Upregulation of imidazoline receptors in the medulla oblongata accounts for the enhanced hypotensive effect of clonidine in aortic barodenervated rats

The present study tested the hypothesis that an upregulation of the imidazoline receptor in the rostral ventrolateral medulla (RVLM) of aortic barodenervated (ABD) rats may account for the enhanced hypotensive effect of clonidine. In vitro autoradiographic radioligand binding studies were utilized to investigate the binding characteristics of imidazoline receptors in the RVLM and nucleus tractus solitarius (NTS), areas that play critical roles in cardiovascular regulation and elicitation of clonidine responses. ABD but not sham operation (SO) caused immediate and significant (P < 0.05) increases in mean arterial pressure (MAP) and heart rate (HR) and an impairment of the baroreflex-mediated HR response (baroreflex sensitivity, BRS). Two days after ABD, these parameters, except BRS, subsided to near-control (SO) levels. Intracisternal (i.c.) administration of clonidine (0.1 micrograms) elicited a 3-fold greater decrease in BP of conscious ABD compared with SO rats (-20.3 +/- 2.6 vs. -7.4 +/- 0.9 mmHg) thus demonstrating the ability of ABD to enhance centrally-mediated hypotensive responses. Autoradiographic visualization of brain sections obtained from separate groups of ABD and SO rats 48 h after surgery preincubated with [3H]idazoxan (2.5-3.5 nM) showed that [3H]idazoxan binding in RVLM, middle NTM (mNTS) and rostral NTS (rNTS) was saturable and of high affinity. Uneven distribution of imidazoline binding sites was evident since in control (SO) rats, Scatchard analysis of binding data revealed similar densities (Bmax) of [3H]idazoxan binding sites in the RVLM and mNTS versus significantly higher density in the rNTS. In ABD rats, the binding dissociation constant (Kd) was significantly decreased in both the RVLM (8.1 +/- 3.1 vs. 21.4 +/- 5.0 nM) and rNTS (12.3 +/- 1.3 vs. 18.6 +/- 3.1 nM) compared with SO rats while the Bmax was not affected. This finding suggests an increased receptor affinity in the RVLM and rNTS of barodenervated rats. The mNTS of ABD rats exhibited significant increases in the Bmax (861 +/- 96 vs. 570 +/- 87 fmol/mg protein) compared with values of SO rats but the receptor affinity was not affected. It is concluded that: (i) aortic baroreceptors exert a tonic inhibitory influence on central imidazoline receptor function; and (ii) the enhanced hypotensive effect of clonidine in conscious ABD rats may be accounted for by the increased affinity of the medullary imidazoline receptors particularly in the RVLM.     

Action of clonidine on the baroreceptor pathway and medullary sites mediating vagal bradycardia

In anaesthetized dogs, clonidine (10 mug/kg i.v.) increased the spontaneous firing of the carotid sinus nerve and decreased blood pressure and heart rate. After transection of the spinal cord, clonidine decreased heart rate and this bradycardia was abolished by selective baroreceptor denervation. Clonidine (1 mug/kg) injected into the vertebral artery of anaesthetized dogs, pretreated with a beta-adrenoceptor blocking agent (S 2395: 50 mug/kg i.v.) potentiated the bradycardia induced by stimulation of the carotid sinus nerve but did not change the hypotension and bradycardia produced by stimulation of the nucleus tractus solitarius or of the nucleus ambiguus. In anaesthetized cats with bilateral destruction of nuclei tractus solitarii, clonidine (10 mug/kg i.v.) decreased blood pressure and heart rate. Clonidine (2 mug/kg), injected into the vertebral artery of anaesthetized dogs pretreated with a beta-adrenergic blocking agent (S 2395: 50 mug/kg i.v.) or guanethidine, induced a bradycardia but the discharges of the carotid sinus nerve were not increased. Selective baroreceptor denervation abolished this bradycardia. In conclusion, these experiments provide direct evidence that the central facilitory effect of clonidine on baroreceptor impulses play a role in the bradycardic effect of the drug. This facilitation is likely localized in the nucleus tractus solitarius at the first synapse of baroreceptor fibres. The vagally mediated bradycardia can be explained by an increase in baroreceptor discharges and by the central facilitation of baroreceptor impulses. The site of the hypotensive effect of clonidine did not seem to be localized in the nucleus tractus solitarius.     

