The cardiovascular and cardiac actions of ecstasy and its metabolites.

The recreational use of 3, 4 methylenedioxymethamphetamine (ecstasy or MDMA) has increased dramatically over the past thirty years due to its ability to increase stamina and produce feelings of emotional closeness and wellbeing. In spite of the popular perception that MDMA is a safe drug, there is a large literature documenting that the drug can produce significant neurotoxicity, especially in serotonergic and catecholaminergic systems. There are also experimental and clinical data which document that MDMA can alter cardiovascular function and produce cardiac toxicity, including rhythm disturbances, infarction and sudden death. This manuscript will review the literature documenting the cardiovascular responses elicited by MDMA in humans and experimental animals and will examine the underlying mechanisms mediating these responses. We will also review the available clinical, autopsy and experimental data linking MDMA with cardiac toxicity. Most available data indicate that oxidative stress plays an important role in the cardiotoxic actions of MDMA. Moreover, new data indicates that redox active metabolites of MDMA may play especially important roles in MDMA induced toxicity.

Chloroephedrine: contaminant of methamphetamine synthesis with cardiovascular activity.

Chloroephedrine is an intermediate and possible contaminant formed when methamphetamine is manufactured using ephedrine or pseudoephedrine as precursors. The purpose of this study was to determine whether this contaminant has biological activity and might contribute to methamphetamine-induced cardiovascular toxicity. In conscious rats, the (-) and (+) isomers of chloroephedrine (0.1 and 1.0 mg/kg, i.v.) dose-dependently increased mean arterial pressure (MAP) and heart rate (HR). The potency of the pressor effects of (-) and (+)-chloroephedrine was between that of ephedrine and pseudoephedrine. The increases in HR elicited by the four stimulants were similar except that the tachycardia elicited by all doses of ephedrine and pseudoephedrine were preceded by a brief decrease in HR. The i.v. administration of 10 mg/kg of (+) or (-)-chloroephedrine produced biphasic (decrease followed by increase) the MAP and HR responses. Ephedrine and pseudoephedrine did not decrease MAP at any dose tested. The initial decrease in HR elicited by (-)-chloroephedrine was significantly reduced and the hypotensive response abolished by atropine, indicating that these components of the MAP and HR responses resulted from vagal activation. The secondary pressor response elicited by (-)-chloroephedrine was significantly reduced and the tachycardia significantly increased by pretreatment with phentolamine (3 mg/kg, i.v.). The increase in HR was reversed by propranolol. These results indicate that (-) and (+)-chloroephedrine have sympathomimetic properties similar to other known sympathomimetic stimulants. In addition, larger doses of chloroephedrine can activate the vagus nerve. The combination of (+)-methamphetamine and (-)-chloroephedrine did not markedly alter the magnitude of the MAP and HR responses of (+)-methamphetamine alone except at high doses of (-)-chloroephedrine (10 mg/kg). Contamination of illicit methamphetamine with chloroephedrine may have toxic consequences.

Cardiovascular and sympathetic responses and reflex changes elicited by MDMA.

The recreational use of 3,4-methylenedioxymethamphetamine (MDMA) has increased as have the number of clinical reports linking MDMA use with cardiovascular toxicity. Nonetheless, the cardiovascular and sympathetic nerve responses elicited by MDMA have not been well characterized. The purpose of this study was to characterize the mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve responses elicited by the acute administration of MDMA and to determine whether neurotoxic doses of MDMA change cardiovascular and/or cardiovascular reflex function. In conscious rats, MDMA or d-amphetamine elicited similar dose-dependent increases in MAP. MDMA elicited significant bradycardia at doses above 1.0 mg/kg. Pretreatment with phentolamine significantly reduced the duration but not the magnitude of the pressor response elicited by MDMA. In pentobarbital-anesthetized rats, MDMA (0.1 mg/kg) increased renal sympathetic nerve activity (RSNA; 33 +/- 10%), while larger doses significantly decreased RSNA (-91 +/- 3%, max). Neurotoxic doses of MDMA (20 mg/kg, s.c., b.i.d. for 4 days) significantly enhanced the bradycardic component of the Bezold-Jarisch reflex elicited by i.v. serotonin when tested either 2 days or 2 weeks after the last neurotoxic treatment. However, neurotoxic treatment did not significantly affect baroreceptor reflex function. These results indicate that the acute administration of MDMA and d-amphetamine produce similar cardiovascular and sympathetic responses. Neurotoxic doses of MDMA can also significantly alter cardiovascular reflex function. These findings raise the possibility that MDMA may have the potential to produce cardiovascular and/or cardiac toxicity similar to that elicited by other amphetamine analogs.

