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PubMed1991

Depression of miniature endplate potential frequency by acetylcholine and its analogues in frog.

1. Acetylcholine (ACh), 7.5 x 10(-5) M, and carbachol, 5 x 10(-6) M (CCh) depressed the frequency of miniature endplate potentials (m.e.p.ps) in the frog (Rana temporaria) sartorius neuromuscular junction with active acetylcholinesterase to about 50-55% of the controls. 2. A similar depression was produced by the nicotinic agonists, nicotine, suberyldicholine and tetramethylammonium. 3. The muscarinic agonists, oxotremorine, methylfurmethide and methacholine were without effect on m.e.p.p. frequency. The muscarinic antagonist, atropine and the nicotinic antagonist, (+)-tubocurarine, had no effect on the depression of m.e.p.p. frequency evoked by CCh. 4. The ganglionic blockers, benzhexonium and IEM-1119, were also without effect on the CCh-evoked depression of m.e.p.p. frequency. 5. Pretreatment of muscles with anticholinesterases did not prevent the CCh-induced drop in m.e.p.p. frequency. 6. The effect of CCh was proportionally the same as in the controls in preparations where the m.e.p.p. frequency was changed by elevation of K+ and in the presence of theophylline, noradrenaline, dibutyryl adenosine 3':5'-cyclic monophosphate (db cyclic AMP) and db cyclic GMP. 7. An inhibitor of Na+,K(+)-ATPase, ouabain, 5 x 10(-5) mol l-1, prevented or reversed the depression of m.e.p.p. frequency by CCh. However, the depression was present in a nominally K(+)-free medium. Insulin and adrenaline, which are considered to be Na+,K(+)-ATPase activators, were without effect on depression of m.e.p.p. frequency. 8. The depression of m.e.p.p. frequency by 5 x 10(-6) M CCh was the same at temperatures between 5 and 30 degrees C with a Q10 near to 1.0. When threshold amounts of CCh were used (6 x 10-7 and 3 x 10-7 M), the depression was less at higher temperatures.9. The receptive structures responsible for the CCh (or ACh)-evoked depression of m.e.p.p. frequency differ pharmacologically from muscarinic, nicotinic ganglionic and neuromuscular junction ACh-receptors as well as from the synaptic cholinesterase, in contrast to previous reports (Duncan & Publicover, 1979).The low temperature-dependence points to the possibility that physical rather than biochemical processes are limiting in this presynaptic effect of cholinomimetics.

Acetylcholine↗
PubMed1983

The role of nicotinic receptors in dog pancreatic exocrine secretion.

1 The effects of pentamethonium, an autonomic ganglion blocker, were studied on the exocrine pancreatic secretion of six conscious dogs given intravenous infusions of urecholine, caerulein or pentagastrin on a background of submaximal doses of secretin. 2 Urecholine-induced protein secretion was not affected but both caerulein- and to a smaller extent, pentagastrin-induced protein secretions were depressed by pentamethonium. 3 These results indicate that intravenous caerulein and pentagastrin, but not urecholine, act at least partially via nicotinic receptors. 4 Volume and bicarbonate output were depressed by pentamethonium when stimulated by intravenous caerulein with a background of secretin, but not when stimulated by pentagastrin on a background of secretin. 5 From these data it is suggested that caerulein and pentagastrin may potentiate secretin-stimulated hydrelatic secretion by different mechanisms.

Animals↗
PubMed1994

Cardiovascular and behavioral responses to nicotinic agents administered intrathecally.

