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M C Churchill

Publications and source records attributed to M C Churchill.

At least 37 records · Page 2Linked to original sources
PubMed1985

Does decreasing extracellular Na inhibit in vitro renin secretion by affecting Na-Ca exchange?

It has been shown previously that in vitro renin secretion is inhibited by partial replacement of extracellular NaCl with either mannitol or choline chloride; the inhibitory effect is attributed to an increase in intracellular Ca, resulting from a decreased rate of Ca efflux via Na-Ca exchange. In the present experiments, we confirmed that partially replacing NaCl with choline chloride inhibited renin secretion from rat renal cortical slices, but we found that atropine completely blocked the effect, suggesting cholinergic mediation. Partially replacing NaCl with mannitol also inhibited renin secretion, but the effect could not be attributed specifically to a reduction in extracellular Na. Moreover, the stimulatory effect of Ca chelation on renin secretion was antagonized by either mannitol- or choline chloride -containing incubation media. These results do not support the hypothesis that lowering extracellular Na inhibits renin secretion by a mechanism involving decreased Ca efflux via Na-Ca exchange.

Animals↗
PubMed1985

Quinacrine antagonizes the effects of Na,K-ATPase inhibitors on renal prostaglandin E2 release but not their effects on renin secretion.

Previous results have demonstrated that two inhibitors of Na-and-K-activated adenosine triphosphatase (ouabain, vanadate) lead to stimulated prostaglandin E2 release and to inhibited renin secretion in the rat renal cortical slice preparation. It was speculated that stimulation of phospholipase A2 activity accounted for the effect on prostaglandin E2 release. We used the same preparation in the present experiments, and showed that another inhibitor of Na-and-K-activated adenosine triphosphatase (K-free incubation medium) stimulates prostaglandin E2 release and inhibits renin secretion. Quinacrine antagonized the stimulatory effects of ouabain, vanadate, and K-free medium on prostaglandin E2 release (consistent with phospholipase A2 involvement), but did not antagonize their inhibitory effects on renin secretion. Collectively, these observations lend further weight to the argument against a mediatory role of prostaglandin synthesis in the renin secretory process.

Animals↗
PubMed1985

Lack of renal effects of DOCA, ACTH, spironolactone, and angiotensin II in Squalus acanthias.

Angiotensin II was infused intravenously in spiny dogfish sharks (Squalus acanthias). There were no significant effects on arterial blood pressure, glomerular filtration rate, urine flow, or Na excretion either in comparison with pre- and postinfusion values or in comparison with values measured in a control group of fish given elasmobranch saline intravenously. In other dogfish, glomerular filtration rate, urine flow, and Na and K excretory rates were measured for 3 days following implantation of desoxycorticosterone (DOCA), adrenocorticotropin (ACTH), or spironolactone; a control group was given no drug. There were no significant differences between these four groups of fish with respect to any of the measured parameters. These results suggest that the dogfish kidney is not a target organ for several substances known to affect renal function, either directly or indirectly, in other animals.

Adrenocorticotropic Hormone↗
PubMed1985

A1 and A2 adenosine receptor activation inhibits and stimulates renin secretion of rat renal cortical slices.

Previous studies by others have demonstrated that exogenous adenosine inhibits renin secretion in vivo. In the present experiments, we studied the effects of three adenosine receptor agonists [N6-cyclohexyladenosine (CHA), 2-chloroadenosine (2-CIA) and 5'-N-ethylcarboxamideadenosine (NECA)] on renin secretion of rat renal cortical slices. The effects were biphasic; submicromolar concentrations inhibited secretion concentration-dependently and the order of potency was CHA greater than 2-CIA greater than NECA. Micromolar and higher concentrations stimulated secretion concentration-dependently and the order of potency was reversed: NECA greater than 2-CIA greater than CHA. These results are consistent with the hypothesis that activation of A1 and A2 adenosine receptors produces inhibition and stimulation of secretion, respectively. Theophylline antagonized both the inhibitory effect of low concentrations of CHA and the stimulatory effect of higher concentrations, providing additional evidence for mediation by activation of cell-surface adenosine receptors. Calcium chelation abolished the inhibitory effect of CHA, suggesting that increased intracellular calcium mediates the inhibitory effect; on the other hand, the inhibitory effect was unaffected by membrane depolarization and calcium channel blockade, suggesting that CHA-induced inhibition is not due to calcium influx through voltage-sensitive calcium channels. Ouabain, vanadate and K-depolarization, all of which are believed to increase intracellular calcium, antagonized CHA- and NECA-stimulated renin secretion, suggesting that the stimulatory effect of these agonists is mediated by decreased intracellular calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Chloroadenosine↗
PubMed1984

Action and mechanism of action of veratrine on renin secretion from rat kidney slices.

