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N Narayanan

Publications and source records attributed to N Narayanan.

At least 55 records · Page 3Linked to original sources
PubMed1991

Inhibitory and stimulatory effects of fluoride on the calcium pump of cardiac sarcoplasmic reticulum.

While studying the effects of membrane phosphorylation on active Ca2+ transport in cardiac sarcoplasmic reticulum (SR) we used NaF (a conventional phosphatase inhibitor) in the Ca2+ transport assay medium to suppress protein dephosphorylation by endogenous phosphatases. Unexpectedly, depending on the experimental conditions employed, NaF was found to cause a strong inhibitory or stimulatory effect on ATP-dependent, oxalate-facilitated Ca2+ uptake (Ca2+ pump) activity of SR. Investigation of this phenomenon using canine cardiac SR revealed the following. Exposure of SR to NaF in the absence of Ca2+ or ATP in the Ca2+ transport assay medium (prior to initiating Ca2+ transport by the addition of Ca2+ or ATP) promoted a striking concentration-dependent inhibitory effect of NaF (50% and 90% inhibition with approx. 4 and 10 mM NaF, respectively) on Ca2+ uptake by SR; the magnitude of inhibition did not differ appreciably with varying oxalate concentrations. In contrast, exposure of SR to NaF in the presence of both Ca2+ and ATP resulted in a concentration-dependent stimulatory effect of NaF (half-maximal stimulation at approx. 2.5 mM NaF with 2.5 mM oxalate in assay) on Ca2+ uptake; the magnitude of stimulation decreased with increasing oxalate concentration (greater than 2-fold at 1 mM oxalate, 10% at 5 mM oxalate). The inhibitory effect prevailed when SR was exposed to NaF in the presence of Ca2+ alone (without ATP) or ATP alone (without Ca2+). Both the inhibitory and stimulatory effects of NaF were specific to fluoride ion, as NaCl (1-10 mM) showed no effect on Ca2+ uptake by SR under identical assay conditions. A persistently less active state of the Ca2+ pump (evidenced by decreased Ca2+ transport rates) resulted upon pretreatment of SR with NaF in the absence of Ca2+ or ATP; presence of Ca2+ and ATP during pretreatment prevented this transition. The inhibitory action of NaF on the Ca2+ pump was accompanied by a two-fold increase in K0.5 for Ca2+ and decrements in Hill coefficient (nH) and Ca(2+)-stimulated ATP hydrolysis, as well as steady-state level of Ca(2+)-induced phosphoenzyme. The stimulatory effect of NaF, on the other hand, was associated with an increase in the ratio of Ca2+ transported/ATP hydrolysed with only minor changes, if any, in the above parameters. These findings imply that the divergent effects of fluoride are dependent on specific conformational states of the Ca(2+)-ATPase which evolve during the catalytic and ion transport cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1991

Ontogeny of cytosolic proteins capable of modulating sarcoplasmic reticulum calcium transport in heart muscle.

In a previous study we described the inhibitory action of a cytosolic protein fraction from heart muscle on ATP-dependent Ca2+ uptake by sarcoplasmic reticulum (SR); further, this inhibition was shown to be blocked by an inhibitor antagonist, also derived from the cytosol (Narayanan et al. Biochim Biophys Acta 735: 53-66, 1983). The present study investigated the ontogenetic expression of the activities of Ca2+ transport inhibitor and inhibitor antagonist in heart cytosol during fetal and postnatal development of the rat. The SR Ca2+ transport inhibitor activity was undetectable in the cytosol of fetal (15- or 20-days gestation) rat heart but was manifested in the cytosol as early as one day after birth and increased progressively thereafter to reach almost adult levels within the first two weeks of postnatal development. The activity of the SR Ca2+ transport inhibitor antagonist was barely detectable in the near-term (20 days gestation) fetus but increased substantially during early postnatal development, in parallel with the rise in activity of the inhibitor. The ontogenetic appearance and increase in the activities of the Ca2+ transport inhibitor and its antagonist correlated well with the concurrent appearance and increase in the amounts of two polypeptides of apparent molecular weights 43 kDa and 64 kDa, which we have tentatively identified as the inhibitor and inhibitor antagonist, respectively. The co-ordinated expression of both the inhibitor and inhibitor antagonist activities in the cytosol during the early postnatal period parallels the morphogenesis and functional maturation of SR in cardiac muscle suggesting likely involvement of these cytosolic proteins in the physiological regulation of SR function.

