Atropine Methyl Bromide Research Articles

Cardiovascular depressor responses to stimulation of substantia nigra and ventral tegmental area.

Experiments were done in alpha-chloralose-anesthetized, paralyzed, and artificially ventilated rats to investigate the effect of L-glutamate (Glu) stimulation of the substantia nigra (SN) and ventral tegmental area (VTA) on arterial pressure (AP) and heart rate (HR). Glu stimulation of the SN pars compacta (SNC) elicited decreases in both mean AP (MAP; -18.9 +/- 1.3 mmHg; n = 52) and HR (-26.1 +/- 1.6 beats/min; n = 46) at 81% of the sites stimulated. On the other hand, stimulation of the SN pars lateralis or pars reticulata did not elicit cardiovascular responses. Stimulation of the adjacent VTA region elicited similar decreases in MAP (-18.0 +/- 2.6 mmHg; n = 20) and HR (-25.4 +/- 3.8 beats/min; n = 17) at approximately 74% of the sites stimulated. Intravenous administration of the dopamine D2-receptor antagonist raclopride significantly attenuated both the MAP (70%) and the HR (54%) responses elicited by stimulation of the transitional region where the SNC merges with the lateral VTA (SNC-VTA region). Intravenous administration of the muscarinic receptor blocker atropine methyl bromide had no effect on the magnitude of the MAP and HR responses to stimulation of the SNC-VTA region, whereas administration of the nicotinic receptor blocker hexamethonium bromide significantly attenuated both the depressor and the bradycardic responses. These data suggest that dopaminergic neurons in the SNC-VTA region activate a central pathway that exerts cardiovascular depressor effects that are mediated by the inhibition of sympathetic vasoconstrictor fibers to the vasculature and cardioacceleratory fibers to the heart.

Lateral hypothalamic injection of GABA(A) antagonist induces gastric vagus-mediated hypocalcemia in the rat.

The involvement of lateral hypothalamic area (LHA) neurons in the regulation of blood calcium homeostasis was investigated in unanesthetized rats. The microinjection of the gamma-aminobutyric acid A receptor antagonist bicuculline methiodide (BM, 4-40 ng x 0.5 microl(-1) x 5 min(-1)) into the LHA decreased the blood concentration of ionized calcium. Total serum calcium also decreased after the BM injection. This hypocalcemic effect was eliminated by a bilateral vagotomy of the gastric branches. An intravenous injection of atropine methyl bromide (a muscarinic antagonist), nadolol (a beta-adrenergic blocker), or ranitidine (a histamine H2 blocker) suppressed the BM-induced hypocalcemia, whereas phenoxybenzamine (an alpha-adrenergic blocker) proved to be ineffective. Although the intra-LHA injection of BM increased the serum gastrin, which is known to have a hypocalcemic effect, neither secretin nor somatostatin (gastrin-release inhibitors) blocked the hypocalcemic response. These results suggest that the hypocalcemia observed after the excitation of LHA neurons was mediated by muscarinic, beta-adrenergic, and histamine H2 receptors through the gastric vagus.

Central muscarinic antinociception induced by ET-142 and SS-20 in rodents

The antinociceptive effects of ET-142 (10–50 mg kg–1 sc; 10–30 μg per mouse icv) and SS-20 (10–50 mg kg–1 sc; 5–30 μg per mouse icv) were examined in mice by using the hot-plate and abdominal constriction tests. A similar antinociceptive profile for both compounds (20–40 mg kg–1 ip) was also observed in rats using the paw pressure test. In the antinociceptive dose-range, ET-142 and SS-20 did not impair mouse gross behavior and motor coordination evaluated, respectively, by the Irwin and rotarod tests. The increase in the pain threshold produced by ET-142 and SS-20 was prevented by atropine, dicyclomine, pirenzepine, and hemicholinium-3, but not by naloxone, atropine methyl bromide, and CGP 35348. In vitro experiments showed that the two investigated compounds amplified electrically evoked guinea pig ileum contractions. On the basis of the above data, it can be postulated that ET-142 and SS-20 exert their antinociceptive effect through a potentiation of central cholinergic transmission. Drug Dev. Res. 42:26–34, 1997. © 1997 Wiley-Liss, Inc.