Effects of mercury on the arterial blood pressure of anesthetized rats.

The available data suggests that hypotension caused by Hg2+ administration may be produced by a reduction of cardiac contractility or by cholinergic mechanisms. The hemodynamic effects of an intravenous injection of HgCl2 (5 mg/kg) were studied in anesthetized rats (N = 12) by monitoring left and right ventricular (LV and RV) systolic and diastolic pressures for 120 min. After HgCl2 administration the LV systolic pressure decreased only after 40 min (99 +/- 3.3 to 85 +/- 8.8 mmHg at 80 min). However, RV systolic pressure increased, initially slowly but faster after 30 min (25 +/- 1.8 to 42 +/- 1.6 mmHg at 80 min). Both right and left diastolic pressures increased after HgCl2 treatment, suggesting the development of diastolic ventricular dysfunction. Since HgCl2 could be increasing pulmonary vascular resistance, isolated lungs (N = 10) were perfused for 80 min with Krebs solution (continuous flow of 10 ml/min) containing or not 5 microM HgCl2. A continuous increase in pulmonary vascular resistance was observed, suggesting the direct effect of Hg2+ on the pulmonary vessels (12 +/- 0.4 to 29 +/- 3.2 mmHg at 30 min). To examine the interactions of Hg2+ and changes in cholinergic activity we analyzed the effects of acetylcholine (Ach) on mean arterial blood pressure (ABP) in anesthetized rats (N = 9) before and after Hg2+ treatment (5 mg/kg). Using the same amount and route used to study the hemodynamic effects we also examined the effects of Hg2+ administration on heart and plasma cholinesterase activity (N = 10). The in vivo hypotensive response to Ach (0.035 to 10.5 microg) was reduced after Hg2+ treatment. Cholinesterase activity (microM h-1 mg protein-1) increased in heart and plasma (32 and 65%, respectively) after Hg2+ treatment. In conclusion, the reduction in ABP produced by Hg2+ is not dependent on a putative increase in cholinergic activity. HgCl2 mainly affects cardiac function. The increased pulmonary vascular resistance and cardiac failure due to diastolic dysfunction of both ventricles are factors that might contribute to the reduction of cardiac output and the fall in arterial pressure.

Effects of mercury on the arterial blood pressure of anesthetized rats

The available data suggests that hypotension caused by Hg2+ administration may be produced by a reduction of cardiac contractility or by cholinergic mechanisms. The hemodynamic effects of an intravenous injection of HgCl2 (5 mg/kg) were studied in anesthetized rats (N = 12) by monitoring left and right ventricular (LV and RV) systolic and diastolic pressures for 120 min. After HgCl2 administration the LV systolic pressure decreased only after 40 min (99 +or - 3.3 to 85 + or - 8.8 mmHg at 80 min). However, RV systolic pressure increased, initially slowly but faster after 30 min (25 + or - 1.8 to 42 + or - 1.6 mmHg at 80 min). Both right and left diastolic pressures increased after HgCl2 treatment, suggesting the development of diastolic ventricular dysfunction. Since HgCl2 could be increasing pulmonary vascular resistance, isolated lungs (N = 10) were perfused for 80 min with Krebs solution (continuous flow of 10 ml/min) containing or not 5 µM HgCl2. A continuous increase in pulmonary vascular resistance was observed, suggesting the direct effect of Hg2+ on the pulmonary vessels (12 + or - 0.4 to 29 + or - 3.2 mmHg at 30 min). To examine the interactions of Hg2+ and changes in cholinergic activity we analyzed the effects of acetylcholine (Ach) on mean arterial blood pressure (ABP) in anesthetized rats (N = 9) before and after Hg2+ treatment (5 mg/kg). Using the same amount and route used to study the hemodynamic effects we also examined the effects of Hg2+ administration on heart and plasma cholinesterase activity (N = 10). The in vivo hypotensive response to Ach (0.035 to 10.5 µg) was reduced after Hg2+ treatment. Cholinesterase activity (µM h-1 mg protein-1) increased in heart and plasma (32 and 65 percent, respectively) after Hg2+ treatment. In conclusion, the reduction in ABP produced by Hg2+ is not dependent on a putative increase in cholinergic activity. HgCl2 mainly affects cardiac function. The increased pulmonary vascular resistance and cardiac failure due to diastolic dysfunction of both ventricles are factors that might contribute to the reduction of cardiac output and the fall in arterial pressure

