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The acute effect ofT-2 toxemia on local blood flow and vascular resistance in hindquarter. mesenteric. and renal vascular beds was continuously measured by the directional pulsed Doppler technique in conscious, male Sprague-Dawley rats. Intravenous injection ofT-2 toxin (I mg/kg) in the conscious rat reduced blood flow and increased vascular resistance in all blood vessels studied but had no significant effect on mean arterial pressure or heart rate. The blood flow in hindquarters gradually decreased to a minimum of -77 ± 9% (mean ±SE) 6 hr after the toxin injection. The hindquarter vascular resistance concomitantly increased to a maximum value of + 323 ± 69% above thc resistance before toxin administration. Mesenteric and renal blood flow initially increased (slightly) and then gradually decreased. The maximum drop of blood flow, -90 ± 13% and -76 ± 13% for the mesenteric and renal vascular beds, respectively, was achieved 4 hr after T-2 toxin injection and the blood flow values remained low for up to 6 hr. Simultaneously with the impairment of
Opioid peptidesandmultiple opioid receptors are found in brain cardiovascular nuclei, autonomic ganglia, the heart, and blood vessels, and opioids induce potent cardiovascular changes. The role of endogenaus opioids in normal cardiovascular homeostasis is unclear; however, current data suggest opioid involvement in stress.
The effect of the selective \(\mu\)-opioid agonist o-Ala\(^2\)-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 output 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 mg/kg 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 \(\mu\)-receptors in the preoptic nucleus might be involved in the integration of peripheral blood ftow in the hypothalamus during affective behavior.
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 capacity of L-649,923-sodium ( ßS, -yR * )-4-(3-( 4-acetyl-3-hydroxy-2-propylphenoxy)propylthio)-- y-hydroxy-ß-methylbenzene butanoate-to block vascular receptors of leukotriene D\(_4\) ( L TD\(_4\)) was examined in the conscious rat. Hindquarter (HQ), renal, and mesenteric blood flow and vascular resistance were evaluated in the conscious rat chronically equipped with miniaturized Doppler probes for organ blood flow measurement by directional pulsed Doppler technique. In addition, cardiac outpul was measured by thermodilution technique in conscious rats equipped with minithermistors in the ascending aorta. Systemic hemodynamic variables. mean arterial pressure, and heart rate were monitored through femoral catheters. L TD\(_4\) (I or 10 \(\mu\)g/kg) produced a marked dose dependent increase in the mesenteric vascular resistance associated with a marked decrease in blood flow whereas no consistent effects were demonstrated in the renal circulation. L TD\(_4\) • at I \(\mu\)g/kg. increased the HQ blood flow whereas the higher dose of LTD\(_4\) produced a biphasic response: an early increase followed by a decrease in blood flow. Infusion of L TD\(_4\) • 3 \(\mu\)g/kg per min over 10 min decreased cardiac output and increased total peripheral resistance. L-649,923 (10 or 30 mg/kg, i.v.) effectively blocked the L TD4-induced mesenteric constriction and the second I phase of HQ vasoconstriction but did not modify the , LTD\(_4\) induced HQ vasodilation. L-649,923 also effectively attenuated the cardiac effects of LTD\(_4\) infusion. I These studies suggest that L-649,923 could preserve cardiac and vascular functions in pathologic states mediated by cysteinylleukotrienes, such as traumatic or endotoxin shock. Key Words: Leukotriene D4 -Cardiovascular system- Leukotriene antagonist- Mesenteric blood tlow-Renal blood flow-Hindquarter blood flowAnaphylaxis.
Background and Purpose: We earlier reported that risk factors for stroke prepare brain stem tissue for a modified Shwartzman reaction, incIuding the development of ischemia and hemorrhage and the production of tumor necrosis factor-a, after a provocative dose of lipopolysaccharide. In the present study, we sought to determine whether blood and central nervous system cells of rats with the stroke risk factor of advanced age produce more proinflammatory and prothrombotic media tors than do those of young rats of the same strain. Methods: Levels of tumor necrosis factor-a and platelet activating factor in the cerebrospinal fluid and tumor necrosis factor-a in the serum of 2-year-old and 16-week-old Sprague-Dawley rats were monitored before and after challenge with lipopolysaccharide. Results: No consistent tumor necrosis factor-a activity was found in the cerebrospinal fluid or blood of control animals. Intravenous administration of lipopolysaccharide (1.8 mg/kg) increased serum tumor necrosis factor-a levels but had no effect on tumor necrosis factor-a in the cerebrospinal fluid. Serum tumor necrosis factor-a increased much more in aged rats than in young rats. When lipopolysaccharide was injected intracerebroventricularly, tumor necrosis factor-a activity in cerebrospinal fluid increased significantly more in old rats than in young rats. Baseline levels of platelet activating factor in cerebrospinal fluid were significantly higher in old rats than in young rats, and the levels increased to a greater degree in aged rats on stimulation. Conclusions: Rats with the stroke risk factor of advanced age respond to lipopolysaccharide with a more exuberant production of tumor necrosis factor-a and platelet activating factor than young rats of the same strain. These findings are consistent with our working hypothesis that perivascular cells are capable of exaggerated signaling of endothelium through cytokines such as tumor necrosis factor-a in animals with stroke risk factors. The effect of such signaling might be to prepare the endothelium of the local vascular segment for thrombosis or hemorrhage in accord with the local Shwartzman reaction paradigm.
