Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac beta-adrenoceptor responsiveness was evaluated in experimental uremia by in vivo and in vitro techniques. Uremia was induced in rats by bilateral nephrectomy for 48 h. In rats with chronic intra-arterial and intravenous catheters, cardiovascular reflexes and the renin-angiotensin system were blocked with atropine, pentolinium, and a converting-enzyme inhibitor, respectively. Blood pressure (BP) and heart rate (HR) were continuously recorded. Cumulative doses of isoproterenol were injected intravenously. In uremic rats, the dose-response curve for the HR response showed a lower maximal response (P less than 0.01) and no significant difference in 50% effective dose values compared with controls, whereas the BP decrease caused by isoproterenol was similar in control and uremic rats. When forskolin was injected intravenously to stimulate adenylate cyclase in a receptor-independent manner, the maximal HR increase was lower in uremic rats (P less than 0.01). beta-Adrenoceptor density and affinity, measured by 125I-cyanopindolol binding to sarcolemmal membranes, was not different between control and uremic rats. Also binding affinities for the agonist isoproterenol were not different between groups. Basal adenylate cyclase activity, as well as activity after maximal stimulation by isoproterenol and by forskolin were lower in uremic than in control rats (P less than 0.01). The results show that the chronotropic response of the heart is reduced in uremia. Such hyporesponsiveness may be due, at least in part, to a reduced activity of cardiac adenylate cyclase.
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PMID:Reduced chronotropic responsiveness of the heart in experimental uremia. 301 Jul 45

The sequence of intracellular events that lead to renin release is incompletely defined. Accordingly, we examined the interrelationship of two important factors in the process: renin release coupled to cAMP and renin release related to a decrease in intracellular calcium activity (Cai). Rat renal cortical slices were used to study these relationships in vitro. In the initial studies, cAMP-coupled renin release was established for isoproterenol (10(-5) M), prostacyclin (PGI2; 10(-6) M), and forskolin (10(-5) M). Each agent caused an increase in renin release and tissue cAMP levels, which were inhibited by the addition of the adenyl cyclase inhibitor 2',5'-dideoxyadenosine (DDA, 10(-5) M) to the media. Diltiazem (10(-4) M) and 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8; 0.6 X 10(-4) M) are believed to decrease Cai by different mechanisms; each of these agents caused a significant increase in renin release. Renin release stimulated by diltiazem, and TMB-8 was not inhibited by either DDA or indomethacin. The calcium ionophore A23187 (17 X 10(-6) M) and vanadate (10(-3) M) were next added to produce an increase in Cai. Both of these agents blunted renin release produced by isoproterenol, PGI2, and forskolin. These results provide strong indirect support for an inverse relationship between Cai and renin release in the juxtaglomerular cell. The results also imply that changes in Cai occupy a step that is distal to cAMP-coupled events in the sequence of intracellular events which culminate in renin release.
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PMID:Importance of calcium in renal renin release. 301 94

Using a renal cortical slice preparation obtained from hibernating ground squirrels, this study investigated whether three major intrarenal prostaglandins (PG) and other agents added at a 10(-5) M dose can affect renin release (RR), and if their effect on RR is correlated with changes in tissue cyclic AMP content (tcAMPc). Resting in vitro levels for RR and tcAMPc during hibernation were found to be comparable to those observed in non-hibernating (NH) mammals. Addition of PGE1 significantly stimulated RR while PGE2 and PGF2-alpha were ineffective. None of the three PG's tested altered resting levels of tcAMPC. When added by itself or in conjunction with any of the three PG's, the phosphodiesterase inhibitor theophylline did not modify resting levels of RR and tcAMPc, but it prevented the previous stimulatory effect of PGE1 alone on RR. Addition of lipid-soluble dcAMP, either alone or in conjunction with any of the three PG's, resulted in an increase in tcAMPc in all instances, no change in resting RR regarding PGE2 and PGF2-alpha, and again the prevention of the stimulatory effect of PGE1 alone on RR. These data suggest that: the resting activity of the renin-angiotensin system (RAS) and the adenylate cyclase-cAMP system (AC-cAMP) of the hibernating ground squirrel is comparable to that of NH species; in contrast, the sensitivity of the RAS of the hibernator to PG stimulation is less than that exhibited by the RAS of NH species when comparable in vitro concentrations of three major PG's are used; PGE1 stimulation of RR in the hibernator is independent of changes in tcAMPc; changes in tcAMPc may be inversely related to those in RR in the hibernator; and the known stimulatory effect of PG's on the renal cortical AC-cAMP of NH species is not seen in the hibernating ground squirrel at comparable PG doses.
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PMID:Prostaglandin E1 (PGE1) stimulates in vitro renin release in the hibernating ground squirrel. 301 51

