Fos-activation of FoxP2 and Lmx1b neurons in the parabrachial nucleus evoked by hypotension and hypertension in conscious rats.

The parabrachial nucleus (PB) is a brainstem cell group that receives a strong input from the nucleus tractus solitarius regarding the physiological status of the internal organs and sends efferent projections throughout the forebrain. Since the neuroanatomical organization of the PB remains unclear, our first step was to use specific antibodies against two neural lineage transcription factors: Forkhead box protein2 (FoxP2) and LIM homeodomain transcription factor 1 beta (Lmx1b) to define the PB in adult rats. This allowed us to construct a cytoarchitectonic PB map based on the distribution of neurons that constitutively express these two transcription factors. Second, the in situ hybridization method combined with immunohistochemistry demonstrated that mRNA for glutamate vesicular transporter Vglut2 (Slc17a6) was present in most of the Lmx1b+ and FoxP2+ parabrachial neurons, indicating these neurons use glutamate as a transmitter. Third, conscious rats were maintained in a hypotensive or hypertensive state for 2h, and then, their brainstems were prepared by the standard c-Fos method which is a measure of neuronal activity. Both hypotension and hypertension resulted in c-Fos activation of Lmx1b+ neurons in the external lateral-outer subdivision of the PB (PBel-outer). Hypotension, but not hypertension, caused c-Fos activity in the FoxP2+ neurons of the central lateral PB (PBcl) subnucleus. The Kölliker-Fuse nucleus as well as the lateral crescent PB and rostral-most part of the PBcl contain neurons that co-express FoxP2+ and Lmx1b+, but none of these were activated after blood pressure changes. Salt-sensitive FoxP2 neurons in the pre-locus coeruleus and PBel-inner were not c-Fos activated following blood pressure changes. In summary, the present study shows that the PBel-outer and PBcl subnuclei originate from two different neural progenitors, contain glutamatergic neurons, and are affected by blood pressure changes, with the PBel-outer reacting to both hypo- and hypertension, and the PBcl signaling only hypotensive changes.

Hemodynamic response patterns to acute behavioral stressors resemble those to cocaine.

Hemodynamic responses to cocaine vary greatly between animals, and the variability is related to the incidence of cocaine-induced cardiomyopathies and hypertension. The variability in cardiac output and systemic vascular resistance responses to cocaine in individuals is correlated with the responses to acute startle (air jet). This experiment was designed to determine whether responses to cocaine and to air jet are related to those evoked by a conditioned stimulus (tone preceding foot shock) and to an unconditioned stimulus (cold water). We verified the relationship in hemodynamic response patterns between cocaine and cold stress using selective receptor antagonists. Rats were instrumented with a pulsed Doppler flow probe on the ascending aorta for determination of cardiac output and with an arterial cannula for recording arterial pressure and heart rate. After recovery, some rats were tested multiple times with four different stimuli: air jet (6 trials), 15-s tone preceding 1-s foot shock (12 trials), cold water exposure (1 cm deep for 1 min, 4-12 trials), and cocaine (5 mg/kg iv, 4-6 trials) while hemodynamic parameters were recorded. Each stimulus was capable of eliciting a pressor response that was associated with variable changes in cardiac output. The cardiac output response to cocaine was correlated with the initial responses to each stressor in individual rats. Responses evoked by cold stress were most similar to those elicited by cocaine. Furthermore, nicardipine (25 microg/kg iv) or atropine methylbromide (0.5 mg/kg iv) pretreatment prevented the cardiac output differences to acute cold stress, as noted after cocaine administration. On the other hand, propranolol (1 mg/kg iv) exacerbated both the decrease in cardiac output and the stress-induced increase in systemic vascular resistance as previously reported with cocaine. Therefore, the initial response to cold water exposure is a reliable method of evoking characteristic hemodynamic response patterns that, as seen with cocaine, may provide a suitable model for identifying the causes for predilection to stress-induced cardiovascular disease.

Hemodynamic response pattern predicts susceptibility to stress-induced elevation in arterial pressure in the rat.

