Pressor effect of centrally administered neuropeptide Y in rats: role of sympathetic nervous system and vasopressin

The haemodynamic effects of intracerebroventricular (i.c.v.) administration of neuropeptide Y (NPY) in urethane-anaesthetized rats were studied. In Sprague-Dawley rats, NPY increased both blood pressure and heart rate in a dose-dependent manner. This response was unaffected by removal of the adrenal medullae or pretreatment with a specific vasopressin antagonist (180 ng/kg i.v.), but was abolished by phenoxybenzamine (1mg/kg i.v.). After pretreatment with propranolol (1mg/kg i.v.), the tachycardia was inhibited and the pressor response was of shorter duration than in controls. In 6-hydroxydopamine treated rats (two doses of 250 micrograms i.c.v., three days apart), NPY still elicited a pressor response and tachycardia, which were significantly higher than controls 15 minutes after the injection. Plasma levels of vasopressin were not altered by i.c.v. administration of NPY. However, in Brattleboro rats the peptide had no haemodynamic effects. Our results suggest that activation of sympathetic nervous system but not release of vasopressin or adrenal catecholamines into the bloodstream mediates the cardiovascular response to NPY. Central vasopressin pathways however may be involved.     

Comparison of the cardiovascular responses to intracerebroventricular administration of tryptamine, 5-hydroxytryptamine, tryptophan and 5-hydroxytryptophan in rats

General characteristics of the cardiovascular responses to intracerebroventricular (i.c.v.) injection of tryptamine, 5-hydroxytryptamine (5-HT), tryptophan and 5-hydroxytryptophan (5-HTP) were compared. Relatively small doses of tryptamine and 5-HT (0.005-0.1 microM) produced considerable, long-lasting and dose-dependent pressor effects, which sometimes were followed by prolonged depressor effects. Tryptophan (0.02-0.5 microM) and 5-HTP (0.02-0.2 microM) caused variable and usually slight, but long-lasting, vascular responses or no vascular response A large dose of tryptamine (0.5 microM) evoked variable vascular effects, while the same dose of 5-HT and 5-HTP evoked marked and prolonged depressor effects. The vascular responses to the drugs were accompanied by variable changes in heart rate. Tryptamine, 5-HT and 5-HTP, in the majority of rats, produced a bradycardia. The present study provides evidence that the cardiovascular response to i.c.v. administration of tryptamine is similar to that of 5-HT, supporting the idea that tryptamine, in addition to 5-HT, participates in the central physiological regulation of the rat cardiovascular system. The role of tryptophan and 5-HTP by themselves in this regulation, if any is of secondary importance.     

The acute effects of capsaicin on the cardiovascular system

Arterial blood pressure and heart rate were recorded from male Wistar rats anaesthetized with urethane. Intravenous injection of capsaicin, 1 microgram, produced a reproducible triphasic effect on blood pressure, comprising an initial fall in blood pressure and heart rate, followed by a transient and then a sustained pressor response. The depressor response and bradycardia were abolished by vagal section. The transient pressor response was altered in shape by hexamethonium. Slow intravenous infusion of capsaicin, 50 micrograms over 12 min, produced only a sustained pressor response accompanied by tachycardia, which was resistant to hexamethonium but abolished by morphine and pithing. Responses to both 1 microgram injection and 50 micrograms infusion of capsaicin were unaffected by the SP antagonist, spantide, but were abolished by capsaicin pretreatment of the rats. Capsaicin induces complex effects on the cardiovascular system, the nature of which varies with the dose and speed of administration.     

