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Chlorisondamine (CSD) has been used to assess the neurogenic contribution to blood pressure (BP) and vasomotor sympathetic tone in animal models. It is assumed that the reduction in BP following CSD administration is associated to decreases in cardiac output (CO) and peripheral resistance, reflecting cardiac and vasomotor sympathetic tone, respectively. Surprisingly, this has not been characterized experimentally in mice, despite the extensive use of this animal model in cardiovascular research. We hypothesize that a specific dose of CSD can selectively block the sympathetic vasomotor tone. To test this hypothesis, we evaluated the effects of different doses of CSD (intraperitoneal) on BP and heart rate (HR) using telemetry, and on CO using echocardiography. BP and HR in normotensive C57Bl/6J mice reduced to a similar extent by all CSD doses tested (1–6 mg/kg). CSD at 6 mg/kg also reduced CO without affecting left ventricular stroke volume or fractional shortening. On the other hand, lower doses of CSD (1 and 2 mg/kg) produced significantly larger BP and HR reductions in DOCA‐salt–induced hypertensive mice, indicating a greater neurogenic BP response. In addition, all doses of CSD reduced CO in hypertensive mice. Our data suggest that the BP response to CSD in mice likely reflects reduced CO and vasomotor sympathetic tone. We conclude that CSD can be used to assess the neurogenic contribution to BP in mice but may not be appropriate for specifically estimating vasomotor sympathetic tone., Ganglionic blocker, chlorisondamine, can be used to assess the neurogenic contribution to BP in mice, but may not be appropriate to specifically estimate the vasomotor sympathetic tone.

Background and Purpose 3,4-Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with stimulatory cardiovascular effects that can lead to serious medical complications. Here we examined the pharmacological mechanisms underlying these cardiovascular actions of MDPV in conscious rats. Experimental Approach Male Sprague-Dawley rats had telemetry transmitters surgically implanted for the measurement of blood pressure (BP) and heart rate (HR). On test days, rats were placed individually in standard isolation cubicles. Following drug treatment, cardiovascular parameters were monitored for 3 h sessions. Key Results Racemic MDPV (0.3–3.0 mg/kg) increased BP and HR in a dose-dependent manner. The S(+) enantiomer (0.3–3.0 mg/kg) of MDPV produced similar effects, while the R(-) enantiomer (0.3–3.0 mg/kg) had no effects. Neither of the hydroxylated phase I metabolites of MDPV altered cardiovascular parameters significantly from baseline. Pretreatment with the ganglionic blocker chlorisondamine (1 and 3 mg/kg) antagonized the increases in BP and HR produced by 1 mg/kg MDPV. The α-adrenergic antagonist prazosin (0.3 mg/kg) attenuated the increase in BP following MDPV, while the β-adrenergic antagonists propranolol (1 mg/kg) and atenolol (1 and 3 mg/kg) attenuated the HR increases. Conclusions and Implications The S(+) enantiomer appears to mediate MDPV's cardiovascular effects, while the metabolites of MDPV do not alter BP or HR significantly. MDPV produces increases in BP and HR through activation of central sympathetic outflow. Mixed-action α/β-receptor blockers may be useful as treatments in counteracting the adverse cardiovascular effects of MDPV.

We recently reported that feeding Sprague Dawley rats a high-salt diet during pregnancy programmed an exaggerated pressor and tachycardic response to restraint in adult female offspring. In the present investigation, a pharmacologic approach was used to determine the contribution of the sympathoadrenal system to the exaggerated response. Injection of a cocktail containing a ganglionic blocker (chlorisondamine) and a beta-adrenoceptor antagonist (propranolol) prevented the stress-induced tachycardia and increase in blood pressure and abolished the difference between high-salt and normal-salt offspring. These data suggest that the prenatal high salt programmed a sympathoadrenal hyperresponsiveness to restraint stress.

Objective This study examined the hypothesis that intracellular cGMP stimulates the release of catecholamines from sympathetic nerve terminals (SNTs) in conscious rats. Methods Conscious rats were prepared to determine the effects of intravenously-administered agents on heart rate (HR) and mean arterial blood pressure (MAP). Results Bolus intravenous injections of the membrane-permeable cGMP analogue, 8-(4-chlorophenylthio)-cGMP (8-CPT-cGMP), elicited immediate and pronounced increases in HR before any changes in MAP were observed. In contrast, injections of cGMP did not elicit changes in HR or MAP. The 8-CPT-cGMP-induced tachycardia was markedly diminished by (1) the β1,2-adrenoceptor antagonist, propranolol, (2) the ganglion blocking agent, chlorisondamine, and (3) bretylium, which blocks Ca2+-dependent mobilization of vesicular stores of catecholamines from SNTs. 8-CPT-cGMP also elicited minor falls in MAP in propranolol-treated rats but elicited pronounced falls in MAP in rats treated with chlorisondamine, bretylium, or combined administration of bretylium and the muscarinic receptor antagonist, methyl-atropine. Conclusions These findings suggest that (1) intracellular cGMP elicits the release of Ca2+-sensitive and Ca2+-insensitive stores of catecholamines from SNTs in conscious rats, and (2) cGMP-mediated release of catecholamines from SNTs antagonizes cGMP-mediated relaxation of vascular smooth muscle in resistance arteries. Taken together, these findings support the concept that increases in intracellular cGMP levels by atrial natriuretic peptide and endothelium- and cardiac-derived nitric oxide regulate sympathetic control of the heart and the microvasculature of conscious rats via cGMP-dependent release of catecholamines.

In this study the hypothesis was tested that chronic infusion of ANG II attenuates acute volume expansion (VE)-induced inhibition of renal sympathetic nerve activity (SNA). Rats received intravenous infusion of either vehicle or ANG II (12 ng · kg−1 · min−1) for 7 days. ANG II-infused animals displayed an increased contribution of SNA to the maintenance of mean arterial pressure (MAP) as indicated by ganglionic blockade, which produced a significantly ( P < 0.01) greater decrease in MAP (75 ± 3 mmHg) than was observed in vehicle-infused (47 ± 8 mmHg) controls. Rats were then anesthetized, and changes in MAP, mean right atrial pressure (MRAP), heart rate (HR), and renal SNA were recorded in response to right atrial infusion of isotonic saline (20% estimated blood volume in 5 min). Baseline MAP, HR, and hematocrit were not different between groups. Likewise, MAP was unchanged by acute VE in vehicle-infused animals, whereas VE induced a significant bradycardia ( P < 0.05) and increase in MRAP ( P < 0.05). MAP, MRAP, and HR responses to VE were not statistically different between animals infused with vehicle vs. ANG II. In contrast, VE significantly ( P < 0.001) reduced renal SNA by 33.5 ± 8% in vehicle-infused animals but was without effect on renal SNA in those infused chronically with ANG II. Acutely administered losartan (3 mg/kg iv) restored VE-induced inhibition of renal SNA ( P < 0.001) in rats chronically infused with ANG II. In contrast, this treatment had no effect in the vehicle-infused group. Therefore, it appears that chronic infusion of ANG II can attenuate VE-induced renal sympathoinhibition through a mechanism requiring AT1 receptor activation. The attenuated sympathoinhibitory response to VE in ANG II-infused animals remained after arterial barodenervation and systemic vasopressin V1receptor antagonism and appeared to depend on ANG II being chronically increased because ANG II given acutely had no effect on VE-induced renal sympathoinhibition.

This study investigates the contribution of the peripheral nervous system to the cardiovascular component of long lasting (40 min) conditioned fear responses to context. The conditioned fear response evoked by reexposure to a footshock chamber was tested 10 min after intravenous injection of either the nicotinic ganglion blocker chlorisondamine (0.6 mg/kg) or the alpha-adrenoceptor antagonist phentolamine (10 mg/kg) in six rats implanted with telemetric probes. Compared to saline controls, chlorisondamine did not change the behavioural component of the response (freezing, ultrasonic vocalizations) but almost completely abolished its cardiovascular component (mean arterial pressure and heart rate). Phentolamine also abolished the pressor response but increased the cardiac response, and ultrasonic vocalizations were reduced by half. The results indicate that the long lasting pressor response of conditioned fear to context is sympathetically mediated like the much shorter pressor response of conditioned fear to a discrete stimulus.