Cocaine or air jet stress evokes pressor responses due to either a large increase in systemic vascular resistance (vascular responders) or small increases in both cardiac output and vascular resistance (mixed responders) in conscious rats. Repeated cocaine administration results in elevated arterial pressure in vascular responders but not in mixed responders. The present study examined the hypothesis that the pattern of cardiovascular responses to an unconditioned stimulus (UCS; air jet) is related to responses to a conditioned stimulus (CS; tone followed by brief foot shock) in individual rats. Our data demonstrate that presentation of the UCS produced variable cardiac output responses that correlated with responses to the CS (n = 60). We also determined whether individual cardiovascular response patterns to acute stress correlated with predisposition to a sustained stress-induced elevation in arterial pressure. Rats were exposed to three different stressors presented one per day successively for 4 wk and during a poststress period of 3 wk while arterial pressure was recorded periodically. Mean arterial pressure was elevated in all rats during chronic stress but, during the poststress period, remained at significantly higher levels in vascular responders but not mixed responders. Therefore, we conclude that acute behavioral stress to a conditioned stimulus elicits variable hemodynamic responses that predict the predisposition to a sustained stress-induced elevation in arterial pressure.

Central corticotropin releasing factor (CRF) and adrenergic receptors mediate hemodynamic responses to cocaine.

Cocaine administration evokes cardiovascular responses that are variable in rats such that the pressor response is attributable to either a large increase in systemic vascular resistance and a decrease in cardiac output (vascular responders) or a smaller increase in systemic vascular resistance and no change or an increase in cardiac output (mixed responders). This study was designed to determine the role of central corticotropin releasing factor (CRF) and adrenergic receptors in mediating specific hemodynamic response patterns. Rats were instrumented for ascending aortic blood flow determination (cardiac output) using a pulsed Doppler system, arterial pressure measurement and for intravenous and intracerebroventricular (icv) administration of drugs. After characterizing the hemodynamic response pattern in individual rats to cocaine (5 mg/kg, i.v., 4-6 trials), selective receptor antagonists were administered icv 10 min before cocaine (5 mg/kg, i.v.). Pretreatment with the CRF antagonist alpha-helical CRF(9-41) (10 microg/5 microl, icv) prevented the decrease in cardiac output in vascular responders without altering hemodynamic responses to cocaine in mixed responders. Astressin (5 microg/5 microl, icv) exerted a similar effect in vascular responders. The alpha(2) receptor antagonist, yohimbine (3 microg/microl, icv) also prevented the decrease in cardiac output in vascular responders. Lower doses of alpha-helical CRF(9-41) (1 and 3 microg) were ineffective whereas higher doses of either CRF antagonist were lethal within 24 h. In contrast, propranolol (3 or 30 microg, icv) pretreatment enhanced the cocaine-induced decrease in cardiac output and increase in systemic vascular resistance noted in vascular responders and resulted in a decrease in cardiac output in mixed responders. We conclude that CRF and adrenoceptors in the CNS play an important role in determining the hemodynamic response pattern to cocaine. Furthermore, central beta-adrenoceptors may be responsible for the reported effects of intravenous propranolol on cocaine-induced responses.

Review of evidence for a novel model of cocaine-induced cardiovascular toxicity.

Cocaine is known to produce life-threatening cardiovascular complications in some but not all individuals. This review considers the premise that an appropriate animal model for cocaine-induced cardiotoxicity should be characterized by varying sensitivity in the population to the deleterious effects of cocaine. We have studied such a model in which physiological, biochemical, and pathological sensitivity to cocaine varies in rats. Our studies have identified a subset of rats that respond to cocaine with a decrease in cardiac output and a substantial increase in systemic vascular resistance (named vascular responders). In contrast, another group, designated mixed responders, is characterized by a smaller increase in systemic vascular resistance and a small increase in cardiac output. We reported that vascular responders are more likely to develop hypertension and cardiomyopathies with repeated cocaine administration. Under chloralose anesthesia, vascular responders have more profound pressor responses to cocaine and an initial brief spike in renal sympathetic nerve activity not usually noted in mixed responders. Vascular responders have higher resting and cocaine-induced dopamine turnover in the striatum. In addition, vascular responders have higher alpha-adrenergic vasoconstrictor tone, whereas mixed responders have higher adrenergic cardiac tone. The difference in cardiac output and systemic vascular resistance responses to cocaine in these two subsets of the population can be prevented by L-type calcium channel, muscarinic, or alpha-adrenergic blockade. Similar hemodynamic response variability is noted with other psychoactive agents and with acute stress, suggesting that the response patterns are not unique to cocaine. We propose that individual hemodynamic response variability is dependent on differences in CNS responsiveness and correlated with the incidence of cardiovascular disease.