Polymorphisms in the human CC chemokine receptor-3 gene

In the present study we investigated the chronopharmacological dependence of dose-dependent hypotensive and cardiochronotropic effects of the imidazoline-like drugs (clonidine, rilmenidine and moxonidine) in stroke-prone spontaneously hypertensive rats (SHR-SP), using radio-telemetric system (Data Sciences, USA). The 24-h blood pressure, heart rate and locomotor activity profiles showed peak values during the rats' active phase during the night period. The degree of hypotensive and bradycardic effects of all drugs were most evident at this time and occurred in the absence of a change in locomotor activity. These studies show that clonidine, rilmenidine and moxonidine decrease blood pressure and heart rate in a time-dependent manner in SHR-SP. It was demonstrated that the degree and duration of hypotensive action of imidazoline-like drugs vary with the time of drug administration.     

On the mechanism of central hypotensive action of clonidine

The hypotensive effect of clonidine in anaesthetised (pentobarbitone) cat has been analysed with the help of pharmacological tools. Application of clonidine (0.1%) to the exposed ventral surface of medulla oblongata produced hypotension (28.6%) and bradycardia (18%). Similar application of glycine (5%) and GABA (10%) also lowered the blood pressure of cat by 20.3% and 29.3%, respectively. The hypotension as well as the bradycardia owing to clonidine were significantly (p less than 0.01) blocked by similar prior application of atropine methylnitrate (1%) and hemicholinium-3 (HC3, 1%), whereas HC3 pretreatment only insignificantly blocked the hypotension produced by glycine (p greater than 0.80) and GABA (p less than 0.70). Topical application of atropine (1%) also blocked (p less than 0.05) the hypotensive effect of clonidine. Intravenous administration of clonidine (50 microgram/kg) produced hypotension (34.6%) after an initial hypertensive response and bradycardia (38.8%). The hypotension was significantly (p less than 0.01) blocked by pretreatment of the cat with intracerebroventricular atropine (4 mg) or HC3 (0.5 mg). Topical application of atropine (1%) to the ventral surface of medulla also significantly (p less than 0.05) reduced the hypotension and bradycardia resulting from intravenous administration of clonidine. It is concluded that an intact cholinergic link in the brainstem is essential for the hypotensive effect of clonidine.     

Influence of application site of a new transdermal clonidine, M-5041T, on its pharmacokinetics and pharmacodynamics in healthy subjects

Influence of application site of a new transdermal clonidine, M-5041T(M), on its pharmacokinetics and pharmacodynamics were evaluated in eight human subjects. One patch of M-6 mg was applied for 3 days on the right chest (first trial), on the left arm (second trial), and on the upper abdomen (third trial). Blood samples for clonidine concentration were taken, and blood pressure (BP) was measured for a 120-hour postapplication period. Plasma concentrations of clonidine increased after application of M in each trial. This parameter in the second trial was significantly greater than that of the first and third trials. The values of maximum plasma concentration and area under the plasma concentration-time curve in the second trial were greater than those of other trials, but the differences did not reach significance. The BP-lowering effect of M in the second trial was significantly greater than that of the third trial. These results suggest that the plasma concentrations of clonidine after application of M and its hypotensive effect are affected by the site of application in human subjects.     

Does a second generation of centrally acting antihypertensive drugs really exist?