This study investigated the cellular basis for the enhanced ganglionic responsiveness to NK1 agonists in the spontaneously hypertensive rat (SHR) in comparison to their normotensive counterpart, the Wistar-Kyoto (WKY) rat. Rats for in vivo studies were anesthetized with pentobarbital and treated with chlorisondamine (10.5 micromol/kg). Extracellular recordings from the external carotid nerve showed a greater responsiveness of decentralized SHR superior cervical ganglia (SCG) to intravenous injection of SP (32 nmol/kg). Blood pressure and heart rate were increased in SHRs, whereas WKY rats responded with a decrease in blood pressure and only slight tachycardia. Membrane properties of SCG neurons, as shown by intracellular microelectrode recordings, were similar between strains. Picospritzer application of the NK1 agonist GR-73632 (100 microM, 1 s) evoked slow depolarization and increased neuron excitability. Spontaneous firing was evoked only in some neurons. Depolarization amplitudes were similar between strains; however, the NK1 agonist depolarized a greater number of neurons in hypertensive rats. In conclusion, SHRs are more responsive to ganglion stimulation by NK1 agonists due to a greater number of responsive cells within the SCG rather than an enhanced responsiveness of individual neurons.

Previous studies have shown that central administration of GABA (gamma -aminobutyric acid), an inhibitory neurotransmitter, preferentially reduces hindquarters and carotid vascular resistances but not renal and coeliac vascular resistances in conscious rats. This study tested the hypothesis that these preferential actions of central GABA receptors are related to differences between vessels in resting autonomic vascular tone in freely moving rats. Rats were chronically implanted with intracisternal cannulas and/or electromagnetic probes to measure regional blood flows. In response to GABA administration, the changes in vascular resistance (arterial blood pressure/regional blood flow) of the hindquarters (n = 23) and carotid (n = 12) vascular beds were significantly and negatively correlated with basal vascular resistance. No such relationship was found for the renal (n = 21), coeliac (n = 13) and superior mesenteric (n = 23) vascular beds. This finding indicates that the responsiveness to GABA of brainstem pathways controlling the hindquarters and carotid vascular beds co-varies with resting resistance in hindquarters and carotid vessels. A similar analysis was performed, correlating the ongoing vascular resistance of each vessel with its response to ganglionic blockade by chlorisondamine. In this case, a significant negative correlation was also found for the hindquarters (n = 26) and carotid (n = 15) vascular beds, but not for the coeliac (n = 17) or superior mesenteric (n = 19) vessels. Together, these findings suggest that central GABA receptors accessible from the cisterna magna preferentially affect two vascular beds which, in the freely moving rat, show resting autonomic vascular tone.

Intravenous injection of substance P (SP) increases blood pressure in normotensive rats by stimulating sympathetic ganglia. This study compared the effects of SP to increase renal nerve firing and blood pressure in normotensive and hypertensive rats treated with chlorisondamine. The increase in renal nerve firing was greatest in spontaneously hypertensive rats (SHR), intermediate in Wistar rats, and least in Wistar-Kyoto (WKY) rats. Blood pressure was increased more in SHR than in Wistar rats. Blood pressure was not increased in WKY rats. Responses to the ganglionic stimulant 1,1-dimethyl-4-phenylpiperazinium were the same in the three strains. These results suggest that there is a selective increase in the action of SP on sympathetic ganglia of SHR and that ganglion responsiveness to SP is correlated with its effect on blood pressure.

Substance P (SP) evokes bradycardia that is mediated by cholinergic neurons in experiments with isolated guinea pig hearts. This project investigates the negative chronotropic action of SP in vivo. Guinea pigs were anesthetized with urethane, vagotomized and artificially respired. Using this model, IV injection of SP (32 nmol/kg/50 μl saline) caused a brief decrease in heart rate (−30 ± 3 beats/min from a baseline of 256 ± 4 beats/min, n = 27) and a long-lasting decrease in blood pressure (−28 ± 2 mmHg from baseline of 51 ± 5 mmHg, n = 27). The negative chronotropic response to SP was attenuated by muscarinic receptor blockade with atropine (−29 ± 9 beats/min before vs −8 ± 2 beats/min after treatment, P = 0.0204, n = 5) and augmented by inhibition of cholinesterases with physostigmine (−23 ± 6 beats/min before versus −74 ± 20 beats/min after treatment, P = 0.0250, n = 5). Ganglion blockade with chlorisondamine did not diminish the negative chronotropic response to SP. In another series of experiments, animals were anesthetized with sodium pentobarbital or urethane and studied with or without vagotomy. Neither anesthetic nor vagotomy had a significant effect on the negative chronotropic response to SP ( F 3,24 = 1.97, P = 0.2198). Comparison of responses to 640 nmol/kg nitroprusside and 32 nmol/kg SP demonstrated that the bradycardic effect of SP occurs independent of vasodilation. These results suggest that SP can evoke bradycardia in vivo through stimulation of postganglionic cholinergic neurons.

The cardiovascular effects of three different acetylcholinesterase inhibitors: physostigmine, tacrine and rivastigmine injected by intravenous (i.v.) route were compared in freely moving Wistar rats. The three drugs significantly increased both systolic and diastolic blood pressure and decreased heart rate. Compared to physostigmine, a 20-fold higher dose of tacrine and a 40-fold higher dose of rivastigmine was necessary to induce a comparable pressor effect. Tacrine was chosen as a model to study the mechanisms underlying the cardiovascular effects of i.v. cholinesterase inhibitors. Atropine totally abolished while methylatropine did not affect tacrine pressor effects. Conversely, both drugs abolished tacrine-induced bradycardia. The alpha1-adrenoceptor antagonist prazosin or the vasopressin V1 receptor antagonist, [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl1, O-Me-Tyr2, Arg8] vasopressin partially but significantly reduced tacrine pressor effect and mostly abolished it when administered concomitantly. The tacrine pressor response was inhibited in a dose-dependent manner by the i.c.v. administration of the non-selective muscarinic receptor antagonist atropine (ID50 = 1.45 microg), the muscarinic M1 receptor antagonist pirenzepine (ID50 = 4.33 microg), the muscarinic M2 receptor antagonist methoctramine (ID50 = 1.39 microg) and the muscarinic M3 receptor antagonist para-fluoro-hexahydro-sila-difenidol (ID50 = 31.19 microg). Central injection of such muscarinic receptor antagonists did not affect tacrine-induced bradycardia. Our results show that acetylcholinesterase inhibitors induce significant cardiovascular effects with a pressor response mediated mainly by the stimulation of central muscarinic M2 receptors inducing a secondary increase in sympathetic outflow and vasopressin release. Conversely, acetylcholinesterase inhibitor-induced bradycardia appears to be mediated by peripheral muscarinic mechanisms.

Abstract —The initial stages of hypertension in the spontaneously hypertensive rat (SHR) are characterized by an increase in cardiac output. Venous capacitance plays an important role in the control of cardiac output. This study tested the hypothesis that venous tone is elevated in the developmental stages of spontaneous hypertension. Male SHR or normotensive Wistar-Kyoto (WKY) rats were instrumented for the measurement of arterial pressure (FAP) and intrathoracic vena caval pressure (FVP). A latex-tipped catheter was advanced into the right atrium via the jugular vein. Mean circulatory filling pressure (MCFP), an index of integrated venomotor tone, was calculated as MCFP=FVP+(FAP−FVP)/VAR. FAP and FVP were recorded after 5 seconds of right atrial balloon inflation. The venous to arterial compliance ratio (VAR) was estimated as 76 for WKY and 106 for SHR. Mean arterial pressure (MAP), heart rate, and MCFP were recorded in conscious rats of 4 to 6 and 8 to 10 weeks of age. In 4- to 6-week-old rats, both MAP and MCFP were significantly elevated in the SHR (MAP, 129±6 mm Hg; MCFP, 6.6±0.4 mm Hg) compared with the age-matched WKY (MAP, 91±6 mm Hg; MCFP, 5.4±0.4 mm Hg), whereas heart rate was not significantly different. The elevations in MAP (SHR, 144±4 mm Hg; WKY, 102±3 mm Hg) and MCFP (SHR, 7.7±0.3 mm Hg; WKY, 6.0±0.2 mm Hg) in SHR were exaggerated at 8 to 10 weeks of age. After ganglionic blockade (chlorisondamine; 10 mg/kg), the differences in MCFP were no longer statistically significant between SHR and WKY at both 4 to 6 weeks of age (3.9±0.2 versus 4.0±0.3 mm Hg) and 8 to 10 weeks of age (5.0±0.3 versus 4.3±0.3 mm Hg, respectively). The differences in MAP at 4 to 6 weeks of age (79±7 versus 67±5 mm Hg, respectively) also were not statistically significant after ganglionic blockade. However, a significant difference in MAP between strains remained after ganglionic blockade in 8- to 10-week-old rats (90±5 versus 63±3 mm Hg, respectively). These findings indicate that venous tone is increased via autonomic effector systems during the developmental stages of spontaneous hypertension. These data also suggest that autonomic mechanisms predominate at very early stages, whereas nonautonomic mechanisms assume more importance in maintaining the elevated MAP as hypertension progresses.

