Potent Alpha Research Articles

In vivo pharmacological profile of SL 84.0418, a new selective, peripherally active alpha 2-adrenoceptor antagonist.

SL 84.0418 is a novel pyrrolo-indole derivative with potent and selective alpha 2-adrenoceptor antagonist activity in vitro and anti-hyperglycemic properties in vivo. In the present study we demonstrated that SL 84.0418 and its active (+) enantiomer, SL 86.0715, show a high degree of selectivity for alpha 2-adrenoceptors in vivo, preferentially blocking alpha 2-adrenoceptors in the periphery. While having no effects on basal blood pressure and heart rate, p.o. (3 and 10 mg/kg) or i.v. (0.3 mg/kg) administered SL 84.0418 or SL 86.0715 antagonized the hypertensive responses mediated by postsynaptic vascular alpha 2-adrenoceptors after the administration of UK 14304 or norepinephrine to pithed rats. The (-) enantiomer of SL 84.0418, SL 86.0714, was devoid of alpha 2-adrenoceptor antagonist properties in vivo, while the (+) enantiomer of SL 84.0418, SL 86.0715, showed alpha 2-adrenoceptor antagonist activity similar to that of the racemate. SL 84.0418 (3 mg/kg p.o.) did not modify the centrally mediated hypotensive and bradycardic effects of i.c.v. administered clonidine. Furthermore, in the mouse, SL 84.0418 potently antagonized the hyperglycemic responses to epinephrine or UK 14304, which are mediated by peripheral alpha 2-adrenoceptors, but failed (in doses up to 30 mg/kg i.p.) to antagonize the clonidine-induced hypolocomotion, which is mediated by central alpha 2-adrenoceptors. These results suggest that SL 84.0418 preferentially antagonizes peripheral alpha 2-adrenoceptors. SL 84.0418 administered to pithed rats (3 mg/kg p.o. or 0.3 mg/kg i.v.) did not modify the vasoconstriction induced by cirazoline (effect mediated by alpha 1-adrenoceptors) nor the tachycardia induced by norepinephrine (effect mediated by beta-adrenoceptors).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of clonidine on the cerebrovascular system in cats.

The effects of clonidine, a potent alpha 2 adrenergic agonist and an imidazole/imidazoline receptor agonist, were examined in the cat cerebrovascular system, measuring cerebral oxygen and carbon dioxide tension (BrPo2, BrPco2) and arterial blood pressure. Intracarotid injection of clonidine (2 micrograms/kg) produced a gradual decrease in systemic blood pressure without initial hypertension, while BrPo2 decreased slightly but significantly. Before and after intracarotid administration of clonidine, cerebrovascular reactivity to carbon dioxide was estimated by changes in BrPo2 and BrPco2 during and after 3 min inhalation of 5% CO2. Clonidine significantly enhanced cerebrovascular reactivity to carbon dioxide. The data suggest that the alpha 2-adrenoceptor and/or imidazoline receptor play an important role in the regulation of cerebral circulation.

Vascular Responsiveness of Rabbit Common Carotid, Renal and Femoral Arteries to α-Adrenoceptor Agonists

The stainless steel cannula inserting method was used to observe vascular effects of alpha-adrenoceptor agonists, phenylephrine (PE), methoxamine (ME), clonidine (CL) and xylazine (XY), on the isolated, perfused rabbit common carotid, renal and femoral arteries. PE and ME induced a dose-dependent vasoconstriction that was readily suppressed by treatment with bunazosin, an alpha 1-adrenoceptor blocker. CL induced a constriction only in common carotid arteries, and this was readily suppressed by bunazosin. In preparations preconstricted by phenylephrine, CL and XY dose-dependently induced vasodilations in the 3 types of arteries, and these vasodilations were not modified by a potent alpha 2-adrenoceptor antagonist, midaglizole. In preparations preconstricted by prostaglandin F2 alpha, CL and and XY did not produce any significant vasodilation, but CL induced a vasoconstriction in common carotid arteries that was completely blocked by bunazosin. Thus, it is concluded that: 1) alpha 1-adrenoceptors are functionally predominant in rabbit peripheral arteries, 2) the alpha 2-adrenoceptor agonist-induced vasodilation may be due to an antagonistic action towards alpha 1-mediated constrictions, and 3) clonidine has alpha 1-adrenoceptor stimulating properties in rabbit common carotid artery but not in renal and femoral arteries.