Influence of verapamil on central and peripheral effects of prostacyclin on circulatory system in rats

The influence of verapamil on cardiovascular effects of prostacyclin (PGI2) in rats was examined. PGI2 administered into the lateral brain ventricle (i.c.v.) or intravenously (i.v.) in a dose of 2.7 x 10(-8)mol evoked hypotension and tachycardia. Pretreatment with verapamil in a dose of 2.0 x 10(-5)mol/kg given intraperitoneally (i.p.) diminished hypotensive effect of PGI2 i.c.v. as well as inhibiting the influence of PGI2 i.c.v. and i.v. upon the heart rate. Bolus injection of PGI2 in a dose of 2.7 x 10(-10), 2.7 x 10(-9) or 2.7 x 10(-8)mol evoked biphasic inotropic and chronotropic effects on isolated rat heart. Short-term increase of the contractile force together with bradycardia and afterwards long-lasting decrease of contractility with sustained, slight tachycardia were observed. Verapamil in a concentration of 1.0 x 10(-6)M blocked biphasic inotropic effect and bradycardia after PGI2 administration. Because some central and peripheral cardiovascular effects of PGI2 were inhibited by verapamil, it is concluded that PGI2 may participate in transmembrane calcium ions movements.     

Hypothalamic alpha-adrenergic blockade modifies drinking and blood pressure responses to central angiotensin II in conscious rats

These experiments investigated in the awake rat the involvement of noradrenergic projections to the rostral hypothalamus in the drinking and pressor responses elicited by intracerebroventricular (i.c.v.) injections of 25 ng of angiotensin II. Phentolamine mesylate in doses of 2.5-125 micrograms injected into the rostral hypothalamus produced a dose-dependent depression of both the drinking and pressor responses elicited by i.c.v. administration of angiotensin II. A paradoxical increase in heart rate was associated with a decrease in pressor responses with increasing doses of phentolamine. This response was due to tissue injections, since pretreatment by injecting 12.5 micrograms of phentolamine into the ventricle did not block either the cardiovascular or drinking responses to i.c.v. injections of angiotensin II. Yohimbine (0.33-3.3 micrograms), DL-propranolol (25 micrograms), and atenolol (25 micrograms) did not, but prazosin (0.7 microgram) did significantly alter the pressor responses. Although yohimbine also was without effect on drinking, prazosin reduced the drinking responses. These results suggest that alpha 1-adrenergic receptors in the rostral hypothalamus are involved in the control of both the drinking and pressor responses elicited by i.c.v. injections of angiotensin II. In the case of propranolol and atenolol, beta-adrenergic receptors altered only the drinking response in a nonspecific manner by eliciting competing behaviors. Whether they are involved in modifying the drinking response only remains to be demonstrated.     

Effects of dynorphin A(1-13) and of fragments of beta-endorphin on blood pressure and heart rate of anesthetized rats.

The effect on blood pressure and heart rate of central administration of dynorphin A(1-13) and of beta-, gamma-, and alpha-endorphin related peptides was studied in urethane-anesthetized rats. Intracerebroventricular (i.c.v., 0.1-10 micrograms) administration of beta-endorphin resulted in a dose-dependent, naltrexone-reversible hypotension and bradycardia. N-terminally modified fragments of beta-endorphin did not reduce blood pressure and heart rate. On the other hand, a dose of 10 micrograms of beta-endorphin(1-27), which lacks the four C-terminal amino acid residues of beta-endorphin, induced a fall in blood pressure and had a biphasic effect on heart rate. These responses, however, were resistant to pretreatment with naltrexone. None of the fragments of beta-endorphin smaller than beta-endorphin(1-27) affected blood pressure when administered i.c.v. in a dose of 10 micrograms. A small transient bradycardia was observed after i.c.v. administration of 10 micrograms of beta-endorphin(1-26), alpha, and gamma-endorphin. The naltrexone-reversible bradycardic response of alpha- and gamma-endorphin was not present in des-tyrosine- and des-enkephalin-alpha- and gamma-endorphin and also not in alpha-endorphin(10-16) and gamma-endorphin(10-17). Upon i.c.v. administration (0.1-50 micrograms) a dose-dependent, naltrexone-reversible decrease in blood pressure and heart rate was induced by dynorphin A(1-13). The present data indicate a hypotensive influence of beta-endorphin, beta-endorphin(1-27), and dynorphin A(1-13), whereas other fragments of beta-endorphin had little or no effect on the cardiovascular parameters investigated.     