We recently showed that, in conscious rats, acute infusions of insulin (10–15 fold increase in plasma insulin) produced decreases in hindquarter vascular resistance, but only if, changes in sympathetic outflow were prevented with a ganglionic blocker. The aim of the present investigation was to determine if similar effects of insulin could be observed in a preparation that allowed direct visualization of striated muscle (cremaster) microvessels. Initial studies with topical application of insulin showed that third-order arterioles (A3), but not first- or second-order arterioles vasodilated in response to 800 μU/ml and 8 mU/ml of insulin. Systemic (euglycemic) infusion of insulin (6 mU/ml, but not 2 mU/ml) also increased A3 arteriole diameter in animals treated with a ganglionic blocker, but not in control rats. These data show that insulin can have a direct vasodilator effect on striated muscle microvessels if concomitant increases in sympathetic outflow are absent. However, the response was only present with supraphysiological doses of the hormone.

Venous capacitance plays an important role in the control of cardiac output. However, the central nervous system sites and neurochemical signals involved in modulating venous function remain to be fully elucidated. The hypothalamic paraventricular nucleus (PVN) is an important site modulating autonomic outflow to the cardiovascular system. The present study tested the hypothesis that removal of tonic GABAergic tone in the PVN would increase peripheral venous tone. Mean circulatory filling pressure was used as an index of venous tone. Arterial pressure, venous pressure, heart rate, and mean circulatory filling pressure (MCFP) were monitored in conscious male Sprague Dawley rats. The rats were challenged with microinjections of bicuculline methiodide (BMI) (25 ng) or vehicle (artificial cerebrospinal fluid) into the PVN. In one group of rats, BMI injections were performed before and after ganglionic blockade with chlorisondamine hydrochloride (10 mg/kg) and atropine (0.4 mg/kg) given subcutaneously. In a second group, BMI injections were performed in chlorisondamine-treated rats whose blood pressure had been returned to control with an infusion of norepinephrine. Injection of bicuculline into the PVN increased MAP (14 +/- 2 to 18 +/- 2 mmHg) and HR (49 +/- 12 to 74 +/- 14 bpm). MCFP also increased significantly by 1.00 +/- 0.17 to 1.39 +/- 0.18 mmHg, indicating an increase in the driving pressure for venous return. Injection of the vehicle did not affect these variables. In both groups, ganglionic blockade significantly attenuated the bicuculline-induced increases in MAP, HR and MCFP. These data indicate that sympathetic drive from the PVN to the venous system is under tonic GABAergic control.

This study tried to assess the possible contribution of the sympathetic nervous system to the onset of two-kidney, one-clip (2K-1C) Goldblatt hypertension.The effect of chlorisondamine administration with or without subsequent splanchnicotomy on the development of hypertension was examined in 2K-1C rats with special reference to norepinephrine synthesis.The 2K-1C rats were treated either with chlorisondamine or chlorisondamine plus subsequent splanchnicotomy, so that the development of hypertension was effectively arrested for 4 weeks. An apparently high rate of release of norepinephrine in 2K-1C rats was reduced by treatment with chlorisondamine plus splanchnicotomy. A similar trend was also seen in plasma norepinephrine concentration and norepinephrine clearance, to a lesser extent. There were significant positive relationships between percent change of systolic blood pressure and apparent rate of release of norepinephrine, plasma norepinephrine concentration and norepinephrine clearance in 2K-1C rats and 2K-1C + chlorisondamine + splanchnicotomy rats. There were no significant relationships in these parameters in sham-treated rats.Increased sympathetic innervation appears to participate in the development of 2K-1C Goldblatt hypertension.

Intravenous cocaine (0.03–3 mg/kg) produced two distinct and temporally separable effects in rats. One is an initial, large, and brief increase in blood pressure (BP) and heart rate (HR) of a rapid onset (abrupt hemodynamic stimulation). A rapid, brief, and intense behavioral arousal accompanied this abrupt hemodynamic stimulation. The other effect of cocaine is a prolonged locomotor activation of a relatively slower onset. Prolonged increases in BP and HR accompanied this locomotor effect. The threshold doses of cocaine to produce abrupt hemodynamic stimulation and locomotion are 0.03 and 0.3 mg/kg, respectively. Dopamine receptor antagonists, SCH 23390 or eticlopride, at a 0.03 mg/kg dose antagonized the locomotion and the parallel prolonged increases in BP and HR, but not the initial brief behavioral arousal and abrupt hemodynamic stimulation responses to cocaine. Peripheral dopamine receptor antagonist, domperidone, altered neither behavioral nor cardiovascular effects of cocaine. Chlorisondamine (1 mg/kg), an autonomic ganglionic blocker, did not alter either the initial brief behavioral arousal or the locomotor responses to cocaine, but it prevented the cardiovascular changes that accompanied both these behavioral responses. Norepinephrine, a direct adrenergic vasoconstrictor, although produced rapid and large increase in BP, did not cause abrupt behavioral arousal or locomotor activation. Unlike cocaine, monoamine reuptake inhibitors that are selective for norepinephrine (nisoxetine, 0.1–1 mg/kg) or serotonin (fluoxetine, 0.3–3 mg/kg) produced neither brief behavioral arousal and abrupt hemodynamic stimulation nor locomotor activation. Dopamine-selective reuptake inhibitor, GBR 12909, also did not elicit the initial brief behavioral arousal and abrupt hemodynamic stimulation. But, GBR 12909, like cocaine, produced a prolonged locomotor effect and parallel increases in BP and HR. These effects of GBR 12909 were prevented by SCH 23390 and eticlopride, but not by domperidone. Similar to cocaine, cardiovascular, but not the locomotor effects of GBR 12909 were prevented by chlorisondamine. Lidocaine (0.3–3 mg/kg), a sodium channel blocker and local anesthetic, produced neither behavioral nor physiological changes. Both cocaine (3 mg/kg) and GBR 12909 (1 mg/kg) increased plasma norepinephrine and epinephrine concentrations. These increases were antagonized by both eticlopride and SCH 23390. These results indicate that behavioral and cardiovascular effects of cocaine are intricately related with respect to the molecular mechanisms involved. Two pharmacodynamic actions of cocaine appear to mediate these effects. One is a dopamine-dependent while the other is a monoamine- and sodium channel-independent novel action. The former mediates cocaine's locomotor effect and the accompanying prolonged increases in BP and HR, while the latter mediates the initial brief behavioral arousal and the accompanying abrupt hemodynamic stimulation.

In the rat, but not in humans and other mammals, chronic administration of insulin produces hypertension. The present aim was to determine the effect of acute insulin infusion on regional vascular resistances and to determine the neurogenic contribution to the response. Conscious rats were infused with insulin (2 or 6 mU/min) before and after ganglionic blockade with chlorisondamine (5 mg/kg). The low dose of insulin produced an increase in arterial pressure and hindquarter vascular resistance; the high dose produced a gradual decrease in arterial pressure and renal resistance. After ganglionic blockade, the hindquarter vasoconstriction produced by the low dose was abolished. The high dose of insulin produced both hindquarter and renal vasodilation. Thus the low dose of insulin had a selective neurogenic vasoconstrictor effect in rat skeletal muscle vascular beds. With higher doses, direct vasodilatory effects in both skeletal muscle and renal vascular beds appeared. This greater sensitivity of the sympathoexcitatory effects of insulin in rats may explain the ability of chronic insulin infusions to increase blood pressure in this species.

Abstract Heme oxygenase is a mammalian enzyme that converts heme to biliverdin and carbon monoxide. Carbon monoxide activates soluble guanylate cyclase and relaxes vascular smooth muscle, and it has been implicated as a potential neuromessenger. The regulatory functions of endogenous carbon monoxide on hemodynamics are not known. Zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) inhibits heme oxygenase in rats and thus permits assessment of the hemodynamic response to inhibition of endogenous carbon monoxide synthesis. In chronically instrumented, awake male Sprague-Dawley rats, ZnDPBG (45 μmol/kg IP) increased mean arterial pressure (19±2%, P P P P 1 -adrenoceptor functions, respectively, ZnDPBG did not affect arterial pressure or heart rate. This suggests that ZnDPBG-induced increases in blood pressure rely on autonomic nervous function. We conclude that the pressor response to heme oxygenase inhibitors results from withdrawal of the inhibitory influence of endogenous carbon monoxide on a pressor mechanism mediated by the autonomic nervous system.

