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Biomedical subjects

J Linden

Publications and source records attributed to J Linden.

159 records · Page 9Linked to original sources
PubMed1979

Quantitative relationship between beta-adrenergic receptor number and physiologic responses as studied with a long-lasting beta-adrenergic antagonist.

The aminobenzyl analog of propranolol, 1- (p-amino-alpha,alpha-dimethylphenethylamino)-3-(1-naphthoxy)-2- propanol, was synthesized and found to be a potent beta-adrenergic blocking agent. The beta-adrenergic receptors of cultured rat C6 glioma cells (2B clone) as assessed by [(125)I]iodohydroxybenzylpindolol binding were decreased 50 and >95% after pretreatment with 8 nM and 1 muM aminobenzylpropranolol, respectively. Unlike propranolol, aminobenzylpropranolol displayed a prolonged blockade of receptors that was maintained during several hours of washing. [(125)I]Iodohydroxybenzylpindolol saturation binding experiments in cells exposed to aminobenzylpropranolol and subsequently washed indicated that the compound effectively diminished receptor number with no change in the affinity of the remaining receptors for iodohydroxybenzylpindolol. Aminobenzylpropranolol inhibited catecholamine-stimulated intracellular cyclic AMP accumulation; with increasing blockade, isoproterenol dose-response curves became progressively shifted to the right but the maximal response was unaltered. Aminobenzylpropranolol inhibited the beta-adrenergic contractile response in atria isolated from rats and guinea pigs. Treatment with 0.1 and 10 muM aminobenzylpropranolol produced decreases of 0.5 and 2 orders of magnitude in the contractile potency of isoproterenol. As in glioma cells, aminobenzylpropranolol failed to decrease the maximal response to isoproterenol. The effects of aminobenzylpropranolol persisted during extensive washing of atria (up to 17 hr). Repeated exposures to isoproterenol at concentrations sufficient to produce maximal tension development also failed to alleviate the blockade. The inotropic potency of histamine in guinea pig atria was not affected by aminobenzylpropranolol. These data suggest that catecholamines are capable of eliciting full biological responses in glioma cells and isolated atria even though the great majority of beta-adrenergic receptors are persistently blocked.

Adrenergic beta-Antagonists↗
PubMed1978

Sodium requirement for the positive inotropic action of isoproterenol on guinea pig atria.

Isoproterenol doses not elicit its characteristic positive inotropic action in contracting guinea pig atria suspended in sodium-free media. However, the ability of isoproterenol to decrease the time to peak tension development during an individual contraction cycle is still present in sodium-free solutions. Removal of sodium diminished but did not eliminate the tissues' ability to elevate adenosine 3',5'-monophosphate in response to isoproterenol. The striking absence of an inotropic action by isoproterenol on atria in sodium-free media suggests that sodium (and possibly a sodium-calcium exchange across the sarcolemma) plays an important role in the inotropic action of catecholamines.

Animals↗
PubMedDate not supplied

VIP elevates platelet cyclic AMP (cAMP) levels and inhibits in vitro platelet activation induced by platelet-activating factor (PAF).

Platelet-activating factor (PAF), a potent endogenous phospholipid released by a variety of mammalian cells, induces platelet activation in vivo and in vitro. Little is known, however, about the physiological modulation of its actions. We have examined the ability of two naturally occurring compounds which stimulate cAMP production, vasoactive intestinal peptide (VIP) and prostacyclin (PGI2), to inhibit PAF-induced platelet aggregation and secretion in vitro. Washed, [3H]serotonin-labeled, rabbit platelets were incubated 60 sec in the presence of VIP, PGI2 or 3-isobutyl-1-methylxanthine (IBMX) and subsequently stimulated with PAF. In separate studies, cAMP levels were determined in similar aliquots of platelets incubated for 30 sec with VIP, PGI2 or IBMX. VIP, PGI2 and IBMX inhibited platelet aggregation and secretion in a dose-dependent manner. Fifty percent inhibition was achieved at final concentrations of 1.7 X 10(6) M VIP, 3.6 X 10(6) M PGI2 and 6.5 X 10(5) M IBMX. IBMX potentiated the inhibitory effects of VIP and PGI2 on PAF-induced platelet activation. VIP and PGI2 elevated platelet cAMP levels four-fold and 50-fold, respectively, in the presence of 10(3) M IBMX. These findings demonstrate that VIP inhibits PAF-induced platelet activation, with a potency comparable to that of PGI2.

1-Methyl-3-isobutylxanthine↗
PubMedDate not supplied

Vasoactive intestinal peptide evokes endothelium-dependent relaxation and cyclic AMP accumulation in rat aorta.

