Characterization of the central sympathoinhibitory action of ketanserin

The present study was designed to determine whether the central sympatholytic effects of ketanserin result from the ability of the drug to block serotonin2 or alpha-1 adrenergic receptors. Ketanserin produced a dose-related inhibition of sympathetic nerve discharge recorded from the inferior cardiac nerve in chloralose-anesthetized cats. Administration of a large dose of prazosin (1 mg/kg i.v.) decreased arterial blood pressure and inhibited sympathetic activity for several hours. Additional doses of prazosin failed to further inhibit sympathetic nerve discharge. Pretreatment with prazosin (1 mg/kg i.v.) also blocked the ability of ketanserin to inhibit sympathetic activity. Conversely, pretreatment with ketanserin blocked the central sympatholytic action of prazosin. In contrast, the alpha-2 adrenergic agonist clonidine inhibited sympathetic activity in animals pretreated with prazosin. The highly selective serotonin2 antagonist, LY 53857, failed to affect arterial blood pressure, heart rate or sympathetic activity recorded from the inferior cardiac nerve. These data, along with earlier results from our laboratory, provide strong evidence to indicate that ketanserin produces a centrally mediated inhibition of sympathetic nerve discharge as a result of the ability of the drug to block alpha-1 adrenergic receptors.     

Central sympathoinhibitory action of a new type of alpha-1 adrenoceptor antagonist, YM-617, in rats.

The structurally new type of alpha-1 adrenoceptor antagonist, YM-617 [R-(-)-5-[2-[(2-(o-ethoxyphenoxy)ethyl]amino)propyl]-2- methoxybenzenesulfonamide hydrochloride], is a phenethylamine derivative which is similar structurally to the catecholamines. The present study was undertaken to elucidate the effect of YM-617 on sympathetic nerve activity and baroreceptor afferent nerve activity in anesthetized rats. Intravenous administration of YM-617 (2, 10 and 50 micrograms/kg) produced a dose-dependent reduction in mean arterial pressure accompanied with bradycardia. YM-617 caused dose-dependent decreases in renal sympathetic nerve activity along with this hypotension. Cardiac sympathetic nerve activity, preganglionic adrenal nerve activity as well as aortic depressor nerve activity was decreased by YM-617. When an equihypotensive dose of YM-617 and a centrally acting antihypertensive drug, clonidine, were compared, the sympathoinhibitory potency of YM-617 was less than that of clonidine. These findings suggest that YM-617 might possess a central sympathoinhibitory action which could play a role in its antitachycardic or bradycardic effect and could be partially responsible for its hypotensive action.     

On the relationship between clonidine hypotension and brain beta-endorphin in the spontaneously hypertensive rat: studies with alpha adrenergic and opiate blockers

The relationship between the centrally mediated hypotensive and bradycardic effects of clonidine to central alpha-2 adrenergic receptor activation, brain beta-endorphin (BE) release and opiate receptor activation was studied in chloralose-anesthetized spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats, using a cerebroventricular perfusion system. Prior treatment of SHRs with i.v. naloxone (2 or 4 mg/kg) or i.c.v. yohimbine (10 or 20 micrograms/kg) reduced the hypotension and bradycardia induced by i.c.v. clonidine, but in Wistar-Kyoto rats naloxone had no similar blocking effects. Prazosin (20 micrograms/kg i.c.v.) reduced the clonidine bradycardia but not the hypotension in SHRs. Hypotension in the SHRs due to i.c.v. alpha-methylnorepinephrine (20 micrograms/kg) was reduced by both naloxone and yohimbine whereas alpha-methylnorepinephrine bradycardia was reduced by yohimbine but not by naloxone. Prior hypothalamic lesions in the SHRs reduced clonidine hypotension, but not bradycardia, and interfered with naloxone blockade of the residual clonidine hypotensive effect. Clonidine lowered immunoreactive BE levels in SHR hypothalamus, medulla and pituitary but did not change BE levels in the i.c.v. perfusate. The findings support the idea that in the SHRs, clonidine hypotension results from alpha-2 adrenergic stimulation of brain, causing BE release and central opiate receptor activation, and they suggest that the hypothalamus is involved in these interactions. Also, clonidine hypotension and bradycardia appear to involve different mechanisms in brain.     