Dexmedetomidine, a potent and highly specific alpha 2 agonist, evokes cytosolic calcium surge in astrocytes but not in neurons

Dexmedetomidine is an extremely potent alpha 2 adrenoceptor agonist which can reduce anaesthetic requirements by up to 90%. However, the precise cellular mechanism of action of this agent is not known. Primary cultures of murine neurons and astrocytes were grown to test the hypothesis that changes in free intracellular calcium may trigger cellular responses to this drug. In astrocyte cultures, experiments revealed a pronounced increase in cytosolic calcium concentration when 100 nM dexmedetomidine was administered. However, in cultured cerebellar granule cell neurons there was no calcium response observed with similar or even higher concentrations of the drug. Results suggest dexmedetomidine may exert its primary effect on the central nervous system via astrocytes.

Presynaptic alpha 2-adrenoceptor-mediated modulation of norepinephrine release from vascular adrenergic neurons in reduced renal mass salt hypertensive rats.

The present study was designed to investigate the presynaptic alpha 2-adrenoceptor function to inhibit norepinephrine (NE) release in blood vessels of reduced renal mass salt hypertensive rats (Na-loaded HT). Isolated perfused mesenteric vasculatures were prepared from Na-loaded HT and normotensive control rats (NT-control), and the NE release and vascular responsiveness were examined. Periarterial nerve stimulation caused a significantly greater release of NE and pressor responses in Na-loaded HT than in NT-control. Yohimbine, a potent alpha 2-adrenoceptor antagonist, demonstrated the facilitatory effects on NE release during nerve stimulation. The effects were significantly attenuated in Na-loaded HT compared with NT-control. These results demonstrate that vascular sympathetic nervous activity might be enhanced in Na-loaded HT. Furthermore, the increased NE release from vascular adrenergic neurons in Na-loaded HT could partially depend on impaired presynaptic alpha 2-adrenoceptor-mediated modulation, which might contribute to the pathogenesis and maintenance of this form of salt-dependent hypertension.

Comparison of Neurologic Responses to the Use of Medetomidine as a Sole Agent or Preanesthetic in Laboratory Beagles

Different dose regimens of medetomidine (a potent alpha 2-adrenergic agonist), adding up to a combined dose of 80 micrograms/kg, were administered to laboratory beagles to determine physiologic responses including neurologic. The study was intended to determine EEG responses where sufficient sedative and analgesic effects are reached with medetomidine and in contrast its effects when used with ketamine or halothane. Cardiopulmonary responses were very similar in each dose regimen, showing the characteristic properties of single doses of 80 micrograms/kg of medetomidine. Effective sedative and analgesic duration seemed to be a function of when the largest dose was administered. Adequate additional sedative and analgesic could be gained from injections at doses of half of the initial one. The potent sedative and analgesic effects of medetomidine confirmed by neurologic evaluation supports its potential use as a premedication to general anesthesia in dogs. In this study, 2 different doses of medetomidine were also tested as premedication to both ketamine HCI and halothane anesthesia. Neorologic responses were determined at the same time cardiopulmonary parameters, anesthetic quality, and dose requirements were recorded. Medetomidine was found to have favorable qualities in conjunction with these anesthetics. Cardiopulmonary parameters remained satisfactory in both groups as preanesthetic medication prior to halothane, but no additional benefits could be seen from doses of 40 micrograms/kg medetomidine compared to 20 micrograms/kg, except a significant 30% reduction in halothane requirement. The positive chronotropic and inotropic properties of ketamine restored the medetomidine-induced bradycardia and produced a short anesthetic period of 15 to 30 min depending on the dose of medetomidine. The quality of anesthesia was better when 40 micrograms/kg medetomidine was used, but recovery was quicker with 20 micrograms/kg medetomidine. Medetomidine significantly reduced cerebral activity as demonstrated by recordings of total amplitude and frequency evaluation of the EEG with compressed spectral analysis. This analytical method was effective in confirming clinical signs of sedation, analgesia, and anesthesia in canine subjects.