Animals↗
PubMed1990

Effects of aging on phospholamban phosphorylation and calcium transport in rat cardiac sarcoplasmic reticulum.

Acceleration of cardiac relaxation upon beta adrenergic stimulation is due, in part, to enhancement in the rate of Ca2+ sequestration by the sarcoplasmic reticulum (SR) Ca2+ pump resulting from cAMP-mediated phosphorylation of the SR protein phospholamban. Our previous studies have shown that in rat myocardium, beta adrenergic activation of adenylate cyclase and the Ca2+ pump activity of SR decline with aging (Mech. Ageing Dev., 19 (1982) 127-139; 38 (1987) 127-143). In the present study, the effect of aging on phospholamban phosphorylation and consequent changes in SR Ca2+ pump activity were evaluated using cardiac SR from 6 (young adult), 12 (adult) and 28 (aged) months old rats. No age-related differences were observed in the rate or maximum level of phospholamban phosphorylation by exogenous cAMP-dependent protein kinase. The rates of ATP-dependent Ca2+ uptake by SR from young adult and aged rats were stimulated upon phospholamban phosphorylation, the percentage stimulation of Ca2+ uptake at varying Ca2+ concentrations (0.24-11.9 microM) was not diminished with aging. However, the rates of Ca2+ uptake by phosphorylated and unphosphorylated SR were remarkably lower (35-50%) in the aged. Regardless of the age of rats, the stimulatory effect of phosphorylation on Ca2+ uptake by SR was due to increase in Vmax of Ca2+ transport with no appreciable changes in K0.5 for Ca2+. These findings imply that in spite of the age-associated decline in SR Ca2+ pump activity, the ability of phospholamban to undergo cAMP-mediated phosphorylation and the relative responsiveness of the SR Ca2+ pump to phospholamban phosphorylation are not diminished in the aging heart.

Adenosine Triphosphate↗
PubMed1989

Regulation of the ATP-dependent calcium uptake activity of heart sarcolemmal vesicles by endogenous cytosolic proteins.

In a previous study we described the inhibitory action of a cytosolic protein fraction from heart muscle on ATP-dependent Ca2+ uptake by sarcoplasmic reticulum; further, this inhibition was shown to be blocked by an inhibitor antagonist, also derived from the cytosol (Narayanan et al. Biochim Biophys Acta 735: 53-66, 1983). The present study examined the effects of the endogenous cytosolic Ca2+ transport inhibitor and its antagonist on ATP-dependent Ca2+ uptake by sarcolemmal vesicles isolated from rat and canine heart. The cytosolic inhibitor caused strong inhibition (up to 97%) of Ca2+ uptake by sarcolemma (SL); this inhibition could be reversed by the cytosolic inhibitor antagonist. Studies on the characteristics of inhibition revealed the following: a) Inhibition was dependent on the concentration of the inhibitor (50% inhibition with approximately 80 micrograms inhibitor protein). b) The inhibitor reduced the velocity of Ca2+ uptake without appreciably influencing the apparent affinity of the transport system for Ca2+ but caused greater than 2-fold decrease in its apparent affinity for ATP. c) The rates of unidirectional passive Ca2+ release from actively Ca2+ loaded SL vesicles were not altered by low concentrations of the inhibitor (less than 100 micrograms/ml) which were effective in producing marked inhibition of Ca2+ uptake; at higher concentrations (greater than 100 micrograms/ml), the inhibitor caused increase in the rates of passive Ca2+ release. These findings demonstrate that the activity of the ATP-driven Ca2+ pump of cardiac SL can be regulated in vitro by endogenous cytosolic proteins.

