R T McCarthy

Yale-New Haven Hospital, New Haven, Connecticut, United States

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Publications (13)105.94 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We have previously reported that parathyroid hormone (PTH) has specific effects on a human umbilical vein endothelial cell line. Further studies were performed to characterize the signaling cascades initiated by PTH. We report that PTH induced the appearance of voltage sensitive calcium channels. Furthermore, PTH increased ceramide but not diacylglycerol content. Since elevations in [Ca(2+)](i) and phospholipid turnover are signals for the activation of protein kinase C (PKC), the cells were screened for PKC isoforms. PTH induced a redistribution of the PKCepsilon to the particulate fractions of cell homogenates. In summary, PTH induced PKC translocation through a calcium-phospholipid pathway in an endothelial cell line.
    Peptides 02/2002; 23(1):79-85. DOI:10.1016/S0196-9781(01)00582-4 · 2.61 Impact Factor
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    ABSTRACT: Acute parathyroid hormone exposure induces vascular smooth muscle relaxation. In contrast, continuous infusion of parathyroid hormone leads to vasoconstriction and an elevation of blood pressure. Despite the known effects of parathyroid hormone on vascular smooth muscle, possible direct effects on the vascular endothelium have not previously been investigated. Using a human umbilical vein endothelial cell line, we found that parathyroid hormone increased both intracellular calcium and cellular cAMP content in these endothelial cells. Furthermore, exposure of these cells to increasing concentrations of parathyroid hormone stimulated both [(3)H]thymidine incorporation and endothelin-1 secretion. Parathyroid hormone/parathyroid hormone-related peptide receptor mRNA could be detected at low levels in these cells. In summary, these data demonstrate that endothelium-derived cells contain functional parathyroid hormone receptors. The potential physiological role of these receptors remains to be determined.
    AJP Endocrinology and Metabolism 10/2000; 279(3):E654-62. · 4.09 Impact Factor
  • Endocrine Reviews 11/1995; 16(5):649-81. · 19.36 Impact Factor
  • Endocrine Reviews 10/1995; 16(5):649-681. DOI:10.1210/edrv-16-5-649 · 19.36 Impact Factor
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    R T McCarthy, C Isales, H Rasmussen
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    ABSTRACT: With the use of whole-cell and single-channel current recordings, we have examined in more detail the site of action of angiotensin II (AII) on multiple populations of voltage-gated calcium channels in bovine adrenal glomerulosa cells. AII (10 nM) enhances whole-cell T-type calcium channel current and increases the activity of single T-type calcium channels in cell-attached patch recordings. The AII-induced enhancement of whole-cell calcium channel currents is dependent on the presence of internal GTP and can be inhibited by the competitive AII-receptor antagonist saralasin (1 microM). These results show that AII augments the T-type calcium channel current in bovine adrenal glomerulosa cells.
    Proceedings of the National Academy of Sciences 05/1993; 90(8):3260-4. DOI:10.1073/pnas.90.8.3260 · 9.81 Impact Factor
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    ABSTRACT: Two populations of voltage-dependent Ca2+ channels, T-type and L-type, are present in bovine adrenal glomerulosa cells. Activation of these channels by cell depolarization with the resultant increase in Ca2+ influx may be one way in which agonists regulate aldosterone secretion. In addition, these channels may be the site of antagonist action. In the present study, we have demonstrated that atrial natriuretic peptide (ANP), an antagonist of aldosterone secretion, alters only the voltage dependence of inactivation of the T-type channel while enhancing the voltage dependence of activation of a subpopulation of L-type channels. These patch-clamp data, which demonstrated contrasting effects of ANP on the activity of T- and L-type Ca2+ channels correlated with changes induced in cytosolic calcium [( Ca2+]i). In the weakly depolarized cell, ANP (greater than 30 pM) lowered [Ca2+]i, in contrast to the strongly depolarized cell, in which ANP (greater than 10 pM) raised [Ca2+]i. Similar alterations in the level of [Ca2+]i in the stimulated cell were induced by the Ca(2+)-channel blocker nitrendipine and the L-type channel agonist, (-)BAY K 8644. With increasing concentrations of extracellular K+ (3.5-60 mM) the rate of aldosterone secretion rose nonmonotonically. ANP inhibited secretion over this broad range of K+ concentrations; however, its potency as an inhibitor of secretion was diminished in the strongly depolarized cell. These data are discussed in the context of a model that proposes a role for sustained Ca2+ influx in cell activation.