It is well known that norepinephrine released from the renal nerves stimulates the secretion of renin by a beta adrenergic mechanism. In the present experiments, we investigated the effects of renin secretion of veratrine, which depolarizes nerve terminals and thereby causes transmitter release. The rat renal cortical slice preparation was used. Veratrine (10-200 microM) stimulated renin secretion in a concentration-dependent manner. Veratrine-stimulated secretion was antagonized by timolol (0.9 and 9.0 microM) and by tetrodotoxin (0.5 and 5.0 microM), a sodium channel blocker. Neither drug abolished completely the stimulatory effect of veratrine. Moreover, veratrine stimulated renin secretion in slices prepared from previously denervated kidneys; this response was not antagonized by timolol. These results are consistent with the hypothesis that veratrine stimulates renin secretion by at least two mechanisms. One component probably consists of veratrine-induced depolarization of renal nerve terminals, release of norepinephrine and activation of juxtaglomerular cell beta adrenergic receptors; the other component appears to be independent of nerve terminals in the preparation. We conclude that the tetrodotoxin-sensitive component of veratrine-stimulated renin secretion in this preparation is an in vitro model of renal nerve-stimulated renin secretion; it should be useful in investigating substances which affect renin secretion by presynaptic modulation of transmitter release.

Animals↗
PubMed1984

Renal effects of 2-chloroadenosine in the two-kidney Goldblatt rat.

Two to four weeks after the left renal artery was clipped and the contralateral kidney was left untouched in Sprague-Dawley rats (the two-kidney Goldblatt preparation), the clips were removed under ether anesthesia. The next day the rats were anesthetized (sodium pentobarbital) and renal functions of both kidneys were measured before and after an i.v. infusion of 2-chloroadenosine (3.6 nMol/min). Then renal cortical renin was measured by incubating tissue homogenate with rat renin substrate and using radioimmunoassay to determine the rate of angiotensin I production. Renal cortical renin was elevated above control in the previously clipped left kidneys and suppressed below control in the right kidneys; on the average, there was a 30-fold difference in renins of the two kidneys. Despite this difference, the 2-chloroadenosine infusion induced similar hemodynamic changes (clearances of inulin and p-aminohippurate, filtration fraction) in the two kidneys. These results are inconsistent with the hypothesis that renal renin is an important determinant of adenosine-induced renal hemodynamic changes.

2-Chloroadenosine↗
PubMed1983

Comparison of the effects of rubidium and potassium on renin secretion from rat kidney slices.

It has been shown previously that both low (less than 2 mM) and high (greater than 45 mM) concentrations of extracellular K inhibit the renin secretory rate of rat kidney slices, and that nonidentical Ca-dependent mechanisms appear to be involved. As Rb can substitute for K in many biological systems, the present experiments were designed to compare the effects of K and Rb on renin secretion of rat kidney slices. Adding either KCl or RbCl to a nominally K-free incubation medium stimulated renin secretory rate in concentration-dependent manners; secretory rate was half-maximally stimulated at approximately 1.5 mM and maximally stimulated at approximately 2-3 mM concentrations of either KCl or RbCl. Ouabain completely abolished the basal secretory rate, in either KCl- or RbCl-containing media. These results suggest that the effects of increasing KCl or RbCl in the range of 0.5-4 mM are attributable to stimulatory effects of Rb and K on Na-K-ATPase activity. Renin secretory rate was greatly inhibited by incubating kidney slices in media containing 60 mM concentrations of either KCl or RbCl. A concentration of methoxy-verapamil which completely blocked the inhibitory effects of 60 mM KCl or of 60 mM RbCl failed to antagonize the inhibitory effects of a nominally K-free medium or of media containing ouabain and either 4 mM KCl or 4 mM RbCl. Taken together with previous results, these observations suggest that Rb can substitute for K in the renin secretory process. Furthermore, they support the hypothesis that inhibitors of Na-K-ATPase, and depolarization inhibit renin secretion by Ca-dependent mechanisms which are not identical.

Animals↗
PubMed1983

Evidence that beta 1-adrenoceptor activation mediates isoproterenol-stimulated renin secretion in the rat.