Tyr-o-Arg\(^2\)-Phe-sarcosine\(^4\) (TAPS), a mu-selective tetrapeptide analog of dermorphin, induced sustained antinociception and stimulated ventilatory minute volume (MV) at the doses of 3 to 100 pmol i.c.v. The doses of 30 and 100 pmol i.c.v. induced catalepsy. The effect of TAPS on MV was in negative correlation with the dose and the maximal response was achieved by the lowest (3 pmol) dose (+63 ± 23%, P < .05). Morphine, an agonist at both mu\(_1\) and mu\(_2\) sites, at a dose of 150 nmol i.c.v. (equianalgetic to 100 pmol of TAPS decreased the MV by 30%, due to a decrease in ventilatory tidal volume. The antinociceptive effect of TAPS was antagonized by naloxone and the mu, receptor antagonist, naloxonazine. Naloxonazine also attenuated the catalepsy produced by 1 00 pmol of TAPS i.c. v. and the respiratory Stimulation produced by 3 pmol of TAPS i.c.v. Pretreatment with 30 pmol of TAPS antagonized the respiratory depression induced by the mu opioid agonist dermorphin (changes in MV after dermorphin alone at 1 or 3 nmol were -22 ± 1 0% and -60 ± 9% and, after pretreatment with TAPS, +44 ± 11 % and -18 ± 5%, respectively). After combined pretreatment with naloxonazine and TAPS, 1 nmol of dermorphin had no significant effect on ventilation. In contrast, pretreatment with a low respiratory stimulant dose (10 pmol i.c.v.) of dermorphin did not modify the effect of 1 nmol of dermorphin. ln conclusion, the antinociceptive, cataleptic and respiratory stimulant effects of TAPS appear to be a related to its agonist action at the mu, opioid receptors. TAPS did not induce respiratory depression (a mu\(_2\) opioid effect) but antagonized the respiratory depressant effect of another mu agonist. Thus, in vivo TAPS appears to act as a mu\(_2\) receptor antagonist.
The selective opioid mu receptor agonist dermorphin increased the locomotor activity of rats dose dependently at 1 0 to 1 00 pmol/kg i.c.v. Respiratory rate, relative tidal volume and respiratory minute volume also increased unrelated to changes in locomotor activity. Higher doses, on the other hand, produced catalepsy and respiratory depression. Pretreatment of the rats with the mu,-selective antagonist naloxonazine (10 mg/kg i.v.) blocked the stimulant locomotor and respiratory effects of low doses of dermorphin (1 0--1 00 pmol/kg), but potentiated the respiratory depressant effect of a high dose (1 0 nmol/kg) of dermorphin. The selective benzodiazepine antagonist flumazenil (5 mg/kg), which has been shown previously to antagonize catalepsy and respiratory depression produced by relatively high doses of dermorphin, did not antagonize the respiratory or locomotor stimulant effect of dermorphin. The data suggest that mu\(_1\)-opioid receptors are responsible for the low dose stimulant effects of dermorphin on locomotor activity and respiration whereas mu\(_2\) receptors mediate the respiratory depressant effect of dermorphin.
lnteractions of p-opioid receptors with the benzodiazepine system were studied by examining the modulatory effects of flumazenil (a benzodiazepine antagonist) and alprazolam (a benzodiazepine agonist) on the respiratory effects ofthe opioid peptide dermorphin. Dermorphin, 1-30 nmol administered i.c.v., to conscious, unrestrained rats decreased ventilation rate (VR) and minute volume (MV) dose-dependently. The ventilatory depression was antagonized by naloxone and by the benzodiazepine antagonist flumazenil. The benzodiazepine alprazolam potentiateri the respiratory inhibition of a small (I nmol) dose of dermorphin but antagonized that of a higher dos:~ (3 nmol). The results suggest that the benzodiazepine/GABA receptor complex modulates respiratory depression induced by centrat p-receptor Stimulation in the rat.
The possibility that \(\mu\)Opioid-induced tachycardia and bradycardia could be mediated by different subtypes of the \(\mu\)·receptor was studied in conscious Sprague-Dawley rats. The selective \(\mu\)·receptor agonist dermorphin and its analog, TAPS (Tyr-o-Arg-Phe-sarcosine), a putative \(\mu _1\)-receptor agonist, were given centrally. Tyr-o-Arg-Phe-sarcosine increased the heart rate, the response being inversely correlated to the dose (an increase of 71 ± 22, 49 ± 14 and 30 ± 17 beats/min at doses of 0.3, 3 and 30 pmol, respectively). Dermorphin induced less clear changes in heart rate (maximum increase of 39 ± 14 beats/min at the dose of 1 pmol). Aftertreatment with the Jl 1-selective antagonist naloxonazine (NAZ), TAPS 30 pmol and dennorphin I pmol decreased heart rate by -22 ± 10 and -24 ± 7 bpm, respectively. The bradycardic effect oflarger doses of dennorphin was potentiated by NAZ (from -25 ± 8 to -97 ± 22 bpm) but abolished by the non-selective antagonist naloxone. These data suggest that the high affinity \(\mu _1\)-opioid receptors mediate tachycardic responses and \(\mu _2\)-receptors mediate bradycardic responses.
