MODULATION BY β-ADRENORECEPTORS OF SPONTANEOUS CONTRACTIONS OF RAT URINARY BLADDER

• 1 Propranolol (0.1 mg/kg i.v.) but not metoprolol (0.2 mg/kg i.v.) pretreatment increased the spontaneous motility triggered by progressive filling of rat urinary bladder without a concomitant effect on bladder capacity, except at high filling volumes. Compared to controls, the spontaneous motility of urinary bladder in propranolol pretreated rats displayed a higher frequency, indicating the existence of a tonic sympathetic inhibition.
• 2 β-adrenoreceptor stimulation by isoprenaline (0.1–10 μg/kg i.v.) or terbutaline (0.1–1 mg/kg i.v.) in vivo produced a dose dependent inhibition of bladder spontaneous motility which was antagonized by propranolol (0.1 mg/kg i.v.) but not by metoprolol (0.2 mg/kg i.v.). Propranolol (0.2 mg/kg i.v.) pretreatment did not antagonize the inhibition of bladder motility produced by intravenous papaverine (0.5 mg/kg).
• 3 Propranolol (0.1 mg/kg i.v.) significantly antagonized the isoprenaline-induced tachycardia (β₁ mediated) and fall in diastolic blood pressure (β₂ mediated) while metoprolol (0.2 mg/kg i.v.) antagonism was confined to β₁ mediated responses.
• 4 Isoprenaline (0.25–1.5 μM) inhibited in a concentration dependent manner field stimulation induced contractions of rat detrusor muscle strips as did tetrodotoxin (0.5 μM). Hexamethonium (50 μM) had no inhibitory effect.
• 5 Our in vivo findings support the view that β₂-adrenoreceptors are responsible for modulating bladder motility mainly by suppressing the onset of spontaneous contractions.

     

SELECTIVE STIMULATION OF VASCULAR POSTJUNCTIONAL α1-ADRENORECEPTORS BY (-)-AMIDEPHRINE IN RATS AND CATS

• 1 The vasopressor and chronotropic responses of (-)-amidephrine and the receptor types involved were studied in pithed rats of different strains and in pithed cats.
• 2 The increase in diastolic pressure of pithed rats after i.v. administration of (-)-amidephrine was not influenced by pretreatment with propranolol (1 mg/kg, i.v.), reserpine (2 times 5mg/kg in 48 h i.p.) or yohimbine (1 mg/kg, i.v.), but was strongly antagonized by prazosin (0.1 mg/kg, i.v.). In pithed cats, the pressor responses were antagonized by prazosin (1 mg/kg, i.v.) but much less so by yohimbine (1 mg/kg, i.v.).
• 3 (-)-Amidephrine elicited minor positive chronotropic responses in pithed rats and pithed cats. This tachycardia was not influenced by propranolol (1 mg/kg, i.v.) but was abolished by prazosin (0.1 – 1.0 mg/kg).
• 4 The results show that (-)-amidephrine acts as a selective agonist at vascular postjunctional α-adrenoreceptors in pithed rats and pithed cats. The positive chronotropic effects are attributable to stimulation of α-adrenoreceptors in the heart.

     

Stimulation of ganglionic muscarinic M1 receptors by a series of tertiary arecaidine and isoarecaidine esters in the pithed rat

The cardiovascular effects of a series of tertiary esters of arecaidine (1-methyl-1,2,5,6-tetrahydro-3-carboxy-pyridine) and isoarecaidine (1-methyl-1,2,5,6-tetrahydro-4-carboxy-pyridine) were investigated in the pithed rat. For some esters (e.g. arecoline, arecaidine propargyl ester, isoarecoline) a prominent elevation in mean arterial pressure and heart rate was observed following an initial short-lasting and atropine-sensitive depressor response and bradycardia (dose range: 0.1-10 mumol/kg i.v.). The increase in blood pressure and heart rate was not affected by pretreatment with mecamylamine (0.5 and 5 mg/kg i.v.), but could be totally blocked by N-methylatropine (500 micrograms/kg i.v.). Furthermore, the M1 receptor antagonist pirenzepine (300 micrograms/kg i.v.) selectively antagonized these stimulatory cardiovascular responses, indicating that these effects are due to an activation of muscarinic M1 receptors in sympathetic ganglia. As tertiary arecaidine and isoarecaidine esters easily penetrate the blood-brain barrier, they might also stimulate central M1 receptors and thus become lead compounds in the search for an effective drug treatment of Alzheimer's disease.     