Central alpha2-receptor mechanisms contribute to enhanced renal responses during ketamine-xylazine anesthesia.

We have recently developed an experimental approach to study central opioid control of renal function in anesthetized rats. This model system uses the intravenous infusion of the alpha2-agonist xylazine to enhance basal levels of urine flow rate and urinary sodium excretion in ketamine-anesthetized rats. This study examined the contribution of central and peripheral alpha2-adrenergic receptor mechanisms in mediating the enhanced renal excretory responses produced by xylazine. In ketamine-anesthetized rats, the enhanced levels of urine flow rate and urinary sodium excretion produced by the intravenous infusion of xylazine were reversed by the intravenous bolus injection of the alpha2-adrenoceptor antagonist yohimbine but not by the alpha1-adrenoceptor antagonist terazosin. In separate animals the intracerebroventricular administration of yohimbine only reduced urine flow rate by approximately 50% but did not alter urinary sodium excretion. The decrease in urine flow rate produced by intracerebroventricular yohimbine was reversed by the intravenous injection of a selective V2-vasopressin receptor antagonist. In a separate group of ketamine- and xylazine-anesthetized rats, the bilateral microinjection of yohimbine into the hypothalamic paraventricular nucleus (PVN) also significantly decreased urine flow rate by 54% without altering urinary sodium excretion. The microinjection of the beta-adrenoceptor antagonist propranolol into the PVN did not alter either renal excretory parameter. These results suggest that during intravenous infusion, xylazine increases urine flow rate by activating alpha2-adrenergic receptors in the PVN, which in turn decrease vasopressin release. The ability of alpha-adrenergic mechanisms in the PVN to selectively influence the renal handling of water, but not sodium, may contribute to the reported dissociation of the natriuretic and diuretic responses of alpha2-adrenoceptor agonists.

Effects of cocaine on adrenal sympathetic nerve discharge in anesthetized rats.

Cocaine increases the circulating levels of plasma catecholamines, presumably via the activation of the sympathoadrenal axis. However, a number of reports have shown that the predominant response to cocaine is a generalized decrease in sympathetic nerve activity. One possible explanation for the increase in plasma catecholamines may be that the adrenal sympathetic nerve is less sensitive to the sympathoinhibitory actions of cocaine than are other nerves. This study compared the effects of cocaine on adrenal and renal sympathetic nerve discharge (SND) recorded simultaneously in pentobarbital-anesthetized rats. Cocaine produced dose-related decreases in both renal and adrenal SND; however, the decreases in adrenal SND were significantly smaller than in renal SND. Cocaine also elicited pressor responses in these rats. The decreases in adrenal SND were similar in baroreceptor intact and sinoaortically denervated rats, indicating that pressor-mediated baroreceptor reflex activation was not responsible for the decrease in adrenal SND. In a separate group of rats, i.v. administration of desipramine decreased both adrenal and renal SND. As with cocaine, the decreases in adrenal SND after desipramine were smaller, suggesting that the differences in the neural responses did not reflect a differential local anesthetic effect of cocaine on the two nerves. In conclusion, these studies showed that cocaine decreases adrenal SND in pentobarbital-anesthetized rats. However, the adrenal sympathetic nerve is less sensitive than the renal nerve to the sympathoinhibitory actions of cocaine. Whether the adrenal SND remaining after cocaine contributes to the increase in plasma catecholamines produced by this drug remains to be determined.