Cardiovascular responses to cocaine are initially mediated by the central nervous system in rats.

Cocaine produces a pressor response reportedly resulting from both potentiation of peripheral catecholamine activity and a centrally mediated sympathoexcitation. In the present study we sought to differentiate the central nervous system and peripheral contributions to the hemodynamic effects of cocaine. In conscious rats, cocaine (5 mg/kg i.v.) produced a pressor response with two distinct components consisting of a brief, substantial increase in mean arterial pressure (MAP) associated with hindquarters and mesenteric vasoconstriction followed by a sustained, modest response associated with mesenteric vasoconstriction and bradycardia. Pentolinium (7.5 mg/kg i.v.) or adrenal demedullation attenuated the peak increase in MAP by attenuating increases in mesenteric and hindquarters vascular resistance, but did not affect the sustained increase in MAP. Methyl atropine (0.5 or 1 mg/kg i.v.) pretreatment reduced the cocaine-induced increase in systemic vascular resistance and enhanced the hindquarters vasodilation during the sustained MAP response. In contrast, adrenal demedullation abolished the hindquarters vasodilation. The bradycardic response was prevented by pentolinium and reduced by methyl atropine. Sympathetic nerve activity was reduced dramatically after cocaine or procaine administration for several minutes in conscious and in chloralose-anesthetized rats. In several anesthetized rats, the sympathoinhibition was preceded by a brief (3-8 sec) increase in renal sympathetic nerve activity. Procaine or cocaine produced little change in cortical cerebral blood flow as estimated by using a laser Doppler flowmeter. These data suggest that cocaine produces an initial, brief centrally mediated sympathoexcitation, but the sustained, modest pressor response is dependent upon peripheral actions that are diminished by baroreflex activation.     

Suppression of renal nerve activity by methionine enkephalin in anesthetized rabbits

Endogenous opioid peptides such as Met-enkephalin have diverse physiological actions, which include hypotension and bradycardia in anesthetized animals. The exact sites, the mechanism and the physiological significance of the cardiodepressant effects are not known. The main purpose of this work was to correlate the effect of Met-enkephalin on the rate of sympathetic nerve discharge with its cardiodepressant actions. Anesthetized male rabbits (2-3 kg) were instrumented for the measurement of blood pressure, heart rate, electrocardiogram and multiunit renal nerve activity (RNA). Intravenous administration of norepinephrine (15 micrograms/kg) or phenylephrine (50 micrograms/kg) produced a rapid increase in blood pressure followed by a reduction of RNA and heart rate. Met-enkephalin administered via the same route in doses of 1, 10, 100 and 1000 micrograms/kg initially decreased the RNA and subsequently reduced blood pressure. The above effects of Met-enkephalin were antagonized by naloxone (1 mg/kg i.v.) given 10 min before the peptide. Naloxone methobromide (1.3 mg/kg i.v.), a quaternary derivative of naloxone, did not block the effects of Met-enkephalin under identical conditions. These results suggest that the hypotensive effect of Met-enkephalin is secondary to its effects on sympathetic outflow. Lack of naloxone methobromide action is due to its inability to cross the blood-brain barrier and is consistent with a centrally mediated action of Met-enkephalin.     

Functional selectivity of nociceptin/orphanin FQ peptide receptor partial agonists on cardiovascular and renal function