Role of cholinergic receptors and cholinesterase activity in hemodynamic responses to cocaine in conscious rats.

It has been suggested that toxicity to cocaine is related to the relative rate of cocaine metabolism by cholinesterases and to activation of cholinergic receptors either directly or by reflex mechanisms. We examined these possibilities by altering cholinesterase activity and blocking cholinergic receptors in rats prone or resistant to cocaine-induced cardiovascular toxicity. Rats were instrumented with a pulsed Doppler flow probe on the ascending aorta for measurement of cardiac output and cannulated for arterial pressure and heart rate determination. In conscious rats, cocaine (5 mg/kg iv) elicited pressor responses and a delayed bradycardia but cardiac output and systemic vascular resistance responses varied greatly between rats. Pretreatment with the nonspecific cholinesterase inhibitors physostigmine (0.1-0.2 mg/kg) or neostigmine (0.1 mg/kg) reduced the pressor response by diminishing the increase in systemic vascular resistance. In contrast, inhibition of cocaine metabolism with the selective plasma cholinesterase inhibitor tetraisopropyl pyrophosphoramide (0.5 mg/kg) or increasing cholinesterase activity with human butyryl cholinesterase (9.9 mg/kg iv) did not alter hemodynamic responses to cocaine. Administration of atropine methyl bromide (0.5-1 mg/kg iv) alone or with physostigmine to prevent the cholinomimetic effects of physostigmine reduced the cocaine-induced decrease in cardiac output noted in some animals. These data suggest that the cocaine-induced decrease in cardiac output observed in some rats is, at least in part, dependent on activation of muscarinic receptors. In addition, the rate of cocaine metabolism is not critical for the initial hemodynamic responses to cocaine in conscious rats.

Mechanisms of hemodynamic responses to cocaine in conscious rats.

Several agents have been used to treat cocaine-related cardiovascular complications and toxicity occurring in sensitive individuals, yet the causes of hemodynamic responsiveness and differential sensitivity to cocaine are unknown. In this study, we sought to examine the role of different mediators in a model of variable cardiovascular responses to cocaine. As noted previously in conscious rats, cardiac output (CO) and systemic vascular resistance (SVR) responses to cocaine (5 mg/kg, i.v.) varied widely. Twenty of 34 rats exhibited cocaine-induced decreases in CO of > or =8% and large increases in SVR (designated vascular responders). The remaining rats with little change or an increase in CO and smaller increases in SVR were named mixed responders. Pretreatment with propranolol (1 mg/kg) or metoprolol (1 mg/kg) reduced heart rate. In mixed responders, propranolol or metoprolol reversed the cocaine-induced increase in CO and stroke volume and enhanced the increase in SVR, making these rats respond like vascular responders. Nicardipine (25 microg/kg) reduced the pressor response and selectively reversed the CO responses in vascular responders. N omega-nitro-L-arginine methyl ester (L-NAME; 2.7 mg/kg) increased arterial pressure by increasing SVR. Cocaine induced greater pressor and SVR responses apparently because of a shift in baseline values elicited by L-NAME alone. Therefore, differences in hemodynamic responses patterns may be the result of differences in beta-adrenergic activation or subsequent calcium channel activation or both. We predict that calcium channel antagonists may be useful to treat cocaine-induced cardiovascular complications, whereas beta-adrenergic antagonists are not likely to be beneficial.

Dynamic transduction properties of in situ baroreceptors of rabbit aortic depressor nerve.

We developed a new method for isolating in situ baroreceptor regions of the rabbit aortic depressor nerve (ADN) and estimated the transfer function from pressure to afferent nerve activity in the frequency range of 0.01-5 Hz by a white noise technique. Complete isolation of the baroreceptor area of the right ADN was made in situ by ligation of the innominate artery and the right subclavian and common carotid arteries. We altered the pressure in the isolated baroreceptor area according to a binary quasi-white noise between 80 and 100 mmHg in 12 urethan-anesthetized rabbits. The gain increased two to three times as the frequency of pressure perturbation increased from 0.01 to 2 Hz and then decreased at higher frequencies. The phase slightly led below 0.2 Hz. The squared coherence value was > 0.8 in the frequency range of 0.01-4 Hz. The step responses estimated from the transfer function were indistinguishable from those actually observed. We conclude that the baroreceptor transduction of the ADN is governed by linear dynamics under the physiological operating pressure range.