The goal of these experiments was to determine if isoproterenol-stimulated renin secretion in the rat is mediated by activation of beta 1- and/or beta 2-adrenoceptors. The rat renal cortical slice preparation was used. The renin secretory rate was a sigmoid function of the logarithm of the isoproterenol concentration; half-maximal and maximal stimulation occurred at approximately 0.01 and 0.1 microM isoproterenol, respectively. Neither timolol (a nonselective beta-antagonist) nor atenolol (a beta 1-selective antagonist) had a significant effect on basal secretory rate, but both shifted the isoproterenol dose-response curve to the right without changing its slope, suggesting competitive antagonism. Timolol was the more potent, but the response to a maximally effective concentration of isoproterenol could be blocked by timolol (0.9 microM), atenolol (110 microM), or a combination of the two (0.45 microM timolol plus 55 microM atenolol). This latter finding is consistent with action of the two antagonists at one and the same site. If it is assumed that timolol antagonizes both beta 1- and beta 2-adrenoceptors and that atenolol antagonizes only beta 1-adrenoceptors, it follows that isoproterenol-stimulated renin secretion in this preparation is mediated by activation of beta 1-adrenoceptors.

Animals↗
PubMed1983

Effects of trifluoperazine on renin secretion of rat kidney slices.

It has been suggested recently that calmodulin acts as an intracellular "Ca-receptor," and that many Ca-dependent cellular activities are mediated in some manner by Ca-calmodulin. The renin-secretory activity of juxtaglomerular cells appears to be inversely related to intracellular Ca concentration (Ca); if Ca-calmodulin is the mediator in the secretory process, it follows that secretory rate should be inversely related to Ca-calmodulin activity. The purpose of these experiments was to determine the effects of trifluoperazine, an inactivator of Ca-calmodulin, on renin secretion of rat kidney slices. Over the range 10(-6) to 10(-4) M, trifluoperazine produced a concentration-dependent increase in renin release. As assessed by lactate dehydrogenase release, the trifluoperazine-induced increase in renin release cannot be attributed to increased cell membrane permeability to proteins. Thus, trifluoperazine stimulated renin secretion in a concentration-dependent manner. This is consistent with an inverse relation between Ca-calmodulin activity and renin secretion. However, in the presence of trifluoperazine, isoproterenol still stimulated and antidiuretic hormone, angiotensin II, high extracellular K concentration, ouabain and vanadate still inhibited renin secretion. Provided these stimulatory and inhibitory effects are associated with decreased and increased Ca, respectively, these observations are inconsistent with the hypothesis that the effects of Ca, on renin secretion are mediated by changes in Ca-calmodulin activity, since increases in Ca promote rather than attenuate the binding of trifluoperazine to calmodulin. It is concluded that trifluoperazine-stimulated renin secretion is mediated by a decrease in Cai produced by inhibition of Ca influx and/or stimulation of Ca efflux and/or sequestration.

Animals↗
PubMed1982

Isoproterenol-stimulated renin secretion in the rat: second messenger roles of Ca and cyclic AMP.

These experiments were designed to elucidate which of two second messengers (cyclic 3',5' adenosine monophosphate [c-AMP]; intracellular calcium [Cai]) was more closely related to the renin secretory process. The rat renal cortical slice preparation was used. Agents which previously were shown to inhibit basal renin secretion by increasing Cai (ouabain, vanadate, angiotensin II, antidiuretic hormone, and 60 mM K) antagonized and/or blocked isoproterenol-stimulated secretion, which is thought to be mediated by adenylate cyclase activation and increased levels of c-AMP. The stimulatory effect of dibutyryl c-AMP was antagonized and/or blocked by the same agents which antagonized and/or blocked isoproterenol-stimulated secretion. Thus, the inhibitory effects of these agents on isoproterenol-stimulated secretion cannot be explained by a Ca-induced decrease in c-AMP production. Secretory rate was stimulated by a potent phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine). A combination of this and dibutyryl c-AMP produced even greater stimulation. Ouabain blocked the stimulatory effect of this combination. These results are not consistent with an invariant direct relationship between c-AMP and renin secretory rate, but are consistent with an inverse relationship between Ca; and renin secretion. Further, they are consistent with the hypothesis that in isoproterenol-stimulated renin secretion. c-AMP is the second and Cai the third or the final messenger.

1-Methyl-3-isobutylxanthine↗
PubMed1982

Ca-dependence of the inhibitory effect of K-depolarization on renin secretion from rat kidney slices.