The cellular mechanism of action of cyclic AMP (cAMP) mediating the beta-adrenergic stimulation of renin secretion was studied, with special reference to its interactions with the inhibitory pathway of renin secretion by Ca2+ calmodulin. Forskolin, a potent stimulator of adenyl cyclase that bypasses the hormone-receptor interactions, stimulated renin secretion in vitro from rabbit renal cortical slices in a concentration-dependent manner. Renin secretion stimulated by submaximal concentration of forskolin was partly or completely antagonized or blocked by raising intracellular Ca2+ concentration by incubating slices in a high-K+ depolarizing medium, but renin secretion stimulated by the maximal effective concentration of forskolin was not inhibited by Ca2+. In addition, the maximal effective concentration of forskolin (10(-5) M) increased renin secretion by a fixed amount independent of medium (by inference, intracellular) Ca2+ concentration in the range of 10(-8) to 10(-6) M in a high-K+ medium. Furthermore, the degree of stimulation of renin secretion by forskolin was greater with greater removal of the inhibitory effect of Ca2+ calmodulin pathway on renin secretion with use of potent calmodulin antagonists, suggesting that the stimulatory effect of cAMP on renin secretion may be maximal in the absence of the inhibitory influence of Ca2+. These results are consistent with the hypothesis that cAMP (by inference, the beta-adrenergic stimulus) stimulates renin secretion through a cellular mechanism independent of that through the Ca2+ -calmodulin pathway.
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PMID:Control of renin secretion by Ca2+ and cyclic AMP through two parallel mechanisms. 301 64

Forskolin (activator of adenyl cyclase), high concentrations of K+ and high renal perfusion pressure (manoeuvres known to increase Ca2+ permeability), and calmidazolium (the specific blocker of calmodulin) were used to investigate the mechanisms whereby adenosine 3',5'-phosphate (cyclic AMP) and Ca2+ interact to control renin secretion and perfusate flow in the isolated perfused rat kidney. Forskolin stimulated renin secretion and caused vasodilation in a dose-dependent manner in medium containing 5 mM-Ca2+. Reducing the Ca2+ concentration to 1.25 mM did not affect the renin stimulatory response but blunted the vasodilation. High K+ concentration reversed the forskolin-induced renin secretion and vasodilation. Conversely, forskolin reversed the high K+-induced renin inhibition of renin secretion and vasoconstriction. These effects of forskolin and high K+ were absent when Ca2+ was withheld from the perfusion medium. High renal perfusion pressure also reversed the forskolin-induced renin secretion. Calmidazolium prevented the inhibition mediated by high K+ and high perfusion pressure and thereby restored the forskolin-induced stimulation. Calmidazolium also caused a prompt and marked vasoconstriction. The calmidazolium-induced stimulation of renin secretion was Ca2+-dependent since the drug was ineffective in the absence of Ca2+. On the other hand, the prompt and potent vasoconstriction was present even in the Ca2+-free medium. These results support the hypothesis that cyclic AMP stimulates renin secretion by a mechanism which involves a lowering of membrane permeability to Ca2+ in addition to lowering cytosolic Ca2+ concentration. High K+ and high renal perfusion pressure inhibit renin secretion by raising the membrane permeability to Ca2+, thereby raising the intracellular Ca2+ concentration which then inhibits renin secretion by a calmodulin-dependent process. A further general conclusion from these studies is that membrane permeability to Ca2+ and cellular Ca2+ concentration are of central importance in the control of renin secretion and renal blood flow.
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PMID:Forskolin and calcium: interactions in the control of renin secretion and perfusate flow in the isolated rat kidney. 302 27