Effects of proposed treatments for cocaine addiction on hemodynamic responsiveness to cocaine in conscious rats.

Several agents may treat cocaine addiction and toxicity including bromocriptine, desipramine, GBR 12909 [1-(2-(bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl) piperazine], diazepam, buprenorphine and dizocilpine. In this study, we sought to determine whether these specific therapeutic agents alter cardiovascular responses to cocaine in conscious rats. Arterial pressure responses to cocaine (5 mg/kg, i.v.) were similar in all rats whereas cardiac output responses varied widely. In 26 of 33 rats (named vascular responders), cocaine induced a decrease in cardiac output of 8% or more. The remaining rats with little change or an increase in cardiac output were classified as mixed responders. Pretreatment with bromocriptine (0.1 mg/kg) or desipramine (1 mg/kg) increased cardiac output in mixed responders and increased systemic vascular resistance in vascular responders similar to the differential effects noted with cocaine. GBR 12909 (0.5-10 mg/kg) elicited a decrease in cardiac output at higher doses. Diazepam (0.1 and 0.5 mg/kg) had small, short-lasting effects on cardiovascular parameters. Buprenorphine (0.3 mg/kg) or the NMDA (N-methyl-D-aspartic acid) receptor antagonist, dizocilpine (0.05 mg/kg), increased arterial pressure, heart rate and cardiac output in vascular responders. Bromocriptine and desipramine prevented the difference in cardiac output responses in vascular and mixed responders by reducing the cocaine-induced decrease in cardiac output in vascular responders. Pretreatment with GBR 12909 (1 mg/kg) had little effect on cardiovascular responses to cocaine except to depress the increase in cardiac output noted in mixed responders. Buprenorphine selectively enhanced the increase in systemic vascular resistance whereas dizocilpine enhanced the pressor response. These data suggest that several treatment regimens for cocaine addiction alter the cardiovascular responses to cocaine and that dopamine D2 receptor activation may be necessary for the decrease in cardiac output noted in vascular responders.

Ethanol alters hemodynamic responses to cocaine in rats.

Cocaine is often used while consuming ethanol despite evidence that this combination may enhance the toxicity of cocaine. In the present study, we examined the cardiovascular effects of ethanol (475 or 950 mg/kg, i.v.) alone and in combination with cocaine (5 mg/kg, i.v.) in conscious rats. Ethanol or cocaine administration produced a consistent pressor response but highly variable cardiac output and systemic vascular resistance responses. The hemodynamic response patterns in individual rats to either drug were similar and related within rats. After ethanol pretreatment, cocaine produced greater decreases in cardiac output. We have proposed that this pattern of responses may reflect a predisposition in individual rats to cocaine-induced cardiomyopathies and hypertension. Furthermore, these data suggest that ethanol administration elicits a similar pattern of hemodynamic responses as previously reported for cocaine or amphetamine administration or acute behavioral stress.

Responses of single neurons in amygdala to interoceptive and exteroceptive stimuli in conscious cats.

The amygdala is critical for behavioral arousal and must therefore integrate a wide variety of inputs. We examined sensory inputs and the degree of convergence to single neurons in the amygdala in conscious freely moving cats. A pressor stimulus elicited responses, predominantly inhibitory, in one-half of the amygdalar neurons tested. Most neurons in the central and basal nuclei responded to carotid chemoreceptor activation typically with an excitation. Almost one-half of all amygdalar neurons tested, particularly in the central nucleus, received orthodromic input from the locus ceruleus, the substantia nigra, and/or the contralateral central nucleus of the amygdala. Exteroceptive sensory stimulation with optic, acoustic, tactile, and olfactory stimuli elicited responses in 33, 55, 39, and 59% of amygdalar neurons, respectively. Two-thirds of the neurons tested with more than one external stimulus modality responded in the same manner to the various stimuli (usually excitation), demonstrating a convergence of exteroceptive stimuli on single amygdalar neurons, particularly in the basal nucleus. Spontaneous and induced behavioral arousal elicited responses in 92 and 86% of neurons, respectively. Most neurons responded to multimodal exteroceptive stimuli and behavioral arousal in the same manner. We suggest that amygdalar inputs are highly varied and, in many cases, relatively nonspecific and that the amygdala integrates a large number of external and internal sensory modalities to regulate autonomic and behavioral responsiveness to various stimuli.