Renal excretory responses produced by central administration of opioid agonists in ketamine and xylazine-anesthetized rats.

This study examined the renal excretory responses produced by the intravenous (i.v.) infusion of the alpha-2 agonist, xylazine, in ketamine-anesthetized rats. In addition, the renal responses produced by the intracerebroventricular (i.c.v.) injection of opioid agonists were also examined with use of this anesthetic paradigm. In male Sprague-Dawley rats, the i.v. infusion of isotonic saline (55 microl/min) containing ketamine alone (1.0 mg/kg/min) produced low levels of urine flow rate (6.3 +/- 1.3 microl/min/gkw) and urinary sodium excretion (0.28 +/- 0.08 microeq/min/gkw). However, after adding xylazine (50 microg/kg/min) to the ketamine infusate, these renal excretory responses were significantly augmented. Steady-state levels of urine flow rate and urinary sodium excretion were attained approximately 120 min after starting the xylazine infusion and were similar in magnitude to the levels of water and sodium excretion previously observed in untreated, conscious rats. In ketamine/xylazine-anesthetized rats, the i.c.v. injection of the mu opioid agonist, dermorphin (0.1 nmol/kg), or the kappa opioid agonist, U-50488H (1 microg total), produced profound and concurrent diuretic and antinatriuretic responses. The pattern (direction and magnitude) of these opioid-induced renal excretory responses was similar to those previously reported in conscious rats. Together, these results indicate that the i.v. infusion of xylazine enhances the renal excretion of water and sodium in ketamine-anesthetized rats. Moreover, the renal responses produced by i.c.v. administration of opioids are similar in ketamine/xylazine-anesthetized and conscious rats. Thus, it appears that the ketamine/xylazine infusion protocol may provide a valid and useful approach to investigate various aspects of the central opioid control of renal function in rats during experimental procedures that require anesthesia.

Metformin inhibits ganglionic neurotransmission in renal nerves.

Intravenous administration of the antihyperglycemic agent metformin decreases arterial pressure and sympathetic nerve activity (SNA). To test the hypothesis that metformin inhibits SNA by interrupting ganglionic neurotransmission, we compared the actions of intravenous administration of metformin and the ganglionic blocker trimethaphan on postganglionic renal and preganglionic adrenal sympathetic nerves in pentobarbital-anesthetized male Sprague-Dawley rats. Intravenous metformin elicited dose-dependent decreases in postganglionic renal SNA (1 mg/kg: 0 +/- 0%; 10 mg/kg: -20 +/- 4%; 100 mg/kg: -92 +/- 3%; n = 7). Conversely, only the maximal dose of metformin affected preganglionic adrenal SNA (100 mg/kg: delta adrenal SNA = -14 +/- 6%; n = 8). Ganglionic blockade with intravenous trimethaphan (5 mg/kg) produced a differential sympathoinhibitory response similar to the response observed after high-dose metformin (delta renal SNA = -100 +/- 3%; delta adrenal SNA = -17 +/- 7%; P < .001). Preganglionic renal neurons were electrically stimulated in the spinal cord, before and during the peak of the sympathoinhibitory response to intravenous metformin, and the magnitude of the stimulus-evoked increases in postganglionic renal SNA were compared. Metformin dose-dependently attenuated the magnitude of the increase in postganglionic renal SNA elicited by stimulation of the spinal cord (30 mg/kg: -23 +/- 8%; 90 mg/kg: -65 +/- 11%; 270 mg/kg: -91 +/- 8%; n = 6 per dose). We conclude that high-dose intravenous metformin interrupts ganglionic neurotransmission in renal nerves.

Characterization of the sympathetic nerve responses to amphetamine: role of central alpha 2-adrenergic receptors.