Electromagnetic flow probes were used to measure regional blood flow responses to central injection of L-proline in conscious rats. Ten min after intracisternal injection of 10 mumol of L-proline, arterial pressure increased from 113 +/- 1.6 (mean +/- SEM, n = 23) to 142 +/- 2.9 mmHg, while the heart rate decreased from 383 +/- 9.6 (n = 23) to 313 +/- 5.4 beats/min, vascular resistance increased an average of 239% in the superior mesenteric artery (n = 8) and 72% in the renal artery (n = 8), without change in the terminal aorta (-6%, n = 7). However, 10 mumol of D-proline induced neither blood pressure increase nor bradycardia 10 min after its injection. After sino-aortic denervation, the heart rate was not decreased by L-proline injection. Ganglionic blockade with chlorisondamine evoked significantly greater pressor action by L-proline injection than that without treatment, but intravenous injection of the vasopressin antagonist, (d(CH2)5(1), O-Me-Tyr2, Arg8)-vasopressin (10 micrograms/kg), promptly dilated the superior mesenteric vascular bed and lowered the arterial pressure. In addition, pretreatment with the vasopressin antagonist alone almost abolished the pressor and vasoconstrictor action induced by L-proline injection. These results indicate that intracisternal injection of L-proline specifically elicited an increase in arterial pressure mainly through marked vasoconstriction of the superior mesenteric artery bed, and that bradycardia was elicited via the baroreflex. Thus, vasopressin release in the blood-stream was involved in these hemodynamic actions.

The role of the baroreflex in the spectral characteristics of mean arterial pressure (MAP) and heart rate (HR) was investigated in 12 control rats and 9 rats with chronic sinoaortic baroreceptor denervation (SAD) during 1) basal conditions and 2) ganglionic blockade with chlorisondamine and restoration of the basal MAP level. In SAD rats, power spectral density of MAP, estimated by a fast Fourier transform, was reduced in the low-frequency (LF, 0.27- to 0.74-Hz) band. Ganglionic blockade highly decreased LF power spectral density of MAP in control rats. No relationship was found between the MAP response to chlorisondamine, taken as an index of the sympathetic vasomotor tone, and the basal LF power spectral density. Transfer function analysis between MAP and HR showed that, in control rats, coherence was high for frequencies surrounding the LF and high-frequency peaks. In SAD rats, coherence was abolished in the LF band but maintained in the high-frequency band. In conclusion, approximately 80% of the LF power spectral density of MAP depends on the sympathetic nervous system activity, and the baroreflex accounts for one-half of this power and for the coherence between MAP and HR oscillations in the LF band.

Prolonged attenuation of vagal action at the heart, proposed to be due to release of the sympathetic cotransmitter neuropeptide Y (NPY), follows stimulation of cardiac sympathetic nerves. It has been shown that pretreatment with reserpine depletes cardiac and neuronal stores of both noradrenaline and NPY, while combined pretreatment with reserpine and the ganglion blocking agent chlorisondamine reduces depletion of NPY, while still depleting noradrenaline. The effects of reserpine pretreatment and combined chlorisondamine and reserpine pretreatment on the inhibition of cardiac vagal action evoked by cardiac sympathetic nerve stimulation (16 Hz, 2 min) were compared in anaesthetised dogs. In dogs with no pretreatment (n = 6), sympathetic stimulation evoked an immediate cardio-acceleration, and a prolonged inhibition of cardiac vagal action, with a maximum percent inhibition (MPI) and time to half-recovery (T50) of 78 +/- 6% and 16 +/- 2 min respectively. In dogs pretreated with reserpine (n = 6, 1 mg/kg, 24 h), the immediate cardio-acceleration (ANOVA, P0.01), and the magnitude (MPI = 31.8%, ANOVA, P0.001) and duration (T50 = 6 +/- 1 min, ANOVA, P0.05) of inhibition of cardiac vagal action following sympathetic stimulation were significantly attenuated. In dogs with combined chlorisondamine (n = 5, 2 mg/kg, 48 and 24 h) and reserpine pretreatment, there was again significantly reduced cardio-acceleration (ANOVA, P0.01), but the inhibition of cardiac vagal action following sympathetic stimulation did not significantly differ from untreated animals (MPI = 79 +/- 8%, T50 = 21 +/- 6 min). Intravenous injections of NPY (25-50 micrograms/kg) evoked prolonged inhibition of cardiac vagal action in untreated and both groups of pretreated animals. These experiments indicate that the cardio-accelerator and vagal inhibitory capacities of sympathetic nerve stimulation can be separated, and are consistent with the sympathetic vagal inhibitory factor being NPY.

We have previously reported that insulin-resistant Zucker obese rats exhibit hypertension associated with impaired vascular smooth muscle (VSM) Ca2+ transport and proposed that this results from failure of insulin to regulate VSM Ca2+ transport in insulin resistance. However, hypertension in insulin-resistant states is generally attributed to hyperinsulinemia, with a consequent stimulation of sympathetic neural activity. Accordingly, the present study was conducted to determine whether the hypertension observed in Zucker obese rats compared with their lean controls was dependent on either increased sympathetic neural activity or exaggerated vascular reactivity. Intra-arterial blood pressure responses to ganglionic blockade with Ecolid (chlorisondamine chloride) and to graded intravenous injections of angiotensin II and norepinephrine were compared in 6- to 8-wk-old male Zucker rats and their lean controls (n = 10/group). The obese rats exhibited significant hypertension before ganglionic blockade (P less than 0.001), and this difference was largely sustained during ganglionic blockade (P less than 0.005). Furthermore, the obese rats exhibited greater pressor sensitivity to both angiotensin II and to norepinephrine during ganglionic blockade (P less than 0.01). Thus enhanced pressor sensitivity, independent of sympathetic neural activity, appears to support hypertension in Zucker obese rats.

To assess the hemodynamic effects of acute changes in extracellular ionized calcium concentration, [Ca2+], seven dogs were chronically instrumented to measure heart rate, aortic, left atrial, and left ventricular (LV) pressures, cardiac output, and coronary and renal blood flows. [Ca2+] was lowered 0.35 mmol ± l-1 by citrate infusion and then increased 0.35 mmol ± l-1 above control level by CaCl2 infusions. This protocol was performed in the conscious dogs with and without ganglionic blockade (chlorisondamine 2 mg ± kg-1). LV dP/dtmax decreased at low [Ca2+] and increased at high [Ca2+] during all conditions. The other hemodynamic variables measured were only slightly changed by changing [Ca2+] without ganglionic blockade and surprisingly even less with ganglionic blockade. Therefore, the lesser hemodynamic effects induced by acute changes in [Ca2+] in the conscious compared with anesthetized dogs cannot be explained by the depressant effects of the anesthetics upon the autonomic nervous system. We have suggested that the binding of Mg2+ to citrate may be of importance for the minor hemodynamic effects in the conscious dogs.

The present study was undertaken to determine whether gamma-aminobutyric acid in the paraventricular nucleus contributes to the regulation of cardiovascular function. Blood pressure and heart rate were recorded and plasma catecholamines were measured in conscious rats receiving microinfusions of either artificial cerebrospinal fluid or a gamma-aminobutyric acid antagonist, bicuculline methiodide, bilaterally into the paraventricular nucleus. Artificial cerebrospinal fluid had no effect on any of the recorded variables. In contrast, infusion of bicuculline into the region of the paraventricular nucleus produced increases in blood pressure (20 +/- 2 mm Hg), heart rate (110 +/- 11 beats/min), and plasma concentrations of norepinephrine (640 +/- 107 pg/ml) and epinephrine (1,266 +/- 267 pg/ml). Pretreatment with a ganglionic blocking agent abolished both the blood pressure (-1 +/- 2 mm Hg) and heart rate (5 +/- 18 beats/min) effects. Bilateral adrenal medullectomy reduced the changes in plasma norepinephrine concentrations (81 +/- 14 pg/ml) significantly and abolished the changes in plasma epinephrine concentrations (5 +/- 4 pg/ml). Conversely, adrenal medullectomy reduced the pressor effects (18 +/- 2 mm Hg) only slightly while the heart rate responses were attenuated (42 +/- 9 beats/min) by approximately 50%. These results suggest that an endogenous gamma-aminobutyric acid system exerts a tonic inhibitory effect on the sympathetic nervous system at the level of the paraventricular nucleus of the hypothalamus.

Intracerebroventricular administration of serotonin (5-HT) to conscious rats increases mean arterial pressure (MAP) and decreases heart rate. To determine the mechanisms involved, 5-HT (2.5 micrograms) was injected intracerebroventricularly into conscious rats pretreated with various neurotransmitter and hormone antagonists. The selective 5-HT2 antagonist LY 53857 abolished the increase in MAP and the bradycardia elicited by 5-HT. The increase in MAP produced by 5-HT was potentiated by chlorisondamine (a ganglionic antagonist), unaffected by prazosin (an alpha 1-antagonist) or a vasopressin V1 antagonist alone, but eliminated by the combined pretreatment with prazosin plus the vasopressin antagonist. In contrast, the bradycardia was eliminated by either the vasopressin V1 antagonist or chlorisondamine. In conclusion, 5-HT injected into the lateral cerebral ventricle of conscious rats induces sympathoexcitation and the release of vasopressin, which results in an increase in MAP; 5-HT also elicits a bradycardia mediated through an interaction of the autonomic nervous system with circulating vasopressin.