We have examined the role of the spinal nicotinic receptors in mediating cardiovascular and behavioral responses in conscious rats. Intrathecal administration of nicotinic agonists to the lumbosacral region of the spinal cord caused a dose-dependent increase in systolic blood pressure, heart rate and a nociceptive (behavioral) response. The order of potencies for the pressor response was l-nicotine > or = cytisine > N-methylcarbamylcholine > or = dimethylphenylpiperazinium > d-nicotine. However, cytisine was the most potent in producing the heart rate increase and nociceptive response. Unlike the other agonists, cytisine also exhibited marked desensitization of the three responses upon repeated administration. The effects of nicotine were antagonized in a dose-dependent fashion by mecamylamine, hexamethonium, alpha-lobeline, dihydro-beta-erythroidine and methyllycaconitine. By contrast, cytisine-induced responses were blocked effectively by mecamylamine and methyllycaconitine, but not by alpha-lobeline or dihydro-beta-erythroidine. However, when alpha-lobeline or dihydro-beta-erythroidine antagonism of the pressor response to cytisine was monitored during the initial minute following intrathecal administration, both antagonists significantly inhibited the response. The competitive ganglionic blocker, trimethaphan, or the elapid alpha-toxin, alpha-bungarotoxin, when administered intrathecally, had no effect on nicotine- or cytisine-elicited responses. The cardiovascular responses to intrathecal nicotine and cytisine have two components. The first is likely mediated through direct sympathetic output and desensitizes rapidly to cytisine, the second is coupled indirectly to the nociceptive response and shows a diminished capacity for rapid desensitization. Agonist and antagonist specificities indicate that the spinal nicotinic receptor differs from those in ganglia and those characterized in brain to date. Although antagonist specificity of the blockade of nicotine and cytisine elicited responses differ, this may be due to the unique desensitization capacity of cytisine rather than an action mediated by distinct receptor subtypes.

Aconitine↗
PubMed1999

Isolation of a muscarinic alkaloid with ocular hypotensive action from Trophis racemosa.

A muscarinic alkaloid with a quaternary nitrogen was isolated from Trophis racemosa. Aqueous solutions (0.5%-2%) of the chloride salt of the alkaloid produced dose-dependent reductions of intra-ocular pressure ranging from 6.6 +/- 0.7 mmHg to 15.7 +/- 0.3 mmHg, (p < 0. 001, n = 5) in dogs. Atropine (0.1 mL of a 1% solution) and pirenzepine at a non selective antagonist dose (0.1 mL of 0.5% solution) for M(1) and M(3) receptors blocked the reduction of intra-ocular pressure, but alpha-adrenoceptor blockade with phenoxybenzamine (0.1 mL of a 1% solution) did not block the reduction of intra-ocular pressure. On the isolated guinea-pig ileum and trachea, the alkaloid produced contractions which were inhibited by atropine (6 x 10(-7) M or 0.4 microg/mL) and by pirenzepine at a non-selective antagonist dose (3.1 x 10(-6) M or 1.3 microg/mL) for M(1) and M(3) receptors. But neither selective blockade of M(2) receptors with gallamine (1.7 x 10(-6) M or 1.5 microg/mL) nor selective blockade of M(1) receptors with pirenzepine (7 x 10(-9) M or 3 ng/mL) inhibited the alkaloid-induced contractions. There was also no inhibition of the alkaloid-induced contractions in the presence of ganglionic nicotinic receptor blockade with pentolinium (5.6 x 10(-7) M or 0.3 microg/mL) and hexamethonium (1.7 x 10(-6) M or 0.6 microg/mL), but nicotine-induced contractions were inhibited by these ganglionic blockers. These results suggest that a muscarinic alkaloid from Trophis racemosa produced ocular hypotension via M(3) receptor stimulation in dogs.

Acetylcholine↗
PubMed2001

Spinal cord stimulation for chronic intractable angina pectoris: a unified theory on its mechanism.

The use of spinal cord stimulation (SCS) for chronic intractable anginal pain was first described in 1987. Numerous studies have demonstrated its efficacy in improving exercise tolerance, decreasing frequency of anginal episodes, and prolonging time to electrocardiographic signs of ischemia. This review will examine the potential mechanisms of this antianginal effect and propose a unified hypothesis explaining it. The effect of SCS involves a mutual interaction of decreased pain, decreased sympathetic tone, and a likely redistribution of myocardial blood flow to ischemic regions. Spinal cord stimulation reduces the transmission of nociceptive impulse via the spinothalamic tract due to an enhanced release of gamma aminobutyric acid (GABA) from dorsal horn interneurons. Improvement of myocardial blood flow at the microvascular level has been demonstrated by positron emission tomography (PET). A decreased sympathetic tone has been shown by norepinephrine kinetics, tests of sympathetic reflexes, and the use of ganglionic blockers. We hypothesize that SCS exerts its beneficial effects by decreasing pain and decreasing sympathetic tone, the result of which is decreased myocardial oxygen consumption along with an improved myocardial microcirculatory blood flow.

Angina Pectoris↗
PubMed2004

Pressor effects of electrical stimulation of medial prefrontal cortex in unanesthetized rats.