The effects of dexmedetomidine, an alpha 2 agonist, on learning and memory, assessed using passive avoidance and water maze tasks in rats

The effects of dexmedetomidine, a specific and potent alpha 2 agonist, on the performance of rats in passive avoidance and water maze tasks were studied. Pre-training administration of subanaesthetic dose (9.0 μg/kg) of dexmedetomidine impaired the retention of the passive avoidance task (assessed 24 hr after training) but it did not affect the training of this task. Smaller doses (0.3, 0.9 and 3.0 μg/kg) did not affect the training or retention of this aversively motivated task. On the other hand, pre-training administration of 0.3 and 0.9 μg/kg dexmedetomidine impaired the acquisition of the water maze task, whereas larger doses (3.0 and 9.0 μg/kg) had no significant effect on spatial learning. Pre-training administration of dexmedetomidine (0.3–9.0 μg/kg) increased swimming speed in rats. Only a large dose (300 μg/kg) of dexmedetomidine, administered immediately after training, impaired the retention of the passive avoidance task and the acquisition of the water maze task. These data agree with previous findings that pharmacological manipulation of the noradrenergic system affects the retention of aversively-motivated (passive avoidance) tasks. The present results suggest that the dose-response curve of dexmedetomidine for impairment of learning/memory differs between the passive avoidance and water maze tasks.

Localization of alpha-2 adrenergic receptors in the human eye.

To elucidate sites of the action of alpha-2 adrenergic drugs, we localized binding sites for a potent alpha-2 adrenergic agonist, UK-14,304, in sections of the human cadaveric eye by an in vitro ligand-binding technique and autoradiography. Its specific binding sites were found in the iris epithelium and ciliary epithelium at a high level, and also in the ciliary muscle, retina, retinal pigment epithelium (and/or choroid). Binding of UK-14,304 to the ocular pigments was prevented by preincubating the eye sections with chloroquine, which reduced the non-specific binding to a low level.

Effects of carvedilol on adrenergic receptor pharmacology in human ventricular myocardium and lymphocytes.

Carvedilol, a new beta-blocker with vasodilating properties due to alpha 1-blockade, was investigated in preparations of human ventricular myocardium. Carvedilol demonstrated a high affinity and is a slightly beta 1-selective competitive beta-blocking agent, with a KD for beta 1-receptors of approximately 4-5 nM and a mild selectivity for beta 1 vs. beta 2 receptors of 6- to 39-fold, depending on the method employed to assess subtype potency. In addition, carvedilol was also a potent alpha 1-blocking agent, with a beta 1:alpha 1 blocking relative potency of 1.7-fold. In human lymphocytes containing beta 2-receptors and in human myocardial membranes containing both beta 1- and beta 2-receptors carvedilol exhibited the unique property of guanine nucleotide modulatable binding. Despite this, no intrinsic sympathomimetic activity of carvedilol was detected in preparations of isolated human heart or in myocardial membranes. Vasodilation related to alpha 1-blockade and the lack of intrinsic activity should translate into improved tolerability and good efficacy in the treatment of heart failure.