Intrathecal capsaicin enhances one-kidney renal wrap hypertension in the rat.

Afferent renal nerves (ARN) have been implicated in the development of one-kidney renal wrap (1K-WRAP) hypertension. The role of renal nerves in desoxycorticosterone acetate-salt (DOCA) hypertension, a low-renin model of hypertension, is controversial. The present study was designed to determine if spinal substance P (SP) and/or calcitonin gene-related peptide (CGRP) in ARN affects the development of 1K-WRAP or DOCA hypertension in adult rats. Selective long-term partial depletion of spinal SP and CGRP within small primary afferent nerve fibers including unmyelinated ARN was achieved by intrathecal administration of capsaicin. After capsaicin treatment, 1K-WRAP hypertension was induced by removing the right kidney and wrapping the left kidney with a figure-8 ligature. In a second group of rats, DOCA hypertension was induced by subcutaneous application of desoxycorticosterone pellets after unilateral nephrectomy. Systolic arterial pressure was monitored for 8 weeks by tail cuff plethysmography after which direct blood pressure measurement was performed followed by immunohistochemistry. Intrathecal capsaicin administration had no significant effect on SP-ir and CGRP-ir of ARN soma located within thoracic dorsal root ganglia whereas immunoreactivity against these peptides was reduced by one third to one half in the dorsal horn, indicating effective long-term spinal depletion of these neuropeptides. Intrathecal capsaicin enhanced the development of 1K-WRAP hypertension, since arterial pressure was greater in the treated group. In contrast, DOCA hypertension was unaffected by capsaicin pretreatment. Considering the neurotoxic action of capsaicin for SP-ir and CGRP-ir unmyelinated primary afferent neurons, we hypothesize that spinal SP, CGRP and/or related peptides existing in ARN and other capsaicin-sensitive unmyelinated primary afferent neurons in the lower thoracic spinal cord may ameliorate 1K-WRAP hypertension, but not DOCA hypertension.

Causes of differential cardiovascular sensitivity to cocaine. II: Sympathetic, metabolic and cardiac effects.

Cocaine elicits a decrease in cardiac output only in a subset of rats; this reduction is mitigated by prazosin, nifedipine, verapamil or pentolinium and exacerbated by propranolol. In the present study, we examined other correlates or causes of differential responsiveness, including differences in cocaine metabolism, sympathetic nerve responses, catecholamine sensitivity and direct cardiac actions. Arterial pressure and heart rate responses to cocaine (5 mg/kg i.v.) were similar in all rats, yet cardiac output responses, as determined by pulsed Doppler flowmetry, varied widely. Cocaine elicited a mean maximal decrease of more than 15% in 17 rats designated responders, whereas the remaining rats (n = 19) were classified as nonresponders. Maximal heart rate responses to phenylephrine- and nitroprusside-induced pressor and depressor stimuli were greater in responders than in nonresponders. Phenylephrine also elicited significantly greater decreases in cardiac output and smaller increases in stroke volume in responders. After we determined the responses to cocaine in conscious rats, animals were anesthetized with alpha-chloralose for renal nerve recording. Several rats (14 of 21 tested) demonstrated an initial brief (2-12 sec) increase in sympathetic activity, whereas all rats subsequently had a delayed sympathoinhibition. Responders were more likely to have sympathoexcitation compared with nonresponders and had an enhanced initial pressor response and a smaller decrease in heart rate. There were no differences in plasma or cerebrospinal fluid levels of cocaine or its metabolites, benzoylecgonine and ecgonine methyl ester. Intravenous benzoylecgonine elicited a pressor response and bradycardia in conscious rats. Finally, there were no differences in contractile, electrocardiographic or coronary vascular responses to cocaine in isolated, perfused hearts from responders and nonresponders. These results suggest that the differential cardiovascular responsiveness to cocaine in rats is mediated, at least in part, by central sympathoexcitation and not by differences in cocaine metabolism or in direct cardiac responsiveness to cocaine.