The medial prefrontal cortex (MPFC) is involved in central nervous system (CNS)-mediated cardiovascular modulation. We compared the cardiovascular effects of electrical stimulation (EE) of the MPFC in unanesthetized rats to those observed after stimulation of the same area in urethane-anesthetized rats. Electrical stimulation (35, 106, 177, 247, 318, and 389 microA rms/10 sec, 60-Hz sine wave) of the MPFC of urethane-anesthetized rats caused depressor responses of stimulus-related intensity. The cardiovascular response to electrical stimulation of the MPFC in unanesthetized rats was characterized by stimulus-related pressor responses. No significant heart rate changes were observed during the EE period in any case. The pressor response to electrical stimulation (106 microA rms/10 sec, 60-Hz sine wave) of the MPFC was not affected by intravenous pretreatment with the vasopressin antagonist dTyr(CH(2))(5)(Me)AVP (50 microg/kg, intravenously), by hypophysectomy, or by intravenous pretreatment with the angiotensin II antagonist losartan (1 mg/kg, intravenously). The pressor response was blocked by intravenous pretreatment with the ganglionic blocker mecamylamine (2 mg/kg, intravenously) but was not affected by adrenal demedullation, thus suggesting involvement of the neural component of the sympathetic nervous system without a major involvement of its hormonal component. Our results confirmed the occurrence of depressor responses after electrical stimulation of the MPFC in urethane-anesthetized rats and evidenced that only pressor responses are observed after its stimulation in unanesthetized rats. The fact that the pressor response to the stimulation of the MPFC was blocked by a ganglioplegic suggests that the MPFC has functional excitatory actions over the sympathetic nervous system.

Adrenal Medulla↗
PubMed1988

Actions of nicotine on the acquisition of an autoshaped lever-touch response in rats.

Experimentally naive male, Sprague-Dawley rats maintained at 85% of their original body weight were trained to touch a retractable lever that was presented on a random interval 48-s schedule. The lever retracted when touched or after 15 s had elapsed, and one 45 mg food pellet was delivered simultaneously with lever retraction or after an 8-s delay. Rats received ten daily sessions each consisting of ten lever presentations. Nicotine (0.25-0.8 mg/kg SC) administration, either 15 min prior to (pre-session) or immediately after (post-session) the daily autoshaping sessions, caused a significant dose-related impairment of acquisition with the post-session injections having the greater effect. Low doses of nicotine (0.025-0.1 mg/kg SC) had little effect on acquisition when injected pre-session or post-session. Injections of 0.45 mg/kg nicotine either immediately (t = 0) or at +5 min after the daily sessions impaired acquisition of the lever-touch response. Nicotine injected at +15, +30, +60, or +120 min had no effect on acquisition. A single intraventricular injection of the ganglionic blocker chlorisondamine (5 micrograms) 2 weeks prior to autoshaping blocked the impairment produced by 0.45 mg/kg nicotine. Post-session injections of nicotine did not alter the lever-touch behavior of well-trained animals, but suppressed responding in animals that were partially trained. Thus, nicotine-induced impairment of the autoshaped lever-touch response is dose dependent, centrally mediated, occurs within 5 min of a SC injection, and may interfere with post-training consolidation processes.

Animals↗
PubMed1996

Modulation of catecholamine storage and release by the pituitary-interrenal axis in the rainbow trout, Oncorhynchus mykiss.

This study examined the effects of pituitary-interrenal hormones on catecholamine storage and release in the rainbow trout Oncorhynchus mykiss. An extract of trout pituitary elicited the release of adrenaline, but not noradrenaline, using an in situ perfusion preparation. A variety of doses of adrenocorticotropic hormone (2-2000 mU) caused the release of both catecholamines in situ which was unaffected by pre-treatment with the ganglion blocker, hexamethonium, or the serotonergic receptor antagonist, methysergide, but was abolished in calcium-free media. Intra-arterial injections of adrenocorticotrophic hormone in vivo caused an elevation of plasma adrenaline but not noradrenaline levels. Injections of cortisol in situ did not elicit catecholamine release. Trout given an intraperitoneal implant of cortisol (50 mg.kg-1 body weight) had significantly higher plasma cortisol concentrations when compared to controls after 7 days of implantation. Increases in the levels of stored catecholamines were observed in various regions of the kidney and posterior cardinal vein following 3 and 7 days of cortisol treatment. The ability of the chromaffin cells to release catecholamines in response to cholinergic stimulation was assessed in situ after 7 days of treatment. Basal (non-stimulated) adrenaline outflowing perfusate levels were greater in the cortisol-treated fish. Cortisol treatment increased the responsiveness of the catecholamine release process to low doses of the cholinoceptor agonist carbachol. Three or 7 days of cortisol treatment did not alter the in vitro activity of the enzyme phenylethanolamine-N-methyl transferase. The results of this study demonstrate that interactions within the pituitary-adrenal axis can influence both catecholamine storage and release in the rainbow trout.