The opioid-like peptide nociceptin/orphanin FQ (N/OFQ) produces marked cardiovascular and renal responses after central or peripheral administration in rats. Due to their ability to behave as full/partial agonists or antagonists in different cellular and tissue assays, the present studies were performed to determine how compounds classified as N/OFQ peptide (NOP) receptor partial agonists ([F/G]N/OFQ(1-13)-NH(2), Ac-RYYRIK-NH(2), and Ac-RYYRWK-NH(2)) affect cardiovascular and renal function in vivo. In conscious Sprague-Dawley rats, intracerebroventricular (i.c.v.) administration of each of the three NOP receptor ligands produced profound cardiovascular (depressor), renal excretory (water diuresis), and renal sympathetic nerve activity (inhibitory) responses that were similar to those produced by i.c.v. injection of the native ligand N/OFQ. In contrast, in other groups of rats, the intravenous (i.v.) bolus injection of these same NOP receptor ligands produced responses unlike N/OFQ; N/OFQ evoked an immediate and profound bradycardia and hypotension with no change in urine output, whereas all purported NOP receptor partial agonists elicited a subtle slow onset hypotension, no change in heart rate, and a marked water diuresis. In other studies, i.v. bolus pretreatment of rats with NOP receptor partial agonists prevented/attenuated the cardiovascular depressor effects produced by a subsequent i.v. bolus N/OFQ challenge without affecting the cardiovascular responses to i.c.v. N/OFQ. Together, these findings demonstrate that in conscious rats, NOP receptor partial agonists produce functionally selective effects on cardiovascular and renal function ranging from full agonist (i.c.v., cardiovascular depressor; i.c.v. and i.v., water diuresis), partial agonist (i.v., submaximal hypotension) to antagonist (i.v., blockade of N/OFQ-evoked bradycardia and hypotension) behavior.     

Naloxone-induced bradycardia in pithed rats: evidence for an interaction with the peripheral sympathetic nervous system and alpha-2 adrenoceptors.

Earlier experiments performed in this laboratory have demonstrated that naloxone infusion (1 mg/kg/min i.v.) into conscious rats results in a bradycardia that has a peripheral component, is dependent on a certain level of sympathetic activity and is sensitive to alpha adrenoceptor blockade (5 mg/kg of phentolamine i.v.). The main objective of this investigation was to examine the underlying mechanism(s) responsible for the peripherally mediated naloxone-induced bradycardia, and to test the hypothesis that naloxone interacts with peripheral inhibitory alpha adrenoceptors associated with depression of peripheral sympathetic activity. Naloxone infusion (1 mg/kg/min i.v.) in pithed rats, in the absence of sympathetic nerve activation, resulted in a bradycardia that could not be blocked by 1 mg/kg (i.v.) of atropine, 5 mg/kg (i.v.) of phentolamine, 0.1 mg/kg (i.v.) of prazosin or 0.5 mg/kg (i.v.) of rauwolscine. Isoproterenol or norepinephrine-induced tachycardia was not blocked by naloxone infusion, suggesting that naloxone does not antagonize the postjunctional activation of cardiac adrenoceptors to cause bradycardia. In the presence of sympathetic nerve activity, naloxone depresses neurogenic tachycardia. This effect was blocked completely by 5 mg/kg (i.v.) of phentolamine or 0.5 mg/kg (i.v.) of rauwolscine, but not 0.1 mg/kg (i.v.) of prazosin or 1 mg/kg (i.v.) of atropine. The results of this investigation suggest that the naloxone-induced bradycardia in pithed rats is mediated postjunctionally and prejunctionally, and that this prejunctional effect is dependent on sympathetic nerve activity and inhibitory alpha-2 adrenoceptors. Furthermore, these results confirm results obtained from conscious rats in an earlier investigation.     

Differentiated responses of renal and adrenal sympathetic nerve activity to intravenous morphine administration in anesthetized rats

The aim of this study was to examine the effect of i.v. morphine on sympathetic nerve activity (SNA) in the rat. Adrenal SNA and renal SNA were recorded simultaneously, together with mean arterial pressure and heart rate, in chloralose-anesthetized, artificially ventilated rats. Separate groups of rats were subjected to vagotomy. In intact rats, i.v. injection of morphine (1 mg/kg) caused an immediate transient depressor response. Within 1-3 sec, renal SNA was markedly inhibited in parallel with hypotension and bradycardia. After a few minutes, mean arterial pressure and renal SNA returned toward base-line levels, and subsequently they declined gradually again below base line. Adrenal SNA, however, showed an immediate brief increase. In the vagotomized rats, an extended renal SNA excitation occurred, accompanied by a rise in mean arterial pressure. After about 15 min, these variables returned toward base-line levels. The adrenal SNA excitation still occurred in the vagotomized rats. The renal depressor and the renal and adrenal pressor responses were all abolished by naloxone pretreatment. It is concluded that i.v. injection of morphine induces a highly differentiated response of SNA. A pronounced immediate increase in adrenal SNA occurs in parallel with renal SNA inhibition. The renal nerve inhibition is mainly reflexly obtained by opioid receptor-mediated activation of vagal afferents. The predominant central action of morphine seems to be sympathetic excitation which is also mediated through opioid receptors.     