Animals↗
PubMed1989

Effects of endogenous calcium transport inhibitor from heart muscle on the active calcium uptake and passive calcium release properties of sarcoplasmic reticulum.

In the present study, the effects of the cytosolic Ca2+ transport inhibitor on ATP-dependent Ca2+ uptake by, and unidirectional passive Ca2+ release from, sarcoplasmic reticulum enriched membrane vesicles were examined in parallel experiments to determine whether inhibitor-mediated enhancement in Ca2+ efflux contributes to inhibition of net Ca2+ uptake. When assays were performed at pH 6.8 in the presence of oxalate, low concentrations (less than 100 micrograms/mL) of the inhibitor caused substantial inhibition of Ca2+ uptake by SR (28-50%). At this pH, low concentrations of the inhibitor did not cause enhancement of passive Ca2+ release from actively Ca2+-loaded sarcoplasmic reticulum. Under these conditions, high concentrations (greater than 100 micrograms/mL) of the inhibitor caused stimulation of passive Ca2+ release but to a much lesser extent when compared with the extent of inhibition of active Ca2+ uptake (i.e., twofold greater inhibition of Ca2+ uptake than stimulation of Ca2+ release). When Ca2+ uptake and release assays were carried out at pH 7.4, the Ca2+ release promoting action of the inhibitor became more pronounced, such that the magnitude of enhancement in Ca2+ release at varying concentrations of the inhibitor (20-200 micrograms/mL) was not markedly different from the magnitude of inhibition of Ca2+ uptake. In the absence of oxalate in the assay medium, inhibition of Ca2+ uptake was observed at alkaline but not acidic pH.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Growth hormone-releasing factor-sensitive adenylate cyclase system of purified somatotrophs: effects of guanine nucleotides, somatostatin, calcium, and magnesium.

The purpose of this study was to characterize the adenylate cyclase system in a purified population of normal somatotrophs derived from rat pituitary and to determine the responses of this system to GRF, somatostatin, guanine nucleotides, and cations. Additionally, experiments were performed to evaluate the interrelationships among changes in adenylate cyclase activity, cellular cAMP levels, and GH release induced by GRF and somatostatin. The results obtained using homogenates and membrane preparations from somatotrophs included the following. 1) GRF caused guanine nucleotide-dependent concentration-related (Ka, approximately 10(-8) M) stimulation of adenylate cyclase activity. 2) Guanine nucleotides were effective in stimulating cyclase in the absence of GRF; the concentration of guanine nucleotide required for half-maximal stimulation was decreased more than 10-fold in the presence of GRF. 3) Adenylate cyclase activity increased with increasing concentrations of free Mg2+ (0.25-20 mM); activation by GRF and guanine nucleotide resulted in an approximately 7-fold increase in the enzyme's affinity for free Mg2+. 4) Somatostatin, up to 10(-6) M, did not alter basal or GRF-stimulated adenylate cyclase activity. 5) Ca2+ (0.5-11.9 microM) produced concentration-dependent inhibition of basal (up to 28%) and GRF-stimulated (up to 47%) cyclase activities; the inhibitory effect of Ca2+ was accompanied by a decrement (2- to 3-fold) in the apparent affinities of the enzyme for both GRF and guanine nucleotide. In intact somatotrophs, GRF produced concentration-dependent stimulation of GH release (Ka, approximately 6 x 10(-11) M), preceded by a marked elevation of cAMP levels. While somatostatin blocked GRF-induced GH release, the augmented cAMP levels were only slightly reduced.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗
PubMed1987

Comparison of ATP-dependent calcium transport and calcium-activated ATPase activities of cardiac sarcoplasmic reticulum and sarcolemma from rats of various ages.