The site of the hypotensive action of imidazoline compounds, such as clonidine, was first identified within the rostroventrolateral part of the brainstem: the nucleus reticularis lateralis. After that, it was shown that imidazolines and related substances reduced blood pressure when applied in this area whereas catecholamines were not capable of producing such an effect. These data led us to suggest the existence of receptors specific for imidazoline-like compounds different from the alpha2-adrenoceptors. Soon after, the existence of imidazoline binding sites was reported in the brain and in a variety of peripheral tissues including the human kidney. As expected, these specific binding sites do not bind the catecholamines. The imidazoline binding sites are already subclassified in two groups: the I1-subtype sensitive to clonidine and idazoxan, and the I2-subtype, sensitive to idazoxan and nearly insensitive to clonidine. Functional studies confirmed that the hypotensive effects of clonidine-like drugs involved imidazoline receptors while their most frequent side effects only involved alpha2-adrenoceptors. However, recent functional evidence suggests that a cross talk between imidazoline receptors and alpha2-adrenoceptors is necessary to trigger a hypotensive effect within the ventral brainstem. Rilmenidine and Moxonidine are the leader compounds of a new class of antihypertensive drugs selective for imidazoline receptors. At hypotensive doses, these drugs are devoid of significant sedative effect. Rilmenidine evoked hypotension when injected within the nucleus reticularis lateralis region; it competed for [3H]-clonidine bound to specific imidazoline binding sites in human medullary membrane preparations but proved more selective for cerebral imidazoline receptors than clonidine. It is suggested that this selectivity might explain the low incidence of their side effects. Additional potentially beneficial actions on cardiac arrhythmias or congestive heart failure enlarge the therapeutic interest of imidazoline-related drugs. Recent binding and functional data throw a new light on the optimal pharmacological profile of this second generation of centrally acting antihypertensive drugs.     

Participation of annexins in protein phosphorylation

Vladimir Zinovievich Gorkin's theory of the transformation of catalytic activity of amine oxidases and, therweby, selectivity of amine oxidases, carried over from my personal acquaintance with Vladimir Zinovievich, significantly influenced our studies into the mechanism of MAO-induced stimulation of pineal melatonin biosynthesis from serotonin. We found that this effect depended on the selective inhibition of MAO-A, but not MAO-B, which resulted in the increased formation of N-acetylserotonin (N-AS), the intermediate precursor of melatonin. The hypotensive effect of clorgyline was attenuated by pinealectomy, suggesting that increased N-AS and/or production might contribute to the hypotensive effect of selective MAO-A inhibition. Basal and isoproterenol-induced pineal levels of N-AS, but not melatonin, were lower in 12 week old (hypertensive) than in 4 week old (normotensive) spontaneously hypertensive (SHR) rats. N-AS decreased blood pressure in 12 week old SHR rats. The hypotensive effect of N-AS was augmented by pinealectome and by pretreatment with the S-adenosylhomocysteine, the inhibitor of N-AS conversion into melatonin. Our data demonstrate that hypotensive effect of N-AS is independent of its conversion to melatonin. We suggest that hypotensive effect of selective MAO-A inhibition might depend on the increased formation of N-AS, but not melatonin. The age-associated decrease in N-AS production may contribute to the developing of hypertension in SHR rats, and the age-associated increase of blood pressure in humans. Our data warrant the clinical trial of N-AS for the treatment of essential hypertension.     

Physiological changes in brushtail possums, Trichosurus vulpecula, transferred from the wild to captivity

The goal of the present study was to examine the interaction of cholecystokinin (CCK-33) and its fragments: C-terminal octapeptide (CCK-8) and C-terminal tetrapeptide (CCK-4) with alpha- and beta-adrenoceptor agonists and antagonists. The effect of this interaction on arterial blood pressure and function of isolated heart was studied in rats. The results indicate that: 1) CCK-33 enhances the influence of catecholamines: noradrenaline and isoprenaline, mainly on the function of isolated heart. This peptide does not change cardiovascular effects of alpha-adrenoceptor antagonist--phentolamine. CCK-33 diminishes the influence of propranolol on the function of isolated heart. The hypotensive effect of beta-adrenoceptor antagonist is not affected by CCK-33. 2) CCK-8 does not alter cardiovascular effects of noradrenaline and isoprenaline. The peptide diminishes the hypotensive effect of phentolamine and reverses the hypotensive effect of propranolol. CCK-8 enhances the influence of propranolol and does not change the influence of phentolamine on the function of isolated heart. CCK-8 enhances bradycardia evoked by propranolol. 3) CCK-4 does not change the influence of noradrenaline and isoprenaline on arterial blood pressure and diminishes the hypotensive effect of phentolamine and propranolol. The peptide does not change cardiac effects of noradrenaline and diminishes the effects of isoprenaline, phentolamine and propranolol. On the basis of the present study, we concluded that CCK-33 and its fragments CCK-8 and CCK-4 modify the cardiovascular action of alpha- and beta-adrenoceptor agonists and antagonists. We suggest that effects we have observed correlate with the activation of the CCK-A receptors (CCK-33, CCK-8) or CCK-B receptors (CCK-4). CCK-related peptides may increase or reduce the effects of catecholamines indirectly through activation of alpha-adrenoceptors. We can not exclude direct action of the peptides on the heart.     