Although amphetamine has profound cardiovascular actions, the role of the sympathetic nervous system in these responses is largely unknown. The purpose of this study was to characterize the sympathetic nerve responses to amphetamine and to determine whether these neural responses involve an action of amphetamine in the rostral ventrolateral medulla (RVLM). In sinoaortically denervated (SAD) and sham-SAD rats, amphetamine dose-dependently increased mean arterial pressure (MAP) and heart rate (HR), while decreasing (-87 +/- 5%, max) renal sympathetic nerve discharge (SND) for 57 +/- 5 min. Comparison of the SND responses in SAD and sham-SAD rats revealed a small but significant contribution of the baroreceptor reflex to the sympathoinhibitory response. In separate studies, the bilateral microinjection of amphetamine into RVLM decreased HR, MAP, and SND. The magnitude and duration of the decrease in SND elicited by amphetamine were significantly attenuated by the prior intravenous (i.v.) administration of idazoxan (alpha 2-adrenergic antagonist). The prior bilateral microinjection of idazoxan or piperoxan into RVLM significantly attenuated the duration of the sympathoinhibitory responses elicited by i.v. amphetamine. Idazoxan and piperoxan also tended to decrease the magnitude of the SND response; however, this reduction was significant at only the highest doses. The MAP and HR responses were unaffected by idazoxan treatment. The microinjection of terazosin (alpha 1-adrenergic antagonist) or propranolol (beta-adrenergic antagonist) into RVLM did not alter the HR, MAP, or SND responses to i.v. amphetamine. We conclude that i.v. amphetamine decreases SND in anesthetized rats, in large part, by a mechanism involving the activation of alpha 2-adrenergic receptors in RVLM.

Blockade of alpha-2 adrenergic receptors in the rostral ventrolateral medulla attenuates the sympathoinhibitory response to cocaine.

The purpose of this study was to determine whether neurons in the rostral ventrolateral medulla play a role in the sympathoinhibitory response elicited by i.v. administration of cocaine and, if so, to identify the type(s) of receptors involved. Adrenergic antagonists were microinjected bilaterally into the rostral ventrolateral medulla in pentobarbital-anesthetized rats in an attempt to block the decrease in sympathetic nerve discharge (SND) elicited by cocaine (1 mg/kg i.v.). After the bilateral microinjection of saline, cocaine elicited a -56 +/- 5% (mean +/- S.E.) decrease in SND lasting 36 +/- 3 min. Cocaine also increased arterial pressure (21 +/- 3 mm Hg). Prior microinjection of the alpha-2 adrenergic antagonist idazoxan (0.3, 3 or 10 nmol) did not alter the magnitude of the sympathoinhibitory response to cocaine; however, the duration of the response was significantly reduced by all 3 doses (range 21 +/- 3 to 11 +/- 2 min). Similarly, microinjection of the alpha-2 adrenergic antagonist piperoxan (10 nmol) decreased the duration (from 45 +/- 8 to 23 +/- 4 min), but not the magnitude of the sympathoinhibitory response. Microinjection of either the alpha-1 adrenergic antagonist terazosin (0.24 nmol) or the beta adrenergic receptor antagonist propranolol (2 nmol) did not attenuate the decrease in SND elicited by cocaine. The cocaine-mediated pressor response was not affected by any of the antagonist treatments. These data show that the decrease in SND elicited by cocaine is mediated centrally and involves, at least in part, the activation of alpha-2 adrenergic receptors in the rostral ventrolateral medulla.

The depletion of monoamines blocks the sympathoinhibitory response to cocaine.