Cocaine acts in the central nervous system to inhibit sympathetic neural activity

Cocaine was administered i.v. to decerebrate cats while monitoring cardiac preganglionic sympathetic nerve activity (SNA), arterial blood pressure (BP) and heart rate (HR). Cocaine, 4 mg/kg i.v., reduced SNA by 55 +/- 6%, but did not significantly affect BP or HR. Cocaine, in doses that were ineffective by the i.v. route, was administered into the vertebral artery and produced decreases in SNA, BP and HR in anesthetized cats. Administration of cocaine into the carotid artery was without effect. Topical administration of cocaine to the intermediate area of the ventrolateral medullary surface (25 micrograms/side) evoked hypotension and bradycardia. Nisoxetine, an inhibitor of norepinephrine uptake, applied bilaterally to the intermediate area (30 micrograms/side) exerted a similar hypotensive effect. Lidocaine administered in doses equivalent to those of cocaine had no significant effect on SNA when given i.v. or on BP when given into the vertebral artery. These results indicate that cocaine inhibits central sympathetic outflow and that the site of action appears to be in the hindbrain at a site that is reached by placement of the drug at the intermediate area of the ventrolateral medulla. The data also indicate that the mechanism of action of cocaine to inhibit sympathetic outflow may be unrelated to its local anesthetic action and may involve inhibition of catecholamine uptake in the ventrolateral medulla.     

Hemodynamic effects of systemic and central administration of alpha-methyldopa.

Systemic and regional hemodynamic changes were measured in five restained conscious rhesus monkeys before and after a 2-hour intravenous infusion of 50 mg/kg of alpha-methyldopa and, in another group of five monkeys, 5 to 10 mg injected into a lateral cerebral ventricle. Both routes of administration evoked similar degrees of hypotension, bradycardia and decreased cardiac output, although the cerebral intraventricular (i.c.v.) injections had more immediate and long-lasting effects. Both groups had a similar pattern of changes in the redistribution of cardiac output and blood flow that lasted at least 4 hours. Blood flow was maintained in the hepatic and renal arteries and decreased in skeletal muscle, heart, brain and skin. In contrast, i.c.v. injections of alpha-methyldopamine and alpha-methylnorepinephrine given at the same site evoked dose-related pressor responses that lasted up to 4 hours. The data suggest that alpha-methyldopa has important central action that inhibits sympathetic outflow, but that its hypotensive effect is either mediated only by endogenously formed metabolites or that its mechanism of action is not directly related to these metabolites at sites around the lateral and third cerebral ventricles in the monkey.     

Effect of clonidine on myocardial cyclic GMP content in the mouse-activation of central and peripheral alpha adrenoceptors

Clonidine (0.23-3.77 mumol/kg i.p.) produced a dose-dependent increase in mouse myocardial cyclic GMP (cGMP) content. This effect was antagonized by yohimbine (0.03-1 mg/kg i.p.), but not by prazosin (1 mg/kg i.p.). The inhibition by yohimbine was biphasic. The cGMP response to clonidine was inhibited by atropine (5 mg/kg i.p.) and methylatropine (0.2-5 mg/kg i.p.). In mice pretreated with the ganglionic blocker hexamethonium, the cGMP response to clonidine persisted. St-91 [(2,6-diethylphenylamino)-2-imidazoline] (0.39-3.94 mumol/kg i.p.), a cogener of clonidine which does not cross the blood-brain barrier, also increased myocardial cGMP content. The potency of clonidine was similar in mice pretreated and nonpretreated with hexamethonium. Methylatropine did not affect the cGMP response to St-91 and to clonidine in ganglionectomized mice and yohimbine was a less potent antagonist. These results indicate that systemic administration of clonidine produces an increase in myocardial cGMP content by both a central and a peripheral action. The increase in cGMP can be due to a direct activation of cardiac prejunctional alpha-2 adrenoceptors and to stimulation of cardiac muscarinic receptors, a response secondary to an action of clonidine on central alpha-2 adrenoceptors.     