We have investigated VIP-induced relaxation and cyclic AMP accumulation in rat thoracic aorta strips, and the importance of endothelium to both actions. The relaxation was greatly attenuated by removal of endothelium, but was unaltered by cyclo-oxygenase or lipoxygenase inhibitors. Similarly, cyclic AMP formation was nearly abolished with loss of endothelium, but was largely unaffected by inhibitors of arachidonate pathways, cytochrome P450 or guanylate cyclase. VIP may stimulate the release of a diffusible factor from endothelium (an EDRF), which activates adenylate cyclase and relaxes aortic smooth muscle.

Animals↗
PubMedDate not supplied

Biochemical mechanisms for the inotropic effect of the cardiotonic drug milrinone.

Milrinone is a new inotropic agent for the treatment of refractory congestive heart failure. Our understanding of the mechanisms(s) of action of this synthetic cardiotonic drug is incomplete. We examined the effects of milrinone and the parent compound amrinone on sarcoplasmic reticulum function (45Ca-uptake and Ca-ATPase); radioligand binding to adenosine, beta-adrenergic, and cholinergic muscarinic receptors; cyclic AMP accumulation; and inhibition of various forms of cyclic AMP phosphodiesterases. Comparisons were made to observe how these effects correlate with the inotropic response of heart. Milrinone was shown to be a potent phosphodiesterase inhibitor that was 40 times more potent than amrinone and 10 times more potent at inhibiting the high-affinity (Km = 0.23 microM) form (Ki = 22 microM) than the low-affinity (Km = 140 microM) form (Ki = 225 microM) of cyclic AMP phosphodiesterase in heart. The potency of milrinone as a phosphodiesterase inhibitor was the same in the presence and absence of calcium. Concentrations of milrinone that increased cyclic AMP accumulation also produced positive inotropy. A comparison of milrinone with amrinone and methylxanthines revealed the order of potency to be isobutylmethylxanthine greater than milrinone greater than theophylline greater than caffeine greater than amrinone. Milrinone and amrinone had no effect on 45Ca-uptake or Ca-ATPase activity in myocyte sarcoplasmic reticulum. However, milrinone did bind weakly to adenosine receptors (KD = 466 microM) but not to cholinergic muscarinic or beta-adrenergic receptors. Also, in combination with isoproterenol high concentrations of milrinone blocked the negative inotropic response to the adenosine agonist phenylisopropyladenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMedDate not supplied

Identification of adenosine receptors in human spermatozoa.

1. The effects of adenosine receptor agonists and antagonists on human sperm motility have been studied. Specific binding sites for adenosine and its analogues on human sperm were also investigated. 2. Agonists stimulated human sperm motility in a dose-dependent manner with a potency order of 5'-N-ethylcarboxamidoadenosine (NECA, EC50 = 0.3 mumol/L) > 2-[p-(carboxyethyl)phenylethylamino]-5'-N- ethylcarboxamidoadenosine (CGS-21680, EC50 = 10 mumol/L) > adenosine (EC50 = 100 mumol/L). 3. NECA-stimulated motility was competitively inhibited by various adenosine receptor antagonists. The potency order was 3,7-dimethyl-1-propargylxanthine > 8-(p-sulfophenyl) theophylline > xanthine amino congener. 4. The radioligand [3H]-NECA bound to sperm membrane in a saturable manner with a Bmax of 21.3 pmol/mg protein and equilibrium Kd of 4 mumol/L. Adenosine agonists and antagonists competed for [3H]-NECA binding with the same rank order of potency as for the stimulation of human sperm motility. 5. GTP gamma s inhibited 63% of specific [3H]-NECA binding with IC50 value of 11 nmol/L. This suggests that the [3H]-NECA binding sites may be coupled to one or more G proteins. 6. These results indicate the presence of adenosine A2 receptors on human sperm which are responsible for adenosine-mediated enhancement of sperm motility.

Adenosine↗
PubMedDate not supplied

Long-term polysomnographic study of the efficacy and safety of zolpidem in elderly psychiatric in-patients with insomnia.

The effects of 20 mg zolipidem were studied in an open, polysomnographically-monitored 179 day trial in 14 elderly psychiatric patients suffering from severe insomnia. After a placebo run-in of 7 days, zolpidem was given for 179 days followed by a 30-day wash-out period. Polysomnographic recordings (PSG) were performed just before active treatment; 30, 90 and 179 days into the treatment period; and at the end of the wash-out period. Statistically significant improvements in total sleep time, sleep efficiency and percentage of rapid eye movement sleep were observed after 30 days, all of which were maintained at 179 days. Sleep stages 1-4 all changed, with a significant decrease in percentage of stage 1, and a significant increase in both percentages of stage 2 and 3, and duration of stages 3 and 4 at the end of active treatment. After a 90-day follow-up period, only stage 3 sleep and sleep efficiency were no longer significantly changed compared to baseline, all other criteria showing maintenance of efficacy. Slow-wave sleep, which was increased during active treatment, decreased in the follow-up period. No serious adverse events were observed. These results suggest that, contrary to other hypnotics, zolpidem, after long-term administration, improves objective sleep parameters and may normalize a disturbed sleep architecture.

Aged↗