Cardiac responses to microinjections of norepinephrine (NE) into the intermediolateral column of the spinal cord (IML) at T2 level were studied in pentobarbital-anesthetized, immobilized and artificially ventilated, male Wistar rats. For describing the effects of NE conveniently, the doses of NE were divided into two ranges. The small dose-range consisted of 20 nl volumes of 50, 75 and 100 micromolar (μM) solutions (i.e. 1, 1.5 and 2 pmole in 20 nl, respectively). The larger dose-range consisted of 20 nl volumes of 2.5, 25, 40 and 50 millimolar (mM) solutions (i.e. 0.05, 0.5, 0.8 and 1 nmole in 20 nl, respectively). Injections of small doses of NE (1–2 pmole) into the IMLincreased heart rate (HR); intravenous injections of these doses did not alter either blood pressure (BP) or HR. Larger doses of NE (0.05–1 nmole) elicited adecrease in HR; intravenous injections of these doses increased HR and BP. Maximum increase in HR was produced by injections of 1.5 pmole of NE into the IML; this effect was blocked by prior injections of prazosin (an α−1adrenergic receptor antagonist; 50 pmole) but not idazoxan (an α−2 adrenergic receptor blocker; 10 pmole) into the IML. Maximum decrease in HR was elicited by injections of 0.8 nmole of NE into the IML; this effect was blocked by idazoxan (10 pmole) but not prazosin (50 pmole). Microinjections of idazoxan (10 pmole) alone increased HR while prazosin (50 pmole) alone was ineffective. Intravenous injections of chlorisondamine (a ganglion blocker) blocked the increase in HR elicited by injections of 1.5 pmole of NE into the IML. Injections of NE, prazosin or idazoxan into the IML did not alter the responses to subsequent injections of glutamate at the same site. The effects of NE remained unchanged in midcollicular decerebrate rats. Vehicles in which NE, prazosin or idazoxan were dissolved, did not elicit a response when injected into the IML. Injections of NE outside the IML failed to elicit any response. These results suggest that NE may have a role to play as a neuromodulator/neurotransmitter in the IML. The pathways involved in these actions of NE in the IML remain to be identified.

Me-Phe 4 -Gly-ol'-enkephalin (DAGO), injected into the medial preoptic nucleus of hypothalamus, on cardiac output and regional blood flow was studied in the conscious rat and the effect of DAGO on renal sympathetic nerve activity and renal blood flow was studied in anesthetized rats. In conscious rats, injections of DAGO (1 or 10 nmol) into the preoptic nucleus increased the blood pressure in a dose-related manner. The maximum rises of mean arterial pressure and pulse pressure after the larger dose were +23 ± 5 mmHg (mean ±SEM, P < 0.01) and + 17 ± 3 mmHg(P < 0.01), respectively. A small dose (0.1 nmol) increased heart rate ( +47 ± 13 bpm, P < 0.05); thc 1 nmol dosc produced bradycardia (- 39 ± 11 bpm, P < 0.05), while the 10 nmol dose initially decreased heart rate ( -68 ± 15 bpm (P < 0.01) and then gradually increased heart rate to a maximum of + 74 ± 13 bpm, (P < 0.0 1). A long-lasting increase in cardiac outpul was also elicited by DAGO, with maximum changes after 1 and 10 nmol of + 14 ± 6% and +22 ± 7% (P < 0.01), respectively. B1ood flow in the hindquarters increascd after DAGO but the mesenteric and renal blood ftow decreased in a dose-related manner. Significant responscs in hindquarter and mesenteric blood fl.ow after DAGO were independent of systemic hemodynamic responses at the dose ofO.l nmol. The vascular resistance in the hindquarters significantly decreased after a small dose of DAGO while the larger doses dose-dependently increased mesenteric and renal vascular resistance. A crucial role of the sympathetic nervous system in the hemodynamic effects of DAGO was demonstrated: (1) by the profound activation of renal sympathetic nerve activity after injections of DAGO (I nmol/100 nl) into the preoptic nucleus, (2) by blockade of the pressor, tachycardic and regional hemodynamic effects of DAGO (I nmol) by the ganglion blocker ch1orisondamine (5 mgjkg i.v.). The results suggest that the pressor effect of DAGO in preoptic nucleus is due primarily to an increase in cardiac output. The differential changes in blood ftow in organs further suggest that the opioid p-receptors in the preoptic nucleus might be involved in the integration of peripheral blood ftow in the hypothalamus during affective behavior. 2 -Me-Phe 4 -Gly-ols-enkephalin (DAGO), chlorisondamine, blood pressure, heart rate, cardiac output, regional blood ftow, sympathetic nerve activity.

The ontogeny of functional sympathetic neural, adrenal medullary, and extra-adrenal components of adrenergic control of heart rate was investigated in borderline hypertensive rats exposed to either high or low sodium chloride (NaCl) from conception through weaning. Borderline hypertensive rats were produced by mating spontaneously hypertensive females with normotensive Wistar-Kyoto males. Females were maintained on diets containing either low (0.12% NaCl) or high (3% NaCl) dietary NaCl throughout pregnancy and lactation. At 28 days of age, baseline heart rates recorded from awake and unrestrained pups did not differ between low and high NaCl-exposed pups. Overall sympathetic tone, inferred from heart rate change after β 1 -adrenergic blockade with atenolol, did not differ between high and low NaCl-exposed pups. Early NaCl exposure did not alter the neural component of sympathetic control of heart rate as inferred from heart rate decrease after bretylium tosylate. Parasympathetic nervous system control, as reflected by tachycardic response to muscarinic receptor blockade with atropine methyl nitrate was also unchanged by early NaCl exposure. The adrenal catecholamine component of sympathetic control of heart rate was inferred from bradycardia following administration of the ganglion blocking agent, chlorisondamine, to pups pretreated with bretylium and atropine methyl nitrate. Pups exposed to low NaCl showed increased adrenal control of heart rate compared to high NaCl-exposed pups. The influence of residual catecholamines on heart rate was inferred from bradycardia following administration of the β 1 -adrenergic receptor blocking agent, atenolol, in pups pretreated with bretylium, atropine methyl nitrate, and chlorisondamine. Residual catecholamine influence was greater in rats exposed to high NaCl. Thus, while overall sympathetic control of heart rate did not differ, pups exposed to low dietary NaCl showed greater adrenal contribution to sympathetic control and pups exposed to high dietary NaCl showed greater extra-adrenal catecholamine contribution.

Cardiovascular Effects of Anatoxin-A in the Conscious Rat. SJREN, A.-L., AND FEUERSTEIN, G. (1990). Toxicol. Appl. Pharmacol. 102,91-100. The effects ofanatoxin-A on mean arterial pressure (MAP), heart rate, cardiac index (CI), and blood flow (BF) in hindquarter (HQ), renal (R). and mesenteric (M) vascular beds were studied after intravenous (iv) and intracerebroventricular (icv) administration in the conscious rat. The pharmacological profile of anatoxin-A was further compared to nicotine administered iv and icv. MAP and heart rate were measured from femoral artery, CI by thermodilution method, and blood flow by Doppler velocimetry. Anatoxin-A and nicotine (30, 100 and 300 1-!g/kg iv) produced an increase in MAP with concomitant bradycardia. The highest doses increased Cl. MBF and RBF decreased due to a vasoconstriction in M and R vasculature. These effects were attenuated by the ganglion blocker chlorisondamine (5 mg/kg, iv). Anatoxin-A ( 100 1-!g/k~ iv) increased plasma epinephrine Ievels by 2- fold with virtually no effect on norepinephrine whereas nicotine ( 100 ~oLg/kg, iv) increased plasma epinephrine and norepinephrine by 20- to 30-fold. Central administration of anatoxin-A and nicotine (30-100 ,ug/kg icv) increased MAP with no effect on heart rate and produced M and R vasoconstriction. In summary, the present study demonstrates that anatoxin-A acts as a nicotinic cholinergic agonist in the c.onscious rat after both systemic and centrat administration. Anatoxin-A and nicotine produced pressor and reno-splanchnic vasoconstrictor responses and at high doses increased cardiac output. These effects were mediated by activation ofthe nicotinic receptors in the adrenal medulla and sympathetic ganglia. However, marked differences were found in the potency ofanatoxin-A versus nicotine to stimulate the sympathoadrenomedullary axis.