Age-associated decline in the Ca2+ pump function of cardiac sarcoplasmic reticulum (SR), and increase in the Ca2+ pump activity of sarcolemma (SL) were suggested by my previous study which compared the ATP-energized in vitro Ca2+ transport activities of these membranes from young (3-4-month-old) and aged (24-25-month-old) rat myocardium (Biochim. Biophys. Acta, 678 (1981) 442-459). In the present study, ATP-dependent Ca2+ transport and Ca2+ sensitive ATPase activities of SR and SL derived from the myocardium of rats aged 3 (young), 6 (young adult), 12 (adult), 18 (aging) and 24 (aged) months were determined so as to further characterize age-related changes in the Ca2+ transport function of these membranes. The rates of ATP-dependent Ca2+ accumulation by SR from 3- and 6-month-old rats were virtually similar whereas the rates of Ca2+ accumulation by this membrane from 12-, 18- and 24-month-old rats were significantly lower when compared to 3- or 6-month-old rats; the magnitude of this age-related decline amounted to approx. 18, 45 and 50%, respectively, for SR from 12-, 18- and 24-month-old animals. In contrast to the above findings with SR, SL from 18- and 24-month-old rats displayed substantially higher rates (approx. 45 and 80% increase, respectively, at 18 and 24 months of age) of ATP-dependent Ca2+ accumulation than SL preparations from 3-, 6- and 12-month-old rats; no significant age-related difference was evident between the latter three age groups. The divergent age-related changes in the Ca2+ accumulating activities of SR and SL were seen at varying Ca2+ concentrations (0.54-25.2 microM). With either membrane, kinetic analysis showed that the velocity of Ca2+ transport, but not the apparent affinity of the transport system for Ca2+ underwent age-related changes. The Ca2+-stimulated ATPase activities of SR and SL were not altered significantly with increasing age from 3 to 24 months. Comparison of the 'combined Ca2+ transport activity' of SR and SL from rats of various ages showed a significant overall age-related decline in the rates of Ca2+ transport via the ATP-driven membrane Ca2+ pumps; this decrement in membrane function was moderate at 12 months of age (approx. 16%) and became pronounced with advancing age thereafter (approx. 35 and 38%, respectively, at 18 and 24 months of age). Similar progressive age-related decline was observed in the ATP-dependent Ca2+ sequestering activity of cardiac homogenates.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1986

Autonomic interactions in the aging heart: age-associated decrease in muscarinic cholinergic receptor mediated inhibition of beta-adrenergic activation of adenylate cyclase.

The ability of the muscarinic receptor agonist, carbachol, to inhibit beta-adrenergic activation of adenylate cyclase was examined in cardiac membranes from 6-month (young adult) and 24-month (aged) old rats in an effort to assess the effect of aging on adrenergic-cholinergic interactions in the heart. At varying concentrations (0.1-100 microM) of carbachol, GTP plus isoproterenol-stimulated adenylate cyclase activity was inhibited 5-39% in cardiac membranes from 6-month-old rats; this inhibition was statistically significant at all but the lowest concentration (0.1 microM) of carbachol used. In contrast, in cardiac membranes from 24-month-old rats, the inhibition of GTP plus isoproterenol-stimulated adenylate cyclase activity by carbachol was very weak (3-20% with 0.1-100 microM carbachol), and statistically insignificant. The muscarinic receptor antagonist, atropine, blocked the inhibition of GTP plus isoproterenol-stimulated enzyme activity by carbachol showing that the observed inhibitory effect of carbachol was muscarinic receptor dependent. The basal adenylate cyclase activity (which showed no significant age-related difference) was unaffected by carbachol. No significant age-related differences were evident in: (a) the concentration of carbachol required for half-maximal inhibition of GTP plus isoproterenol-stimulated adenylate cyclase activity; (b) the density of muscarinic receptor sites; and (c) their agonist and antagonist binding affinities. The GTP plus isoproterenol-stimulated cyclase activity measured in the absence of carbachol was approximately 70% lower in cardiac membranes from 24-month-old, compared to 6-month-old rats, confirming an age-associated decline in beta-adrenergic activation of the cyclase observed in our previous study [Mech. Ageing Dev., 19: (1982) 127-139]. The above findings suggest an apparent age-related decline in the postsynaptic antiadrenergic action of cholinergic stimulus in the heart; thus, exaggerated cholinergic antagonism of beta-adrenergic stimulus does not seem to contribute to the impaired adrenergic control of the heart in aging. On the other hand, autonomic imbalance, due to excessive weakening of the antiadrenergic influence of cholinergic stimulus, may compromise the ability of the cholinergic system to counteract the tendency of unrestrained adrenergic drive to increase ventricular vulnerability to fibrillation; this, in turn, may favor the high incidence of cardiac arrhythmias in aging.