Central sympathetic control of spinal endothelin release in the rat.

Endothelin and its receptors have been identified in the spinal cord. Intrathecal administration of endothelin-3 produces hypotension in anesthetized rats. The present study was designed to identify whether endothelin-3 is released upon changes in sympathetic nervous activity. Endothelin-3-like immunoreactivity in spinal superfusates was directly correlated with resting arterial pressure. Endothelin-3 levels were enhanced by hypothalamic stimulation and by hemorrhage-induced hypotension and reduced by nitroprusside-induced hypotension. These findings suggest that sympathetic activation enhances endothelin-3 release but that nitroprusside may act directly to suppress release. We propose that endothelin-3 plays a role in spinal regulation of sympathetic outflow.

Causes of differential cardiovascular sensitivity to cocaine. I: Studies in conscious rats.

Cocaine produces apparent myocardial ischemia in some individuals without deleterious effects in others. The authors identified a subset of rats in which cocaine produces a decrease in cardiac output and an increase in cardiomyopathies. In the present study, several potential causes of this differential responsiveness were examined in conscious rats instrumented for cardiac output determination by using pulsed Doppler flowmetry. Although arterial pressure and heart rate responses to cocaine (5 mg/kg i.v.) were similar in all rats, cardiac output responses varied widely. Specifically, in 17 of 36 rats, cocaine elicited a maximum decrease of greater than 15% that was relatively consistent with repeated trials. These rats were designated responders, whereas the remaining rats with little change or an increase in cardiac output were classified as nonresponders. Pentolinium (7.5 mg/kg) or adrenal demedullation reduced the peak cardiac output responses in both groups such that there was no longer a difference between responders and nonresponders. Prazosin (0.1 mg/kg) reduced the cocaine-induced pressor responses in all rats and selectively reduced the decrease in cardiac output in responders. Propranolol (1 mg/kg) reduced the peak pressor response but enhanced the decrease in cardiac output in responders. Neither indomethacin (5 mg/kg) or heparin (300 units) pretreatment altered the cocaine-induced cardiac output or peripheral vascular effects in either responders or nonresponders. Amphetamine (1 mg/kg) elicited smaller pressor responses but still evoked a net decrease in cardiac output in responders.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunocytochemical co-localization of substance P and calcitonin gene-related peptide in afferent renal nerve soma of the rat.

Substance P, calcitonin gene-related peptide and somatostatin immunoreactivities have been demonstrated in putative afferent renal nerve fibers in the rat. Utilizing retrograde-tracing and immunohistochemistry, we labeled afferent renal nerve soma throughout dorsal root ganglia T9 to L1. Most (85%) of afferent renal nerve perikarya were immunoreactive for calcitonin gene-related peptide, 21% had substance P immunoreactivity and none had somatostatin immunoreactivity. All renal afferents immunoreactive for substance P also contained calcitonin gene-related peptide. These results provide evidence that calcitonin gene-related peptide and substance P are present and co-localized in afferent renal nerves, and therefore, mediate transmission of afferent renal input to the spinal cord in the rat.

Nonadrenergic mechanisms of cocaine-induced regional vascular responses in rats.

The pressor response to cocaine is a consequence of mesenteric vasoconstriction and hindquarters vasodilation as a result of activation of alpha 1- and beta-adrenergic receptors, respectively. In the present study, evidence for additional, nonadrenergic effects of cocaine-induced changes in regional blood flow was obtained using pulsed Doppler flowmetry in conscious rats. Cocaine produced dose-dependent initial peaks (within 1 min) in mean arterial pressure concomitant with an increase in hindquarters and mesenteric vascular resistance. The sustained, modest pressor response was associated with hindquarters vasodilation and bradycardia. The cocaine-induced vasodilation was enhanced by pretreatment with indomethacin (5 mg/kg), prevented by ibuprofen (12.5 mg/kg) or 3-amino-1-[m-(trifluoromethyl)-phenyl]-2-pyrazoline (BW755C, 10.5 mg/kg) pretreatment, and unaffected by meclofenamate administration (2.5 mg/kg). Equipotent local anesthetic doses of procaine produced equivalent hindquarters vasodilator responses and more modest pressor responses. Dial-urethane anesthesia did not affect hindquarters vasodilation in response to cocaine or procaine but did reduce the mesenteric vasoconstrictor and pressor responses. These data demonstrate that the cocaine-induced hindquarters vasodilation is not mediated solely by beta-adrenergic receptors but is also dependent upon eicosanoids. Furthermore, the cocaine-induced vasodilation may be due, in part, to a direct local anesthetic effect but is not dependent upon a locomotor or behavioral stress induced increase in blood flow.

