise in children and adults.

We hypothesized that the O2 uptake (Vo2) response to high-intensity exercise would be different in children than in adults. To test this hypothesis, 22 children (6-12 yr old) and 7 adults (27-40 yr old) performed 6 min of constant-work-rate cycle-ergometer exercise. Sixteen children performed a single test above their anaerobic threshold (AT). In a separate protocol, six children and all adults exercised at low and high intensity. Low-intensity exercise corresponded to the work rate at 80% of each subject's AT. High-intensity exercise (above the AT) was determined first by calculating the difference in work rate between the AT and the maximal Vo2 (delta). Twenty-five, 50, and 75% of this difference were added to the work rate at the subject's AT, and these work rates were referred to as 25% delta, 50% delta, and 75% delta. For exercise at 50% delta and 75% delta, Vo2 increased throughout exercise (O2 drift, linear regression slope of Vo2 as a function of time from 3 to 6 min) in all the adults, and the magnitude of the drift was correlated with increasing work rates in the above-AT range (r = 0.91, P less than 0.0001). In contrast, no O2 drift was observed in over half of the children during above-AT exercise. The O2 drifts were much higher in adults (1.76 +/- 0.63 ml O2.kg-1.min-2 at 75% delta) than in children (0.20 +/- 0.42, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Oxygen cost and oxygen uptake dynamics and recovery with 1 min of exercise in children and adults.

To test the hypothesis that O2 uptake (VO2) dynamics are different in adults and children, we examined the response to and recovery from short bursts of exercise in 10 children (7-11 yr) and 13 adults (26-42 yr). Each subject performed 1 min of cycle ergometer exercise at 50% of the anaerobic threshold (AT), 80% AT, and 50% of the difference between the AT and the maximal O2 uptake (VO2max) and 100 and 125% VO2max. Gas exchange was measured breath by breath. The cumulative O2 cost [the integral of VO2 (over baseline) through exercise and 10 min of recovery (ml O2/J)] was independent of work intensity in both children and adults. In above-AT exercise, O2 cost was significantly higher in children [0.25 +/- 0.05 (SD) ml/J] than in adults (0.18 +/- 0.02 ml/J, P less than 0.01). Recovery dynamics of VO2 in above-AT exercise [measured as the time constant (tau VO2) of the best-fit single exponential] were independent of work intensity in children and adults. Recovery tau VO2 was the same in both groups except at 125% VO2max, where tau VO2 was significantly smaller in children (35.5 +/- 5.9 s) than in adults (46.3 +/- 4 s, P less than 0.001). VO2 responses (i.e., time course, kinetics) to short bursts of exercise are, surprisingly, largely independent of work rate (power output) in both adults and children. In children, certain features of the VO2 response to high-intensity exercise are, to a small but significant degree, different from those in adults, indicating an underlying process of physiological maturation.

Adult↗
PubMed1991

Maturation of ventilatory responses to 1-minute exercise.

To test the hypothesis that ventilatory responses to exercise mature during growth in healthy children, we examined CO2 production (VCO2) and minute ventilation (VE) before, during, and for 10 min after 1-min bursts of cycle ergometry exercise. Ten children (range: 7-11 y old) and 13 adults (26-42 y old) exercised at work rates corresponding to 50 and 80% of the anaerobic or lactate threshold, 50% of the difference between anaerobic threshold and maximum O2 consumption, 100% of maximum O2 consumption, and 125% of maximum O2 consumption (125% max). Gas exchange was measured breath by breath. Children recovered faster from high-intensity (above anaerobic threshold) exercise as judged by the time constant of single exponential curve-fits to postexercise VCO2 [55 +/- 10 s (1 SD) at 125%. max in children compared with 92 +/- 17 s at 125% max in adults; p less than 0.001] and VE (58 +/- 10 s at 125% max in children compared with 125 +/- 37 s in adults, p less than 0.001). Although we found no significant difference between VCO2 and VE recovery times in children, VE was significantly slower than VCO2 in adults for high-intensity exercise. Moreover, recovery times in adults increased with work intensity but were independent of them in children. Whereas the CO2 costs [calculated as total CO2 produced above baseline per unit work done (mL.J-1)] increased with work intensity in adults, no similar significant relationship was observed in children.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Heart rate recovery from 1 minute of exercise in children and adults.