EVIDENCE FOR MEDETOMIDINE AS A SELECTIVE AND POTENT AGONIST α2-ADRENORECEPTORS

• 1 The activity on α-adrenoreceptors of medetomidine (±)-4-(α,2,3-trimethylbenzyl)imidazole), an α-methyl derivative of detomidine, has been characterized in vivo and in vitro using detomidine, MPV 207, MPV 295, azepexole, clonidine and xylazine for reference purposes.
• 2 Medetomidine (1–100 μg/kg i.v.) was a hypotensive and bradycardic compound in anaesthetized rats. Furthermore, it induced vasopressor (PD₅₀ 1.7 μg/kg) and sympatho-inhibitory (ID₅₀ 1.6 μg/kg) actions in pithed rats, the effects being antagonized by idazoxan (0.3 mg/kg i.v.) but not by prazosin (0.1 mg/kg i.v.). Medetomidine (30–300 μg/kg i.m.) had an α₂-adrenoreceptor mediated sedative effect on chicks.
• 3 Medetomidine was, overall, more potent than detomidine, MPV 207, clonidine, xylazine, MPV 295 or azepexole in central (sedation in the chick) and peripheral (cardiac presynaptic in the pithed rat) actions on α₂-adrenoreceptors. Clonidine had, however, about an equal potency to medetomidine in the vascular smooth muscle of the pithed rat.
• 4 Like detomidine and MPV 295, medetomidine had no agonistic activity in the rat aortic ring, but high concentrations antagonized methoxamine-induced contractions, giving a pA₂ value of 5.68 for α₁-adrenoreceptor antagonism.
• 5 The overall lipophilicity (log P') of medetomidine in the octanol/buffer (pH 7.4, 24–26°C, HPLC technique) was 2.80.
• 6 In summary, the experimental data suggest that medetomidine is a lipophilic compound with selective α₂-adrenoreceptor-stimulating properties and high potency. It may, therefore, prove to be a suitable pharmacologic tool for interventions in α₂-adrenoreceptor mediated effects in the autonomic nervous system.

     

MODIFICATION OF THE VASOMOTOR ACTIONS OF METHYSERGIDE IN THE FEMORAL ARTERIAL BED OF THE ANAESTHETIZED DOG BY CHANGES IN SYMPATHETIC NERVE ACTIVITY

• 1 Methysergide has been shown to have a remarkably selective vasoconstrictor action in the carotid arterial bed of the anaesthetized dog following intravenous administration. However we have now shown that under conditions which produce sympathetic blockade methysergide will also constrict the femoral arterial bed and the mechanism involved has been investigated.
• 2 Methysergide (10–100 μg/kg i.v.) produced small but variable effects on femoral arterial blood flow in the anaesthetized dog. However following ganglion blockade (mecamylamine 5 mg/kg i.v.), section of the lumbar sympathetic chain between L₄-L₅ or catecholamine depletion with syrosingopine, methysergide consistently caused dose-related decreases in femoral arterial flow which were associated with increases in femoral arterial vascular resistance.
• 3 Intravenous infusion of methysergide (10 μg/kg/min) or 5-hydroxytryptamine (5-HT, 10 μg/kg/min) inhibited the increases in femoral arterial vascular resistance produced by stimulation of the lumbar sympathetic chain by 70% and 44% respectively whilst increases in vascular resistance produced by close intra-arterially administered noradrenaline were potentiated by 25% and 11% respectively.
• 4 Our results show that the vasomotor actions of methysergide in the dog femoral arterial bed are dependent on the degree of sympathetic activity. This suggests that in the dog the post-junctional vasoconstrictor action of methysergide can be masked by a pre-junctional inhibitory effect on sympathetic nerves which may be mediated through stimulation of a specific pre-junctional receptor for 5-HT.