Recent studies have shown that cocaine decreases, rather than increases sympathetic nerve discharge (SND). Whether these sympathoinhibitory responses are the result of cocaine's actions on monoaminergic transmission (i.e. blockade of neuronal uptake or stimulation of transmitter release) or its local anesthetic actions is not known. The purpose of the present study was to determine the degree to which cocaine's actions on monoaminergic transmission are involved in mediating the sympathoinhibitory response to this drug. We examined the mean arterial pressure, heart rate and splanchnic sympathetic nerve responses elicited by cocaine (1 mg/kg, i.v.) in pentobarbital-anesthetized rats depleted of monoamines. Monoamines were depleted by administering reserpine (10 mg/kg, i.p.) either 24, or 48 and 24 h before the experiment. The rats were also given alpha-methyl-p-tyrosine (200 mg/kg, i.p.) 2 h before the experiment. Vehicle-treated rats served as controls. Depletion of monoamines markedly reduced resting arterial pressure and heart rate and significantly attenuated the pressor response and tachycardia elicited by tyramine (1 mg/kg, i.v.). In control rats, cocaine elicited marked (-64 +/- 4%) and prolonged (44 +/- 4 min) decreases in SND. The magnitude (-34 +/- 11%) and duration (23 +/- 6 min) of these responses were significantly attenuated after 1 day of monoamine depletion. After 2 days of depletion, the sympathoinhibitory response was abolished and was replaced by a small, brief increase in SND (10 +/- 3%). The pressor responses were similar in control and depleted rats, while the bradycardic response (-33 +/- 4 bpm) was significantly reduced after 1 and 2 days of monoamine depletion to -20 +/- 3 and -15 +/- 2 bpm, respectively. We conclude that a functionally intact monoaminergic system is essential for the sympathoinhibitory response to cocaine. Whether the pressor responses result from a non-monoaminergic or a reserpine and/or alpha-methyl-p-tyrosine resistant catecholaminergic mechanism is unknown.

Sympathetic nerve responses elicited by cocaine in anesthetized and conscious rats.

Recent evidence suggests that cocaine decreases rather than increases sympathetic nerve discharge (SND). The purpose of the present study was to provide the first complete characterization of the dose-response relationships of cocaine (0.005-3 mg/kg, IV) for arterial pressure, heart rate, and lumbar, splanchnic, or renal SND in pentobarbital-anesthetized rats. Cocaine was also tested in conscious rats. In pentobarbital-anesthetized rats cocaine elicited prolonged (lasting up to 56 min), dose-dependent decreases in SND on all three nerves. The splanchnic nerve was significantly more sensitive to the inhibitory actions of cocaine than was the lumbar nerve. Cocaine increased arterial pressure and elicited bradycardia at doses above 0.5 mg/kg. Comparison of the dose-response curves of cocaine for splanchnic SND in sham-operated and sinoaortically deafferentated (SAD) rats showed that the baroreceptor reflex made only a minor contribution to the magnitude of sympathoinhibitory response. However, the duration of the sympathoinhibitory response was significantly shorter in SAD than in sham animals. In conscious rats, cocaine (0.1 and 1.0 mg/kg) elicited a pattern of neural and cardiovascular responses similar to that seen in anesthetized rats, except that the prolonged sympathoinhibitory responses were preceded by a brief (lasting < 10 s) increase in SND. From these data we conclude that cocaine produces prolonged decreases in SND in conscious and anesthetized rats. These sympathoinhibitory responses do not appear to result from baroreceptor reflex activation and may involve a central mechanism of action.

Ouabain amplifies contractile responses to phenylephrine in rat tail arteries in hypertension.

Ouabain, a cardiac glycoside, binds to the alpha-subunits of Na+, K(+)-ATPase and inhibits Na+ pump activity. It has been proposed that endogenous ouabain, by inhibiting vascular Na+, K(+)-ATPase, can increase vascular resistance and thus may contribute to hypertension. One of the consequences of inhibition of the membrane Na+ pump is enhanced responsiveness of vascular smooth muscle to vasopressor substances. The purpose of the present study was to determine whether ouabain can enhance the responsiveness of the vasculature in hypertension. In the present study 100 microM ouabain enhanced the contractile response elicited by phenylephrine in isolated, perfused tail arteries from spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. The enhanced contractile response was more pronounced in the arteries of the SHR. We demonstrated that this concentration of ouabain inhibits the Na+ pump activity, measured as ouabain-sensitive 86Rb uptake, by about 65%, in isolated tail arteries. We conclude that ouabain can sensitize the vascular smooth muscle to the effects of vasopressor substances and this effect is more pronounced in genetically hypertensive rats. Endogenous ouabain may contribute to the pathophysiology of hypertension by enhancing vascular tone.

Lesions in rostral ventromedial or rostral ventrolateral medulla block neurogenic hypertension.

