Impaired cardiac and sympathetic autonomic control in rats differing in acetylcholine receptor sensitivity.
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Acetylcholine receptors (AChR) are important in premotor and efferent control of autonomic function; however, the extent to which cardiovascular function is affected by genetic variations in AChR sensitivity is unknown. We assessed heart rate variability (HRV) and baroreflex sensitivity (BRS) in rats bred for resistance (FRL) or sensitivity (FSL) to cholinergic agents compared with Sprague-Dawley rats (SD), confirmed by using hypothermic responses evoked by the muscarinic agonist oxotremorine (0.2 mg/kg i.p.) (n > or = 9 rats/group). Arterial pressure, ECG, and splanchnic sympathetic (SNA) and phrenic (PNA) nerve activities were acquired under anesthesia (urethane 1.3 g/kg i.p.). HRV was assessed in time and frequency domains from short-term R-R interval data, and spontaneous heart rate BRS was obtained by using a sequence method at rest and after administration of atropine methylnitrate (mATR, 2 mg/kg i.v.). Heart rate and SNA baroreflex gains were assessed by using conventional pharmacological methods. FRL and FSL were normotensive but displayed elevated heart rates, reduced HRV and HF power, and spontaneous BRS compared with SD. mATR had no effect on these parameters in FRL or FSL, indicating reduced cardiovagal tone. FSL exhibited reduced PNA frequency, longer baroreflex latency, and reduced baroreflex gain of heart rate and SNA compared with FRL and SD, indicating in FSL dual impairment of cardiac and circulatory baroreflexes. These findings show that AChR resistance results in reduced cardiac muscarinic receptor function leading to cardiovagal insufficiency. In contrast, AChR sensitivity results in autonomic and respiratory abnormalities arising from alterations in central muscarinic and or other neurotransmitter receptors. (+info)
Sympathetic and parasympathetic component of bradycardia triggered by stimulation of NTS P2X receptors.
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We have previously shown that activation of P2X purinoceptors in the subpostremal nucleus tractus solitarius (NTS) produces a rapid bradycardia and hypotension. This bradycardia could occur via sympathetic withdrawal, parasympathetic activation, or a combination of both mechanisms. Thus we investigated the relative roles of parasympathetic activation and sympathetic withdrawal in mediating this bradycardia in chloralose-urethane anesthetized male Sprague-Dawley rats. Microinjections of the selective P2X purinoceptor agonist alpha,beta-methylene ATP (25 pmol/50 nl and 100 pmol/50 nl) were made into the subpostremal NTS in control animals, after atenolol (2 mg/kg i.v.), a beta1-selective antagonist, and after atropine methyl bromide (2 mg/kg i.v.), a muscarinic receptor antagonist. The bradycardia observed with activation of P2X receptors at the low dose of the agonist is mediated almost entirely by sympathetic withdrawal. After beta1-adrenergic blockade, the bradycardia was reduced to just -5.1 +/- 0.5 versus -28.8 +/- 5.1 beats/min in intact animals. Muscarinic blockade did not produce any significant change in the bradycardic response at the low dose. At the high dose, both beta1-adrenergic blockade and muscarinic blockade attenuated the bradycardia similarly, -37.4 +/- 6.4 and -40.6 +/- 3.7 beats/min, respectively, compared with -88.0 +/- 11 beats/min in control animals. Double blockade of both beta1-adrenergic and muscarinic receptors virtually abolished the response (-2.5 +/- 0.8 beats/min). We conclude that the relative contributions of parasympathetic activation and sympathetic withdrawal are dependent on the extent of P2X receptor activation. (+info)
Functional genomic analysis of alkaloid biosynthesis in Hyoscyamus niger reveals a cytochrome P450 involved in littorine rearrangement.
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Tropane alkaloids are valuable pharmaceutical drugs derived from solanaceous plants such as Hyoscyamus niger (black henbane). The biosynthesis of these molecules, including the nature of the enigmatic rearrangement of (R)-littorine to (S)-hyoscyamine, is not completely understood. To test the hypothesis that a cytochrome P450 enzyme is involved in this rearrangement, we used virus-induced gene silencing to silence a cytochrome P450, CYP80F1, identified from H. niger roots by EST sequencing. Silencing CYP80F1 resulted in reduced hyoscyamine levels and the accumulation of littorine. Hyoscyamine was observed in CYP80F1-expressing tobacco hairy roots supplied with (R)-littorine. Expression in yeast confirmed that CYP80F1 catalyzes the oxidation of (R)-littorine with rearrangement to form hyoscyamine aldehyde, a putative precursor to hyoscyamine, and without rearrangement to form 3'-hydroxylittorine. Our data strongly support the involvement of CYP80F1 in the rearrangement of littorine to hyoscyamine. (+info)
Effects of flutropium on experimental models of drug- and allergy-induced rhinitis in guinea pigs.