Adenosine analogs selective for the A1 subclass of adenosine receptors, such as N6-cyclohexyladenosine (CHA), inhibit renin secretion in in vitro preparations. Ca chelation blocks the inhibitory effect, consistent with mediation by increased intracellular free Ca2+, and it has been suggested that intracellular Ca2+ could increase as a result of receptor-induced inhibition of adenylate cyclase followed by decreased Ca efflux from the renin-secreting cells. Pertussis toxin blocks receptor-induced inhibition of adenylate cyclase in many cells, and in others, it blocks receptor-induced phosphotidylinositol response. In the present studies, pertussis toxin treatment stimulated the basal renin secretory rate of rat renal cortical slices and blocked the inhibitory effect of CHA but not the inhibitory effect of K-depolarization. These data support the hypothesis that a pertussis toxin substrate, such as Ni, is involved in CHA-, but not in K-depolarization, -induced inhibition of renin secretion.
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PMID:Pertussis toxin reverses adenosine receptor-mediated inhibition of renin secretion in rat renal cortical slices. 302 86

alpha 2-Adrenoceptors were first described pharmacologically ten years ago. Within three years their capacity to inhibit adenylate cyclase had been demonstrated in many tissues. They were demonstrated biochemically in the kidneys in 1981 even before any renal physiological effects of their activation were known. They predominate numerically over alpha 1-adrenoceptors in renal membranes and their density is increased in genetic forms of rat hypertension. alpha 1-Adrenoceptors normally mediate the vasoconstriction and sodium- and water-retaining effects of sympathetic neuronally released norepinephrine. Norepinephrine or epinephrine must be infused to activate alpha 2-adrenoceptors, suggesting that renal alpha 2-adrenoceptors are extrajunctional, whereas alpha 1-adrenoceptors are postjunctional. When alpha 1-adrenoceptors are chronically blocked, renal alpha 2-adrenoceptor density increases and they assume a location at postjunctional sites, the otherwise exclusive domain of alpha 1-adrenoceptors. Results from microdissection studies have established that alpha 2-adrenoceptors are present on most segments of the nephron and that their activation can suppress adenosine 3,'5'-cyclic monophosphate (cAMP) accumulation induced by most renal hormones. However, failure of alpha 2-adrenoceptor activation to suppress cAMP accumulation in some tubular segments induced by certain hormones suggests compartmentalization of adenylate cyclase regulation that is hormone-function specific. In view of the potent inhibitory effects of alpha 2-adrenoceptor stimulation on hormone activated cAMP accumulation in several discrete areas of the nephron, we suggest that alpha 2-adrenoceptors fulfill important regulatory role(s) in renal function. To date, alpha 2-adrenoceptor activation has been shown to reverse vasopressin-induced sodium and water retention, and arachidonic acid- and furosemide-induced cAMP, sodium, and water excretion in the isolated perfused kidney. Thus the effects are qualitatively and quantitatively dependent in these studies on the hormone being infused and are therefore hormone-function specific. Physiological effects of alpha 2-adrenoceptor activation of thyrocalcitonin and on parathyroid hormone-induced effects have not been studied. alpha 2-Adrenoceptor activation can inhibit renin release in some model systems and can activate a sodium-hydrogen antiporter system in proximal tubules. The physiological roles of these actions are unknown.
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PMID:Renal alpha 2-adrenoceptors and the adenylate cyclase-cAMP system: biochemical and physiological interactions. 302 68