Renin secretion of rat kidney slices was studied as a function of extracellular K concentration. Independently of osmolality and extracellular Na and Cl concentrations, increasing K inhibited secretory rate in a concentration-dependent manner. At 60 mM K, rates were only a few per cent (1.6 +/- 0.8 and 3.5 +/- 0.5%, depending on Na and/or osmolality) of the rate measured at 4 mM K. Lowering extracellular Ca concentration from 2.65 X 10(-3) to less than 10(-8) M stimulated secretion and abolished the inhibitory effect of 60 mM K; these effects were reversible. Methoxy-verapamil and verapamil antagonized the inhibitory effect of 60 mM K in concentration-dependent manners; methoxy-verapamil was the more potent. Lowering Ca from 3.0 to 0.25 mM potentiated the antagonistic effects of both drugs. These results are consistent with the hypothesis that depolarization of juxtaglomerular cells opens voltage-sensitive Ca channels and that the influx of Ca mediates the inhibitory effect of depolarization on renin secretion. The results are consistent with the more general hypothesis that intracellular Ca plays an inhibitory coupling role in the control of renin secretion.

Animals↗
PubMed1980

Separate and combined effects of ouabain and extracellular potassium on renin secretion from rat renal cortical slices.

1. Renin secretion of rat renal cortical slices was measured as a function of extracellular K and ouabain concentrations in the incubation medium.2. A sigmoid relationship was found between renin secretion and log K concentration over the range 1.0-4.0 mM. Secretion was maximal at about 2.25 mM-K and half-maximal at about 1.43 mM-K.3. In media containing 4.0 mM-K, ouabain at 10(-8), 10(-7), and 10(-6)M did not affect renin secretion. Higher concentrations of ouabain inhibited secretion. A sigmoid relationship was found between% inhibition of secretion and log ouabain concentration (10(-6)-10(-3)M). Inhibition was half-maximal at 2.3 x 10(-5)M and complete at 10(-3)M-ouabain.4. Lowering extracellular K concentration from 4.0 to 2.25 mM shifted the dose-effect curve of ouabain to the left. At 2.25 mM-K, inhibition of renin secretion was half-maximal at 10(-5)M-ouabain.5. The inhibitory effect of 2 x 10(-5)M-ouabain (twice the dose for 50% inhibition) in media containing 2.25 mM-K was nearly identical to the combined effect of lowering K to 1.43 mM (the concentration required for 50% inhibition) and adding 10(-5)M-ouabain. This observation suggests that ouabain and low extracellular K act at a common site, presumably on Na, K-ATPase activity, to inhibit renin secretion.6. Neither 10(-3)M-ouabain nor K-free medium inhibited renin secretion when the concentration of free Ca in the medium was lowered to < 10(-8)M. Therefore it is proposed that as a result of Na, K-ATPase inhibition, (a) intracellular Na increases, (b) intracellular Ca increases via Na-Ca exchange, provided that extracellular Ca exceeds 10(-8)M, and that (c) Ca accumulation, in some unknown manner, inhibits renin secretion from rat renal cortical slices.

Animals↗
PubMed1980

Biphasic effect of extracellular [K] on isoproterenol-stimulated renin secretion from rat kidney slices.

It is known that large changes in extracellular K concentration [K], in either direction from normal, lead to depolarization of the cell and it has been suggested that depolarization inhibits the secretion of renin from juxtaglomerular cells. In the present experiments, renin secretion of rat kidney slices was examined as a function of [K]. Increases in [k] (from 4-45 or to 60mM) inhibited basal and isoproterenol-stimulated renin secretion, independently of changes in [Na], [Cl] and osmolality. At 4, 45 and 60 mM K, reductions in extracellular [Na] also inhibited secretion; the combined effect of isoproterenol. The Ca antagonist D-600 antagonized the inhibitory effects of high [K], restoring both the basal and the isoproterenol-stimulated secretory rates to normal values. Decreasing [K] (from 2.5-1.0 mM) also inhibited basal and isoproterenol-stimulated secretion, and this effect was not antagonized by D-600. On the basis of the known actions of D-600 and the present observations, it is suggested that depolarization per se does not inhibit renin secretion but that increases in intracellular [Ca] (resulting from depolarization-induced Ca influx in the presence of high [K] or from changes in the rate of Na-Ca exchange in the presence of low [K]) antagonize both basal and isoproterenol-stimulated renin secretion.

Animals↗