Dicentrine, a natural vascular α1‐adrenoceptor antagonist, isolated from Lindera megaphylla

1. The pharmacological activity of dicentrine, isolated from Lindera megaphylla, was determined in rat isolated thoracic aorta, guinea-pig isolated trachea and human platelet-rich plasma. 2. Dicentrine was found to be a potent alpha 1-adrenoceptor blocking agent in rat thoracic aorta as revealed by its competitive antagonism of noradrenaline- (pA2 = 8.19 +/- 0.09) or phenylephrine (pA2 = 9.01 +/- 0.10)-induced vasoconstriction. These effects still persisted in denuded aorta. It was less potent than prazosin (pA2 = 10.60 +/- 0.10), but was more potent than phentolamine (pA2 = 7.53 +/- 0.10) or yohimbine (pA2 = 6.20 +/- 0.05). 3. Inositol monophosphate formation induced by noradrenaline (3 microM) in rat thoracic aorta was suppressed by dicentrine (3-10 microM) and prazosin (3 microM). 4. A high concentration of dicentrine (30 microM) did not affect the aortic contraction induced by the thromboxane receptor agonist U-46619 (1 microM), angiotensin II (1 microM), high potassium (60 mM) or carbachol (3 microM). 5. Contraction of guinea-pig trachea caused by histamine or carbachol was slightly inhibited by dicentrine (30 microM), while beta-adrenoceptor relaxation to isoprenaline in trachea was not affected. 6. Aggregation in human platelet-rich plasma induced by adrenaline (10 microM) was blocked by yohimbine (5 microM). A high concentration of dicentrine (greater than 30 microM) caused slight inhibition of aggregation, the release reaction and thromboxane formation. Complete blockade was obtained with 150 microM dicentrine. 7. It is concluded that dicentrine is a potent, selective alpha 1-adrenoceptor antagonist in vascular smooth muscle.

Tissue‐Specificity of Hydroxylation and N‐Methylation of Arylalkylimidazoles

Hydroxylation and N-methylation of three potent alpha 2-adrenoceptor agonists detomidine, medetomidine and dexmedetomidine by rat brain, kidney, liver and lung were studied in vitro. NADPH-dependent hydroxylation of the 3'-methyl group was catalyzed mainly by the microsomal fraction of liver. Monooxygenation by the other tissues was negligible. The hepatic monooxygenase reaction was characterized by high affinity (Km 5.5-9.8 microM) and low capacity (Vmax 29-66 pmol/min. per mg protein). Statistically significant (P less than 0.05) differences between the Km and Vmax values of medetomidine and dexmedetomidine were observed suggesting stereoselective oxidation of the drug molecule. N-Methylation of the arylalkylimidazoles occurred mainly in the cytosolic fraction of the kidney. With S-adenosylmethionine as the methyl donor, the transferase activities in other tissues were less than 10% of the specific activity of the renal enzyme (about 7 pmol/min. per mg protein for medetomidine). Even the renal enzyme showed a relatively low capacity (Km 250-300 microM and Vmax 15-33 pmol/min. per mg protein). Different tissue distributions of the arylalkylimidazole N-methyltransferase and histamine N-methyltransferase suggest that they are two distinct enzyme species. Based on these results, aliphatic hydroxylation is the major (metabolic) elimination mechanism of the arylalkylimidazole drugs, and liver is the principal eliminating organ. The importance of N-methylation is diminished by its low capacity and probable regeneration of the parent drug by demethylation.

Pyrimido[5,4-b]indole derivatives. 1. A new class of potent and selective alpha 1 adrenoceptor ligands.

A number of 3-substituted pyrimido[5,4-b]indole-2,4-diones (7-23) were evaluated for their in vitro alpha 1 adrenoceptor affinity by radioligand receptor binding assays. Some compounds bearing a (phenylpiperazinyl)alkyl side chain were potent alpha 1 adrenoceptor ligands. The most active derivative in displacement of [3H]prazosin from rat cortical membranes was 3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]pyrimido[5,4-b]indol e- 2,4-dione (10) (Ki = 0.21 nM). Discrete modifications in the structure resulted in higher selectivity (greater than 10,000 times) for alpha 1 than alpha 2, beta 2, and 5HT1A receptors. Some compounds also had affinity for the 5HT1A receptor. The most selective alpha 1 ligand was 3-[2-[4-(2-chlorophenyl)piperazin-1-yl]ethyl]pyrimido[5,4-b)indole - 2,4-dione (13).