Central muscarinic antinociception induced by ET‐142 and SS‐20 in rodents

The antinociceptive effects of ET-142 (10–50 mg kg–1 sc; 10–30 μg per mouse icv) and SS-20 (10–50 mg kg–1 sc; 5–30 μg per mouse icv) were examined in mice by using the hot-plate and abdominal constriction tests. A similar antinociceptive profile for both compounds (20–40 mg kg–1 ip) was also observed in rats using the paw pressure test. In the antinociceptive dose-range, ET-142 and SS-20 did not impair mouse gross behavior and motor coordination evaluated, respectively, by the Irwin and rotarod tests. The increase in the pain threshold produced by ET-142 and SS-20 was prevented by atropine, dicyclomine, pirenzepine, and hemicholinium-3, but not by naloxone, atropine methyl bromide, and CGP 35348. In vitro experiments showed that the two investigated compounds amplified electrically evoked guinea pig ileum contractions. On the basis of the above data, it can be postulated that ET-142 and SS-20 exert their antinociceptive effect through a potentiation of central cholinergic transmission. Drug Dev. Res. 42:26–34, 1997. © 1997 Wiley-Liss, Inc.

Cardiovascular responses to glutamate stimulation of diagonal band of Broca.

Experiments were done in alpha-chloralose-anesthetized, paralyzed, and artificially ventilated rats to investigate the effect of L-glutamate stimulation of the diagonal band of Broca (DBB) on arterial pressure (AP) and heart rate (HR). Stimulation of the horizontal limb of the DBB (hDB) elicited decreases in both mean AP (MAP; -32.3 +/- 2.5 mmHg; n = 37) and HR (-32.5 +/- 3.8 beats/min; n = 33) at 84% of the sites stimulated. Stimulation of the vertical limb of the DBB (vDB) elicited significantly smaller decreases in MAP (-9.7 +/- 1.0 mmHg; n = 19) and HR (-13.5 +/- 1.8 beats/min; n = 7) at approximately 13% of the sites stimulated. Intravenous administration of the muscarinic receptor blocker atropine methylbromide had no effect on the magnitude of the MAP and HR responses to stimulation of the hDB. In contrast, administration of the nicotinic receptor blocker hexamethonium bromide abolished both the depressor and the bradycardic responses elicited by stimulation of the hDB. These data indicate that the hDB contains neurons that exert cardiovascular depressor effects and that these circulatory effects are mediated by the inhibition of sympathetic vasoconstrictor fibers to the vasculature, and cardioacceleratory fibers to the heart.

Cardiovascular effects of neurotensin microinjections into the nucleus of the solitary tract

Neurotensin (NT) immunoreactivity and binding sites have been demonstrated to be extensively distributed throughout the caudal nucleus of the solitary tract (NTS). In this study, the cardiovascular effects of microinjecting the tridecapeptide neurotensin (NT) or its analogues NT 1–8 and [ d-Trp 11]NT into NTS were investigated in the chloralose-anesthetized, paralyzed and artificially ventilated rat. Microinjection of NT (10 pmol) elicited decreases in arterial pressure (AP) (−34 ± 3 mm Hg) and heart rate (HR) (−28 ± 2 beats/min), whereas microinjection of equimolar amounts of the NT fragment NT 1–8 elicited a significantly smaller depressor response (−14 ± 3 mm Hg), but the bradycardic (−22 ± 4 beats/min) response was similar in magnitude to that elicited by NT. On the other hand, microinjection of [ d-Trp 11]NT did not elicit cardiovascular responses from sites in NTS. In addition, the prior injection of [ d-Trp 11]NT into cardiovascular responsive sites in the NTS did not significantly reduce the AP or HR response to NT. The depressor response elicited by NT was not affected by bilateral vagotomy but was abolished by either C1–C2 spinal cord transection or the i.v. administration of the nicotinic receptor blocker hexamethonium bromide. The cardiac slowing was partially attenuated by either bilateral vagotomy (−19 ± 2 beats/min, i.v. administration of atropine methyl bromide (−17 ± 4 beats/min), i.v. administration of hexamethonium bromide (−11 ± 4 beats/min) or by spinal cord transection (−12 ± 3 beats/min), and completely abolished after total autonomic blockade or by combined bilateral vagotomy and spinal cord transection. These data have demonstrated that within a restricted region of the caudal NTS NT activates neurons that contribute to vasodepressor responses as a result of sympatho-inhibition and to bradycardia responses as a result of vagal excitation and sympatho-inhibition. Furthermore, these data suggest that NT may act as a neurotransmitter or modulator in central cardiovascular reflex pathways.