Urethane inhibits cardiovascular responses mediated by the stimulation of alpha-2 adrenoceptors in the rat

Clonidine and oxymetazoline (4.0 microgram/kg i.v. or i.a.) evoked a marked bradycardia in either methylatropine-pretreated conscious or pentobarbital-anesthetized (55 mg/kg i.p.), vagotomized rats. Urethane (1.2 g/kg i.p.) inhibited by more than 50% this effect which is mediated through the stimulation of peripheral and/or central neuronal alpha-2 adrenoceptors. However, in adrenalectomized rats only the inhibition of oxymetazoline by urethane was significantly less pronounced. In pithed rats in which the adrenal glands were either left untouched or surgically removed, urethane significantly attenuated the clonidine or oxymetazoline-induced decreases in experimental neural sympathetic tachycardia although it neither changed the base-line nor the experimentally elevated heart rate. Urethane, in contrast to pentobarbital, increased plasma epinephrine concentrations in intact but not in adrenalectomized or in pithed rats. Elevation of plasma epinephrine did not result from the low arterial pressure level associated with urethane anesthesia since the increase of this parameter with vasopressin did not abolish the effect of urethane. Furthermore, guanethidine-pretreated rats, when anesthetized with urethane, exhibited a higher heart rate and plasma adrenaline value than those anesthetized with pentobarbital. The elevated heart rate was decreased by either propranolol or adrenalectomy. The bradycardia produced by injecting clonidine into the lateral cerebral ventricles of either intact or adrenalectomized rats was markedly less in urethane- than in pentobarbital-anesthetized animals. Whereas in pentobarbital-anesthetized rats the peak heart rate effects of i.v. or i.c.v. clonidine were similar, in urethane-anesthetized animals the effects of clonidine were more inhibited when it was given centrally than when it was given peripherally. In pithed rats, the cumulative dose-pressor response curves elicited by the relatively selective alpha-2 adrenoceptor agonists, B-HT 930 and M-7, were depressed by urethane significantly more than those produced by the relatively selective alpha-1 adrenoceptor agonists, phenylephrine and cirazoline, or by angiotensin II. Urethane also decreased the pressor responses evoked by clonidine, oxymetazoline and norepinephrine which stimulate both alpha-1 and alpha-2 adrenoceptors. However, the extent of this inhibition was less than that of B-HT 920 and M-7 but greater than that of cirazoline and phenylephrine. These results show that urethane inhibits cardiovascular responses that are mediated by peripheral and central alpha-2 adrenoceptors. Furthermore, urethane increases the central drive to the adrenal medulla and this leads to the secretion of epinephrine. This may be partly responsible for the inhibitory activity of urethane on oxymetazoline-induced bradycardia. Although the basic mechanism by which urethane impairs responses mediated by alpha-2 adrenoceptors remains to be determined, it is advised that urethane anesthesia should be avoided, particularly for cardiovascular studies.     

Mechanisms mediating the positive inotropic and chronotropic changes induced by dopexamine in the anesthetized dog

Mechanisms contributing to the increments in heart rate (HR) and cardiac contractile force (CCF) produced by dopexamine (DPX) were studied in anesthetized dogs. Intravenous infusions of DPX (4.0 micrograms/kg/min) produced increments in HR, CCF and renal blood flow and decrements in mean arterial pressure (MAP). The sequential administration of atenolol (0.5 mg/kg i.v.) administered at a dose selective for beta-1 adrenoceptors, propranolol (2.5 mg/kg i.v.) and the DA1 dopamine receptor antagonist, SCH 23390 (10 micrograms/kg i.v.) blocked the DPX-induced changes in HR, CCF, MAP and renal blood flow, respectively. After ganglionic blockade, the increments in HR and CCF produced by DPX (4.0 and 16.0 micrograms/kg i.v.) were reduced 90 and 76%, respectively, with little or no change in its hypotensive effect. In separate dogs, administration of the beta-2 adrenoceptor agonist salbutamol (0.55 microgram/kg i.v.) produced a comparable decrement in MAP but smaller increments in HR and CCF than produced by DPX (16.0 micrograms/kg i.v.). DPX (64 micrograms/kg i.v.) also produced greater increments in HR during cardioaccelerator nerve stimulation (1 Hz, 0.5 msec, supramaximal voltage) than before nerve stimulation. Therefore, we tested the effect of DPX (1.0, 4.0 and 8.0 micrograms/kg/min i.v.) on the increments in HR, CCF and MAP produced by norepinephrine (0.25 microgram/kg i.v.) and the indirect acting sympathomimetic amine, tyramine (60 micrograms/kg i.v.). DPX potentiated the increments in HR, CCF and MAP produced by norepinephrine and suppressed those produced by tyramine. Thus, the positive inotropic and chronotropic effects of DPX in the intact dog are due primarily to baroreceptor-mediated stimulation and inhibition of neuronal uptake of norepinephrine.     