     

The central sympatho-inhibitory effect of 5,6-dihydroxy-2-dimethylaminotetralin (M7) is mediated by α2-adrenoceptors

M7 (5,6-dihydroxy-2-dimethylaminotetralin) produces in anesthetized rats a hypotensive response previously attributed to peripheral dopaminergic mechanisms. We re-examined the effects of this drug on arterial blood pressure, heart rate and sympathetic nerve activity in anesthetized rats and dogs. M7 (1–100 μg/kg i.v.) produced in the rats transient dose-dependent pressor effects, with bradycardia and sympatho-inhibition, followed by long-lasting dose-dependent hypotension, bradycardia and sympatho-inhibition. The sympatho-inhibitory and hypotensive effects were comparable in baroreceptor-denervated rats and were reversed by idazoxan (0.1 mg/kg i.v.). The sympatho-inhibitory response induced by M7 (1–100 μg/kg) was prevented by treatment with the specific α₂-adrenoceptor antagonist, 2-methoxy-idazoxan (0.03 mg/kg i.v.). This central effect of M7 was not altered by treatment with the α₁-adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.) and was reduced by treatment with the α₂-adrenoceptor antagonists, yohimbine (1 mg/kg i.v.) or idazoxan (0.3 mg/kg i.v.), and the dopaminergic antagonists, haloperidol (0.5 mg/kg i.v.) or sulpiride (3 mg/kg i.v.). Bilateral microinjections of M7 (0.3–3 nmol) into the rostroventral medulla in the rat produced dose-dependent hypotension, bradycardia and sympathetic nerve inhibition which were reversed and prevented by bilateral microinjection of 2-methoxy-idazoxan (1 nmol) into the same sites. Microinjections of 2-methoxy-idazoxan into the rostroventral medulla also inhibited the central effects of M7 at 0.03 mg/kg i.v. In anesthetized dogs, M7 administered into the cisterna magna (1–10 μg/kg) reduced arterial blood pressure, heart rate and sympathetic nerve activity; these effects were reversed by administration of 2-methoxy-idazoxan (0.03 mg/kg i.v.). In conclusion, M7, a rigid catecholamine, produces a potent central sympatho-inhibitory and hypotensive effect by activation of α₂-adrenoceptors.     

Effects of mianserin, desipramine and maprotiline on blood pressure responses evoked by acetylcholine, histamine and 5-hydroxytryptamine in rats.

1 In rats anaesthetized with pentobarbitone, intravenous administration of desipramine (0.1 mg/kg), maprotiline (0.5 mg/kg) or mianserin (0.3-3.0 mg/kg) did not modify the blood pressure lowering effects of acetylcholine (0.25-1.0 micrograms/kg, i.v.) which were significantly reduced by atropine (3.0 micrograms/kg, i.v.). 2 Maprotiline and mianserin, like promethazine (0.1 mg/kg, i.v.), inhibited the vasodepressor responses evoked by histamine (2.5-10.0 micrograms/kg,i.v.). however, desipramine was inactive against histamine. 3 In pithed rats, the pressor effects of intravenous 5-hydroxytryptamine (5-HT: 5.0-20.0 micrograms/kg) were antagonized by mianserin (0.01-0.3 mg/kg, i.v.) and cyproheptadine (0.01 mg/kg) but were unaffected by maprotiline and desipramine. 4 In syrosingopine pretreated rats given mianserin 0.1 mg/kg, intravenously, 5-HT (20.0 micrograms/kg, i.v.) produced a significant fall in blood pressure which could be reduced by a large dose of mianserin (10.0 mg/kg, i.v.). 5 In conclusion, desipramine, maptrotiline and mianserin, in doses previously found to inhibit noradrenaline neuronal reuptake in the rat cardiovascular system, lack muscarinic receptor antagonist properties. Whilst maprotiline and mianserin blocked vascular histamine receptors, only mianserin (10.0 mg/kg, i.v.). 5 In conclusion, desipramine, maptrotiline and mianserin, in doses previously found to inhibit noradrenaline neuronal reuptake in the rat cardiovascular system, lack muscarinic receptor antagonist properties. Whilst maprotiline and mianserin blocked vascular histamine receptors, only mianserin, like cyproheptadine, was a potent antagonist of the 5-HT receptors that mediate increases in blood pressure in rats. Finally, the vasodepressor effects of 5-HT in syrosingopine pretreated rats given a small dose of mianserin were antagonized by a large dose of mianserin, suggesting that 5-HT may activate two distinct types of receptors in the rat.     