Potential role of the autonomic nervous system in the immunosuppressive effects of acute morphine administration

These studies investigated the role of the autonomic nervous system in mediating the immunosuppressive effect of morphine on blood lymphocyte proliferation in rats. To determine the contribution of the autonomic nervous system, rats were pretreated with the ganglionic blocker chlorisondamine (5 mg/kg) prior to morphine (7 mg/kg) administration. Ganglionic blockade with chlorisondamine completely antagonized the inhibitory actions of morphine, suggesting that intact ganglionic transmission was required for the inhibition to occur. Blockade of postganglionic parasympathetic neurotransmission with atropine methylbromide (1 mg/kg) or blockade of sympathetic neurotransmission with the α-adrenoceptor antagonist phentolamine (1 mg/kg) did not attenuate the suppressive effect of morphine. Blockade of β-adrenoceptors with propranolol (2.5 mg/kg) resulted in partial antagonism, but this action was not shared by the peripherally acting β-adrenoceptor antagonist nadolol (6 mg/kg). These results suggest that the inhibitory effect of morphine on blood lymphocyte proliferation may be mediated through activation of the autonomic nervous system; however, individual blockade of either the parasympathetic or sympathetic division of the autonomic nervous system was not sufficient to antagonize this immunosuppressive effect.

Intracerebroventricular injection of methylatropine suppresses insulin response to oral glucose load in rats

Hepatic glucoreceptor-vagal afferent inputs to the central nervous system and pancreatic vagal efferent stimuli are important for insulin secretion. In the present study, we examined the effect of intracerebroventricular (i.c.v.) injection of atropine methyl bromide (methylatropine) on the insulin response following glucose ingestion in rats. When rats were injected with methylatropine i.c.v., the plasma glucose concentration increased, the insulin response reduced, and glucagon-like peptide-1 (7–36) amide (tGLP-I) was unchanged following an oral glucose load, compared with the controls. The plasma insulin response following an intravenous glucose load was not affected by i.c.v. or intraperitoneal injection of methylatropine. A transient increase in plasma insulin after selective hepatic vagotomy was inhibited by i.c.v. injection of methylatropine. Arterial blood pressure or pulse rate was not changed by i.c.v. injection of methylatropine. These results show that the central nervous system plays an important role in the vagal control of the insulin response to glucose ingestion. In rats, for the insulin response soon after glucose ingestion (early phase insulin response), direct neural control (hepatic vagal afferent-central nervous system-pancreatic vagal efferent) of the islet B cells seems more important than the intestinal insulinotropic hormone, tGLP-1.

The function of 5-HT3 receptors on colonic transit in rats.