The pharmacology of fluparoxan: a selective α2‐adrenoceptor antagonist

1. This paper describes the pharmacology of the novel alpha 2-adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti-depressant. Idazoxan and yohimbine were included in many studies for comparison. 2. In the rat isolated, field-stimulated vas deferens and the guinea-pig isolated, field-stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the alpha 2-adrenoceptor agonist UK-14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the alpha 1-adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an alpha 2: alpha 1-adrenoceptor selectivity ratio of greater than 2500. 3. In the conscious mouse, fluparoxan (0.2-3.0 mg kg-1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine-induced hypothermia and antinociception. In the rat, UK-14304-induced hypothermia (ED50 = 1.4 mg kg-1, p.o. or 0.5 mg kg-1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg-1 p.o. or 1.3 mg kg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67-6 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4. In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pKi = 5.5) binding sites in rat brain. 5. We conclude that fluparoxan is a highly selective and potent alpha 2-adrenoceptor antagonist. The density of rat brain [3H]-dihydroalprenolol binding sites was reduced by 26% when fluparoxan was administered chronically for 6 days at a dose of 12 mg kg- 1 orally twice daily. The down-regulation of beta-adrenoceptors by fluparoxan is consistent with its antidepressant potential.

INVESTIGATIONS INTO INTERACTIONS BETWEEN DOXAZOSIN AND ENALAPRILAT AT α1‐ADRENOCEPTORS IN ANAESTHETIZED RATS

1. In anaesthetized intact Sprague-Dawley rats, the angiotensin-converting enzyme inhibitor enalaprilat, 1 mg/kg, had no significant effect on the pressor responses to the alpha 1-adrenoceptor agonist phenylephrine (PE). Doxazosin 1 mg kg was found to be a potent alpha 1-adrenoceptor antagonist. 2. The combination of enalaprilat 1 mg/kg plus doxazosin 1 mg/kg was 3.3-fold more potent in antagonizing alpha 1-adrenoceptors than doxazosin 1 mg/kg alone. 3. After treatment of rats with deoxycorticosterone acetate (DOCA) twice weekly for 5 weeks, the alpha 1-adrenoceptor antagonist action of doxazosin in anaesthetized rats was not potentiated by enalaprilat 1 mg/kg. 4. Since DOCA treatment suppresses renin activity, these findings strongly support the hypothesis that angiotensin II can modulate the functional activity of alpha 1-adrenoceptor in vascular smooth muscle.

Pharmacological Features of Vascular Responses of Isolated Dog and Monkey Lingual Arteries to Vasoactive Substances

Using a perfusion technique of isolated vessels, vasoconstrictor responses to alpha-adrenoceptor agonists (norepinephrine [NE], phenylephrine [PE], clonidine, xylazine and tyramine) and KCl were investigated in isolated, perfused dog and monkey lingual arteries. A stainless steel cannula was inserted into the lingual artery segment and perfused with Krebs-Henseleit solution at a constant flow rate. In dog lingual arteries, the agonists induced vasoconstrictions with the following order of potency: NE greater than PE greater than tyramine much greater than clonidine greater than xylazine greater than KCl. In monkey preparations, the order was NE greater than PE much greater than clonidine greater than or equal to tyramine greater than xylazine greater than KCl. In both preparations, NE- and PE-induced constrictions were blocked by bunazosin (an alpha-1 adrenoceptor antagonist), but not influenced by midaglizole (a potent alpha-2 antagonist). Diltiazem (a Ca entry blocker) significantly attenuated NE-induced vasoconstrictions in dog lingual arteries, but did not significantly influence these in monkey preparations. These results suggest that: [1] these arteries contain mostly alpha-1 but scarcely any alpha-2 adrenoceptors; [2] in dog preparations, tyramine induced a marked vasoconstriction which may contribute to investigation on the mechanisms of catecholamine releases from sympathetic nerve terminals; and [3] different blocking effects of diltiazem may indicate that extracellular Ca++ influx may have varying degrees of importance in alpha-1 adrenoreceptor-mediated constrictions in different species, although participation of an intracellular mechanism might not be ruled out.