Neurogenic hypertension results from the removal of inhibitory baroreceptor afferent input to vasomotor systems in the central nervous system. We sought to determine whether the bilateral destruction of neurons in the rostral ventrolateral or rostral ventromedial medulla, made using microinjections of N-methyl-D-aspartic acid (30 nmol in 200 nL), would block the acute increase in arterial pressure after sinoaortic deafferentation in pentobarbital-anesthetized rats. Bilateral lesions of the rostral ventrolateral or rostral ventromedial medulla decreased mean arterial pressure (107 +/- 4 to 78 +/- 5 and 115 +/- 3 to 94 +/- 3 mm Hg, respectively). In rostral ventrolateral or rostral ventromedial medulla lesioned rats, sinoaortic deafferentation failed to increase arterial pressure. Sham lesions or lesions placed rostral to the rostral ventrolateral or rostral ventromedial medulla did not significantly lower arterial pressure. Subsequent sinoaortic deafferentation significantly increased mean arterial pressure (109 +/- 3 to 145 +/- 4 and 109 +/- 5 to 141 +/- 3 mm Hg, respectively). In eight rats we used an infusion of angiotensin II to return arterial pressure to control levels after lesion of the rostral ventrolateral (n = 4) or rostral ventromedial (n = 4) medulla. In these animals, sinoaortic deafferentation failed to increase arterial pressure. We conclude that neurons in the rostral ventrolateral and rostral ventromedial medulla are involved in the normal maintenance of arterial pressure and the development of hypertension after sinoaortic deafferentation in pentobarbital-anesthetized rats.

Chronic lesion of rostral ventrolateral medulla in spontaneously hypertensive rats.

We studied the effects of chronic selective neuronal lesion of rostral ventrolateral medulla on mean arterial pressure, heart rate, and neurogenic tone in conscious, unrestrained spontaneously hypertensive rats. The lesions were placed via bilateral microinjections of 30 nmol/200 nl N-methyl-D-aspartic acid. The restimulation of this area with N-methyl-D-aspartic acid 15 days postlesion failed to produce a pressor response. One day postlesion, the resting mean arterial pressure was significantly decreased in lesioned rats when compared with sham rats (100 +/- 7 versus 173 +/- 4 mm Hg, p less than 0.05). Fifteen days later, the lesioned group still showed values significantly lower than the sham group (150 +/- 6 versus 167 +/- 5 mm Hg, p less than 0.05). No significant heart rate differences were observed between the sham and lesioned groups. The ganglionic blocker trimethaphan (5 mg/kg i.v.) caused similar reductions in mean arterial pressure in both lesioned and sham groups. The trimethaphan-induced hypotension was accompanied by a significant bradycardia in lesioned rats (-32 +/- 13 beats per minute) but a tachycardia in sham rats (+33 +/- 12 beats per minute) 1 day postlesion. Therefore, rostral ventrolateral medulla neurons appear to play a significant role in maintaining hypertension in conscious spontaneously hypertensive rats. Spinal or suprabulbar structures could be responsible for the gradual recovery of the hypertension in the lesioned rats.

Identification of cardiovascular neurons in the rostral ventromedial medulla in anesthetized rats.

Recent studies have identified a region in the rostral ventromedial medulla (RVMM) of rats that appears to be involved in cardiovascular function. Since these studies used either microinjection of lidocaine or electrical stimulation, the exact contribution of intrinsic neurons as opposed to fibers of passage could not be determined. The present study was performed to map the location of neurons in RVMM from which changes in mean arterial pressure could be elicited by the microinjection of the excitatory amino acid analogue N-methyl-D-aspartic acid (NMDA) (20 ng/50 nl), which selectively activates cell bodies in barbiturate-anesthetized rats. Microinjection of NMDA into RVMM most often (53%) elicited pressor responses (31 +/- 7 mm Hg). On the basis of these responses, RVMM was determined to encompass a large portion of the nucleus gigantocellularis 0.5-1.5 mm lateral to the midline, 0.5-3.5 mm above the ventral surface, and extending from the rostral to the caudal pole of the facial nucleus. Depressor responses (-21 +/- 3 mm Hg) were found at all levels of RVMM but were most concentrated and of the largest magnitude in the rostral and caudal poles of RVMM. Microinjection of the inhibitory neurotransmitter glycine (500 mM) was used to determine whether neurons in RVMM were contributing to the maintenance of arterial pressure. Microinjection of glycine decreased arterial pressure (-15 +/- 2 mm Hg) throughout most of RVMM. Unexpectedly, increases in mean arterial pressure (24 +/- 3 mm Hg) were elicited by microinjection of glycine into the same region in RVMM in which NMDA most frequently elicited pressor responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Central nervous system and the pathogenesis of hypertension. Sites and mechanisms.