Adenylyl Cyclases↗
PubMed1985

Microsomal phosphorylase in rat heart: depletion following adrenalectomy and restoration by in vivo administration of dexamethasone.

Phosphorylase activities were determined in homogenates, particulate and soluble fractions of heart muscle from control, adrenalectomized, and adrenalectomized dexamethasone-treated rats so as to assess the influence, if any, of glucocorticoids on the subcellular distribution of this enzyme. The specific activities (enzyme activity expressed as units per mg protein) and recoveries (enzyme activity expressed as units per fraction/g tissue) of both the active form of phosphorylase (phosphorylase a) and total phosphorylase (phosphorylases a and b) were essentially similar in homogenates and 10,000 X g particulate fractions prepared from hearts of control, adrenalectomized, and adrenalectomized dexamethasone-treated rats. Interestingly, however, the specific activities and recoveries of active as well as total phosphorylase were markedly lower (70-80%; P less than 0.001) in cardiac microsomes of adrenalectomized compared to control rats. On the other hand, the specific activities and recoveries of phosphorylase (active and total) were significantly higher (30-60%; P less than 0.01 or 0.001) in the cytosol fraction of heart muscle from adrenalectomized compared to control rats. Treatment of adrenalectomized rats with dexamethasone (a synthetic glucocorticoid) restored the specific activities and recoveries of phosphorylase in heart microsomal and cytosol fractions to control levels. No appreciable differences were observed in the specific activity ratios of phosphorylase a to phosphorylases a and b in any of the subcellular fractions of cardiac muscle from control, adrenalectomized, and adrenalectomized dexamethasone-treated rats. The above findings suggest a potential involvement of glucocorticoids in the maintenance of the membrane-associated (microsomal) pool of phosphorylase and, therefore, in the cellular compartmentalization of this enzyme in heart muscle.

Adenosine Triphosphate↗
PubMed1984

Effects of age on glycogen synthase and phosphorylase activities in rat liver.

The activities of glycogen synthase and phosphorylase were determined in homogenates and subcellular fractions of liver from young adult (6 months' old), adult (12 months' old) and aged (24 months' old) rats. The specific activities (enzyme activity expressed as units per mg protein) of the active form of glycogen synthase (synthase a) as well as of total synthase (synthase a + b) were significantly lower in liver homogenates of aged compared to young adult or adult rats. The age-associated decrease in the specific activity of synthase a was most marked in the 10 000 g and 100 000 g particulate fractions of liver. The specific activities of the active form of phosphorylase (phosphorylase a) as well as of total phosphorylase (phosphorylase a + b) were also significantly lower in liver homogenates of aged compared to young adult or adult animals. The age-related decrease in the specific activity of phosphorylase a was most pronounced in the 10 000 g particulate fraction of liver. Analysis of the specific activity ratios of glycogen synthase a/glycogen synthase a + b indicated a disproportionately greater age-related decrement in the active form of this enzyme. No such age-related difference was evident in the specific activity ratios of phosphorylase a/phosphorylase a + b. The age-associated decrease in the activities of glycogen synthase (a or a + b) and phosphorylase (a or a + b) was also discernible when the enzyme activities were expressed as units per g liver; this decrement in enzyme activity was reflected in all subcellular fractions examined. The levels of plasma insulin, plasma glucose and liver glycogen were not significantly different in rats of the three age groups used in these studies. The reduced activities of liver glycogen synthase and phosphorylase in aged rats is indicative of a likely diminution in the turnover of glycogen in liver during aging. Such an age-associated deficit in liver glycogen metabolism may contribute, at least in part, to the generally observed glucose intolerance upon aging.