Identification of human platelet a2‐adrenoceptors with a new antagonist [3H]‐RX821002, a 2‐methoxy derivative of idazoxan

1. The binding of a new alpha 2-adrenoceptor antagonist, [3H]-RX821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline), was investigated in human platelet membranes and compared with [3H]-yohimbine binding parameters. 2. Analysis of kinetic data revealed association and dissociation time courses consistent with a simple biomolecular reaction. Saturation isotherms showed that [3H]-RX821002 labelled a higher total number of alpha 2-binding sites (224 +/- 31 vs 168 +/- 24 fmol mg-1 protein) than [3H]-yohimbine and with higher affinity (Kd: 0.92 +/- 0.06 vs 1.51 +/- 0.08 nM). Moreover [3H]-RX821002 exhibited a lower percentage of nonspecific binding 3. The difference in total binding is due to a better labelling of the alpha 2-adrenoceptors in the low affinity state by [3H]-RX821002 since the labelled receptors number in high affinity state was identical with the two radioligands. 4. [3H]-RX821002 binding displayed a specificity similar to that obtained with [3H]-yohimbine. The potency of various compounds acting on adrenoceptors was: yohimbine greater than oxymetazoline greater than UK14304 greater than (-)-adrenaline greater than prazosin greater than or equal to (+)-adrenaline greater than isoprenaline. This order of potency is classical for an alpha 2A-adrenoceptor. 5. RX821002 is a more potent alpha 2-adrenoceptor antagonist than yohimbine on adrenaline-induced platelet aggregation. 6. These results indicate that [3H]-RX821002 is a suitable ligand for the identification of human platelet alpha 2-adrenoceptors.

Reduction of the N‐type calcium current by noradrenaline in neurones of rabbit vesical parasympathetic ganglia.

1. Intracellular and single-electrode voltage-clamp recordings were made from neurones of vesical parasympathetic ganglia (VPG) isolated from the rabbit urinary bladder. 2. Noradrenaline (NA, 0.5-5 microM) shortened the duration of the action potentials and depressed the amplitudes of both spike after-hyperpolarization and after-current. 3. Voltage-dependent calcium currents (ICa) were recorded by using microelectrodes filled with 2 M-caesium chloride in a superfusing solution containing tetraethylammonium (TEA, 50 mM) and tetrodotoxin (TTX, 500 nM). Noradrenaline (0.5-5 microM) depressed both the ICa and the tail current evoked by depolarizing voltage jumps from -100 to -50 mV to -30 to +20 mV. 4. Substitution of barium for calcium also produced an inward current (IBa) with no obvious tail current. Noradrenaline (1 microM) reduced the magnitude of the IBa without affecting the voltage dependence of the current-voltage relationship for IBa. 5. Yohimbine (1 microM), but not prazosin (1 microM) or propranolol (1 microM), antagonized the NA-induced inhibition of the IBa. UK 14304, a potent alpha 2-adrenoceptor agonist, mimicked NA in depressing the IBa. 6. The transient low-threshold (T), the transient high-threshold (N) and the slowly inactivating high-threshold (L) calcium currents co-existed in VPG neurones. 7. Noradrenaline reduced the IBa evoked at clamp potentials more positive than -20 mV from holding potentials near the resting membrane potential (-70 to -50 mV). Under these conditions, the IBa consisted primarily of N- and L-current components. In contrast, NA had no effect on the isolated T- and L-currents. It is concluded that NA selectively inhibits the N-type calcium channels by an action at alpha 2-adrenoceptors in the rabbit VPG neurones.