A large body of evidence indicates that the central nervous system plays an essential role in the pathogenesis of hypertension. However, in many cases the specific brain regions involved and the mechanisms by which these regions promote hypertension are not known. In recent years, research in this and other laboratories has attempted to determine the mechanisms by which neural and humoral signals arising in response to pathological conditions (often occurring in the periphery) interact with the central nervous system to produce hypertension. In this article, we illustrate the coupling of peripheral and central factors in the pathogenesis of hypertension by examining the central actions of angiotensin II and mineralocorticoids in the expression of renal hypertension and mineralocorticoid-salt hypertension, respectively. We also review recent data from this laboratory illustrating the involvement of medullary vasomotor centers in the development of neurogenic hypertension after sinoaortic deafferentation and in the maintenance of hypertension in the spontaneously hypertensive rat.

Role of renal nerves in experimental hypertension: evaluation of neurogenic mechanisms.

To evaluate neurogenic mechanisms underlying variations in arterial pressure associated with removal of baroreflexes, renal sympathetic nerve activity (RSNA) was recorded in conscious unrestrained rats 1 day and 14 days following sinoaortic deafferentation (SAD) or sham operation. Fluctuations in RSNA and heart rate (HR) were correlated stastistically with moment to moment changes in pressure. One day and 14 days after SAD, the lability of mean arterial pressure (MAP) was increased, whereas the lability of RSNA and HR were reduced at 1 day and unchanged at 14 days. Arterial pressure and RSNA were negatively correlated in sham rats, however in rats with SAD negative correlations were virtually absent and positive correlations appeared only infrequently. These results indicate that SAD reduces variability of both RSNA and HR and that lability of arterial pressure appears to not be driven by variations in sympathetic discharge. To examine the central origins of RSNA in anesthetized rats we blocked neuronal transmission in two vasomotor regions of rostral medulla, rostral ventrolateral medulla (RVLM) and rostral ventromedial medulla (RVMM) using bilateral microinjections of lidocaine. Blockade of either or both RVLM and RVMM produced an equivalent marked reduction in arterial pressure but reduced RSNA to only 40% of control. Ganglionic blockade had little additional effect on arterial pressure but abolished the residual RSNA. These findings suggest that a substantial fraction of RSNA may be non-vasomotor in function and that this activity may originate from spinal sites or from supraspinal sites other than RVLM or RVMM.

Differential regulation of sympathetic nerve activity by lateral and medial subregions of the rostral ventral medulla.

Microinjections of lidocaine were used to examine the contributions of two subregions of the RVM, RVLM (2 mm lateral to midline) and RVMM (1 mm lateral to midline) to the maintenance of AP and SNA in urethane-anesthetized rats. Lidocaine microinjected into either site reduced AP to similar levels. Blockade of RVLM and RVMM produced a small further reduction in AP and essentially abolished neurogenic maintenance of AP. Blockade of either RVLM or RVMM elicited similar falls in RSNA. In contrast, inactivation of RVLM elicited larger falls in lumbar chain (LSNA) and splanchnic (SSNA) SNA than did inactivation of the RVMM. Combined blockade of RVLM and RVMM essentially eliminated LSNA, while RSNA and SSNA were reduced only 60%. From these data we conclude that (1) RVLM and RVMM contribute equally to the neurogenic maintenance of AP; (2) RVLM and RVMM differentially control the activity of individual sympathetic nerves; and (3) a substantial portion of RSNA and SSNA originates outside the RVM and may not be involved in vasomotor control.