The function of serotonin (5-HT)3 receptors on colonic transit was investigated in unanesthetized rats. The colonic transit was accelerated by 5-HT (10 mg/kg, s.c.), 2-methyl-5-HT (30 mg/kg, s.c.), neostigmine (0.03-0.1 mg/kg, s.c.), corticotropin releasing factor (CRF; 1 microgram intracerebroventricular administration) and restraint stress (for 45 minutes). A potent and selective 5-HT3 receptor antagonist, azasetron (+/-)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro- 4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide monohydrochloride ; 0.01-10 mg/kg, p.o. inhibited the 5-HT-, CRF- and stress-accelerated colonic transit in a dose-dependent manner. Ondansetron (10 mg/kg, p.o.) and granisetron (1 mg/kg, p.o) also inhibited the stress-accelerated colonic transit, but azasetron was more effective than these two drugs. Atropine methylbromide (0.1 mg/kg, s.c.) and tetrodotoxin (0.01 mg/kg, s.c.) inhibited the accelerated colonic transit under stress conditions, but methysergide (10 mg/kg, s.c.), SDZ205-557 (10 mg/kg, s.c.), domperidone (30 mg/kg, p.o.), trimebutine (300 mg/kg, p.o.), did not. Azasetron (10 micrograms) administered intracerebroventricularly did not inhibit the stress-induced acceleration. These results suggest that endogenous 5-HT which is released through stress accelerates the colonic transit via the 5-HT3 receptors and finally a cholinergic mechanism. It is considered that azasetron inhibits colonic transit particularly under stress conditions through the blockade of the peripheral 5-HT3 receptors. Azasetron may improve bowel function in stress-related colonic dysfunction like irritable bowel syndrome.

Effect of various pretreatments on the hypothermic activity of repin in naive rats

Repin is a sesquiterpene lactone found in Centaurea solstitialis, a plant responsible for Parkinson-like disease in horses. Repin, on intraperitoneal (i.p.) injection, produces a dose-dependent and highly significant hypothermia in naive rats. The hypothermia is long-lasting with a peak 3 h after the injection and a return to normal temperature after more than 8 h. The effects of atropine sulfate, atropine methylbromide, propranolol, metergoline, ketanserin, diphenhydramine and apomorphine pretreatment on repin-induced hypothermia were investigated. None of the pretreatments directly antagonized repin's hypothermic effect. However, partial but significant reversals of hypothermia by atropine sulfate, metergoline, ketanserin, diphenhydramine and apomorphine were observed 2–4 h after the repin injection. These late-onset effects are probably due to secondary physiological mechanisms. On the other hand, propranolol, at 20 mg/kg i.p., clearly accentuated both the early-onset (30–90 min) and late-onset (2–4 h) hypothermic effects of repin.

Effect of various pretreatments on the hypothermic activity of repin in naive rats

Repin is a sesquiterpene lactone found in Centaurea solstitialis , a plant responsible for Parkinson-like disease in horses. Repin, on intraperitoneal (i.p.) injection, produces a dose-dependent and highly significant hypothermia in naive rats. The hypothermia is long-lasting with a peak 3 h after the injection and a return to normal temperature after more than 8 h. The effects of atropine sulfate, atropine methylbromide, propranolol, metergoline, ketanserin, diphenhydramine and apomorphine pretreatment on repin-induced hypothermia were investigated. None of the pretreatments directly antagonized repin's hypothermic effect. However, partial but significant reversals of hypothermia by atropine sulfate, metergoline, ketanserin, diphenhydramine and apomorphine were observed 2–4 h after the repin injection. These late-onset effects are probably due to secondary physiological mechanisms. On the other hand, propranolol, at 20 mg/kg i.p., clearly accentuated both the early-onset (30–90 min) and late-onset (2–4 h) hypothermic effects of repin.

Activation of the hypothalamic dorsomedial nucleus stimulates intestinal motility in rats