The effect of the selective 5-HT2 agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) on arterial pressure (AP), heart rate (HR), renal blood flow (RBF) and plasma renin activity (PRA) was determined in conscious rats. DOI increased AP and PRA, but decreased HR and RBF. All responses to DOI were abolished by central (LY 53857) or peripheral (xylamidine) 5-HT2 antagonists. Prazosin did not alter the AP or HR response to DOI. Chlorisondamine abolished the bradycardia but slightly increased the hypertension produced by DOI, while enalapril attenuated the pressor response. No further reduction was produced by the combination of enalapril and prazosin. Propranolol attenuated but did not eliminate the renin response, and blocked the bradycardia elicited by DOI. The data suggest that DOI activates 5-HT2 receptors located on vascular smooth muscle and/or the circumventricular organs of the brain to: (1) increase AP and reflexly decrease HR, (2) decrease RBF and (3) increase PRA. The hypertension is mediated by angiotensin II and direct vascular effects whereas the increase in PRA is mediated by an interaction of increased sympathetic nerve activity and decreased renal perfusion pressure.

The hypothalamic paraventricular nucleus (PVN) plays an important role in the sympathoexcitatory response to elevated plasma angiotensin II (Ang II). However, the mechanism by which Ang II influences sympathetic activity is not fully understood. In this study, we tested the hypothesis that GABA(γ-aminobutyric acid)-ergic function in the PVN is reduced by peripheral infusion of Ang II. To accomplish this, rats received either intravenous Ang II (12 ng/kg per minute) or vehicle (D5W) for 7 days, and renal sympathetic nerve activity (SNA), mean arterial pressure (MAP), and heart rate (HR) responses were recorded after unilateral PVN microinjection of the GABA-A receptor antagonist bicuculline methiodide (BMI, 0.1 nmol). Results indicate that in contrast to a significant increase in renal SNA, MAP, and HR observed in vehicle-infused rats ( P P

Chlorisondamine and mecamylamine are nicotinic antagonists that produce both ganglionic and central blockade. Chlorisondamine, when administered as a large systemic dose, produces a persistent central block, despite being charged. The present study evaluated the cardiovascular effects of chlorisondamine. Shortly after administration, chlorisondamine (0.10, 1, and 10 mg/kg i.m.) lowered blood pressure significantly and decreased heart rate at the low dose (0.1 mg/kg i.m.) and increased heart rate at the high dose (10 mg/kg i.m.). Mecamylamine (1 and 10 mg/kg i.m.) also lowered blood pressure and heart rate. After both antagonists, heart rate returned to baseline values within 90 min and blood pressure within 24 h. Low doses of nicotine (0.01-0.03 mg/kg i.m.) lowered blood pressure but did not affect heart rate. Higher doses (0.10-3.2 mg/kg i.m.) transiently increased blood pressure and heart rate. Subsequent to antagonist administration, nicotine was administered to determine whether either drug blocked the cardiovascular effects of nicotine. Chlorisondamine (0.1, 1, and 10 mg/kg i.m.) administered 30 min before nicotine blocked the increases in blood pressure and heart rate. Only the high dose (10 mg/kg i.m.) of chlorisondamine administered 24 h before nicotine produced a blockade of nicotine's pressor effect. This block diminished within 3 days. Mecamylamine (1 mg/kg i.m.) antagonized only nicotine's tachycardic effect. Longer pretreatment with mecamylamine (10 mg/kg, 24 h before nicotine challenge) did not antagonize the cardiovascular effects of nicotine. Thus, chlorisondamine produces a longer lasting blockade of nicotine's cardiovascular effects than mecamylamine.

We tested the hypothesis that in spontaneously hypertensive rat (SHR) NO produced centrally influences the resting arterial blood pressure by attenuating mechanisms involving prostaglandins, angiotensin II, endothelin and sympathetic nervous system. L-NAME (200 micro g/5 micro l), an inhibitor of NO synthase, administered intracerebroventricularly (i.c.v.) to awake and freely moving rats increased mean arterial blood pressure (MABP) in a biphasic pattern: an early transient increase within 1 min and a late prolonged response starting at 45 min and persisting for the duration of experiment (180 min). The two pressor responses involve different neurochemical mechanisms and, based on their latencies, they appear to reflect different anatomical sites of action of L-NAME. The late, but not the early pressor response, was prevented by pretreatment with chlorisondamine (2.5 mg/kg, i.v.), a ganglionic blocker, indicating its dependence on the sympathetic nervous system. Both pressor responses were abolished by i.c.v. pretreatment with indomethacin (200 micro g/5 micro l, i.c.v.), an inhibitor of cyclo-oxygenase, showing that they are mediated by prostaglandin(s). In contrast, losartan (25 micro g/5 micro l), an angiotensin II AT(1) receptor antagonist, had no effect. The initial pressor response was also attenuated by pretreatment with the endothelin ET(A)/ET(B) receptor antagonist, PD 145065 (48 micro g/2 micro l, i.c.v.). Intravenous pretreatment with another ET(A)/ET(B) receptor antagonist, L-754,142 (15 mg/kg as a bolus+15 mg/kg/h for 180 min), however, attenuated both responses to L-NAME. It is possible that L-754,142 crossed the blood-brain barrier and blocked, in addition, central ET(A)/ET(B) receptors. These studies show that NO synthesized in the brain attenuates pressor mechanisms involving prostaglandin, endothelin and sympathetic nervous system, but not angiotensin II, to modulate resting arterial blood pressure.

The aim of our study was to estimate the involvement of the peripheral N-methyl-D-aspartate receptors in regulation of cardiovascular function. For this purpose we examined the effects of intravenous injection of the agonists - NMDA (0.025; 0.05 and 1.0 mg/kg iv) and 1R-3R-ACPD (0.025; 0.05 and 1.0 mg/kg iv) - and antagonist of NMDA receptors DL-AP7 (0.02; 0.07 and 0.2 mg/kg iv). To determine if the effects of NMDA come from central or peripheral action we observed the effect during blockade of autonomic ganglion by using the nicotinic receptor antagonist - chlorisondamine (1.25 mg/kg iv). Administration of NMDA in three doses evoked slight hypotension after injection of the medium dose, 0.05 mg/kg. In the condition of pretreatment with 1.25 mg/kg chlorisondamine the hypotensive effect of NMDA was markedly reduced, what might suggest that NMDA-induced hypotension raised from the action within the brain. The competetive NMDA receptor antagonist DL-AP7 slightly increased the blood pressure. None of the injected drug had an influence on the heart rate in our in vivo study. It is concluded that the peripherally localized NMDA receptors may take a part in regulation of cardiovascular system, since their stimulation or blockade evoked the changes of systemic pressure.

When exposed to extreme cold or injected with the α 2 -adrenoceptor agonist, clonidine, infant rats emit ultrasonic vocalizations (USVs). Based upon the cardiovascular changes that accompany these two manipulations, especially decreased venous return, it was hypothesized that USVs are the acoustic by-product of the abdominal compression reaction (ACR), a maneuver that increases venous return. If this hypothesis is correct, then other anithypertensive drugs that decrease venous return should evoke USVs. In Experiment 1, sodium nitroprusside (SNP, 400 μg/kg), a direct-acting dilator of arteries and veins, was administered to 15-day-old rats under thermoneutral conditions while cardiac rate and ultrasound production were monitored. In Experiment 2, femoral artery pressure was monitored after SNP administration. Infants responded to SNP administration with decreased arterial pressure and tachycardia and, in addition, significantly increased ultrasound production. In Experiment 3, chlorisondamine (5 mg/kg), a ganglionic blocker that causes vasodilation and bradycardia, and hydralazine (20 mg/kg), a selective dilator of arteries, was administered to 15-day-olds. As predicted, chlorisondamine evoked ultrasound production and hydralazine did not. These results introduce SNP and chlorisondamine as only the second and third known agents capable of independently evoking USVs in thermoneutral conditions, and provide further support for the notion that ultrasound production is triggered by decreased venous return.

This study tested the hypothesis that dietary soy would attenuate the development of hypertension in female spontaneously hypertensive rats (SHR). Female SHR and control Wistar-Kyoto rats were obtained at 4 wk of age, randomly assigned to either an ovariectomized (OVX) group or a sham-operated group, and placed on a soy diet or control casein diet. After a minimum of 8 wk on their respective diets, mean arterial pressure (MAP) and heart rate (HR) were recorded before and after inhibition of nitric oxide synthase, air-jet stress, or ganglionic blockade. The major finding of this study is that MAP was reduced in the OVX SHR consuming soy diet compared with the casein-fed controls (150 ± 4 vs. 164 ± 3 mmHg). Plasma genistein concentrations were increased in the soy-fed OVX SHR (1.23 ± 0.31 μM) compared with the casein-fed OVX SHR (nondetectable). However, there was no difference in plasma genistein concentrations between sham-operated and OVX SHR (1.37 ± 0.42 vs. 1.23 ± 0.31 μM). Inhibition of nitric oxide synthase increased MAP and decreased HR in all groups; diet did not affect this response. Air-jet stress increased MAP and HR in all groups. However, these responses were exaggerated in the soy-fed SHR. Finally, ganglionic blockade abolished the antihypertensive effect of soy diet in the OVX SHR. These findings indicate that dietary soy exerts an antihypertensive effect in OVX SHR. This effect does not involve the nitric oxide system but may be related to an as yet undefined interaction with the autonomic nervous system.