Previous studies demonstrated that the time required for oxygen uptake, CO2 production, and minute ventilation to return to baseline levels after 1-min bursts of exercise is different in children compared with adults. To test the hypothesis that the heart rate (HR) recovery time after exercise is also different in children compared with adults, we examined HR in 10 children (range 7-11 y old) and 12 adults (26-42 y old) for 10 min after 1 min of cycle ergometer exercise. Each subject exercised at work rates corresponding to 80% of the lactate or anaerobic threshold (AT), 50% of the difference between AT and maximal O2 uptake (delta), 100% of maximal uptake, and 125% of maximal uptake. Gas exchange was measured breath by breath. In adults, the HR recovery time increased significantly with work intensity as judged by the time constant of a single exponential curve fit to postburst-exercise HR [23 +/- 8 (SD) s at 80% AT, 55 +/- 16 at 50% delta, 74 +/- 13 at 100% of maximal uptake, and 83 +/- 20 at 125% of maximal uptake]. HR recovery time tended to increase with work intensity in children (16 +/- 7, 20 +/- 4, 23 +/- 7, and 27 +/- 9; for 80% AT, 50% delta, 100% of maximal uptake, and 125% of maximal uptake respectively), but to a much smaller extent, and the HR recovery time was significantly smaller in children in the high-intensity (above AT) range of exercise (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Evaluation of the role of GTP hydrolysis in the interaction between Mg2+ and GTP in regulating agonist binding to the adenosine A1 receptor.

Binding of agonists to adenosine receptors is reduced by GTP, whereas it is enhanced by Mg2+. The effect of GTP can be completely reversed by divalent cations, in contrast to the effect of the nonhydrolyzable analogue 5'-guanylylimidodiphosphate (GPPNHP). The present study addresses the role of divalent cation-stimulated specific and nonspecific GTP-ases in this reversal process. Under the conditions commonly employed in binding assays, almost all GTP is rapidly converted to GMP and Pi, indicating that maintenance of GTP levels is essential for the proper interpretation of results. A combination of a GTP-generating system and a competing substrate for high Km GTP-ases minimizes GTP breakdown. In the presence of these additions, the reversal of GTP effects is almost eliminated, and the inhibitory effects of both GTP and GPPNHP on agonist binding are reduced by divalent cations to a similar extent. Besides enhancing nonspecific GTP hydrolysis, Mg2+, but not Mn2+ or Ca2+, also stimulates specific agonist-dependent GTP-ase activity. Thus, it is evident that specific regulatory effects of Mg2+ and other divalent cations can only be identified when other, nonspecific, effects have been evaluated and controlled.

Adrenergic Agonists↗
PubMed1991

Oxygen uptake and heart rate responses during hypoxic exercise in children and adults.

Control of ventilation and heart rate during exercise appears to undergo maturation, while aerobic metabolism (VO2) may not. Since we had previously found that hypoxia during exercise produced different ventilatory responses in children (C) compared to adults (A), we hypothesized that VO2 and heart rate kinetics during exercise would show similar maturational responses to hypoxia. To test this hypothesis, we examined the responses during progressive (ramp) and constant work rate tests in children and adults breathing either room air or hypoxic gas (FiO2 = 0.15). When corrected for body weight, children and adults had similar values for lactic acidosis threshold (LAT) (C: 29.1 +/- 5.0 ml.min-1.kg-1; A: 27.9 +/- 4.3) and VO2max (C: 40.7 +/- 8.6 ml.min-1.kg-1; A: 45.2 +/- 6.7) during normoxia. Hypoxia significantly lowered LAT (C: 27.5 +/- 5.4 ml.min-1.kg-1; A: 23.2 +/- 3.8; both P less than 0.05) and VO2max (C: 37.7 +/- 8.3 ml.min-1.kg-1; A: 40.1 +/- 5.3; both P less than 0.05) in both children and adults. Metabolic efficiency (delta VO2/delta work rate) and the VO2-heart rate relationship (delta VO2/delta HR/kg) were similar in the two groups and unaffected by hypoxia. During the constant work rate exercise, VO2 kinetics (time constant during phase 2 of the response (pi 1) and the O2 deficit) were similar between children and adults and were significantly slowed by hypoxia, consistent with current understanding of the control of oxidative metabolism. Finally, heart rate was increased at rest and during exercise with hypoxia, while the time to reach 75% of the end-exercise response was delayed significantly, in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Effects of pertussis toxin on caudate neuron electrophysiology: studies with dopamine D1 and D2 agonists.