Blockade of gamma-aminobutyric acidA (GABAA) receptors in the dorsomedial nucleus of the hypothalamus (DMH) in rats induced cardiovascular and behavioral changes resembling those associated with emotional stress. The purpose of this study was to test the hypothesis that microinjection of the GABA antagonist bicuculline methiodide (BMI) into the DMH of anesthetized rats would produce increases in intestinal motility measured manometrically with saline-filled cannulas. Arterial pressure and heart rate were also recorded. Microinjection of BMI (15-30 pmol/15 nl) into the region of the DMH elicited reproducible and dose-related increases in jejunal motility, colonic motility, heart rate, and arterial pressure. Similar microinjection at sites anterior to the DMH into or nearer to the hypothalamic paraventricular nucleus elicited significantly attenuated cardiovascular effects accompanied by either no change in intestinal function or changes that were significantly reduced. Either vagotomy or treatment with atropine methyl bromide (1 mg/kg i.v.) blocked the increase in jejunal motility and reduced but did not abolish the colonic stimulation. Increases in heart rate and arterial pressure were essentially unaffected by either intervention. The observations suggest that disinhibition of neurons in the DMH increases jejunal motility through vagal cholinergic pathways and enhances colonic motility through vagal and nonvagal cholinergic and noncholinergic pathways.

Dorsomedial hypothalamic GABA regulates anxiety in the social interaction test

Blockade of GABA A function in the region of the dorsomedial hypothalamus (DMH) of rats is known to elicit a constellation of physiologic responses including increases in heart rate (HR), mean arterial blood pressure (BP), respiratory rate and plasma catecholamine levels, as well as behavioral responses such as increases in locomotor activity and anxiogenic-like effects as measured in a conflict test and the elevated plus-maze test. The aim of the present study was to test the effects of microinjecting GABA A antagonists bicuculline methiodide (BMI) and picrotoxin, as well as the GABA A agonist muscimol, into the DMH of rats placed in the social interaction (SI) test. Muscimol decreased HR and BP but increased SI, whereas the GABA antagonists increased HR and BP but decreased SI time. Blocking the HR changes elicited by GABAergic drugs injected into the DMH with systemic injections of atenolol and atropine methylbromide did not block their effects on SI.

Interaction between the central histaminergic and the muscarinic cholinergic systems.

Histamine (HA) was given intracerebroventricularly (icv) to rats anaesthetized with pentobarbital. During the first minute after administration, HA alone elicited a small fall in blood pressure (BP) and a decrease in heart rate (HR), followed by a distinct increase in those parameters. Pretreatment with naloxone (Nx) in a dose of 0.1 microgram icv significantly decreased the rise in BP and augmented the increase in HR. When the rats were premedicated with atropine methyl bromide (ATMB), 15 min before histamine, higher doses of ATMB (100 micrograms icv or 25 micrograms ip) significantly inhibited the histamine induced BP rise. However, a very small dose (0.1 microgram) of ATMB stimulated the hypertensive response, but only after its peripheral and not central application. These changes were significantly reversed by icv pretreatment with Nx. HA-induced changes in HR, in contrast to BP, were not significantly modified by ATMB.

Cardiovascular effects of NaCl microinjections into the nucleus of the solitary tract

The nucleus of the solitary tract (NTS) was systematically explored in the α-chloralose-anesthetized rat for sites that elicited changes in mean arterial pressure (MAP) and heart rate (HR) during microinjections (20 nl) of phosphate-buffered saline (PBS; pH 7.2–7.4) or NaCl solutions containing various concentrations of NaCl (104–326 mM). Decreases in MAP (range 7–83 mmHg) and HR (range 10–70 bpm) were consistently elicited from sites in the caudal medial and commissural subnuclei of NTS. Microinjection of PBS or NaCl into other NTS subnuclei or area postrema did not elicit cardiovascular responses. Microinjection of LiCl in PBS elicited cardiovascular responses that were significantly smaller than those elicited by microinjection of NaCl in PBS at the same NTS site. Injections of either a hyperosmotic (400 mOsm/kg) or a hyposmotic (204 mOsm/kg) solution of mannitol into NaCl-sensitive sites did not elicit cardiovascular responses. Finally, most of the sites in NTS that elicited cardiovascular responses during microinjection of glutamate (1 M) did not respond to microinjections of PBS. Administration of atropine methyl bromide had no effect on the magnitude of the depressor response to injections of PBS into NTS, but significantly attenuated (32%) the HR response. Subsequent administration of the ganglionic blockers hexamethonium bromide or arfonad abolished both the depressor and bradycaric responses. These data suggest that within a restricted region of the caudal NTS there exists a pool of neurons sensitive to changes in extracellular Na + concentrations that, when activated by the sodium, elicit vasodepressor responses as a result of sympathoinhibition and bradycardia as a result of vagal excitation and sympathoinhibition.