A study on prevalence of resistance to antituberculosis drugs in Japan: comparison of results in the local facilities and in the reference laboratory

These experiments compare the effects of a neutral endopeptidase inhibitor, retrothiorphan, 1-[(1-mercaptomethyl-2-phenyl)ethyl]amino-1-oxopropanoic acid, a converting enzyme inhibitor, enalaprilat, and the combination of the two inhibitors on changes in blood pressure and renal function induced by exogenous and endogenous bradykinin in deoxycorticosterone acetate (DOCA)-salt rats. Enalaprilat potentiated the exogenous bradykinin-induced hypotensive responses while retrothiorphan potentiated the effects on urinary cyclic-GMP (cGMP) and bradykinin. The combination potentiated the exogenous bradykinin-induced hypotensive effects and the bradykinin-induced urinary excretion of cGMP, bradykinin and prostaglandin. The bradykinin B2 receptor antagonist, Hoe 140, had no effect on the enalaprilat- and retrothiorphan-induced changes in blood pressure and renal function. In conclusion, while angiotensin-converting enzyme and neutral endopeptidase are involved in the vascular and renal catabolism of exogenous bradykinin, the effects of the peptidase inhibitors do not appear to depend on the protection of endogenous bradykinin under acute conditions in DOCA-salt rats.     

Stress and neurosteroids in adult and aged rats

The progesterone derivative 3 alpha-hydroxy-5 alpha-pregnan-20 one (allopregnanolone/AP) and the deoxycorticosterone derivative 3 alpha-21-dihydroxy-5 alpha- pregnan-20 one (allotetra-hydrodeoxycorticosterone/THDOC) are endogenous neuroactive steroids endowed with neuromodulatory actions in the central nervous system. Their best-characterized membrane-receptor-dependent action consists in the amplification of GABA-gated chloride currents mediated by specific interactions with the GABAA receptor complex, which appears responsible for the pharmacological effects (anxiolytic, anticonvulsant, hypnotic/anaesthetic) of exogenously administered AP and THDOC. Several acute stress paradigms and different negative allosteric modulators (isoniazid and FG 7142) of GABAA receptors time dependently increase brain and plasma concentrations of AP and THDOC only in intact or sham-operated but not in adrenalectomized-orchiectomized rats. These results suggest that acute stress and inhibitors of GABAA receptors increase the brain and plasma neurosteroid concentrations via a reduction of the inhibitory action exerted by GABA on the hypothalamic-pituitary-adrenal axis. The comparison between the time course of the changes in GABAA receptor function and of their behavioral correlates (proconflict behavior) and that of the changes of endogenous neuroactive steroids are consistent with the view that AP and THDOC may play a role in restoring the GABAergic tone to prestress conditions, by limiting the duration and the extent of its stress-induced reduction. The acute stress-elicited increase of AP and THDOC is observed in adult as well as in aged rats, which show a reduced basal GABAergic transmission and a greater response to the effect of stress in terms of their brain cortical neuroactive steroid concentrations than adult rats.     

Effect of modulators of protein tyrosine kinase activity on gender-related differences in vascular reactivity at reduced temperature

We used the isolated-muscle-bath technique to examine the effect of protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) inhibitors on the response of rings of tail artery from male and female rats to cooling and reduced temperature in the absence and presence of two PTK-dependent (clonidine and serotonin) and one PTK-independent (phenylephrine, PE) agonists. At 37 degrees C, reactivity to clonidine, serotonin, and PE was the same in tail artery from female and male rats. At 25 degrees C, reactivity to clonidine and serotonin, but not PE, was greater in tail artery from female rats compared with those from male rats. Sodium orthovanadate (SOV) eliminated the gender-related difference in the contractile effect of clonidine and serotonin at 25 degrees C. The sensitivity to relaxation by genistein was considerably greater for clonidine and serotonin at both temperatures as compared with PE. At 25 degrees C the sensitivity to genistein was greater for the clonidine and serotonin-contracted rings from female rats. In the presence of SOV, temperature reduction led to contraction of rat-tail artery. This effect was greater in rings from female rats. Our results strongly implicate differences in the activity of the PTK transduction pathway as the cause of the observed gender-related differences in agonist-mediated contraction at 25 degrees C and in cold-induced vasoconstriction.     