The selective D1 and D2-agonists SKF-38393 and N-0437 respectively, were tested in caudate pretreated with PT. A paired recording paradigm was used where the contralateral untreated caudate served as a control. Micropipettes were used to locally apply SKF-38393 and N-0437 onto neurons in both control and PT-pretreated caudate. A significant attenuation of the responses to the D2 agonist were observed after PT administration. Only 1 out of 12 cells tested on the PT side demonstrated any response to locally applied N-0437, whereas 90% of the neurons responded to the drug on the control side. Neurons from both the PT-pretreated and control caudates responded to locally applied SKF-38393. In addition to the specific D1 and D2 receptor agonists, DA and the indirect dopamine agonist PCP were tested for changes in responsiveness. Dopamine was equally efficacious at both control and PT-pretreated caudate neurons, which suggest that dopamine locally applied from the micropipette can interact with the unperturbed D1 receptors in the PT-pretreated caudate. On the other hand, the response to PCP was significantly attenuated after PT administration, which suggest that endogenously released DA preferentially interacts with the D2 receptor subtype. Taken together these data suggest an important role for the D2 receptor in the physiology of dopamine responsiveness in the caudate nucleus.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Differential expression of low molecular weight form of Gs-alpha in neostriatum and cerebellum: correlation with expression of calmodulin-independent adenylyl cyclase.

Adenylyl cyclase of neostriatal plasma membranes is far less responsive to stimulation by Ca2+/calmodulin than is the enzyme from cerebellum. When these tissues were investigated with antibodies against known G-proteins, no difference could be detected in any G-protein species, other than Gs. Whereas the cerebellum expressed predominantly the large form of Gs-alpha, the neostriatum expressed mainly lower molecular weight forms. The possibility is considered that there is selective association between lower molecular weight forms of Gs and calmodulin-independent forms of adenylyl cyclase.

Adenylyl Cyclases↗
PubMed1990

Potent and cooperative feedback inhibition of adenylate cyclase activity by calcium in pituitary-derived GH3 cells.

Calcium (Ca2+) ion concentrations that are achieved intracellularly upon membrane depolarization or activation of phospholipase C stimulate adenylate cyclase via calmodulin (CaM) in brain tissue. In the present study, this range of Ca2+ concentrations produced unanticipated inhibitory effects on the plasma membrane adenylate cyclase activity of GH3 cells. Ca2+ concentrations ranging from 0.1 to 0.8 microM exerted an increasing inhibition on enzyme activity, which reached a plateau (35-45% inhibition) at around 1 microM. This inhibitory effect was highly cooperative for Ca2+ ions, but was neither enhanced nor dependent upon the addition of CaM (1 microM) to EGTA-washed membranes. The inhibition was greatly enhanced upon stimulation of the enzyme by vasoactive intestinal peptide (VIP) and/or GTP. Prior exposure of cultured cells to pertussis toxin did not affect the inhibition of plasma membrane adenylate cyclase activity by Ca2+, although in these membranes, hormonal (somatostatin) inhibition was significantly attenuated. Maximally effective concentrations of Ca2+ and somatostatin produced additive inhibitory effects on adenylate cyclase. The addition of phosphodiesterase inhibitors demonstrated that inhibitory effects of Ca2+ were not mediated by Ca2(+)-dependent stimulation of a phosphodiesterase activity. These observations provide a mechanism for the feedback inhibition by elevated intracellular Ca2+ levels on cAMP-facilitated Ca2+ entry into GH3 cells, as well as inhibitory crosstalk between Ca2(+)-mobilizing signals and adenylate cyclase activity.

Adenylate Cyclase Toxin↗