Activation of midbrain presumed dopaminergic neurones by muscarinic cholinergic receptors: an in vivo electrophysiological study in the rat

1. Extracellular single-unit recording and iontophoresis were used to examine the effects of different cholinoceptor agonists and antagonists on the firing rate and firing pattern of A9 and A10 presumed dopaminergic neurones in the anaesthetized rat.
2. Administration of low currents (1–5 nA) of the selective muscarinic agonists oxotremorine M (Oxo M) and muscarine and of the non-selective muscarinic/nicotinic agonist carbamylcholine (CCh) produced a dose-dependent increase in firing rate in most of the A9 and A10 presumed dopaminergic neurones tested. Oxo M-induced activation could be completely blocked by iontophoretic application of the muscarinic antagonist butyl-scopolamine or systemic administration of the muscarinic antagonist scopolamine (300 μg kg⁻¹, i.v.).
3. Iontophoretic application of the selective nicotinic agonist methylcarbamylcholine (MCCh), but not nicotine, induced a consistent increase in firing rate. Surprisingly, the excitatory effect of MCCh was significantly reduced by the selective muscarinic antagonist scopolamine (300 μg kg⁻¹, i.v.), but not by the selective nicotinic antagonist mecamylamine (2.2 mg kg⁻¹, i.v.). Mecamylamine (3 mg kg⁻¹, i.v.) was also ineffective in reducing the CCh-induced activation of presumed dopamine neurones, suggesting that both CCh and MCCh increased the activity of dopamine neurones via an interaction with muscarinic receptors.
4. Iontophoretic application of the endogenous agonist acetylcholine (ACh) had no or little effect on the firing activity of A10 presumed dopaminergic neurones. However, concomitant application of neostigmine, a potent cholinesterase inhibitor, with acetylcholine induced a substantial activation of these neurones. This activation consisted of two components; one, which was prevalent, was scopolamine (300 μg kg⁻¹, i.v.)-sensitive, and the other was mecamylamine (2 mg kg⁻¹, i.v.)-sensitive.
5. In addition to their effect on firing activity, Oxo M, muscarine and concomitant neostigmine/ACh caused a significant increase in burst firing of A10 neurones, but not of A9 neurones.
6. These data suggest that dopamine cells, both in the A9 and A10 regions, possess functional muscarinic receptors, the activation of which can increase their firing rate and, for A10 neurones, their amount of burst activity. These cholinoceptors would be able to influence the activity of the midbrain dopamine system greatly and may play a role in, and/or be a therapeutic target for, brain disorders in which dopamine is involved (e.g., Parkinson''s disease, drug addiction and schizophrenia).

     

ATTENUATION OF PRESSOR RESPONSES TO SYMPATHETIC STIMULI IN THE RAT BY ENALAPRIL

Intravenous administration to pithed Wistar rats of the angiotensin converting enzyme inhibitor enalapril (0.1-1.0 mg/kg) lowered the diastolic blood pressure and reduced pressor responses occurring during electrical stimulation (1-30 Hz) of the spinal sympathetic outflow. These doses of enalapril given intravenously also attenuated pressor responses to intravenous injection of the muscarinic ganglion stimulant McNeil-A-343 (50, 100, 150 micrograms/kg) and noradrenaline (0.1-5.0 micrograms/kg). Enalapril (1.0 mg/kg, i.v.) reduced pressor responses to the nicotinic ganglion stimulant 1,1-dimethyl-4-phenyl-piperazinium (300 micrograms/kg, i.v.). These results confirmed that the actions of enalapril resemble those of captopril in the pithed rat, by causing reductions in both blood pressure and pressor responses to sympathetic stimuli.     

In vivo antimuscarinic actions of the third generation antihistaminergic agent, desloratadine

Background

Muscarinic receptor mediated adverse effects, such as sedation and xerostomia, significantly hinder the therapeutic usefulness of first generation antihistamines. Therefore, second and third generation antihistamines which effectively antagonize the H₁ receptor without significant affinity for muscarinic receptors have been developed. However, both in vitro and in vivo experimentation indicates that the third generation antihistamine, desloratadine, antagonizes muscarinic receptors. To fully examine the in vivo antimuscarinic efficacy of desloratadine, two murine and two rat models were utilized. The murine models sought to determine the efficacy of desloratadine to antagonize muscarinic agonist induced salivation, lacrimation, and tremor. Desloratadine's effect on the cardiovascular system was explored in both rodent models.