Effect of water deprivation on the centrally-mediated hypertensive response to clonidine in freely moving, normotensive rats

Effects of water deprivation on pressor responses to centrally and peripherally administered clonidine was investigated in freely moving, normotensive rats with chronic guide cannula and catheters implanted into the abdominal aorta via the femoral artery. In normal hydrated rats, intracerebroventricularly (i.c.v.) injected clonidine (10 and 20 micrograms) produced a dose-dependent and long-lasting rise in mean blood pressure (MBP) concomitant with a decrease in heart rate. However, a significant depressor response was not observed for up to 90 min. In 48 hr dehydrated rats, the pressor response to i.c.v. injected clonidine (10 and 20 micrograms) was significantly depressed and a depressor response appeared. Intravenously (i.v.) administered clonidine (25 micrograms/kg) in normal hydrated rats also produced a long-lasting pressor response following an initial rapid rise in MBP. The long-lasting pressor response to i.v. injected clonidine was abolished after water deprivation for 48 hr, whereas the initial rise in MBP was less affected. These results suggest that clonidine elicits centrally-mediated pressor response, which is influenced by body fluid volumes.     

Divergent effects of pirenperone, a 5-HT2 antagonist, on the pressor and tachycardic responses to 5-HT in guinea-pigs

The effects of pirenperone and cyproheptadine on the pressor and tachycardic responses to 5-hydroxytryptamine (5-HT) and to dimethylphenylpiperazinium (DMPP) were compared. Both 5-HT antagonists suppressed in a dose-dependent manner the pressor effect of 5-HT, whilst did not noticeably affect the tachycardic effect of 5-HT and the cardiovascular effects of DMPP. On the molecular base, pirenperone was 15 times more potent antagonist of the pressor response to 5-HT than cyproheptadine. It is concluded that not only the 5-HT receptors in arterial smooth muscle but also the 5-HT receptors in sympathetic ganglia and the adrenal medulla responsible for the pressor response to 5-HT are sensitive to the 5-HT antagonists and probably analogous to the central 5-HT2 receptors. The 5-HT receptors in cardiac tissue mediating tachycardia differ in their pharmacological properties from those in arterial smooth muscle responsible for contraction. It is suggested that the ganglionic components of the pressor and tachycardic responses to 5-HT are mediated via different populations of 5-HT receptors in sympathetic ganglia.     

Pressor, tachycardic and feeding responses in conscious rats following i.c.v. administration of dynorphin. Central blockade by opiate and alpha 1-receptor antagonists

Experiments were designed to determine the hemodynamic responses of conscious, unrestrained rats given intracerebroventricular (i.c.v.) injections of dynorphin A-(1-13) and the possible central receptor mechanisms mediating those changes. Male Sprague-Dawley rats (300 gb. wt.) received i.c.v. injections (by gravity flow in a total volume of 3 or 5 microliter) of control solutions of sterile saline (SS) or dimethylsulfoxide (DMSO) or 1.5, 3.0 or 6.1 nmol of dynorphin A-(1-13). Blood pressure and heart rate changes were monitored over 2 h after administration; as well, feeding activity was visually assessed and scored over this period. Other groups of conscious rats were pretreated i.c.v. with equimolar doses (3.0-24.4 nmol) of specific receptor antagonists (naloxone HCl, phentolamine HCl, propranolol HCl, yohimbine HCl or prazosin HCl) 10 min before subsequent i.c.v. administration of SS or DMSO/SS or 6.1 nmol of dynorphin A-(1-13). I.c.v. injection of dynorphin A-(1-13) caused a dose-related pressor response, associated temporally with tachycardia. As well, dynorphin evoked feeding activity and some grooming, which occurred when the rats were hypertensive and tachycardic and decreased as heart rate and blood pressure returned to control levels. I.c.v. pretreatment studies indicated that naloxone HCl (12.2 nmol), phentolamine HCl (12.2 nmol) and prazosin HCl (6.1 nmol) blocked the pressor response, tachycardia as well as feeding activity of rats subsequently given dynorphin. The results suggest the pressor and tachycardic effects of conscious rats following i.c.v. dynorphin administration may, in part, be due to behavioral activation (feeding). As well, these data indicate that both opioid as well as alpha 1-adrenergic receptors within the CNS are involved in mediating the pressor, tachycardic and feeding responses of conscious rats given i.c.v. injections of dynorphin A.     