Adrenocorticotropic Hormone↗
PubMed1995

Dysautoregulation in patients with hypertensive intracerebral hemorrhage. A SPECT study.

In patients with hypertensive intracerebral hemorrhage, changes in regional cerebral blood flow (rCBF) following drug-induced blood pressure reduction were examined by SPECT. METHODS. The subjects were 68 patients with hypertensive intracerebral hemorrhage. The site of cerebral hemorrhage was the thalamus in 28 patients, and the putamen in 40 patients. RCBF was measured by SPECT using the 133Xe inhalation method. To reduce blood pressure, trimethaphan camsilate (an autonomic ganglion blocker) and diltiazem hydrochloride (a calcium antagonist) were used. RESULTS. 1. In the acute period, mean CBF declined as the mean arterial blood pressure declined by more than 20% in both the putaminal and the thalamic hemorrhage group (p < 0.01). 2. During the chronic period, a greater reduction in blood pressure was needed to induce mean CBF reduction. 3. Neither of the two drugs significantly reduced the mean arterial blood pressure, but the group receiving trimethaphan demonstrated a 7.9 approximately 7.5% decreased in CBF, group while the receiving diltiazem showed a 2.2 approximately 2.4% decrease (p < 0.05). CONCLUSIONS. In patients with hypertensive intracerebral hemorrhage, a 20% or more drug-induced decrease in blood pressure resulted in a decrease in mean CBF. During the acute period of intracerebral hemorrhage, blood pressure showed reduced by 20%. Clinically, diltiazem was more effective than trimethaphan.

Adult↗
PubMed1975

The cholinergic system and nociception in the primate: interactions with morphine.

In Experiment 1 the shock titration task was used to evaluate the antinoceptive properties of 5 different classes of cholinergic compounds in the rhesus monkey. Only scopolamine and high doses of physostigmine were effective in elevating the shock threshold. The apparent antinociceptive effect of physostigmine, however, was difficult to separate from its nonspecific behavioral depressant effect and was probably not related to an increase in cholinergic tone. Experiment 2 examined the interaction of morphine with arecoline, scopolamine and physostigmine. Only scopolamine (0.05 and 0.1 mg/kg) and high doses of physostigmine (0.1 mg/kg) interacted with morphine in the shock titration paradigm. The multiplicative interaction of morphine with scopolamine was confirmed in Experiment 3 over a wider range of doses. It was concluded that morphine and the cholinergic compounds produce antinociceptive effects through different mechanisms of the pain system.

Analgesia↗
PubMed1982

Peripheral catecholamine release by alpha-latrotoxin in the rat.

Intraarterial injection of alpha-latrotoxin (alpha LTx), the major toxin of the black widow spider (Latrodectus mactans tredecimguttatus) venom, into carotid catheterized rats, induced prompt and marked rises in plasma adrenaline and noradrenaline concentrations, indicating that the toxin stimulates catecholamine release from both the adrenal medulla and sympathetic nerve terminals. Pretreatment with the ganglionic blocker chlorisondamine greatly reduced the plasma adrenaline response to alpha LTx but had almost no effect on the noradrenaline response, indicating that alpha LTx-stimulation of sympathetic nerve terminals is direct, whereas catecholamine release from the adrenal medulla is probably mediated by preganglionic release of acetylcholine. In vitro, alpha LTx induced a dose-dependent release of 3H-noradrenaline from rat irides preincubated with this radioactive amine and this effect was not changed by chlorisondamine plus atropine. By contrast, the toxin had no effect on 3H-noradrenaline release from suspensions of cultured rat chromaffin cells. Specific, high affinity binding of 125I-alpha LTx in iris and adrenal medulla homogenates was found to be exceedingly low, suggesting that it might be restricted to nerve terminals. No 125I-alpha LTx binding was seen nor could any effect of the toxin on 14C-5-hydroxytryptamine release be found in rat blood platelet preparations. alpha LTx binding and its amine releasing effect seem, therefore, to be specific for neurons and absent from other cells, even those, like adrenomedullary cells and blood platelets, which share with neurons their origin and/or other important characteristics.