Predominance of postsynaptic mechanism in vagal suppression of sympathetic tachycardia in the dog

The amplitude of reduction in heart rate induced by vagal stimulation is greater when the background level of sympathetic tone is increased (accentuated antagonism). Both pre- and postsynaptic muscarinic mechanisms have been proposed to account for this phenomenon. We attempted to clarify the relative importance of each mechanism by comparing the magnitude of vagal bradycardia during neurally induced tachycardia with that during nonneurally induced tachycardia in the anesthetized dog. Graded tachycardia was induced by raising the stimulus frequency of cardiac sympathetic nerve stimulation stepwise from 1 to 3 and 5 and 10 Hz, and it was also induced by norepinephrine infusion (0.3-10 micrograms/min into the right coronary artery), isoproterenol infusion (0.1 and 0.3 micrograms/kg/min i.v.) and glucagon injection (3-30 micrograms/kg i.v.). The magnitude of the bradycardia produced by vagal nerve stimulation at 3 Hz was determined during the resting state and during the tachycardic state produced by cardiac nerve stimulation and by drug administration. The magnitude of vagal bradycardia was greater during tachycardic state than during the resting state regardless of the means through which tachycardia was produced. Vagal bradycardia during norepinephrine or isoproterenol infusion was of the same magnitude as that during the cardiac sympathetic nerve stimulation when they were compared at the same heart rate. Vagal bradycardia during the glucagon-induced tachycardia was greater than that which occurred during sympathetic tachycardia. Temporary bradycardia resulting from a single-pulse vagal nerve stimulation was augmented markedly during the cardiac sympathetic nerve stimulation, whereas a 2-sec interruption of the cardiac sympathetic nerve stimulation did not alter the sustained tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological characterization of alpha adrenoceptors involved in the antinociceptive and cardiovascular effects of intrathecally administered clonidine

The effects on nociception, blood pressure and heart rate of clonidine administered intrathecally to the lumbar level were determined in conscious rats and in rats anesthetized lightly with pentobarbital. In anesthetized rats, intrathecal (i.t.) clonidine (3.2-32.0 micrograms) inhibited the nociceptive tail-flick reflex and had biphasic effects on blood pressure; lesser doses (1.0-10.0 micrograms) produced depressor effects, whereas a greater dose (32.0 micrograms) produced a marked pressor response. Clonidine also produced biphasic effects on blood pressure in conscious rats, with the dose-response function shifted upward and to the left of that observed in anesthetized rats. The depressor and antinociceptive effects of 3.2 micrograms of clonidine were antagonized by pretreatment with yohimbine (30.0 micrograms i.t.) but not by prazosin (30.0 micrograms i.t.) or by yohimbine (0.1 mg/kg i.v.). Thus, these effects of clonidine are mediated by spinal alpha-2 adrenoceptors. The pressor response to 32.0 micrograms of clonidine (i.t., lumbar) was accompanied by marked bradycardia, and similar cardiovascular effects were observed when this dose of clonidine was administered either i.v. or to the cervical level of the spinal cord. The pressor response to 32.0 micrograms of clonidine (i.t., lumbar) was not reduced significantly by i.t. pretreatment with yohimbine (30.0 micrograms) or prazosin (30.0 micrograms), but was diminished significantly by i.v. pretreatment with yohimbine (1.0 mg/kg), prazosin (0.1 mg/kg) or phentolamine (2.0 mg/kg). Neither chlorisondamine (2.5 mg/kg i.v.) or the V1-vasopressin receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(o-methyl)tyrosine]Arg8-vasopressin (10.0 micrograms/kg i.v.) reduced the clonidine-produced pressor response. After i.t. injection of 32.0 micrograms of [3H]clonidine, peak levels of radioactivity in the blood were observed at 2 min and corresponded to a blood concentration of 38.8 ng/ml. Injection of an i.v. bolus dose (2.5 micrograms/kg) sufficient to produce these blood levels resulted in a transient pressor response. These results suggest that after i.t. administration of greater doses of clonidine, sufficient amounts of the drug are rapidly redistributed systemically to produce pressor effects by stimulation of vascular alpha adrenoceptors.     