Vagal afferents reflexly inhibit exercise in conscious rats

Activation of vagal afferents reflexly inhibited locomotion induced by stimulation of the mesencephalic locomotor region in decerebrate cats. However, this reflex has not been tested in intact mammals. Therefore, the purpose of this study was to test the hypothesis that vagal afferent stimulation would inhibit somatomotor activity in the intact conscious rat. Six Sprague-Dawley rats were chronically instrumented with carotid arterial and femoral venous catheters and electromyogram (EMG) electrodes inserted into the biceps femoris muscle. Cardiac autonomic efferent blockade [atropine methyl bromide (14 mg.kg-1, i.v.) and metoprolol (14 mg.kg-1, i.v.)] and alpha-adrenergic receptor blockade [phenoxybenzamine (5 mg.kg-1, i.v.)] was achieved to prevent bradycardia and hypotension. Vagal afferents were stimulated (phenyl-biguanide 2.5 and 5.0 micrograms.kg-1 i.v.) during steady state exercise (9.0 m.min-1, 10% grade). Phenyl-biguanide decreased exercise EMG activity 30 +/- 6% and 54 +/- 10% in a dose dependent manner without significantly altering mean arterial pressure or heart rate. We speculate that this reflex may serve as a negative feedback mechanism to indirectly reduce myocardial oxygen demands during exercise.

Effect of glutamate stimulation of bed nucleus of the stria terminalis on arterial pressure and heart rate

Experiments were done in the chloralose-anesthetized, paralyzed, and artificially ventilated rat to determine the cardiovascular responses elicited during chemical stimulation of bed nucleus of the stria terminalis (BST) and to investigate the components of the peripheral autonomic nervous system that mediate these responses. Neurons in BST were selectively stimulated by the microinjection (10-20 nl) of the excitatory amino acid L-glutamate (1 M). Stimulation of BST elicited decreases in mean arterial pressure (n = 105) of -6 to -55 mmHg. These depressor responses were on occasion (n = 60) accompanied by decreases in heart rate ranging between -10 and -40 beats/min. The largest depressor responses were consistently elicited from a crescent-shaped region of BST around the dorsolateral, lateral, and ventrolateral surfaces of the anterior commissure. Intravenous administration of the muscarinic receptor blocker, atropine methylbromide, had no affect on the magnitude of the mean arterial pressure and heart rate responses. On the other hand, administration (intravenous) of the nicotinic receptor blocker, hexamethonium bromide or arfonad, abolished both the depressor response and cardiac slowing during stimulation of BST. These data suggest that the BST depressor and the bradycardia responses are mediated by inhibition of both sympathetic vasoconstrictor fibers to the vasculature and cardioacceleratory fibers to the heart, respectively.

Gastric vagus mediates immobilization-induced hypocalcemia in rats.

The involvement of the parasympathetic nervous system in the etiology of stress-induced hypocalcemia was investigated in the rat. Atropine methyl bromide (0.1 and 0.6 mg/kg ip) given 20 min before immobilization (IMB) was observed to suppress the induction of hypocalcemia in a dose-dependent manner. A vagotomy of the bilateral cervical trunks also abolished the IMB-induced hypocalcemia. A vagotomy on either the thyroid/parathyroid branches or the celiac branches had no effect on the IMB-induced hypocalcemia, but a vagotomy on the gastric branches completely abolished it. Pretreatment with either secretin (2 and 6 micrograms/kg ip), an inhibitor of gastrin release, or cimetidine (5 and 10 mg/kg ip), a histamine H2-receptor antagonist, diminished the IMB-induced hypocalcemia. The concentration of serum gastrin increased significantly during IMB. It is thus concluded that the decreased levels of plasma calcium caused by IMB are due to the activation of the vagus innervating the stomach. Gastrin and histamine are also involved as a consequence of the activation of the vagus.