Aging↗
PubMed1983

Inhibition of sarcoplasmic reticulum calcium pump by cytosolic protein(s) endogenous to heart and slow skeletal muscle but not fast skeletal muscle.

Cytosol from rabbit heart and slow and fast skeletal muscles was fractionated using (NH4)2SO4 to yield three cytosolic protein fractions, viz., CPF-I (protein precipitated at 30% saturation), CPF-II (protein precipitated between 30 and 60% saturation), and cytosol supernatant (protein soluble at 60% saturation). The protein fractions were dialysed and tested for their effects on ATP-dependent, oxalate-supported Ca2+ uptake by sarcoplasmic reticulum from heart and slow and fast skeletal muscles. CPF-I from heart and slow muscle, but not from fast muscle, caused marked inhibition (up to 95%) of Ca2+ uptake by sarcoplasmic reticulum from heart and from slow and fast muscles. Neither unfractionated cytosol nor CPF-II or cytosol supernatant from any of the muscles altered the Ca2+ uptake activity of sarcoplasmic reticulum. Studies on the characteristics of inhibition of sarcoplasmic reticulum Ca2+ uptake by CPF-I (from heart and slow muscle) revealed the following: (a) Inhibition was concentration- and temperature-dependent (50% inhibition with approx. 80 to 100 micrograms CPF-I; seen only at temperatures above 20 degrees C). (b) The inhibitor reduced the velocity of Ca2+ uptake without appreciably influencing the apparent affinity of the transport system for Ca2+. (c) Inhibition was uncompetitive with respect to ATP. (d) Sarcoplasmic reticulum washed following exposure to CPF-I showed reduced rates of Ca2+ uptake, indicating that inhibition results from an interaction of the inhibitor with the sarcoplasmic reticulum membrane. (e) Concomitant with the inhibition of Ca2+ uptake, CPF-I also inhibited the Ca2+-ATPase activity of sarcoplasmic reticulum. (f) Heat-treatment of CPF-I led to loss of inhibitor activity, whereas exposure to trypsin appeared to enhance its inhibitory effect. (g) Addition of CPF-I to Ca2+-preloaded sarcoplasmic reticulum vesicles did not promote Ca2+ release from the vesicles. These results demonstrate the presence of a soluble protein inhibitor of sarcoplasmic reticulum Ca2+ pump in heart and slow skeletal muscle but not in fast skeletal muscle. The characteristics of the inhibitor and its apparently selective distribution suggest a potentially important role for it in the in vivo regulation of sarcoplasmic reticulum Ca2+ pump, and therefore in determining the duration of Ca2+ signal in slow-contracting muscle fibers.

Animals↗
PubMed1983

Effects of adrenalectomy and in vivo administration of dexamethasone on ATP-dependent calcium accumulation by sarcoplasmic reticulum from rat heart.

ATP-dependent Ca2+ accumulation and (Mg2+ + Ca2+)ATPase activities were determined in cardiac sarcoplasmic reticulum (SR) from control, adrenalectomized and adrenalectomized-dexamethasone-treated rats. SR from adrenalectomized rats displayed significantly diminished rates (approximately 40 to 50%, P less than 0.001) of Ca2+ accumulation compared to SR from control rats. The decreased Ca2+ accumulating activity of the membranes from adrenalectomized compared to control rats could be observed at varying Ca2+ concentrations (0.5 to 11.9 microM); kinetic analysis showed that the velocity of Ca2+ transport but not the apparent affinity of the transport system for Ca2+ was altered by adrenalectomy. ATPase activities (with Mg2+ or with Mg2+ + Ca2+) of SR were not altered significantly following adrenalectomy. In vivo administration of dexamethasone to adrenalectomized rats led to a partial (75 to 80%) yet significant (P less than 0.01 to 0.05) restoration of Ca2+ accumulating activity of SR towards normal; dexamethasone-treatment caused decrease in basal (Mg2+)ATPase activity and enhancement in (Mg2+ + Ca2+)ATPase activity. When added in vitro, dexamethasone had no effect on Ca2+ accumulating and ATPase activities of SR from control or adrenalectomized rats. These findings imply an important role for glucocorticoids in the maintenance of membrane Ca2+ transport function, and therefore, normal myocardial contractility.