The pharmacology of carvedilol

Carvedilol is a potent antihypertensive agent with a dual mechanism of action. At relatively low concentrations it is a competitive beta-adrenoceptor antagonist and a vasodilator, whereas at higher concentrations it is also a calcium channel antagonist. The antihypertensive activity of carvedilol is characterized by a decrease in peripheral vascular resistance, resulting from the vasodilator activity of the compound, with no reflex tachycardia, as a result of beta-adrenoceptor blockade. The antihypertensive activity of carvedilol is associated with an apparent "renal sparing" effect in that the reduction in mean arterial blood pressure does not compromise renal blood flow or urinary sodium excretion. Studies on the mechanism of action of carvedilol indicate that the compound is a potent competitive antagonist of beta 1- and beta 2-adrenoceptors with a dissociation constant (KB) of 0.9 nM at both beta-adrenoceptor subtypes. Carvedilol is also a potent alpha 1-adrenoceptor antagonist (KB = 11 nM), which accounts for most, if not all, of the vasodilating response produced by the compound. At concentrations above 1 microM, carvedilol is a calcium channel antagonist. This activity can be demonstrated in vivo at doses that represent the higher end of the antihypertensive dose-response curve. Although the calcium-channel blocking activity of carvedilol may not contribute to the antihypertensive activity of the compound, it may play a prominent role in certain peripheral vascular beds, such as the cutaneous circulation, where marked increases in blood flow are observed. The data indicate that carvedilol is an antihypertensive agent that is both a beta-adrenoceptor antagonist and a vasodilator.(ABSTRACT TRUNCATED AT 250 WORDS)

The synthesis and pharmacological evaluation of indole congeners of the calcium entry blocker verapamil

Based on the notion of a bioisosteric relationship between catechol-(phenol-) and indole-amines, indole congeners of the calcium entry blocker verapamil were synthesized and examined as calcium entry blockers and as alpha 1-adrenoceptor antagonists in isolated tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat. Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive activity, albeit slightly less than verapamil. Indole 23 possessed both calcium entry blockade and potent alpha 1-adrenoceptor activity in vitro but in vivo was less active than verapamil as an antihypertensive agent.

Clinical Evaluation of Medetomidine, a Novel Sedative and Analgesic Drug for Dogs and Cats

Medetomidine, a potent alpha 2-adrenoceptor agonist, was investigated in open, multicenter clinical trials with patients of various canine and feline breeds (1736 dogs and 678 cats). The purpose of the study was to find an optimal dose of medetomidine for sedation and analgesia in clinical practice and to study how well the intended procedure could be performed under the influence of the drug. The mean dose (i.m.) of medetomidine used for examinations, clinical procedures and minor surgical interventions was 40 micrograms/kg, and for radiography 30 micrograms/kg. In cats the dose was 80-110 micrograms/kg. On the doses chosen, almost all animals were recumbent and 72% of the dogs and 85% of the cats were in a slight anaesthetic stage, unable to rise. The evaluation of the overall suitability of medetomidine (% of cases) in different indications was "very satisfactory" or "satisfactory" in 95% of dogs and 81-96% of cats. Side effects reported were limited almost exclusively to vomiting and muscle jerking in dogs (12% and 0.5% of the cases) and to vomiting in cats (65%). Medetomidine seems to suffice for pharmacological restraint of dogs and cats. The concomitant use of medetomidine (80-100 micrograms/kg) and ketamine (7 mg/kg) in cats (n = 295) provided a good anaesthesia (20-40 min). The recovery was smooth. The present study shows that medetomidine provides an effective level of sedation and analgesia for clinical use.