Exogenous adenosine affects renal hemodynamics, renal tubular transport processes, and the secretion of renin. However, adenosine is not a selective agonist; it activates both A1 and A2 cell-surface receptors and it binds to an intracellular P-site that inhibits adenylate cyclase activity. Recent in vitro studies have suggested that activation of A1- and A2- adenosine receptors results in opposite effects on renin secretion. The purpose of these experiments was to examine the renal effects of A1- and A2-adenosine receptor agonists in vivo. 5'-N-ethylcarboxamide adenosine (NECA), 2-chloroadenosine (2-CLA), and N6-cyclohexyladenosine (CHA) were infused intravenously at rates that produced comparable decreases in systemic arterial blood pressure. All three of these adenosine analogues produced comparable decreases in para-aminohippurate (PAH) and inulin clearances and in Na and K excretion rates. CHA, an A1-selective agonist, markedly decreased plasma renin concentration (PRC), whereas NECA, an A2-selective agonist, markedly increased PRC; 2-CLA, a nonselective agonist, produced a smaller increase in PRC. Taken together, these results suggest that occupation of A1- and A2-receptors inhibits and stimulates renin secretion in vivo, independently of the effects of these adenosine receptor agonists on arterial blood pressure, renal hemodynamics, and tubular Na and K transport.
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PMID:Renal effects of selective adenosine receptor agonists in anesthetized rats. 302 72

Microelectrode recordings were performed in renin-containing epithelioid (JG) and vascular smooth muscle (VSM) cells of the afferent arteriole in the isolated hydronephrotic mouse kidney. Both cell types had a membrane potential of about -75 mV and exhibited small, spontaneous depolarizing transients, probably resulting from random transmitter release by sympathetic axon terminals. Substances depressing renin secretion, such as angiotensin II, arginine-vasopressin, and alpha 1-adrenergic agents reversibly depolarized both JG and VSM cells. On a molar basis, the action of angiotensin II was strongest. Stimulators of renin release, e.g. isoproterenol, histamine, and prostaglandin E2 did not influence the membrane potential of both cell types. VIP and NPY, possible co-transmitters of norepinephrine, as well as AP II, were also without effect. It is proposed that suppression of renin secretion from JG cells is mediated by depolarization and Ca2+ influx, whereas stimulation is triggered independently from membrane potential changes, e.g. by adenylate cyclase activation.
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PMID:Epithelioid cells: membrane potential changes induced by substances influencing renin secretion. 351 56

The effects of neuropeptide Y (NPY) were studied in the isolated rat kidney, which was perfused at constant perfusion pressure with a synthetic medium. In this preparation NPY produced concentration (1-100 nM)-dependent inhibition of renin release and vasoconstriction. In kidneys perfused at constant flow, inhibition of renin release by NPY was even more pronounced, excluding a flow-dependent washout effect. The simultaneous infusion of the calcium channel antagonist methoxyverapamil (2 microM) or of the calmodulin inhibitor calmidazolium (1 microM) did not prevent these effects of NPY, suggesting that calcium-dependent reactions are not primarily involved. Inhibition of renin release by NPY was also observed in tissue pieces prepared from the hydronephrotic rat kidney, in which tubular elements are lacking. This indicates that inhibition of renin release by NPY is not dependent on the presence of macula densa cells or on changes of intrarenal hemodynamics. In isolated kidneys from rats pretreated with pertussis toxin (2 micrograms/100 g ip) both effects of NPY, renal vasoconstriction and inhibition of renin release, were almost completely abolished. The pertussis toxin-sensitive factor mediating the effects of NPY is most likely the Ni-coupling protein of the adenylate cyclase complex. Accordingly, our data suggest that NPY induces renal vasoconstriction and inhibits renin release by inhibition of adenylate cyclase activity in vascular smooth muscle and renin-producing cells.
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PMID:Neuropeptide Y inhibits renin release by a pertussis toxin-sensitive mechanism. 354 37


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