Stroke risk factors prepare rat brainstem tissues for a modified localized Shwartzman reaction
(1988)
Stroke risk factors such as hypertension, diabetes, advanced age, and genetic predisposition to stroke were demonstrated to prepare rat brainstem tissues for a modified local Shwartzman reaction. A single intracisternal injection of endotoxin provoked the reaction, and affected rats manifested neurologie deficits accompanied by pathologie lesions. Brainstem infarcts developed in only a small proportion of rats without recognized risk factors after intracisternal injection of endotoxin. Thus, stroke risk factors, whieh are ordinarily regarded as operating through acceleration of atherosclerosis, may predispose to brain ischemia by local effects on brain mierocirculation such as those thought to underlie preparation of a tissue for the local Shwartzman reaction.
CARDIOVASCULAR and vasopressin (A VP) responses to hcmorrhagc wcrc studicd in rats with lesions of the hypothalamic supraoptic nuclei (SONL). Bleeding caused hypotension and increase in heart rate (HR) and A VP. SONL rats failed to fully recover from bleeding as compared to normal rats. Plasma A VP in SONL rats was in the normal in basal conditions, but failed to increase to levels attained in normal rats throughout the post-hemorrhage period. These data suggcst that the supraoptic nuclei are the primary regulatory sitcs for A VP release in rcsponse to hemorrhage and that lack of adequate A VP release significantly retards blood pressure recovery after bleeding.
We have previously reported that analgesic doses of morphine accelerate mortality of rats exposed to hemorrhage (Feuerstein and Siren: Circ Shock 19:293-300, 1986). To study the potential mechanisms involved in this phenomenon, rats were chronically implanted with catheters in the femoral vessels and morphine (1.5 or 5 mg/kg) was administered 30 min or 24 hr after bleeding (8.5 mll300 g over 5 min) while arterial blood pressure and heart rate were continuously monitored. Furthermore, the effect of morphine (5 mg/kg) on cardiac output (CO) response to hemorrhage was studied in rats chronically equipped with a mini thermistor for CO monitoring by a thermodilution technique. In addition, plasma catecholamines (HPLC), plasma renin activity (PRA, RIA), vasopressin (RIA), pH, and blood gases were also determined. Morphine administration 30 min after hemorrhage produced a pressor response and tachycardia which were in marked contrast to its depressor effect in intact rats. Morphine elevated PRA and epinephrine but not vasopressin, while blood pH and gases showed no consistent change as compared to salinetreated hemorrhaged rats. Morphine given after the bleeding resulted in enhanced cardiac depression in response to a second bleed of 2 m1l300 g. Our data suggest that activation of pressor mechanisms by morphine during hypovolemic hypotension might enhance vasoconstriction in essential organs, depress cardiac function, and further reduce effective tissue perfusion.
Lipoxin A (LXA\(_4\)) and lipoxin B\(_4\)(LXB\(_4\)) are newly discovered lipoxygenase-interacting products of leukocytes which might have a role in cardiovascular events associated with anaphylaxis. We have tested this possibility by systemic administration of both LXA\(_4\) and LXB\(_4\) to the conscious rat while monitaring systemic and regional hemodynamic changes. LXA\(_4\) and' LXB\(_4\) (l-100 pg/kg) produced dose-dependent constriction of the mesenteric vessels, up to + 123±23% and +50±9% for LXA\(_4\)/B\(_4\) , respectively. Dose-related changes were not observed in arterial blood pressure, heart rate, renal (LXB\(_4\)) and hindquarter blood ftow. We suggest that LXA\(_4\) and LXB\(_4\) might affect selective vascular beds, such as the mesenteric vessels, and contribute to variations in blood flow in specific pathophysiological states.
The endogenous opioid system includes three major families of peptides [22): dynorphins (derived from pre-proenkephalin B); endorphins (derived from pre-proopiomelanocortin) and enkephalins (derived from pre-proenkephalin A). Multiple species of opioid peptides are derived from these major precursors and many of them possess potent cardiovascular properties. Multiple forms of opioid receptors have been defined in the central nervous system. Although the relationship of these receptors to the multiple actions of the opioid systems is not weil understood, some predications can be made: in vitro the dynorphin-related peptidesbind preferentially to kappa-opioid receptors; the enkephalins bind preferentially to delta and JL-opioid receptors and while beta-endorphin binds to mu- and delta-, but not to kappa-opioid receptors. While littleis known on the roJe ofthe opioid system in normal cardiovascular regulation, it has become clear that cardiovascular stress situations substantially modify the activity ofthe endogenous opioid system. This review focuses on the mu-opioid system in the hypothalamus with special emphasis on its potential roJe in cardiovascular control of both normal and pathophysiologic states.