Cholinergic neurons and the cardiovascular response produced by central injection of substance P in the normotensive rat

The role of cholinergic neurons in central cardiovascular regulation is not well understood, however, activation of brain cholinergic neurons in several species evokes a hypertensive response. As with central cholinergic stimulation, intracerebroventricular (i.c.v.) injection of substance P (sP) elicits a pressor response in unanesthetized rats. The purpose of this study was to determine whether the cardiovascular effects following i.c.v. injection of this neuropeptide are mediated by central cholinergic neurons. Therefore, the cardiovascular response to sP was examined in control rats, and in animals pretreated centrally with classical pre- and post-synaptic cholinergic antagonists. Drugs were administered directly into the lateral ventricle while rats were freely-moving in their home cages. I.c.v. injection of sP produced a dose - dependent increase in arterial pressure and heart rate. The hypertensive response was significantly reduced by pretreatment with hemicholinium-3. This dose (20 ug) of hemicholinium-3 is capable of producing a maximal depletion of brain acetylcholine levels. The increase in heart rate to substance P was not as sensitive to hemicholinium-3 pretreatment as was blood pressure. Central pretreatment with the nicotinic receptor antagonist, hexamethonium was more effective than the muscarinic antagonist, atropine in blocking the pressor response to sP. Hexamethonium did not significantly alter the tachycardic response to the peptide, but atropine produced a small, but significant reduction in the response. Therefore, the pressor response to central injection of sP may be mediated to a large extent through cholinergic pathways involving nicotinic receptors.     

Cardioselective profile of AF-DX 116, a muscarine M2 receptor antagonist

AF-DX 116 (see chemical name below) is a competitive antagonist of muscarine receptors in peripheral organs. In contrast to pirenzepine, its behaviour in functional experiments indicates selectivity for the M2 muscarinic subtype. In pithed rats AF-DX 116 inhibits vagally-induced bradycardia, an M2 response, (ED50 32 micrograms/kg i.v.) in preference to the M1-mediated pressor response to McN-A-343 (ED50 211 micrograms/kg i.v.). AF-DX 116 further discriminates among M2 receptors, showing a high affinity for the cardiac muscarine receptors. In isolated preparations, AF-DX 116 has a tenfold higher affinity for the muscarine receptors of the heart (pA2 7.33) than for those in smooth muscles (pA2 6.39-6.44). The same profile appears from animal studies, where the compound is a more potent antagonist of either endogenously or exogenously activated cardiac muscarine responses as compared to vascular, smooth muscle or secretory responses. In general, the ratios of potencies (ED50) observed in cardiac vs. other muscarine mediated functions ranged between 30 and 50. Atropine showed no discrimination, inhibiting all muscarine responses in the same range of doses. In the conscious dog intravenous AF-DX 116 increased basal heart rate, and completely reversed the reflex bradycardia induced by clonidine. Tachycardia was dose-related (ED50 79 micrograms/kg i.v.), and occurred independently of background sympathetic tone. AF-DX 116 clearly distinguishes between M1- and M2-mediated responses; it also emphasizes the long-recognized heterogeneity among the peripheral M2 subtypes. AF-DX 116, for its pronounced cardioselectivity, may have a therapeutic potential in the treatment of sinus bradycardia.     