Results

In the pithed rat, both desloratadine (1.0 mg/kg, i.v.) and the muscarinic M₂ selective antagonist, methoctramine (0.5 mg/kg, i.v.), inhibited negative inotropic (left ventricular dP/dt) effects caused by oxotremorine, a nonselective muscarinic agonist (p < 0.05). Negative chronotropic effects caused by oxotremorine were inhibited by desloratadine, methoctramine, and the muscarinic M₃ selective antagonist, 4-DAMP (1.0 mg/kg, i.v.). A late positive inotropic event observed after the initial decrease was inhibited by all three test compounds with desloratadine and 4-DAMP being the most efficacious. In the conscious animal, inhibition of baroreflex-mediated bradycardia was evaluated. Unlike atropine (0.5 mg/kg, i.v.), desloratadine did not alter this bradycardia. The antimuscarinic action of desloratadine on salivation, lacrimation, and tremor was also explored. In urethane-anesthetized (1.5 g/kg, i.p.) male ICR mice (25–35 g) desloratadine (1.0, 5.0 mg/kg) did not inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, unlike atropine (0.5 mg/kg) and 4-DAMP (1.0 mg/kg). In conscious mice, desloratadine failed to inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, lacrimation, and tremor. However, desloratadine did inhibit oxotremorine-induced tremor in phenylephrine pretreated animals.

Conclusion

The presented data demonstrate that the third generation antihistamine, desloratadine, does not significantly antagonize peripheral muscarinic receptors mediating salivation and lacrimation, therefore, xerostomia and dry eyes should not be observed with therapeutic use of desloratadine. Our data also indicate when administered to a patient with a compromised blood-brain barrier, desloratadine may cause sedation. Patients with compromised cardiovascular systems should be closely monitored when administered desloratadine based on our results that desloratadine has the ability to interfere with normal cardiovascular function mediated by muscarinic receptors.     

Cardiovascular effects of intracerebroventricular GABA,glycine and muscimol in the rat

Summary Intracerebroventricular (i.c.v.) injections of gammaaminobutyric acid (GABA, 125–2,000 g), glycine (250–2,000 g) and muscimol (0.5–4 g) caused dose-dependent reductions of blood pressure and heart rate in conscious rats. Low doses of muscimol (<0.12 g) were hypertensive. The cardiovascular depression induced by GABA was antagonized by bicuculline (3.5 mg/kg i.p.), while that induced by glycine was counteracted more effectively by strychnine (0.7 mg/kg i.v.) than by bicuculline. The cardiovascular response to GABA, but not to glycine, was potentiated by pretreatment with pentobarbitone (50 mg/kg i.p.). It was prolonged by diazepam (5 mg/kg i.p.) and aminooxyacetic acid (AOAA, 25 mg/kg i.p., 4h) but not by AOAA (1 h) or nipecotic acid (1–100 g i.c.v.). Following treatment with d-amphetamine (5 mg/kg i.p.) or reserpine (10 mg/kg i.p., 6h) the cardiovascular depression induced by GABA was attenuated. Propranolol (2.5+2.5 mg/kg i.v. + s.c.) or atropine (2 mg/kg i.v.) alone partially counteracted and in combination completely prevented the negative chronotropic response to GABA. Neither central noradrenaline depletion by means of -MMT (after carbidopa) and -MT nor pretreatment with phenoxybenzamine (20 g i.c.v.) influenced the response to GABA. The arterial hypotension induced by GABA was prolonged after a high dose of atropine (10 mg/kg i.v.) but appeared attenuated by a low dose (2 mg/kg i.v.) or by physostigmine (0.1 mg/kg i.v.). Central serotonergic activation by means of 5-hydroxytryptophan after benzerazid antagonized the cardiovascular actions of GABA. Spiroperidol (0.05 mg/kg i.v.) and apomorphine (1 mg/kg i.v.) did not affect the blood pressure reduction in response to GABA.It is concluded that i.c.v. GABA causes cardiovascular depression by activation of GABA receptors and that the response is mediated by the sympathetic and vagal systems. There were no indications for an involvement of central noradrenergic of dopaminergic mechanisms while a decreased central cholinergic and an increased serotonergic activity possibly contribute to the cardiovascular effects of GABA.     