Central adenosine signaling plays a key role in centrally mediated hypotension in conscious aortic barodenervated rats

We tested the hypothesis that clonidine-evoked hypotension is dependent on central adenosinergic pathways. Five groups of male, conscious, aortic baroreceptor-denervated (ABD) rats received clonidine (10 microg/kg i.v.) 30 min after i.v. 1) saline, 2) theophylline (10 mg/kg), or 3) 8-(p-sulfophenyl)theophylline (8-SPT) (2.5 mg/kg) or 1 h after i.p. 4) dipyridamole (5 mg/kg) or 5) an equal volume of sesame oil. Blockade of central (theophylline) but not peripheral (8-SPT) adenosine receptors abolished clonidine hypotension. In contrast, dipyridamole substantially enhanced the bradycardic response to clonidine. In additional groups, intracisternal (i.c.) dipyridamole (150 microg) and 8-SPT (10 microg) enhanced and abolished, respectively, clonidine (0.6 microg i.c.)-evoked hypotension. Because clonidine is a mixed I1/alpha2 agonist, we also investigated whether adenosine signaling is linked to the I1 or the alpha2A receptor by administering the selective I1 (rilmenidine, 25 microg) or alpha2A [alpha-methylnorepinephrine (alpha-MNE), 4 microg] agonist 30 min after central adenosine receptor blockade (8-SPT; 10 microg i.c.) or artificial cerebrospinal fluid. The hypotensive response elicited by rilmenidine or alpha-MNE was abolished in 8-SPT-pretreated rats. To delineate the role of the adenosine A2A receptor in clonidine-evoked hypotension, i.c. clonidine (0.6 microg) was administered 30 min after central adenosine receptor A2A blockade [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-epsilon]-1,2,4-triazolo[1,5-c]-pyrimidine (SCH58261); 150 microg i.c.]. The latter virtually abolished the hypotensive and bradycardic responses elicited by clonidine. In conclusion, central adenosine A2A signaling plays a key role in clonidine-evoked hypotension in conscious aortic barodenervated rats.     

Central alpha-2 adrenoceptor-mediated hypertensive response to clonidine in conscious, normotensive rats

Possible involvement of central alpha-2 adrenoceptors in the hypertensive response to i.c.v. injected clonidine was investigated in free-moving, normotensive rats. Clonidine (2-50 micrograms) injected i.c.v. produced a dose-dependent and long-lasting pressor response associated with bradycardia in conscious rats, but a long-lasting depressor response in anesthetized rats. The pressor response to clonidine (20 micrograms i.c.v.) was antagonized in a dose-dependent manner by central (i.c.v.) pretreatment with yohimbine (20-100 micrograms) and was abolished by a high dose (100 micrograms), whereas the same dose of yohimbine injected i.v. had less effect on the response. Central pretreatment with prazosin (10 and 20 micrograms) inhibited, but did not abolish, the pressor response to clonidine. However, systemic (i.v.) pretreatment with the same dose of prazosin (10 and 20 mu) was more effective in reducing the clonidine-induced pressor response than central pretreatment with the drug. The pressor response to clonidine (20 micrograms i.c.v.) was not significantly modified by central pretreatment with pyrilamine (50 and 100 micrograms), cimetidine (50 and 100 micrograms), ketanserin (50 and 100 micrograms) or procaine (100 micrograms). The selective alpha-2 adrenoceptor agonist, BHT-920, injected i.c.v. (5-50 micrograms) also produced a dose-dependent pressor response which was abolished by either anesthesia or central pretreatment with yohimbine, but not with prazosin, whereas the selective alpha-1 adrenoceptor agonist, methoxamine (10-100 micrograms i.c.v.), caused a slight increase in mean blood pressure only at higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Picrotoxin- and bicuculline-sensitive inhibition of cardiac vagal reflexes.