Pathophysiological response of the blood coagulation system in acute glomerulonephritis

1. The effects of clonidine on blood pressure, cerebral norepinephrine content and vascular structures of the kidneys were investigated in 21 SHR. Although the body weight was not affected by long term clonidine treatment up to 36 weeks, the syatolic blood pressure was significantly reduced. The reduction of the blood pressure was already obvious after 1 week administration of clonidine but the effect was more prominent after long term treatment of 30 weeks or longer. 2. The cerebral norepinephrine content was significantly lower in SHR, regardless of with or without clonidine treatment, than in the control Wistar rats. Although the cerebral norepinephrine content was slightly increased following clonidine treatment SHR, the increase was not statistically significant. 3. Angiographic study of the kidneys revealed a poor opacification of the blood vessels and glomeruli in SHR compared with the control Wistar rats. There was no difference in the sizes of the arcuate and interlobular arteries in SHR and the control Wistar rats, although the medial muscular hypertrophy of the arteries was slightly more prominent in the SHR histologically. The more prominent in the SHR histologically. The angiographic and histologic findings of the renal arteries were not altered following long term clonidine treatment. A possibility was considered that the renal arterioles are mainly functionally affected in SHR.     

Drug effects on intraocular pressure and vascular flow in the bovine perfused eye using radiolabelled microspheres

A novel technique is described in which the effect of the beta-adrenoceptor antagonists timolol and carteolol, and the vasodilators sodium nitroprusside (SNP) and verapamil on intraocular pressure (IOP) and the distribution of ocular flow in the bovine arterially perfused eye is investigated using radiolabelled microspheres. At maximum IOP-reducing dose timolol was found to significantly reduce perfusion in the choroid and, at higher dose, it was found to significantly reduce perfusion in the iris. By contrast, a maximal IOP-reducing dose of carteolol markedly reduced perfusion in the iris, ciliary body and choroid. Vasoconstriction induced by carteolol was not inhibited by the alpha-antagonist phentolamine. Against a background of vascular tone induced by noradrenaline, SNP and verapamil were found to significantly increase perfusion in the iris, ciliary body and choroid. The effects of these drugs upon the vasculature of the bovine perfused eye are varied and complex and may not bear a direct relationship to their ocular hypotensive effect.     

Patterns of amino acid variability in NSI-like and SI-like V3 sequences and a linked change in the CD4-binding domain of the HIV-1 Env protein

We used intracellular recording techniques to investigate the actions of clonidine on hypoglossal motoneurons (HMs) in rat brainstem slices. Clonidine (10-100 microM) produced a small (2-6 mV), dose-dependent hyperpolarization in HMs, accompanied by an increase in peak input resistance (RN). It also slowed the time course of the depolarizing 'sag' of the voltage response to constant hyperpolarizing current steps. These effects were mimicked by the alpha2-adrenoceptor (alpha2-AR) agonist guanabenz, but not by the Ih-imidazoline receptor agonists moxonidine or rilmenidine. Recorded in single-electrode voltage clamp mode, clonidine decreased input conductance of HMs and reduced the amplitude of a hyperpolarization-activated inward current (Ih). Clonidine's effect on Ih was three-fold: it shifted the half-activation voltage (V1/2) in the hyperpolarizing direction (by 4.4 +/- 0.7 mV at a dose of 10 microM), decreased the maximal current (by approximately 20%), and slowed the time course of Ih activation at all voltage steps. At the most hyperpolarized potential steps, clonidine slowed activation of Ih dramatically, yielding a striking increase in the activation time constant. The alpha2-AR antagonists yohimbine and idazoxan reduced clonidine's effect on V1/2 and on the Ih activation time course, but neither blocked clonidine's reduction of the maximal current, nor its strong slowing of Ih activation at the most hyperpolarized steps. We were unable to mimic or occlude clonidine's actions with the adenylate cyclase inhibitor SQ 22536 nor with the non-specific protein kinase inhibitor H-7. We conclude that clonidine hyperpolarizes HMs via a reduction of the amount of Ih that is active at rest, and that the response is mediated in part by alpha2-ARs. Some effects of clonidine on these neurons do not appear to be receptor-mediated, and may be due to physical block by clonidine of Ih channels.     