Intravenous administration of the alpha2-adrenoceptor antagonist, idazoxan, elicits variable cardiovascular effects, depending on experimental conditions. In this study, the effects of idazoxan were investigated in rats with high, low, or no basal sympathetic tone. In a group of conscious Sprague-Dawley rats (n = 9), mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nervous activity (RSNA) were recorded. Idazoxan (250 microg/kg, i.v.) induced a transient decrease in MAP (-12+/-3 mm Hg) that was accompanied by increases in HR (49+/-14 beats/min) and RSNA (53+/-14%). In six of nine rats, a light pentobarbitone anesthesia was given. Basal RSNA was decreased (6.0+/-1.3 microV from 12.8+/-4.1 microV; p

Intravenous (i.v.) injection of the antidiabetic drug metformin rapidly lowers mean arterial pressure (MAP) in spontaneously hypertensive rats (SHR). However, if autonomic ganglia or alpha-adrenoceptors are first blocked then metformin rapidly raises MAP in SHR. This study was conducted to further characterize the adrenergic mechanisms of these opposing i.v. actions of the drug.Conscious, undisturbed female SHR with indwelling vascular catheters were used to measure acute effects of i.v. metformin (100 mg/kg; before and after sustained ganglionic blockade, GB, with chlorisondamine, 5 mg/kg) on: (1) circulating levels of catecholamines, (2) MAP after pharmacologic modulation of beta- as well as alpha-adrenoceptors and (3) all the above in the absence as well as presence of the adrenal medulla.Plasma norepinephrine (NE) and epinephrine (E) levels (pg/ml) were rapidly increased by i.v. metformin (8 SHR, p0.05) both before GB (delta NE = +146 +/- 41; delta E = +119 +/- 31) and after GB (delta NE = +79 +/- 24; delta E = +120 +/- 32). Similar increases in plasma NE (though not E) were seen in SHR without adrenal medullae. Blockade of beta-adrenoceptors with propranolol (pro; 3 mg/kg, 8 SHR) enhanced the rapid depressor response to i.v. metformin before GB (delta MAP, mmHg: -38 +/- 4 with pro vs -17 +/- 3 without pro; p0.05) and attenuated the rapid pressor response to i.v. metformin after GB (delta MAP, mmHg: +8 +/- 3 with pro vs +30 +/- 4 without pro; p0.05). Results were similar in SHR without adrenal medullae. Finally, if baseline MAP under GB was raised back to hypertensive levels with i.v. infusion of either NE or phenylephrine then i.v. metformin did not raise but rather reduced MAP in SHR.The acute depressor action of i.v. metformin in female SHR (1) is most likely due to a direct vasodilator action which includes inhibition of alpha-receptor-mediated vasoconstriction and (2) is buffered by an acute beta-receptor-mediated pressor action likely due to a direct metformin-induced release of NE from postganglionic sympathetic nerve endings.

Bradykinin (BK) is a peptide which evokes remarkably different changes in cardiovascular function. Systemic bolus injection of BK results in a rapid drop in blood pressure via an endothelium-dependent mechanism. On the other hand, local administration of BK can activate a powerful pressor reflex by stimulating afferent nerves located in the abdominal viscera, the heart, and the kidney. In the present study, the cardiovascular and renal hemodynamic effects during sustained (intravenous infusion) and transient (intravenous bolus injection) elevations in circulating BK were characterized and the receptor mechanism eliciting these effects was investigated. Mean arterial pressure (MAP), heart rate (HR), and renal blood flow (RBF) were recorded from conscious unrestrained rats while five-point cumulative dose-response curves were constructed during infusion or bolus injection of BK (5-80 microg kg(-1)). Infusion of BK produced dose-dependent increases in MAP (maximum response = 27 +/- 3 mmHg) accompanied by a significant tachycardia (maximum response = 159 +/- 20 bpm), a 28 +/- 6% increase in RBF, and no changes in renal vascular resistance (RVR). The BK-induced increases in MAP, HR, and RBF were abolished after treatment with a ganglion blocker (maximum responses: MAP = 2 +/- 3 mmHg, HR = 13 +/- 4 bpm, RBF = 4 +/- 2%) or with an agent which blocks B2-receptors (maximum responses: MAP = 1 +/- 1 mmHg, HR = 6 +/- 5 bpm, RBF = 6 +/- 2%). In marked contrast, bolus administration of BK resulted in hypotensive responses (maximum decline in MAP = -37 +/- 4 mmHg), reflex tachycardia (maximum increase in HR = 45 +/- 9 bpm), increases in RBF (maximum response = 13 +/- 4%), and significant reductions in RVR (maximum response = 38 +/- 5%). These responses were also prevented when B2-receptors were blocked (maximum responses: MAP = 3 +/- 2 mmHg, HR = 17 +/- 6 bpm, RBF = 3 +/- 3%, RVR = 9 +/- 4%). In summary, BK infusions activated a cardiopressor reflex while BK injections caused hypotension. These opposite effects were both mediated via B2-receptors. These findings suggest that BK can have complex effects on the cardiovascular system that may be dependent on the sites, magnitude, and duration of elevated BK concentrations.

Previous research in infant rats suggested that brown adipose tissue (BAT), by providing warm blood to the heart during moderate cold exposure, protects cardiac rate. This protective role for BAT thermogenesis was examined further in the present study. In experiment 1, 1-wk-old rats in a warm environment were pretreated with saline or chlorisondamine (a ganglionic blocker), and then BAT thermogenesis was stimulated by injection with the β3-agonist CL-316243. In experiment 2, pups were pretreated with chlorisondamine and injected with CL-316243, and after BAT thermogenesis was stimulated the interscapular region of the pups was cooled externally with a thermode. In both experiments, cardiac rate, oxygen consumption, and physiological temperatures were monitored. Activation of BAT thermogenesis substantially increased cardiac rate in saline- and chlorisondamine-treated pups, and focal cooling of the interscapular region was sufficient to lower cardiac rate. The results of these studies support the hypothesis that BAT thermogenesis contributes directly to the modulation of cardiac rate.

Cardiovascular and metabolic parameters were evaluated in 15 female spayed dogs before and after they became obese on either a saturated fat (LD, lard, n=8) or unsaturated fat (CO, corn oil, n=7) diet. Body weight and body fat increased significantly in both groups, although no differences occurred between diet groups. Dogs receiving the LD diet exhibited a greater increase in mean arterial pressure than those receiving the CO diet (p

Endothelins (ET) within the central nervous system (CNS) alter systemic cardiovascular responses and arginine vasopressin (AVP) secretion. These experiments were designed to ascertain whether the rise in systemic arterial pressure after central administration of ET-1 is mediated by enhancing sympathetic outflow and/or circulating AVP. In Long-Evans (LE/LE) rats, intracerebroventricular injection of 1-10 pmol ET-1 dose dependently increased mean arterial pressure (MAP). Peak response occurred 7-12 min after ET-1 and was inhibited by ETA receptor antagonism. Systemic vasopressin (V1) receptor blockade did not inhibit the pressor response, and rats with central diabetes insipidus (DI/DI) displayed an identical rise in MAP. Ganglionic blockade prevented ET-1-induced hemodynamic effects. Peak plasma AVP levels occurred 60 min after ET-1, as the pressor response began to wane. In sinoaortic-denervated LE/LE rats, ET-1 elicited a 10-fold increase in AVP secretion that coincided with the hemodynamic changes and was blocked by BQ-123. Thus ET-1 via ETA receptors within the CNS induced a concentration-dependent increase in systemic arterial pressure mediated by enhanced sympathetic outflow but not by circulating AVP. Reflex baroreceptor activation attenuated AVP release.

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 alpha-adrenoceptor antagonist phentolamine (1 mg/kg) did not attenuate the suppressive effect of morphine. Blockade of beta-adrenoceptors with propranolol (2.5 mg/kg) resulted in partial antagonism, but this action was not shared by the peripherally acting beta-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.