Adrenal Medulla↗
PubMed1996

Mechanisms mediating insulin-induced hypotension in rats. A role for nitric oxide and autonomic mediators.

The mechanisms associated with insulin-induced cardiovascular inhibitory responses were evaluated in untreated normal rats and in normal rats pretreated with an antagonist of nitric oxide (NO) production (L-NAME), with cholinergic, alpha- and beta-adrenergic antagonists, or after ganglionic blockade. Male Wistar rats were anesthetized with a mixture of urethane and alpha-chloralose and placed on a electric heating pad. The femoral artery and vein were cannulated for measurements of mean arterial pressure (MAP), heart rate, plasma glucose, blood sampling, and intravenous injections. Intravenous injection of insulin (5.0 U/kg) in untreated rats resulted in a significant and sustained decrease in arterial blood pressure (average 24%) and in a slight decrease in heart rate. These cardiovascular responses were blocked by L-NAME and by the cholinergic antagonist atropine, suggesting an involvement of NO and the cholinergic receptors, or an effect of insulin on the central nervous system parasympathetic center. The ganglionic blocker hexamethonium attenuated the insulin-induced response. On the other hand, the hypotensive effect of insulin persisted after sympathetic blockade with the alpha-1 antagonist prazosin and the beta-1 antagonist atenolol. We conclude that the insulin-induced decrease in blood pressure is due to both increased cholinergic outflow and to NO production and that an enhanced sympathetic activity possibly mediated by a reactive release of norepinephrine or epinephrine modulates this response.

Animals↗
PubMed1993

Observations on atrial natriuretic peptide, sympathetic activity and renal Ca2+ pump in diabetic and hypertensive rats.

The relationship between atrial natriuretic peptide (ANP) and peripheral sympathetic nervous system function was studied in diabetic and hypertensive rats. Animals were studied in diabetic and hypertensive rats. Animals were divided into four groups: control, diabetic, hypertensive and diabetic plus hypertensive. Diabetes was induced by streptozotocin (65 mg/kg) injection and hypertension by abdominal aortic constriction. Studies were performed at 1 and 6 weeks. Plasma ANP was increased at 1 week in all groups except controls. Noradrenaline turnover, an index of sympathetic activity in kidney, was attenuated in all pathological groups unlike controls. These changes were associated with increased activity of Ca2++Mg2+ ATPase, which is known to serve as a Ca2+ pump in kidney cortex basolateral membrane. In contrast, at 6 weeks, Ca2++Mg2+ ATPase was significantly decreased only in the diabetic plus hypertensive group which also showed signs of congestive heart failure, increased sympathetic activity and decreased plasma ANP levels. Intracerebral microdialysis of the extracellular space around the paraventricular nucleus (PVN) of the hypothalamus showed a decreased concentration of ANP in the diabetic plus hypertensive group. Infusion of ANP and pentolinium, a ganglionic blocker in diabetic plus hypertensive Ca2+ restored pump activity towards control values; ANP alone had no effect. Our results indicate decreased plasma ANP levels, increased sympathetic drive and a depressed kidney Ca2+ pump in diabetic plus hypertensive rats with heart failure. The relationships between these factors, and the potential modulating role of ANP is discussed.

Animals↗
PubMed1983

Pathogenesis of circulatory reactions triggered by nervous reflexes during the implantation of bone cements.