    The American journal of physiology 11/1991; 261(4 Pt 2):F706-19. · 3.28 Impact Factor
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    ABSTRACT: In the bovine adrenal glomerulosa cell, calcium influx through voltage-dependent calcium channels is critical to maintaining an aldosterone secretory response. In patch clamp, atrial natriuretic peptide (ANP) inhibits T-type calcium channel current yet stimulates L-type calcium channel current. In the present study the channel effects of ANP observed in the patch-clamp configuration were extended and related to populations of cells. We observed the following. (i) The effect of ANP on T-channel current resulted in the reduction in the open state probability. ANP decreased the mean open state duration from 14.2 to 1.8 ms/sweep. (ii) In the weakly depolarized cell stimulated by 8 mM K+, ANP reduced the level of aequorin luminescence (a measure of cytosolic calcium) and completely inhibited the stimulated rate of aldosterone secretion, returning it to prestimulation values. These effects are consistent with a decrease in net calcium channel influx and the reported inhibition of T-channel current. In contrast, the calcium channel blocker, nitrendipine, which at low dose selectively blocks L-type calcium channel flux, only slightly reduced luminescence, and partially inhibited the sustained secretory response. (iii) In the strongly depolarized cell, stimulated by 60 mM K+, ANP increased the level of aequorin luminescence consistent with an increase in net calcium channel influx and the reported stimulation of L-channel current. These results indicate that under physiological conditions the inhibition of T-type calcium channels may be involved in the inhibition of the aldosterone secretion induced by ANP.
    Canadian Journal of Physiology and Pharmacology 11/1991; 69(10):1553-60. DOI:10.1139/y91-231 · 1.55 Impact Factor
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    ABSTRACT: Atrial natriuretic peptide (ANP) inhibits the secretion of aldosterone stimulated by any of these major physiological agonists: angiotensin II, adrenocorticotropic hormone, or K+. The stimulatory actions of each of these agonists depend on calcium influx through voltage-dependent calcium channels. Because two types of calcium channels have been previously described in bovine glomerulosa cells (T- and L-type), the patch-clamp technique was used to evaluate the effect of ANP on each voltage-dependent calcium channel type. ANP was found to differentially modulate these two channel types, stimulating L-current while inhibiting T-current. Inhibition of T-current resulted from a shift in the voltage dependence of inactivation to more negative potentials within the physiological range. These results indicate that the ANP-induced inhibition of aldosterone secretion may be partially mediated via a reduction of the calcium current through T-type channels.
    The American journal of physiology 04/1990; 258(3 Pt 2):F473-8. · 3.28 Impact Factor
  • Endocrine Reviews 12/1989; 10(4):496-518. DOI:10.1210/edrv-10-4-496 · 19.36 Impact Factor
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    R T McCarthy, C J Cohen
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    ABSTRACT: Calcium channel currents were studied in the A10 and A7r5 cell lines derived from rat thoracic aorta muscle cells. The whole-cell variation of the patch voltage clamp technique was used. Results with each cell line were nearly identical. Two types of Ca channels were found in each cell line that are similar to the L-type and T-type Ca channels found in excitable cells. Nimodipine block of the L-type Ca channels in both cell lines is more potent than in previously studied tissues. The kinetics of nimodipine block are accounted for by a model that postulates 1:1 drug binding to open Ca channels with an apparent dissociation constant (KO) of 16-45 pM. In A7r5 cells, the rate of onset of nimodipine block increases with the test potential, in quantitative agreement with the model of open channel block. The apparent association rate (f) is 1.4 x 10(9) M-1 s-1; the dissociation rate (b) is about 0.024 s-1. In anterior pituitary cells (GH4C1 cells), KO is 30 times larger; b is only twice as fast, but f is 15 times slower. The comparative kinetic analysis indicates that the high-affinity binding site for nimodipine is similar in both GH4C1 and A7r5 cells, but nimodipine diffuses much faster or has a larger partition coefficient into the plasmalemma of A7r5 cells than for GH4C1 cells. Unusually high-affinity binding was not observed in earlier 45Ca flux studies with A10 and A7r5 cells. The model of open channel block accounts for the discrepancy; only a small fraction of the Ca channels are in the high affinity open state under the conditions used in 45Ca flux studies, so an effective binding constant is measured that is much greater than the dissociation constant for high-affinity binding.