Inhibitory effects of piribedil on adrenergic neurotransmission

The effects of piribedil on responses to sympathetic stimulation were investigated in anaesthetized dogs. Piribedil (1 mg/kg i.v.) impaired the vasoconstrictor responses to lumbar sympathetic chain stimulation of the perfused hindlimb without changing the effects of noradrenaline. Piribedil (2 mg/kg i.v.) depressed the chronotropic responses to stimulation of the right anterior ansa and the inotropic response to stimulation of the left anterior ansa. Stimulation of the splanchnic nerve induced frequency dependent increases in systemic blood pressure. Piribedil antagonized this effect. Piribedil (1 mg/kg i.v.) attenuated the constrictor responses of the perfused mesenteric artery to postganglionic sympathetic stimulation and reduced the decreases in renal blood flow caused by stimulation of sympathetic renal nerves. The inhibitory effects of piribedil were preferential on responses induced by low frequency stimulation of nerves. The hypertensive, vasoconstrictor and tachycardic effects of noradrenaline and tyramine were not affected. The effects of piribedil were reversed by haloperidol (0.5 mg/kg i.v.) or pimozide (0.2 mg/kg i.v.).     

Pharmacological analysis of the mode of action of mandelamidine with sustained antihypertensive effect. (II). Mechanism of transient hypotensive action of mandelamidine]

The mode of a transient hypotensive action of dl-Mandelamidine (MA) was studied in both anesthetized and unanesthetized animals. In the blood pressure of unanesthetized rats, a transient hypotensive action of MA (1 approximately 30 mg/kg i.v.) like papaverine (1 approximately 10 mg/kg i.v.) was much less predominant than in rats anesthetized with urethane (1.5 g/kg s.c.). The transient hypotensive action of MA (10 mg/kg i.v.) in rats anesthetized with urethane (1.5 g/kg s.c.) was not reduced when MA was injected continuously. Moreover C6 (5 mg/kg i.v.), propranolol (1 mg/kg i.v.), diphenhydramine (10 mg/kg i.v.) and atropine (2 mg/kg i.v.) did not block this transient hypotensive action. MA blocked the pressor action of epinephrine (3 mug/kg i.v.) in three minutes, but then potentiated it. MA (10 mug/kg i.a. approximately 1 mg/kg i.a.) caused a temporary vasodilation on the perfused leg artery and vertebral artery in dogs anesthetized with sodium pentobarbital (30 mg/kg i.v.). In the perfused leg artery, atropine (2 mg/kg i.v.) and propranolol (1 mg/kg i.v.) did not block the vasodilation of MA, and MA showed no marked blocking effect of the vasoconstriction of norepinephrine (0.2 mug/kg i.a.). In the dog heart-lung preparation and the guinea-pig heart, MA showed inhibiting effects. On the contraction of the cat nictitating membrane elicited by the stimulation of the postganglionic cervical sympathetic nerve, the blocking action of MA (1 mug/kg i.a. approximately 1 mg/kg i.a.) was much less predominant than that of phentolamine (10 mug/kg i.a.). In the rabbit descending aorta, MA (3 X 10(-4) g/ml) antagonized non-competitively the contraction elicited by norepinephrine. These findings suggest that a transient hypotensive action of MA depends upon the inhibiting effects on the cardiovascular system, and the adrenergic alpha-blocking effect of MA may be very weak.     

Antihypertensive and vasorelaxant effects on KRN2391 in spontaneously hypertensive rats

• 1.1. In conscious spontaneously hypertensive rats (SHR), the oral administration of KRN2391 (0.1–3.0 mg/kg) produced a dose-dependent decrease in blood pressure. The antihypertensive effect of KRN2391 was about 2 and 20 times more potent than those of pinacidil and nifedipine, respectively, but about 2 times less potent than that of cromakalim.
• 2.2. During oral administration of KRN2391 (0.5 and 1.0 mg/kg) once daily for 5 weeks, its antihypertensive effect did not diminish in conscious SHR.
• 3.3. In anaesthetized SHR, KRN2391 (3–100 μg/kg, i.v.) produced a decrease in blood pressure in a dose-dependent manner. Its antihypertensive effect was antagonized by glibenclamide (20 mg/kg, i.v.).
• 4.4. In isolated aorta obtained from SHR, KRN2391 (0.01–100 μM) produced a concentration-dependent relaxation. Its concentration-relaxation curve was shifted to the right by glibenclamide (1 μM) and methylene blue (3 μM).
• 5.5. These results indicate that the antihypertensive effect of KRN2391 in SHR is due to its direct action on vascular smooth muscle based on a K⁺ channel opening action and a nitrate action. In addition, KRN2391 is absorbed from the gastrointestinal tract into blood and does not induce tolerance despite possessing some nitrate action.