Anticholinergic sensitivity in the aging rat septohippocampal system as assessed in a spatial memory task

The effects of central cholinergic blockade on spatial memory were tested in aged and basal forebrain-lesioned rats using the Morris Water Maze. In Experiment 1, aged rats (18–21 months old) were characterized as behaviorally impaired or nonimpaired based on water maze performance prior to an atropine sulfate challenge. In the atropine test (50 mg/kg, IP), both the impaired and the nonimpaired rats showed a severe disruption of their search behavior compared to young subjects. This effect was due to blockade of central receptors since peripheral cholinergic blockade using atropine methylbromide did not produce any impairments. Experiment 2 investigated effects of atropine on rats with septal lesions (SL), nucleus basalis lesions (NBL), and rats with both lesions combined (SL + NBL). Before drug treatment, the groups with septal lesions (SL and SL + NBL groups) displayed a moderate impairment in locating the platform site. However, similar to the aged rats, the septal-lesioned rats exhibited severe impairments in the water maze during the atropine treatment. This effect was not seen in the normal controls or in the NBL rats. Aged rats, either impaired or nonimpaired in a spatial memory task, showed a pronounced sensitivity to pharmacological blockade of central cholinergic neurotransmission which resulted in severe deficits in spatial navigation in the water maze. Since the same behavioral deficit was produced by cholinergic blockade in young rats with septal lesions, we concluded that the impaired water maze performance seen in the aged rats during cholinergic blockade resulted from impaired function in the septohippocampal system.

In vivo correlation of doppler waveform analysis with arterial input impedance parameters

Previous studies have confirmed that Doppler waveform analysis (DWA) offers a valid reflection of changes in peripheral vascular resistance. However, the ability of the pulsatility index (PI), a parameter of DWA, to reflect the dynamic components of the circulation, as assessed by arterial input parameters, remains uncertain. In addition, the state of the central circulation is considered an important factor influencing the accuracy of this technique. This study evaluated the ability of the aortic PI to reflect alterations of input impedance in a chronically instrumented lamb model that was subjected to pharmacologic alteration of the circulation. Pressure, volumetric flow and continuous-wave Doppler frequency shift measurements were recorded from the infrarenal abdominal aorta. The parameters of input impedance, peripheral vascular resistance ( Zpr), characteristic impedance ( Zo) and reflection coefficient ( Rc), were determined and then correlated with changes in the aortic P1. Initially, perturbations of the circulatory state were created with a vasodilator, hydralazine (HY) and a vasoconstrictor, phenylephrine (PE). During a second set of experiments, the effect of the reflex heart rate (HR) responses on the PI was evaluated. This was accomplished by inhibiting reflex HR responses to these vasoactive agents with either trimethophan (TM) or atropine methyl bromide (AMB). In response to HY and HY with TM, significant decreases in the PI and impedance parameters occurred. Administration of PE and PE with AMB resulted in significant increases in PI and each of the impedance parameters. HY and PE induced changes in PI correlated significantly with changes in volumetric flow ( r = 0.82, 0.80; p < 0.001), mean arterial blood pressure ( r = 0.64, 0.70; p < 0.001) and Zpr ( r = 0.77, 0.80; p < 0.001), but not with Zo ( r = 0.34, 0.36) and Rc ( r = 0.26, 0.31). However, when reflex HR responses were inhibited during the administration of the vasoactive agents, HY with TM and PE with AMB, induced changes in PI correlated significantly with Zo ( r = 0.93, 0.89; p < 0.001) and Rc ( r = 0.84, 0.83; p < 0.001), and the correlation with mean arterial pressure ( r = 0.78, 0.87; p < 0.05) and Zpr ( r = 0.92, 0.91; p < 0.05) was significantly greater. These findings indicate that the PI accurately assesses pharmacologically induced changes in the downstream arterial input impedance. The accuracy of this assessment is enhanced further when central circulatory factors such as changes in HR are considered.