Clonidine and methohexital-induced epileptic magnetoencephalographic discharges in patients with focal epilepsies

PURPOSE: During presurgical evaluation, 14 patients with medically intractable focal epilepsies underwent magnetoencephalographic (MEG) recordings for focus localization. To increase the number of epileptic discharges required for MEG analysis, we administered methohexital (MHT), a short-acting barbiturate known to provoke epileptic activity. We also investigated the spike-provoking properties of clonidine in comparison with MHT. METHODS: Patients were briefly anesthetized with intravenously administered MHT after being premedicated orally with clonidine. Numbers and locations of epileptic MEG discharges were assessed after clonidine premedication as well as during MHT anesthesia. Results were compared with baseline MEG recordings. RESULTS: MHT increased the frequency of focal epileptic discharges in 8 of 13 patients ( of the 14 patients did not receive MHT after premedication with clonidine). Premedication with clonidine also increased focal epileptic discharges in 9 of 14 patients. The numbers of epileptic signals and numbers of spikes contributing to MEG source localizations were significantly increased in MEG recordings under both treatment conditions (clonidine premedication and MHT anesthesia) as compared with baseline MEG recordings. CONCLUSIONS: Our results confirmed the selective proconvulsive effects of MHT on the epileptic focus, as previously suggested by EEG and electrocorticographic (ECoG) investigations. However, our present data establish for the first time that clonidine increases epileptic activity in patients with seizure disorders and indicate that clonidine is suitable as an activating agent for localization of epileptogenic foci by MEG. This effect of clonidine on specific epileptic activity also indicates that specific care must be taken when clonidine is used as an antihypertensive drug in patients with seizure disorders.     

Gas-liquid chromatographic determination of clonidine and some analogues in rat brain tissue. Brain concentrations and hypotensive activity

A simple and sensitive gas-liquid chromatographic method has been developed for the quantitative determination of clonidine and some structurally related imidazolidines in rat brain tissue. The aqueous brain homogenates are first purified and then extracted into benzene. Samples are injected directly into the gas chromatograph. The extraction procedure is selective, and the use of a phosphorus-nitrogen detector enables accurate determinations corresponding to brain concentrations down to at least 10ng/g. The rat brain concentrations of clonidine and its derivatives achieved at the moment of maximal decrease in arterial pressure are proportional to the doses administered intravenously, and are not influenced by the effect of the compounds on the blood pressure or by the method of anaesthesia employed. It is concluded that, for the linear part of the dose-response curves for these compounds, the brain concentration is a measure of the hypotensive effect.     

Differences in the behavioral profile of circling under amphetamine and apomorphine in rats with unilateral lesions of the substantia nigra.

In rats with severe depletion of striatal dopamine, produced by a unilateral injection of 6-hydroxydopamine into the substantia nigra, amphetamine (AM) induces circling toward the side of the lesion and apomorphine (AP) induces circling in the opposite direction. In Exp I we showed that under AP, circling may be related to an asymmetry in stepping, but under AM it is not. Under AP, rats rotate almost exclusively by stepping (backwards) with the contralateral hindlimb while pivoting on the ipsilateral hindlimb. Under AM, they rotate using a variety of stepping patterns, and there is no consistent asymmetry in using one hindleg for stepping and the other one for bearing weight. Rotations induced by AP and AM involve at least one and two variables, respectively (turning and turning plus forward progression). Exp II revealed that under AP the direction of circling in a pool of water is reversed by edges, but under AM it is not. Under AP, rats swim in the contraversive direction when in the middle of the pool but in the ipsiversive direction when swimming along the edge of the pool. Under AM, they show little attraction for the edge and continue swimming in the ipsiversive direction, regardless of their position in the pool. Different behavioral mechanisms may underlie the rotations induced by AP and AM. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparative effects of central administration of naloxone and clonidine on the blood pressure and heart rate response to anterior and posterior hypothalamic stimulation