The present studies investigated the mechanisms mediating the cardiovascular changes induced by intracerebroventricular injection of serotonin (5-HT; 100 nmol) in conscious rats. At 5 min after 5-HT injection, arterial pressure and plasma levels of epinephrine were elevated and heart rate was reduced. The pressor response was abolished either by bilateral adrenalectomy or by pretreatment with chlorisondamine plus vasopressin V1 receptor antagonist. The bradycardic response was attenuated by pretreatment with chlorisondamine or a combination of methylatropine, propranolol, and vasopressin V1 receptor antagonist. At 20 min postinjection, arterial pressure and heart rate were both decreased. The reduction of heart rate at this time point was not blocked by the following pretreatments given alone or in combination: methylatropine, propranolol, vasopressin V1 and V2 receptor antagonists, adenosine A1 receptor antagonist, angiotensin-converting enzyme inhibitor, and chlorisondamine. These results suggest that immediately after intracerebroventricular injection of 5-HT, arterial pressure is elevated through the release of epinephrine and vasopressin and that heart rate is reduced via reciprocal changes in cardiac parasympathetic and sympathetic tone. In contrast, adrenergic, cholinergic, vasopressinergic, purinergic, and angiotensinergic mechanisms do not mediate the bradycardia observed at 20 min postinjection.

The cardiovascular profile of the 5-HT1-like receptor agonist sumatriptan has been studied in anaesthetised rabbits pretreated with chlorisondamine (0.5 mg kg-1 i.v.) and enalapril (0.3 mg kg-1 i.v.) to eliminate autonomic reflexes and minimise endogenous vasoconstrictor tone. Under these conditions sumatriptan (2-100 micrograms kg-1 i.v.) produced modest increases in carotid vascular resistance but had no significant influence on heart rate, blood pressure or mesenteric vascular resistance. In a similarly pretreated group of animals in which vasoconstrictor tone was elevated by infusion of angiotensin (100 ng kg-1 min-1 i.v.) sumatriptan caused moderate increases in blood pressure (55 +/- 5 to 65 +/- 5 mm Hg after 25 micrograms kg-1 i.v.) and mesenteric vascular resistance (1.4 +/- 0.2 to 1.6 +/- 0.2 mm Hg min ml-1 after 25 micrograms kg-1 i.v.) and tended to produce a greater carotid vasoconstriction (3.6 +/- 0.5 to 4.7 +/- 0.7 mm Hg min ml-1 after 25 micrograms kg-1). These effects were antagonised by methiothepin 0.3 mg kg-1 i.v. implying the involvement of 5-HT1-like receptor stimulation. Hence, the presence of angiotensin produces a modest amplification of the vasoconstrictor effects of sumatriptan and, in particular, unmasks a constriction of the mesenteric vascular bed. The degree of synergy observed between these two vasoconstrictors was, however, less marked than might have been expected on the basis of previous isolated tissue studies.

Autonomic control of cardiovascular function was evaluated in nine dogs before and after a high-fat overfeeding regimen. Body weight increased significantly (from 19.8 +/- 0.9 to 29.5 +/- 2.1 kg; P < 0.01) with overfeeding. Mean arterial pressure (MAP) increased from 94.6 +/- 2.1 to 105.5 +/- 3.7 mmHg (P < 0.05), and heart rate (HR) increased from 94.8 +/- 3.5 to 112.3 +/- 5.6 beats/min (P < 0.01). After ganglionic blockade with chlorisondamine, dose response of MAP and HR to methoxamine (alpha-agonist) or isoproterenol (beta-agonist) was evaluated. Peak MAP response to methoxamine was blunted in obese dogs. HR response to isoproterenol was not different between lean and obese dogs. Atropine in the presence of propranolol increased HR from 80.8 +/- 7 to 202.8 +/- 8.9 beats/min in lean dogs and from 113.8 +/- 12.1 to 131.7 +/- 18.2 in obese dogs. These data suggest the increase in HR observed in obese dogs may be due to a decrease in parasympathetic inhibition rather than an increase in sympathetic stimulation. The blunted response to methoxamine in obese hypertensive dogs suggests that the sympathetic control of peripheral vascular resistance is altered in obesity.

The present study was conducted to develop a standardized ganglionic blockade protocol to assess neurogenic pressor activity in conscious rats. Rats were instrumented with arterial and venous catheters for measurement of arterial pressure and heart rate and for administration of three different ganglionic blockers (trimethaphan, hexamethonium, and chlorisondamine). To investigate the role of the pressor hormones angiotensin II (AII) and arginine vasopressin (AVP) in modulating the cardiovascular responses to ganglionic blockade, we also administered ganglionic blockers to rats pretreated with AVP and AII receptor antagonists. The peak depressor responses to trimethaphan (20 mg/kg; -45 +/- 2 mm Hg), hexamethonium (20 mg/kg; -44 +/- 2 mm Hg), and chlorisondamine (2.5 mg/kg; -47 +/- 3 mm Hg) were not different from each other. With trimethaphan, there was a significantly enhanced peak depressor response after blockade of AT1/V1 receptors (-45 +/- 2 vs -59 +/- 2 mm Hg). No significant differences were observed for hexamethonium or chlorisondamine after hormonal blockade (-44 +/- 2 vs. -46 +/- 3 and -47 +/- 3 vs -48 +/- 4 mm Hg, respectively). These observations suggest that, for hexamethonium and chlorisondamine, the peak depressor response to ganglionic blockade is a consistent measure of neurogenic pressor activity in the conscious rat. This response is not influenced by circulating AII or AVP. On the other hand, trimethaphan should be used carefully due to its complex interactions with other systems, particularly under conditions in which AVP or AII may be altered.

We have previously demonstrated that cerebroventricular administrations (i.c.v) of potassium chloride solutions (KCl; 0.375-1.25 mumoles/5 microliters) elicit ouabain-sensitive, concentration-dependent decreases in the blood pressure and heart rates of anesthetized, normotensive Sprague-Dawley (SD) rats. These studies have suggested an inverse relationship between Na(+)-pump activity in the central nervous system (CNS) and central sympathetic outflow. Such a view is further supported by the present studies showing that i.c.v. injections of KCl failed to produce any alterations in the blood pressures of rats pretreated with an autonomic ganglionic blocker, chlorisondamine. In the present studies, depressor responses to i.c.v. potassium chloride were considered as functional indices for evaluation of neuronal Na(+)-pump activity in 8 and 12 week old (8 wk and 12 wk) SHR, WKY and Sprague-Dawley (SD) rats. Basal arterial blood pressures of 8 wk-old SD and SHR, and the responsiveness of these two groups to i.c.v. potassium chloride solutions are similar and they both are significantly greater than that of age matched WKY. However, in the 12 wk-old groups, arterial pressure of SHR was significantly greater than that of WKY as well as SD, whereas the depressor responses to KCl in SHR were significantly greater than that of only WKY. Pretreatment of the rats with i.c.v. ouabain abolished the differences in the hypotensive responses to i.c.v. potassium chloride that existed between various groups but not the differences in the basal blood pressures. Evaluation of these data suggest that a) the centrally mediated hypotensive responses to K+ in various groups could depend upon Na+, K(+)-pump activity in C.N.S. and/or on basal central sympathetic discharge; b) central sympathetic activity is greater in SHR only when compared to WKY but not to SD; c) since the central Na(+)-pump activity and sympathetic tone appears to be similar in SHR and SD, mechanisms other than the increases in sympathetic activity must play a prominent role in the development of spontaneous hypertension; d) attenuation of neuronal Na(+)-pump activity cannot account for greater sympathetic tone in SHR and SD-rats when compared to WKY.

The cardiovascular effects of the centrally injected D-arginine were investigated in the conscious rat chronically instrumented with cisternal, arterial, and venous cannulae, as well as an electromagnetic flow probe around the superior mesenteric artery, renal artery, or terminal aorta (hindquarter). Intracisternal injection of D-arginine (10 mumol) increased arterial blood pressure and hindquarter flow lasting for 60 min or more. Previous injection of the beta-adrenoceptor blocker, propranolol (2 mg/kg, I.V.), markedly attenuated the hindquarter vasodilation caused by D-arginine; this response suggests the release of adrenaline. Peripheral resistance, calculated as arterial pressure divided by regional flow, increased in both the superior mesenteric artery (60%) and the renal artery (45%) 5 min after intracisternal injection of D-arginine. In the hindquarter, however, peripheral resistance decreased by 35% and arterial pressure increased by 25%. The pressor effect was significantly attenuated by producing ganglionic blockade with chlorisondamine (5 mg/kg, I.V.). The total peripheral blood flow increased from 12.9 to 15.9 ml/min/100 g body weight. This response indicates that the pressor effect of D-arginine is due to an increase of cardiac output rather than of peripheral resistance. Centrally administered D-arginine appears to activate the sympatho-adrenal system, especially the release of adrenaline.