The cardiovascular actions of centrally administered neuropeptide Y

The cardiovascular actions of intracerebroventricular (i.c.v.) administration of neuropeptide Y (NPY) were examined in conscious, unrestrained rats. A prolonged decrease in heart rate (HR) and a fall in mean arterial pressure (MAP) were obtained following i.c.v. administration of NPY (1 and 10 micrograms). Passive immunization with an antiserum directed against NPY confirmed that the slowing of HR following i.c.v. administration of NPY was mediated via a central nervous mechanism and not from leakage of NPY out of the brain. Administration of NPY into different brain parenchymal regions identified a putative site of action in the rostral region of the solitary tract. The mechanism of the decrease in HR caused by centrally administered NPY was investigated by i.c.v. administration of NPY to animals that were pretreated with agents that altered autonomic tone. Administration of NPY to atropine-treated animals produced a reversal of the atropine-induced tachycardia, suggesting that the NPY-induced decrease in HR was not due to augmented vagal tone. However, administration of NPY to animals pretreated with propranolol did not significantly lower HR below that obtained with propranolol alone. These data suggest that i.c.v. administration of NPY may cause a decrease in cardiac sympathetic outflow. The effects of centrally administered NPY on baroreflex function were studied. The changes in HR caused by NPY did not significantly alter baroreflex set-point or gain. These studies provide evidence that NPY acted within a brainstem region to decrease sympathetic nervous outflow, resulting in a decrease in HR and MAP.     

Nociceptin/orphanin FQ increases blood pressure and heart rate via sympathetic activation in sheep.

This study was undertaken to examine the cardiovascular effects of nociceptin/Orphanin FQ (OFQ). Nociceptin/OFQ (10-300 nmol/kg, IV) stimulates an increase in mean blood pressure (MBP) and heart rate (HR) in chronically catheterized sheep. Pretreatment with phenoxybenzamine (5 mg/kg) attenuated the pressor response, consistent with sympathetically mediated vasoconstriction. Furthermore, the lack of a reflex bradycardia suggests either blunting of the baroreflex by nociceptin/OFQ or direct beta-adrenergic activation. The bradycardic response to norepinephrine (0.6 microg/kg, IV) remained intact after nociceptin/OFQ administration, demonstrating that nociceptin/OFQ does not blunt the baroreflex. Additionally, the increase in HR was completely reversed by pretreatment with propranolol. These data suggest that nociceptin/OFQ plays a role in cardiovascular regulation via sympathetic activation.     

Antinociceptive effect of the agonist of 5-HT1A receptors buspirone in the model of abdominal pain in dogs

We have demonstrated that activation of 5-HT1A receptors with buspirone promotes visceral analgesia in awake dogs. The administration of 0.035 mg/kg (i.m.) of the drug caused depression of viscero-motor (contraction of the abdominal muscles) and pressor (increase in the heart rate) responses to noxious distension of the large intestine. An increase in the dose to 0.07 and 0.14 mg/kg did not enhance the antinociceptive effect of buspirone but triggered basal tachycardia. The obtained results provide evidence of the inhibitory role of 5-HT1A receptors in modulating visceral pain sensitivity and the possibility of an exciting effect of their activation on the cardiovascular system.     

Cardiovascular effects of the essential oil of Croton zehntneri leaves and its main constituents, anethole and estragole, in normotensive conscious rats

Cardiovascular effects of the essential oil of Croton zehntneri (EOCZ) were investigated in conscious rats. In these preparations, intravenous (i.v.) injections of EOCZ (1-20 mg kg(-1)) and its main constituents anethole and estragole (both at 1-10 mg kg(-1)) elicited brief and dose-dependent hypotension and bradycardia (phase I) that were followed by a significant pressor effect associated with a delayed bradycardia (phase II). The initial hypotension and bradycardia (phase I) of EOCZ were unchanged by atenolol (1.5 mg kg(-1), i.v.) or L-NAME (20 mg kg(-1), i.v.) pretreatment, but were respectively reversed into pressor and tachycardic effects by methylatropine (1 mg kg(-1), i.v.) pretreatment. The subsequent pressor effect and the delayed bradycardia (phase II) remained unaffected by atenolol, but were abolished by L-NAME and methylatropine pretreatment, respectively. In rat endothelium-containing aorta preparations, the vasoconstrictor responses to phenylephrine were enhanced and reduced, respectively, by the lower (1-30 microg mL(-1)) and higher (300-1000 microg mL(-1)) concentrations of EOCZ. Only the enhancement of phenylephrine-induced contraction was abolished by either the incubation with L-NAME (50 microM) or in the absence of the endothelium. These data show, for the first time, that i.v. administration EOCZ induces an initial hypotension followed by a pressor response, two effects that appear mainly attributed to the actions of anethole and estragole. The EOCZ-induced hypotension (phase I) is mediated by a cholinergic mechanism and seems to result mainly from the concomitant bradycardia. The pressor response of EOCZ (phase II) seems to be caused by an indirect vasoconstrictive action of EOCZ most likely through inhibition of endothelial nitric oxide production.     