     

Analysis of CNS sympatho-inhibition produced by guanabenz

The effects of guanabenz on several autonomic systems were observed in vagotomized, anesthetized cats with the aim of determining, in a quantitative sense, the degree to which guanabenz produces a clonidine-like central nervous system action. Guanabenz given as a single dose (50 μg/kg i.v.) produced a transient hypertension associated with a more sustained bradycardia and depression of centrally (hypothalamic) evoked electrodermal responses (EDR). Increasing cumulative doses of guanabenz (3–1000 μg/kg i.v.) also resulted in a dose-related depression of EDR amplitude, transient hypertension followed by hypotension, sustained bradycardia, and mydriasis. All responses were antagonized by pretreatment with yohimbine (0.5 mg/kg i.v.). The ED₅₀ for depression of the centrally evoked EDR was in the range of 50–100 μg/kg i.v. in the non-pretreated preparations. Guanabenz (100 μg/kg i.v.) was shown to be devoid of significant ganglionic blocking properties. These experiments suggest that guanabenz acts like clonidine in the CNS and that an α₂-adrenergic inhibitory mechanism is involved in its myriad of central autonomic effects.     

PRESYNAPTIC DOPAMINE RECEPTORS MEDIATE THE INHIBITORY ACTION OF DOPAMINE AGONISTS ON STIMULATION-EVOKED PRESSOR RESPONSES IN THE RAT

1 The effects of the dopamine agonists TL-99, M-7 (N, N-dimethyl analogues of aminotetralins) and N, N-din propyldopamine (NNPD) on stimulation-evoked pressor responses and tachycardia in pithed Sprague-Dawley rats were investigated when pressor responses to the compounds per se had subsided. Various antagonists were used to characterise the effects of the dopamine agonists. 2 M-7 (3 μg/kg i.v.) and NNPD (1 mg/kg i.v.), but not TL-99 (1–30 μg/kg i.v.), inhibited pressor responses evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 3 M-7 (3 μg/kg i.v.), but neither NNPD (1 mg/kg i.v.) nor TL-99 (1–30 μg/kg), inhibited tachycardia evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 4 The inhibition of stimulation-evoked pressor responses by M-7 and NNPD was prevented by pimozide, metoclopramide and sulpiride but not by yohimbine, atropine, cimetidine or propranolol. 5 The inhibition of stimulation-evoked tachycardia by M-7 was prevented by yohimbine (and to a certain extent by sulpiride) but not pimozide, metoclopramide, atropine or cimetidine. 6 Pressor responses elicited by TL-99, M-7 and NNPD were selectively antagonised by yohimbine, but not by prazosin, indicating that these responses were mediated by stimulation of vascular postsynaptic α₂-adrenoreceptors. 7 This study demonstrates that, in the rat, presynaptic dopamine receptors exist on sympathetic pre- or postganglionic nerve endings to blood vessels, but not on sympathetic pre- or postganglionic nerve endings to the heart, where inhibition by M-7 of stimulation-evoked tachycardia is mediated by stimulation of presynaptic α₂-adrenoreceptors.     

两面针结晶8的解痉和镇痛作用研究

结晶-8,是从两面针提出的一种单体。当浓度为1×10^-6～1×10^-4g/ml对正常离体豚鼠回肠活动无影响,但对乙酰胆硷、匹鲁卡品、氯化钡及组织胺所致肠肌收缩有明显的松弛作用;结晶-8腹腔注射10 mg/kg有明显抑制小鼠扭体反应;8～20 mg/kg明显提高家兔及大鼠痛阈,200μg/kg脑室注射亦有明显提高大鼠痛阈。其镇痛作用不被丙烯吗啡(5 mg/kg)所拮抗,而被利血平(4 mg/kg)所对抗。表明结晶-8的解痉作用直接作用于肠平滑肌。而镇痛作用具有中枢性,与吗啡受体无直接关系,但与脑内单胺类介质有关。     

Presynaptic facilitation by the new nootropic drug nebracetam, of ganglionic muscarinic transmission in the dog cardiac sympathetic ganglion.