Coronary vascular effects of cocaine in rats.

It has been suggested that ischemia secondary to coronary vasoconstriction is responsible for adverse cardiovascular effects of cocaine. However, the reported coronary vascular effects of cocaine vary considerably. We sought to determine the effects of cocaine on the coronary vasculature in anesthetized and conscious rats. Rats anesthetized with chloralose were instrumented for estimation of ascending aortic and coronary blood flows using pulsed Doppler velocitometry. Cocaine administration resulted in bradycardia and a biphasic mean arterial pressure response. Cocaine elicited highly variable increases in coronary vascular resistance and decreases in cardiac output. Decreases in coronary blood flow and rate-pressure product were directly correlated. Prazosin significantly attenuated the cardiac output but not the coronary vascular responses to cocaine. Propranolol, on the other hand, significantly shortened the duration of both responses. Conscious rats, instrumented for coronary blood flow determination, also exhibited cocaine-induced increases in coronary vascular resistance, yet the changes in coronary blood flow were not correlated with the rate-pressure product. These results provide the first evidence that cocaine produces equivalent increases in coronary vascular resistance in conscious and anesthetized rats. However, because the relationship between coronary blood flow and rate-pressure is different between the two preparations, as are other cardiovascular responses, we suggest that anesthesia alters the mechanism(s) by which cocaine affects the rat coronary vasculature.

Cocaine-induced myocardial ultrastructural alterations and cardiac output responses in rats.

Cocaine use has been associated with profound functional and pathological myocardial responses in otherwise asymptomatic humans, yet a number of individuals appear to tolerate large doses of the drug. This study was designed to determine whether there is a relationship between the differential effects of cocaine administration on cardiovascular responses and on the development of cardiomyopathies in rats. After instrumentation for determination of cardiac output, conscious, freely moving rats were treated with cocaine (5 mg/kg) or saline intravenously twice daily for 14 days before removing the myocardium for analysis. Although most cardiovascular responses were similar, cocaine administration elicited consistent decreases in cardiac output in some rats, whereas others showed little change or an increase. While little change was evident at low magnification, electron microscopy revealed diffusely distributed myocardial lesions including focally dilated sarcoplasmic reticulum and myofibrillar derangement, early signs of mitochondrial alterations, and foci of myocardial fibrosis. The incidence of these alterations was greater in rats with a decrease in cardiac output. We also observed these lesions in a subset of rats treated with cocaine without cardiac output instrumentation. These data represent the first evidence that there is a relationship between cocaine-induced functional and pathological alterations and that rats, like humans, may be differentially sensitive to these effects.

Stress and cocaine elicit similar cardiac output responses in individual rats.

Cocaine use and behavioral stress elicit variable cardiovascular responses in individuals. In the present study, we examined the effects of cocaine or stress on arterial pressure, heart rate, and cardiac output in conscious rats. Rats were instrumented for determination of ascending aortic blood flow as an index of cardiac output using pulsed Doppler flow-metry. Cocaine administration elicited consistent decreases in cardiac output in some rats, whereas others had increases. In contrast, the pressor and heart rate responses were similar in these two groups of animals. Air jet stress also elicited a decrease in cardiac output only in a subset of conscious rats, yet produced equivalent pressor responses in all rats. Cardiac output responses to cocaine and air jet stress were closely correlated in individual rats, indicating that these stimuli evoke similar hemodynamic responses in individual rats. These observations suggest that the rat may provide a model for understanding differential cardiovascular sensitivity to cocaine and/or stress in humans.