The purpose of this study was to examine the roles of brain opioid receptors, using the opioid receptor antagonist naloxone, and brain alpha 2 adrenergic and imidazole receptors, using their agonist clonidine, in the hypertension and tachycardia induced by electrical stimulation of the AHA and PHA area. Unanesthetized and unrestrained Wistar rats 300-400 g that had previously had catheters inserted into the lateral cerebral ventricle and femoral artery and electrodes in AHA or PHA areas received intracerebral (ICV) administration of naloxone or clonidine prior to hypothalamic stimulation. AHA and PHA stimulation with current strength from 0.5 to 2.0 mA produced a significant (p < 0.05) and dose dependent increase in BP and heart rate. Naloxone reduced the increase in BP with AHA stimulation at all but the highest stimulation current intensity. Clonidine also blunted the BP increase to AHA stimulation but to a lesser degree than naloxone. The combination of both naloxone and clonidine completely prevented the increase in BP even at high current intensities. Both naloxone and clonidine prevented the increase in heart rate with AHA stimulation. In contrast to AHA stimulation, naloxone did not alter the BP increase produced by PHA stimulation while clonidine prevented the effects of PHA stimulation. Heart rate did not increase with PHA stimulation. These data suggest that (i) the mechanisms involved in the hypertensive response to AHA are different from that of PHA. (ii) the endogenous opioid system is more operative in mediating the BP elevation produced by AHA but not PHA stimulation (iii) activation of the central alpha adrenergic or imidazole receptors can suppress hypertensive response to both AHA and PHA but is more effective for PHA than AHA stimulation.     

Enhancement of pressor response to intravenous phenylephrine following oral clonidine medication in awake and anaesthetized patients

Clonidine, an alpha 2-adrenergic agonist, augments the pressor response to intravenous ephedrine. If this effect is partly due to clonidine-induced potentiation of alpha 1-adrenoceptor-mediated vasoconstriction, it is also assumed that clonidine would enhance the pressor effect of phenylephrine as an alpha 1-adrenergic agonist. The authors studied haemodynamic responses to intravenous phenylephrine in 80 patients who received either preanaesthetic medication with clonidine approximately 5 micrograms.kg-1 po (clonidine group, n = 40), or no medication (control group, n = 40). Each group was further divided into either awake subjects (n = 20) or subjects anaesthetized with enflurane and nitrous oxide in oxygen (n = 20). Haemodynamic measurements were made at one-minute intervals for ten minutes after phenylephrine 2 micrograms.kg-1 iv was injected as a bolus. The magnitudes of maximal mean blood pressure increases in the clonidine group (26 +/- 7% (mean +/- SD) for awake and 32 +/- 15% for anaesthetized subjects) were greater (P < 0.05) than in the control group (13 +/- 7% for awake and 18 +/- 7% for anaesthetized subjects). However, there was no difference in the pressor effect of phenylephrine between awake and anaesthetized patients in both groups. Oral clonidine preanaesthetic medication, 5 micrograms.kg-1, augments the pressor responses to phenylephrine 2 micrograms.kg-1 iv in awake and anaesthetized patients. These results suggest that the enhancement of the pressor responses to phenylephrine following oral clonidine may be due to clonidine-induced potentiation of alpha 1-adrenoceptor-mediated vasoconstriction. This implies that restoration of blood pressure can be achieved effectively by phenylephrine in hypotensive patients with clonidine premedication.     

Some problems in giving notice of the name of a disease: with special reference to Alzheimer''s disease and vascular dementia

Tetramethylpyrazine (TMP) is a compound purified from a medicinal plant Ligusticum wallichii Franch. Its effects on in vivo blood pressure, in vitro vascular contractility, and intracellular calcium regulation in rats were examined in the present study to see if it was a possible calcium antagonist in the vascular tissue. Data showed that TMP was hypotensive and had a direct vascular effect. It not only blocked the entry of extracellular calcium through calcium channels but also inhibited the release of intracellular stored calcium in the vascular smooth muscle cell. It was a true calcium antagonist.