Effects of nebracetam (4-aminomethyl-1-benzylpyrrolidine-2-one hemifumarate, WEB 1881 FU, CAS 118607-07-1), a new nootropic drug, on impulse transmission in the cardiac sympathetic ganglia were studied in spinal dogs by monitoring heart rate as an indicator of the ganglionic function. The ganglionic stimulants were given directly into the cardiac sympathetic ganglia through the right subclavian artery (i.a.). Nebracetam, 5 mg/kg, i.v. caused a slight and temporal increase in heart rate. After nebracetam, the frequency-response curves of heart rate for preganglionic stellate stimulation (0.25-4 Hz) were not altered in the untreated and atropine-pretreated animals, but the curves (2.5-40 Hz) were shifted to the left in the hexamethonium-pretreated animals. The enhancement of ganglionic muscarinic transmission was dose-dependent on nebracetam i.v. at doses ranging from 0.5 to 15 mg/kg, with a maximal effect at 5 mg/kg. This enhanced muscarinic transmission by nebracetam was almost abolished after subsequent administration of pirenzepine 0.5 mg/kg i.v. The enhancement in the muscarinic transmission by nebracetam was also eliminated after depletion of acetylcholine at preganglionic sites caused by treatment with hemicholinium-3 in combination with preganglionic stimulation. Furthermore, nebracetam failed to affect dose-dependent post-ganglionic stimulation by McN-A-343 (1-32 micrograms), 1,1-dimethyl-4-phenylpiperazinium (1-32 micrograms) and angiotensin II (0.1 and 0.2 micrograms) administered i.a. directly to the ganglia. These results suggest that nebracetam facilitates the ganglionic muscarinic transmission through acting on presynaptic sites.     

Monte Carlo simulation analysis of ceftobiprole,dalbavancin, daptomycin,tigecycline, linezolid and vancomycin pharmacodynamics against intensive care unit‐isolated methicillin‐resistant Staphylococcus aureus

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Pharmacological Evidence that Histamine H3 Receptors Mediate Histamine‐Induced Inhibition of the Vagal Bradycardic Out‐flow in Pithed Rats

In vivo stimulation of cardiac vagal neurons induces bradycardia by acetylcholine (ACh) release. As vagal release of ACh may be modulated by autoreceptors (muscarinic M₂) and heteroreceptors (including serotonin 5‐HT₁), this study has analysed the pharmacological profile of the receptors involved in histamine‐induced inhibition of the vagal bradycardic out‐flow in pithed rats. For this purpose, 180 male Wistar rats were pithed, artificially ventilated and pre‐treated (i.v.) with 1 mg/kg atenolol, followed by i.v. administration of physiological saline (1 ml/kg), histamine (10, 50, 100 and 200 μg/kg) or the selective histamine H₁ (2‐pyridylethylamine), H₂ (dimaprit), H₃ (methimepip) and H₄ (VUF 8430) receptor agonists (1, 10, 50 and 100 μg/kg each). Under these conditions, electrical stimulation (3, 6 and 9 Hz; 15 ± 3 V and 1 ms) of the vagus nerve resulted in frequency‐dependent bradycardic responses, which were (i) unchanged during the infusions of saline, 2‐pyridylethylamine, dimaprit or VUF 8430; and (ii) dose‐dependently inhibited by histamine or methimepip. Moreover, the inhibition of the bradycardia caused by 50 μg/kg of either histamine or methimepip (which failed to inhibit the bradycardic responses to i.v. bolus injections of acetylcholine; 1–10 μg/kg) was abolished by the H₃ receptor antagonist JNJ 10181457 (1 mg/kg, i.v.). In conclusion, our results suggest that histamine‐induced inhibition of the vagal bradycardic out‐flow in pithed rats is mainly mediated by pre‐junctional activation of histamine H₃ receptors, as previously demonstrated for the vasopressor sympathetic out‐flow and the vasodepressor sensory CGRPergic (calcitonin gene‐related peptide) out‐flow.