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The effects of flutropium on histamine (Hist)-induced increase in intranasal pressure in non-sensitized guinea pigs and nasal mucosa capillary permeability in passively sensitized guinea pigs were investigated. Flutropium (0.3%), atropine (0.3%), diphenhydramine (0.01%) and cimetidine (0.1%) were directly inhaled into the nasal cavities by an ultrasonic nebulizer for 20 min, followed by inhalation of Hist (0.1%) for 10 min. Flutropium, atropine and diphenhydramine had an inhibitory action on the Hist-induced increase in intranasal pressure in guinea pigs. Cimetidine had no effect on this system. In passively sensitized guinea pigs (the challenge was performed 48 hr after sensitization), a 0.1-1.0 mg/kg injection of flutropium (i.v.) dose-dependently inhibited the allergic nasal mucosa capillary permeability. Atropine (10 mg/kg, i.v.) had no inhibitory action on this system. These results suggest that inhalation into the nasal cavities and i.v. injection of flutropium are effective in experimental models of drug- and allergy-induced rhinitis of the guinea pig. (+info)
Disinhibition of the cardiac limb of the arterial baroreflex in rat: a role for metabotropic glutamate receptors in the nucleus tractus solitarii.
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The nucleus tractus solitarii (NTS) is the first site of integration for primary baroreceptor afferents, which release glutamate to excite second-order neurones through ionotropic receptors. In vitro studies indicate that glutamate may also activate metabotropic receptors (mGluRs) to modulate the excitability of NTS neurones at pre- and postsynaptic loci. We examined the functional role of metabotropic glutamate receptors (mGluRs) in modulating the baroreceptor reflex in the rat NTS. Using the working heart-brainstem preparation, the baroreflex was activated using brief pressor stimuli and the consequent cardiac (heart rate change) and non-cardiac sympathetic (T8-10 chain) baroreflex gains were obtained. Microinjections of glutamate antagonists were made bilaterally into the NTS at the site of termination of baroreceptor afferents. NTS microinjection of kynurenate (ionotropic antagonist) inhibited both the cardiac and sympathetic baroreflex gains (16 +/- 5% and 59 +/- 11% of control, respectively). The non-selective mGluR antagonist MCPG produced a dose-dependent inhibition of the cardiac gain (30 +/- 3% of control) but not the sympathetic gain. Selective inhibitions of the cardiac gain were also seen with LY341495 and EGLU suggesting the response was mediated by group II mGluRs. This effect on cardiac gain involves attenuation of the parasympathetic baroreflex as it persists in the presence of atenolol. Prior NTS microinjection of bicuculline (GABA(A) antagonist) prevented the mGluR-mediated attenuation of the cardiac gain. These results are consistent with the reported presynaptic inhibition of GABAergic transmission by group II mGluRs in the NTS and constitute a plausible mechanism allowing selective feed-forward disinhibition to increase the gain of the cardiac limb of the baroreflex without changing the sympathoinhibitory component. (+info)
Pharmacological analysis of agonist-antagonist interactions at acetylcholine muscarinic receptors in a new urinary bladder assay.
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1. Agonist-antagonist interactions at acetylcholine (ACh) muscarinic receptors have been analysed by use of an improved urinary bladder assay, isolated and intact, from the mouse. With 5-methylfurmethide as agonist, validated cumulative concentration-effect curves were obtained in less than 7 min by re-dosing before the response plateaux began to fade. 2. The pKB value estimated for pirenzepine was 6.76. The pKB values estimated for atropine and N-methylatropine from data obtained at concentrations which produced dose-ratios greater than 20 and 60 were 8.90 and 9.58, respectively. 3. The deviation from simple competitive behaviour at low dose-ratios with atropine and N-methylatropine was consistent with the operation of saturable antagonist removal processes. The deviation observed with atropine was corrected by pre-incubation with methylbutyrate, an alternative substrate for 'atropine esterase'. 4. The simple competitive behaviour of N-methylatropine was restored following pre-incubation with the neuronal choline uptake blocker hemicholinium-3 (HC-3). However, the pKB estimated for N-methylatropine under these conditions was low. This latter result could be accounted for by the observed behaviour of HC-3 as a competitive antagonist of ACh muscarinic receptors (pKB = 4.01). 5. We conclude that the modified mouse urinary bladder assay is suitable for the quantitative analysis of muscarinic receptor interactions. In addition, we postulate the existence of a previously undescribed uptake mechanism for quaternary muscarinic receptor antagonists. (+info)
alpha2A-adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice.
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Effects of muscarinic antagonists on experimental nasal secretion in guinea pigs.
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The effects of muscarinic antagonists on acetylcholine (ACh)- and histamine-induced nasal secretion were investigated in guinea pigs. Inhalations of flutropium (0.01 to 0.3%) and atropine (0.03 to 0.3%) into the nasal cavities dose-dependently inhibited the nasal secretion induced by ACh. The inhibitory action of flutropium was slightly stronger than that of atropine. Inhalations of pirenzepine (0.3%) and gallamine (0.3%) had no effect on the ACh-induced nasal secretion. However, 4-DAMP dose-dependently inhibited the nasal secretion induced by ACh. Inhalations of flutropium (0.3%) and diphenhydramine (0.3%) showed a similar inhibitory action on the histamine-induced nasal secretion. These results suggest that 1) inhalation into the nasal cavities of flutropium was effective in experimental model of ACh- and histamine-induced nasal secretion, 2) M3-cholinergic receptors may be dominant in the nasal secretion induced by ACh and 3) the experimental model of drug-induced nasal secretion in guinea pigs used in the present study can be employed to develop therapeutic drugs for nasal secretion. (+info)