Potentiation of the carotid artery occlusion reflex by a cholinergic system in the posterior hypothalamic nucleus

Bilateral occlusion of the common carotid arteries of urethane-anesthetized rats evoked a pressor response of 14 ± 1 mm Hg. Injection into the lateral cerebral ventricle of neostigmine (0.2–1.0 μg) or physostigmine (10–15 μg) caused a dose-dependent increase in basal blood pressure and in the magnitude of the carotid artery occlusion (CAO) pressor reflex. Neostigmine (1 μg) and physostigmine (15 μg) caused nearly maximal and approximately equal degrees of cholinesterase inhibition in several brain regions. The recovery of the cardiovascular parameters and of brain cholinesterase activity was significantly faster following physostigmine compared to neostigmine. Prior intracerebroventricular injection of atropine (0.3 μg) or hemicholinium-3 (20 μg) prevented the increases in basal pressure and the CAO pressor response. Potentiation of the CAO reflex also followed injection of physostigmine or neostigmine into the posterior hypothalamic nucleus and of injection of physostigmine intravenously. Injection of atropine bilaterally into the posterior hypothalamic nucleus prior to intravenous injection of physostigmine prevented the potentiation of the CAO reflex but not the increase in basal blood pressure. These results indicate that acetylcholine in the posterior hypothalamic nucleus serves as a neurotransmitter in a pathway which can potentiate the pressor response to carotid artery occlusion and thus modulate baroreceptor reflexes.     

The cardiovascular effects of a chimeric opioid peptide based on morphiceptin and PFRTic-NH2

MCRT (YPFPFRTic-NH₂) is a chimeric opioid peptide based on morphiceptin and PFRTic-NH₂. In order to assess the cardiovascular effect of MCRT, it was administered by intravenous (i.v.) injection targeting at the peripheral nervous system and by intracerebroventricular (i.c.v.) injection targeting at the central nervous system. Naloxone and l-NAME were injected before MCRT to investigate possible interactions with MCRT. Results show that administration of MCRT by i.v. or i.c.v. injection could induce bradycardia and decrease in mean arterial pressure (MAP) at a greater degree than that with morphiceptin and PFRTic-NH₂. When MCRT and NPFF were coinjected, we observed a dose-dependent weakening of these cardiovascular effects by MCRT. Because naloxone completely abolished the cardiovascular effects of MCRT, we conclude that opioid receptors are involved in regulating the MAP of MCRT regardless of modes of injection. The effect of MCRT on heart rate is completely dependent on opioid receptors when MCRT was administered by i.c.v. instead of i.v. The central nitric oxide (NO) pathway is involved in regulating blood pressure by MCRT under both modes of injection, but the peripheral NO pathway had no effect on lowering blood pressure mediated by MCRT when it was administered by i.c.v. Based on the results from different modes of injection, the regulation of heart rate by MCRT mainly involves in the central NO pathway. Lastly, we observed that the cardiovascular effects of MCRT such as bradycardia and decrease of blood pressure, were stronger than that of its parent peptides. Opioid receptors and the NO pathway are involved in the cardiovascular regulation by MCRT, and their degree of involvement differs between intravenous and intracerebroventricular injection.     