Adenosine Triphosphatases↗
PubMed1983

Effects of age on muscarinic cholinergic receptors in rat myocardium.

Atrial and ventricular myocardium from young (3-4 months old), young adult (7-8 months old), and aged (24-25 months old) rats were used to study the influence of age on cardiac cholinergic muscarinic receptors. The density of muscarinic receptors (expressed as fmol/mg protein or pmol/g tissue), determined by the specific binding of [3H]quinuclidinyl benzylate [( 3H]QNB), was significantly greater (24-29%) in atria of aged rats compared with that in atria of young or young adult rats. The muscarinic receptor density in ventricles was found to be essentially similar in all age groups studied. Antagonist as well as agonist binding characteristics of muscarinic receptor sites were examined in atria and ventricles from young and aged rats. No significant age-related difference was observed in the dissociation constant (KD) of atrial or ventricular receptors for the antagonist ligand [3H]QNB (KD apparent (nM): 1.04 +/- 0.16 and 0.91 +/- 0.12, respectively, for young and aged atria; 0.75 +/- 0.08 and 0.76 +/- 0.10, respectively, for young and aged ventricles). Similarly, the concentrations of muscarinic antagonist atropine and agonist carbachol causing 50% inhibition of [3H]QNB binding to the receptor sites (IC50) in atria and ventricles were not altered by age. Age-related difference was also not evident in the Hill coefficients for [3H]QNB, atropine, and carbachol. These results indicate that diminished responsiveness of the aged heart to vagal stimulation and exogenously administered cholinergic agents reported in the literature cannot be attributed to an age-related reduction in the number of cardiac muscarinic receptors or their affinities toward agonist or antagonist ligands.

Aging↗
PubMed1982

Alterations in the properties of beta-adrenergic receptors of myocardial membranes in aging: impairments in agonist-receptor interactions and guanine nucleotide regulation accompany diminished catecholamine-responsiveness of adenylate cyclase.

The effects of age on cardiac beta-adrenergic receptor linked adenylate cyclase system were studied using homogenates and membrane fractions of ventricular myocardium from young (3-4 months' old) and aged (24-25 months' old) rats. The number of beta-adrenergic receptor sites and the basal adenylate cyclase activities were essentially similar in young and aged hearts. On the other hand, striking age-associated alterations were seen in the properties of beta-receptors and adenylate cyclase in cardiac membranes. (A) The beta-receptor affinities for catecholamine agonists were reduced 10- to 20-fold in aged compared to young heart; the receptor affinity for antagonists were unaffected by age. (B) Guanine nucleotides caused a 9- to 17-fold reduction in beta-receptor affinity for isoproterenol in young heart; this guanine nucleotide-promoted reduction in receptor affinity for agonist was virtually absent in aged heart. (C) Guanine nucleotide-dependent stimulation of adenylate cyclase by isoproterenol was only 20-50% in aged heart compared to three-fold in young heart; beta-receptor-independent activation of the cyclase by guanine nucleotides and NaF were also reduced similarly in aged heart. These results demonstrate a marked age-associated deterioration in the functional integrity of beta-receptor linked adenylate cyclase system in aged heart. Further, the findings identify beta-receptor and guanine nucleotide regulatory protein as the components of the cyclase system affected in aging. It is suggested that the failure to form a "high-affinity" agonist-receptor complex, owing to the age-related decrement in receptor affinity for agonists, and the apparent inability of guanine nucleotide regulatory protein to effect appropriate molecular transitions at the level of both beta-receptor and the catalytic unit (i.e. the cyclase enzyme), contribute to the loss of catecholamine- and guanine nucleotide-responsiveness of adenylate cyclase in aged heart. This age-associated abnormality provides a biochemical basis for the well-recognized decline in adrenergic control of aging myocardium.

Adenylyl Cyclases↗