Circulatory and respiratory reactions during the implantation of joint endoprostheses have been observed for years. The components of the bone cements used for anchoring (methyl methacrylate monomer) or the outpour of bone marrow substances from the affected bone marrow cavity are thought to be chiefly responsible for these effects. However, our previous investigations demonstrated unambiguously that reactions of this type can be attributed to direct nervous-reflex mechanisms triggered by the pressure rise in the medullary canal, and that, in addition, bone marrow embolism plays a part in serious circulatory incidents. The investigations on which the present paper is based have confirmed the mechanism of circulatory reactions triggered by direct nervous reflex and have shown once again that the release of cement monomers is not of any significance, at least not in animal experiments. In regard of the characteristics of these reflex processes, it has been possible to show by both surgical and pharmacologic interventions in the vegetative nervous system, performed before and during pressure experiments, that these reflex processes are caused not so much by an increase of the vagus tone as by a central inhibition of the sympathicus. Neither administrations of atropine nor bilateral cervical vagotomy are able to prevent the reactions. This was only possible under the influence of a ganglion blocker.

Animals↗
PubMed1990

Bispyridinium (oxime) compounds antagonize the "ganglion blocking" effect of pyridostigmine in isolated superior cervical ganglia of the rat.

The "antidotal effectiveness" of several bispyridinium compounds (HGG 12, HGG 65, HGG 70, HI 6, HLö and HLö 12) against the acetylcholinesterase (AChE) inhibitor pyridostigmine was evaluated in isolated superior cervical ganglia of the rat. Compound action potential amplitudes were inhibited by pyridostigmine in a concentration-dependent manner. HI 6 and atropine proved to be the most effective compounds in antagonizing the "ganglion blocking" action of pyridostigmine. Their relative effectiveness (PE value) was 5.4 and 4.2, respectively. All of the six bispyridinium compounds inhibited carbachol-induced, nicotinic, ganglionic surface depolarizations. The antinicotinic potencies of HI 6 and HLö 7 were about one order of magnitude lower (apparent KI values: 294 and 330 mumol/l) than the antinicotinic potencies of HGG 12, HGG 65, HGG 70 and HLö 12 (apparent KI values ranging from 19 to 41 mumol/l). The antinicotinic potencies of the bispyridinium compounds did not correlate with their in vitro protection of synaptic transmission in sympathetic ganglia. Moreover, the effectiveness of atropine points to the importance of antimuscarinic properties of possible "antidotes" for the maintenance of ganglionic transmission in cases of AChE poisoning.

Acetylcholine↗
PubMed2005

Chronotropic effect of D-Ala2,Leu5,Arg6-enkephalin (dalargin) is associated with activation of peripheral kappa-opioid receptors.

Intravenous infusion of D-Ala2,Leu5,Arg6-enkephalin (dalargin) caused bradycardia in narcotized rats. This effect was not observed during opioid receptor blockade with naloxone, naloxone methiodide, and norbinaltorphimine. Dalargin and (-)-U-50,488 added to Krebs-Henseleit perfusion solution for isolated rat heart decreased heart rate. Ganglionic blocker hexamethonium potentiated the negative chronotropic effect of dalargin. The negative chronotropic effect of dalargin is probably associated with activation of cardiac kappa-opioid receptors. It should be noted that dalargin caused tachycardia in some animals. This reaction was not observed after treatment with hexamethonium. The positive chronotropic effect of dalargin is probably related to modulation of the parasympathetic autonomic nervous system. Agonists and antagonists of delta-opioid receptors caused persistent bradycardia. We hypothesized that selective delta-opioid antagonists exhibit properties of partial delta-receptor agonists.

Animals↗
PubMed2005

Mechanisms and significance of the increased brain uptake of tryptophan.

Changes in brain tryptophan concentrations may affect the synthesis of brain serotonin (5-hydroxytryptamine, 5-HT). Concentrations of tryptophan are regulated more than those of any other amino acid. Such stimuli as acute stress, carbohydrate ingestion, and treatment with various drugs increase the brain content of tryptophan. Treatment of rats and mice with interleukin-1 (IL-1), interleukin-6 (IL-6), lipopolysaccharide (LPS), and beta-adrenoceptor agonists, as well as a variety of stressors, such as footshock and restraint, all increase brain concentrations of tryptophan. The peak effect following both acute stress and beta-adrenoceptor agonist administration occurs within 30-60 min, whereas the peak effect following LPS and the cytokines occurs much later at around 4-8 h. Experiments using the ganglionic blocker chlorisondamine, and beta-adrenoceptor antagonists suggest that the sympathetic nervous system plays an important role in the modulation of brain tryptophan concentrations. The mechanisms involved in the increases observed in brain tryptophan are discussed, as well as their possible biological significance.

Animals↗