Receptor subtype specific activation of the rat gastric vagal afferent fibers to serotonin

Systemic administration (i.v.) of serotonin (5-HT) evoked a transient vagal afferent nerve discharge, bradycardia, and hypotension in the rat. The half-effective dose of 5-HT for nerve discharge was 13 micro g/kg. The time- and dose-dependent kinetics of the nerve discharge rate were similar to the change of heart rate. The afferent neuronal discharge was mimicked by a selective 5-HT3 receptor agonist, 1-phenylbiguanide hydrochloride (PBA), and inhibited by a selective 5-HT3 antagonist, granisetron. The 5-HT(3/4) agonist, cisapride partially activated the vagus nerve, but the 5-HT4 agonist, RS6733 had no effect on the vagal afferent activity. Intra-gastric perfusion of lidocaine, moreover, abolished the 5-HT-induced vagal activation. These results indicate that the 5-HT transmission signal in the gastric mucosa inputs to the brain stem via 5-HT3 receptor-mediated vagal nerve afferent.     

Cardiovascular effects of centrally administered endothelin-1 and its relationship to changes in cerebral blood flow

Intracerebroventricular (i.c.v.) injection of endothelin-1 (ET-1; 100 ng, i.c.v.) produced an initial pressor (24%) (peak at 3 min following ET-1 administration) and a delayed depressor (−40%) (30 and 60 min following ET-1 administration) effects in urethane anesthetized rats. The pressor effect of ET-1 was due to an increase (21%) in cardiac output, while the depressor effect of ET-1 was associated with a marked decrease (−46%) in cardiac output. Stroke volume significantly decreased at 30 and 60 min after the administration of ET-1. No change in total peripheral vascular resistance and heart rate was observed following central administration of ET-1. The effects of ET-1 on blood pressure, cardiac output and stroke volume were not observed in BQ123 (10 μg, i.c.v.) treated rats. Blood flow to the cerebral hemispheres, cerebellum, midbrain and brain stem was not affected at 3 min, but a significant decrease in blood flow to all the regions of the brain was observed at 30 and 60 min following central administration of ET-1. BQ123 pretreatment completely blocked the central ET-1 induced decrease in blood flow to the brain regions. It is concluded that the pressor effect of centrally administered ET-1 is not accompanied by a severe decrease in brain blood flow, however, a subsequent decrease in blood pressure is associated with a decrease in blood flow to the brain. The cardiovascular effects of ET-1 including decrease in brain blood flow are mediated through central ET_A receptors.     

Pressor effects of systemic administration of methionine and leucine enkephalin in the conscious rat

Experiments were designed using conscious Sprague-Dawley rats to determine the blood pressure (BP) and heart rate (HR) responses to intravenous doses of (1) the adrenal catecholamines noradrenaline (NA) and adrenaline (A), (2) adrenal pentapeptides methionine enkephalin (ME) and leucine enkephalin (LE), (3) combination (i.v.) injections of both ME or LE with NA or A that modulate the hemodynamic responses when the adrenal catecholamines were given alone, and (4) the possible receptor mechanisms mediating the resultant BP and HR response to i.v. pentapeptide administration. NA (0.48 and 2.4 nmol) and A (0.3 and 1.5 nmol) given i.v. evoked potent, dose-related pressor responses associated with reflex bradycardia. ME and LE (1.6 - 48 nmol) elicited transient (10-20 s) increases in mean arterial pressure (MAP), which was associated either with no change in mean heart rate (MHR), such as ME, or with slight bradycardia (i.e., LE). Combining ME or LE (16 nmol) with NA (2.4 nmol) or A (0.3 or 1.5 nmol) did not change MAP and MHR from when these respective doses of NA or A were given alone. However, 16 nmol of ME or LE with a low dose of NA (0.48 nmol) increased the pressor response compared with NA (0.48 nmol) given alone. Other experiments whereby specific receptor blockers (naloxone, diprenorphine, atropine, propranolol, phentolamine or guanethidine) were given i.v. 5 min before subsequent i.v. administration of LE or ME (16 nmol) indicated that only phentolamine or guanethidine could completely suppress the pressor responses of LE and ME. Naloxone and diprenorphine pretreatment attenuated the pressor response of LE but did not affect the BP response to ME.(ABSTRACT TRUNCATED AT 250 WORDS)