Transmission in the cardiac vagal reflex pathway can be inhibited by stimulation of the hypothalamic defense region or somatic afferent nerves. A pharmacological analysis of inhibitory modulation of reflex vagal bradycardia was undertaken in the present study. Picrotoxin (0.5--1.5 mg/kg i.v.) or bicuculline (0.5--1.5 mg/kg i.v.) produced a dose-related blockade of inhibition of reflex vagal bradycardia elicited by stimulation of the lateral hypothalamus or branches of the brachial plexus in spinal (C1 or C8 transected) cats. In contrast, strychnine and pentylenetetrazol failed to change the heart rate responses produced by stimulation of the hypothalamus or brachial plexus afferents. Picrotoxin and bicuculline also blocked inhibition of reflex vagal bradycardia produced by stimulation of the inferior olive in decerebrate spinal cats. This observation supports the contention that these agents act in the brain stem to block inhibitory modulation of reflex vagal bradycardia. In addition, picrotoxin and bicuculline lowered basal heart rate in spinal cats but not in decerebrate spinal cats. This observation suggests that tonic suprabulbar inhibition of reflex vagal bradycardia also is sensitive to blockade by picrotoxin and bicuculline.     

Intrathecal administration of a substance P receptor antagonist: studies on peripheral and central nervous system hemodynamics and on specificity of action

Regional central nervous system and peripheral hemodynamic effects of the intrathecal (i.t.) administration of a substance P (SP) receptor antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P ([D-Arg]-SP), were studied in anesthetized rats. It was found that [D-Arg]-SP (3.3 nmol i.t.) reduced mean arterial pressure and cardiac output due to a reduction in stroke volume. Total peripheral resistance was not altered. Whereas most vascular beds showed no alterations in vascular resistance, a renal vasoconstriction was noted. The hypotensive effect of [D-Arg]-SP was blocked by phentolamine (10 mg/kg i.v.) but not by propranolol (1 mg/kg i.v.). In the absence of changes in vascular arterial resistance due to [D-Arg]-SP, it appears that a change in venous return may contribute to the [D-Arg]-SP-induced reduction in stroke volume. These data provide evidence that a spinal cord SP system may tonically affect sympathetic neurons controlling venous, but not arterial, vasomotor tone. [D-Arg]-SP (i.t.) did not alter brain blood flow but significantly decreased blood flow in the thoracolumbar spinal cord 15 to 20 min after administration. The reduction in spinal cord flow did not appear to be responsible for the [D-Arg]-SP-induced hypotension because kainic acid (i.t.), an agent that interacts with glutamate receptors, produced similar pressor responses in the presence and absence of [D-Arg]-SP. In addition, whereas the pressor effect of low doses of a SP agonist [pGlu5, MePhe8, MeGly9]-substance P (5-11) were blocked by [D-Arg]-SP, a higher dose produced the typical pressor effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of respiratory neural discharges by clonidine and 5-hydroxytryptophan

Activation of receptors for norepinephrine or serotonin in the central nervous system by i.v. injection of clonidine (10-50 micrograms/kg) or 5-hydroxytryptophan (20-40 mg/kg) inhibits phrenic neural discharges in anesthetized, artificially ventilated cats. Clonidine induces a rapid and complete inhibition of phrenic nerve activity which lasts for 1 to 3.2 hr. The inhibition is prevented by prior administration of phenoxybenzamine (10 mg/kg) or tolazoline (3 mg/kg). 5-Hydroxytryptophan, injected after inhibition of peripheral amino acid decarboxylase (carbidopa, 30-50 mg/kg), elicits a gradual but complete inhibition of phrenic nerve discharges which persists for 1 to 10 hr and is unaltered by alpha or beta adrenoceptor blocking agents. The inhibitions produced by clonidine and 5-hydroxytryptophan are overcome transiently during hypercapnia. Stimulation of carotid body chemoreceptors by i.a. injections of lobeline, doxapram or 0.015 N HCl in saline also briefly reinstates phrenic nerve discharges after inhibition by clonidine. Inhibition is also overcome during electrical stimulation of the carotid sinus nerve.