Lisinopril improves arterial function in hyperlipidaemia.
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Endothelial function is defective in hypercholesterolaemia, and animal models have suggested that angiotensin-converting enzyme inhibitors may prevent arterial damage. We studied the effect of 6 months treatment with lisinopril on endothelial function in a group of patients with hypercholesterolaemia. Forty patients were studied. Forearm blood flow responses to acetylcholine and sodium nitroprusside were assessed by venous occlusion plethysmography. Subjects were then randomized in a double-blind fashion to receive either lisinopril, 20 mg/day (n=20), or placebo (n=20) for 6 months. Plethysmography was then repeated. Baseline variables between groups were comparable. In the lisinopril group blood pressure fell significantly [systolic: 145+/-4 to 128+/-4 mmHg (P<0.001); diastolic: 84+/-2 to 74+/-2 mmHg (P<0.001)]. An improvement was found in the vasodilatory response (expressed as a ratio of the infused/control arm) to acetylcholine, e.g. 3.33+/-0.3 (pre) versus 4.45+/-0.48 (post) at 30 microg/ml (P<0.03), and also to nitroprusside, e.g. 3.0+/-0.2 (pre) versus 3.86+/-0.3 (post) at 3.2 microg/ml (P<0.01). In the placebo group vasodilatation did not change significantly in response to acetylcholine, and nitroprusside responses were unchanged. The data presented suggest that 6 months of lisinopril therapy have a beneficial effect on arterial function in subjects with hyperlipidaemia. Further work should now investigate whether angiotensin-converting enzyme inhibitors are beneficial in reducing mortality and morbidity in hypercholesterolaemia. (+info)
Cholinergic modulation of neostriatal output: a functional antagonism between different types of muscarinic receptors.
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It is demonstrated that acetylcholine released from cholinergic interneurons modulates the excitability of neostriatal projection neurons. Physostigmine and neostigmine increase input resistance (RN) and enhance evoked discharge of spiny projection neurons in a manner similar to muscarine. Muscarinic RN increase occurs in the whole subthreshold voltage range (-100 to -45 mV), remains in the presence of TTX and Cd2+, and can be blocked by the relatively selective M1,4 muscarinic receptor antagonist pirenzepine but not by M2 or M3 selective antagonists. Cs+ occludes muscarinic effects at potentials more negative than -80 mV. A Na+ reduction in the bath occludes muscarinic effects at potentials more positive than -70 mV. Thus, muscarinic effects involve different ionic conductances: inward rectifying and cationic. The relatively selective M2 receptor antagonist AF-DX 116 does not block muscarinic effects on the projection neuron but, surprisingly, has the ability to mimic agonistic actions increasing RN and firing. Both effects are blocked by pirenzepine. HPLC measurements of acetylcholine demonstrate that AF-DX 116 but not pirenzepine greatly increases endogenous acetylcholine release in brain slices. Therefore, the effects of the M2 antagonist on the projection neurons were attributable to autoreceptor block on cholinergic interneurons. These experiments show distinct opposite functions of muscarinic M1- and M2-type receptors in neostriatal output, i.e., the firing of projection neurons. The results suggest that the use of more selective antimuscarinics may be more profitable for the treatment of motor deficits. (+info)
Dependence of nicotinic acetylcholine receptor recovery from desensitization on the duration of agonist exposure.
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When subjected to prolonged exposure to nicotinic agonists, nicotinic acetylcholine receptors undergo desensitization, resulting in an inactive receptor that does not allow for the passage of ions. The induction of desensitization of diverse nicotinic acetylcholine receptor subtypes in muscle, ganglia, or brain is likely to play important modulatory roles in synaptic transmission. Furthermore, nicotinic receptor desensitization may contribute to behavioral changes in humans or animals subjected to prolonged nicotine exposure pharmacologically or through the use of tobacco products. We investigated the recovery from desensitization of muscle-type nicotinic acetylcholine receptors in TE671/RD cells induced by exposure to acetylcholine or nicotine. Rates of recovery from desensitization are dependent on the length of agonist exposure and on the agonist used to induce desensitization. Increasing the time of exposure results in an increase in the time constant of recovery for both agonists. The recovery from nicotine-induced desensitization is consistently faster than the recovery from acetylcholine-induced desensitization regardless of whether nicotine or acetylcholine is used to assess levels of desensitization. These findings suggest the existence of more than one state of receptor desensitization and that nicotinic agonists vary in their efficiency of inducing receptors to states of differing depths of desensitization. (+info)
Effects of ethanol on recombinant human neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes.
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Alcohol and tobacco use is highly correlated in humans, and studies with animal models suggest an interaction of alcohol with neuronal nicotinic acetylcholine receptors (nAChRs). The aim of the present study was to characterize the effect of acute ethanol treatment on different combinations of human nAChR (hnAChR) subunits expressed in Xenopus oocytes. Ethanol (75 mM) potentiated ACh-induced currents in alpha2beta4, alpha4beta4, alpha2beta2, and alpha4beta2 receptors. This effect was due to an increase in Emax, without a change in the EC50 or Hill coefficient. hnAChR alpha2beta4 did not develop tolerance to repeated applications of ethanol or continuous exposure (10 min). The alpha3beta2 and alpha3beta4 combinations were insensitive to ethanol. Low concentrations of ethanol (25 and 50 mM) significantly inhibited homomeric alpha7 receptor function, but these receptors showed highly variable responses to ethanol. These results indicate that ethanol effects on hnAChRs depend on the receptor subunit composition. In light of recent evidence indicating that nAChRs mediate and modulate synaptic transmission in the central nervous system, we postulate that acute intoxication might involve ethanol-induced alterations in the function of these receptors. (+info)
Two pharmacologically distinct components of nicotinic receptor-mediated rubidium efflux in mouse brain require the beta2 subunit.