    The Journal of General Physiology 11/1989; 94(4):669-92. DOI:10.1085/jgp.94.4.669 · 4.57 Impact Factor
  • Annals of the New York Academy of Sciences 02/1989; 568:73-80. DOI:10.1111/j.1749-6632.1989.tb12492.x · 4.31 Impact Factor
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    ABSTRACT: Ca channel currents were studied in freshly dispersed bovine adrenal glomerulosa cells to better understand the control of aldosterone secretion by extracellular K concentration (Ko) and angiotensin II (AII). The whole-cell variation of the patch voltage clamp technique was used. Two types of Ca channels were found. One type is similar to the "T-type" Ca channels found in many excitable cells. These channels deactivate slowly (tau approximately equal to 7 ms at -75 mV) and inactivate rapidly during strong depolarizations. The second channel type activates and inactivates at more positive potentials than the T-type Ca channels and deactivates rapidly. These channels are similar to the "L-type" Ca channels found in muscle and nerve. Our studies provide three reasons for concluding that T-type Ca channels have an important role in mediating stimulus-secretion coupling in response to high K+ or AII: (i) aldosterone secretion and steady-state current through T-type Ca channels are biphasic functions of Ko and both increase in parallel for Ko = 2-10 mM; (ii) nitrendipine blocks the T-type Ca channels and the stimulation of aldosterone secretion by high K+ or AII with similar potency; (iii) AII increases Ca entry through the T-type Ca channels.
    Proceedings of the National Academy of Sciences 05/1988; 85(7):2412-6. DOI:10.1073/pnas.85.7.2412 · 9.81 Impact Factor
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    C J Cohen, R T McCarthy
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    ABSTRACT: 1. Ca channels were studied in the GH4C1 clonal cell line derived from rat anterior pituitary cells. The whole-cell variation of the patch-electrode voltage-clamp technique was used. 2. Two types of Ca channels were found. One type ('slowly inactivating' channels) is insensitive to changes in holding potential, does not inactivate during test pulses lasting several seconds, and deactivates very quickly upon repolarization. For holding potentials less than -40 mV, a second type of Ca channel is available for opening. This population ('transient' channels) differs from the first type in that it activates at more negative potentials, inactivates rapidly with either Ca or Ba as the charge carrier, deactivates about 10 times more slowly upon repolarization, and is less selective for Ba over Cs. 3. Nimodipine preferentially blocks the slowly inactivating channels. Block of these channels is time- and voltage-dependent, such that block is maximized by long depolarizations. 4. A comparison of the voltage dependence of steady-state nimodipine block with the voltage dependence of channel activation indicates that channel block is directly proportional to the number of open channels. The results are accounted for by a model that postulates 1:1 high-affinity drug binding to open Ca channels. The apparent dissociation constant for binding to open channels is 517 pM. Similar binding constants were previously reported for the inhibition of high-K-induced hormone secretion and high-affinity ligand binding of [3H]nimodipine to isolated plasma membranes. 5. The rate of onset of nimodipine block increases with the test potential, in quantitative agreement with the model of open-channel block. The apparent association rate is about 9.6 X 10(7) M-1 s-1; the dissociation rate is about 0.050 s-1. At therapeutic concentrations (less than 10 nM) nimodipine block takes many seconds to reach equilibrium. 6. Nimodipine should have little effect on stimulus-secretion coupling in healthy pituitary cells in vivo because: (a) the drug binds very weakly to the transient channels that are open at normal resting potentials, and (b) negligible high-affinity binding occurs during spontaneous activity because the onset of block is very slow.
    The Journal of Physiology 07/1987; 387(1):195-225. DOI:10.1113/jphysiol.1987.sp016570 · 4.54 Impact Factor

Publication Stats

557 Citations
105.94 Total Impact Points

Institutions

  • 1993–2002
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 1995
    • Georgia Health Sciences University
      • Institute of Molecular Medicine and Genetics
      Augusta, GA, United States
  • 1991
    • Yale University
      • Department of Internal Medicine
      New Haven, Connecticut, United States