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Nicotinic agonist-stimulated efflux of 86Rb+ from mouse brain synaptosomes was monitored continuously by on-line radioactivity detection. The concentration-effect curve following a 5-s stimulation with acetylcholine was biphasic (EC50 = 7.2 and 550 microM). alpha-Bungarotoxin (100 nM) did not inhibit the response, but dihydro-beta-erythroidine (DHbetaE) blocked both phases with differing potency (average IC50 =.22 and 8.9 microM for responses activated by low and high acetylcholine concentrations, respectively). Differential sensitivity DHbetaE inhibition was used to measure stimulation of 86Rb+ efflux by 17 nicotinic agonists, which differed markedly in potency and efficacy. All agonists were more potent at the DHbetaE-sensitive site. Both components were inhibited by the six antagonists tested. Methyllycaconitine and DHbetaE were more potent for the DHbetaE-sensitive component, whereas hexamethonium was more potent at the DHbetaE-resistant component. Both DHbetaE-sensitive and DHbetaE-resistant responses were reduced more than 95% in beta2-null mutant mice, establishing the requirement for the beta2 subunit for both components. Both components were widely, but not identically, distributed throughout the brain. The DHbetaE-sensitive component appears to be identical with agonist-stimulated 86Rb+ efflux described previously and is likely to be mediated by alpha4beta2 receptors. The DHbetaE-resistant component is a novel, active, and widely distributed response mediated by nicotinic receptor(s) that also require the beta2 subunit. (+info)
Studies on cyclic nucleotides in the adrenal gland. V. Adenylate cyclase in the adrenal medulla.
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Effects of various chemical agents eliciting the catecholamine-release on the adenylate cyclase-cyclic AMP generating system have been studied in the secretory process of the bovine adrenal medulla slices. Cyclic AMP levels were not affected at the interval of the maximal increase of the catecholamine-release by acetylcholine, but increased gradually some time after the end of the release/or at the beginning of the restoration of catecholamine in the medulla tissue. This delayed increase in the medullary cyclic AMP is not attributed to a direct involvement in 'stimulus-secretion coupling process' of the medullary secretion, but rather may be caused by release of intracellular catecholamine. (+info)
Involvement of CB1 cannabinoid receptors in the EDHF-dependent vasorelaxation in rabbits.
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1. It was recently suggested that an endogenous cannabinoid could represent an endothelium-derived hyperpolarizing factor (EDHF). The aim of the present study was to clarify whether CB1 cannabinoid receptors are involved in the nitric oxide (NO)- and prostanoid-independent vasodilation produced by acetylcholine in rabbits. 2. Pithed rabbits received indomethacin. Noradrenaline was infused to raise blood pressure, and vasodilation was elicited by bolus injections of acetylcholine. The NO-synthase inhibitor Nomega-nitro-L-arginine methylester inhibited the acetylcholine-evoked vasodilation by about 40%. The remaining vasodilation was unaffected by the CB1 cannabinoid receptor antagonist SR141716A, but was inhibited by the potassium channel blocker tetraethylammonium. In addition, the mixed CB1/CB2 cannabinoid receptor agonist WIN55212-2 did not elicit vasodilation. 3. No CB1 cannabinoid receptors were involved in the prostanoid- and NO-independent vasodilation produced by acetylcholine. An exogenous cannabinoid also did not cause vasodilation. Therefore, it is unlikely that an endogenous cannabinoid serves as an EDHF acting at smooth muscle CB1 cannabinoid receptors in the rabbit. (+info)
Inhibitory effect of 4-aminopyridine on responses of the basilar artery to nitric oxide.
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1. Voltage-dependent K+ channels are present in cerebral arteries and may modulate vascular tone. We used 200 microM 4-aminopyridine (4-AP), thought to be a relatively selective inhibitor of voltage-dependent K+ channels at this concentration, to test whether activation of these channels may influence baseline diameter of the basilar artery and dilator responses to nitric oxide (NO) and cyclic GMP in vivo. 2. Using a cranial window in anaesthetized rats, topical application of 4-AP to the basilar artery (baseline diameter = 240+/-5 microm, mean +/- s.e.mean) produced 10+/-1% constriction. Sodium nitroprusside (a NO donor), acetylcholine (which stimulates endothelial release of NO), 8-bromo cyclic GMP (a cyclic GMP analogue), cromakalim (an activator of ATP-sensitive K+ channels) and papaverine (a non-NO, non-K+ channel-related vasodilator) produced concentration-dependent vasodilator responses that were reproducible. 3. Responses to 10 and 100 nM nitroprusside were inhibited by 4-AP (20+/-4 vs 8+/-2% and 51+/-5 vs 33+/-5%, respectively, n=10; P<0.05). Responses to acetylcholine and 8-bromo cyclic GMP were also partially inhibited by 4-AP. In contrast, 4-AP had no effect on vasodilator responses to cromakalim or papaverine. These findings suggest that NO/cyclic GMP-induced dilator responses of the basilar artery are selectively inhibited by 4-aminopyridine. 4. Responses to nitroprusside were also markedly inhibited by 10 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (an inhibitor of soluble guanylate cyclase; 16+/-4 vs 1+/-1% and 44+/-7 vs 7+/-1%; n=10; P<0.05). 5. Thus, dilator responses of the rat basilar artery to NO appear to be mediated by activation of soluble guanylate cyclase and partially by activation of a 4-aminopyridine-sensitive mechanism. The most likely mechanism would appear to be activation of voltage-dependent K+ channels by NO/cyclic GMP. (+info)