Pharmacological characterization of apomorphine-induced hypothermia in the spontaneously hypertensive rat

The dopamine agonist apomorphine was more potent in eliciting hypothermia in spontaneously hypertensive rats (SHRs) than in normotensive Wistar rats (NWRs), while normotensive Wistar-Kyoto rats (WKYs) were intermediate in response. Various drug interventions were attempted in an effort to explain the greater sensitivity of SHRs to apomorphine. Haloperidol produced abolition of apomorphine-induced hypothermia in SHRs but at greater doses than required for antagonism of the drug effect in WKYs and NWRs. Chronic hydralazine treatment that reduced the high blood pressure of SHRs failed to appreciably influence the magnitude of apomorphine-induced hypothermia, compared to the response in control SHRs that received no hydralazine. These findings suggested to us that the enhanced hypothermic effect of apomorphine in SHRs was entirely dopamine receptor-mediated and that it was also independent of the high blood pressure. We also found that chronic lithium treatment that had no influence upon apomorphine-induced hypothermia in WKYs and NWRs significantly reduced the drug effect in SHRs. Based on this finding, we suggest that the greater hypothermic effect induced by apomorphine in SHRs might be due to a supersensitivity of hypothermia-mediating dopamine receptors in the hypertensive strain.     

Increased ganglionic responses to substance P in hypertensive rats due to upregulation of NK(1) receptors

Intravenous injection of substance P (SP) increases renal nerve firing and heart rate in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) by stimulating sympathetic ganglia. Blood pressure is increased in SHRs but lowered in WKYs. This study assesses the role of neurokinin-1 (NK(1)) receptors in mediating the ganglion actions of SP. Rats for functional studies were anesthetized and then treated with chlorisondamine. Renal nerve, blood pressure, and heart rate responses to intravenous injection of the NK(1) receptor agonist GR-73632 were similar but less than those to equimolar doses of SP in SHRs. GR-73632 only slightly increased renal nerve firing and heart rate and lowered blood pressure in WKYs. The NK(1) receptor antagonist GR-82334 (200 nmol/kg iv) blocked the ganglionic actions of GR-73632 and the pressor response to SP in SHRs. It reduced the renal nerve and heart rate responses by 52 and 35%. This suggests that the pressor response to SP is mediated by ganglionic NK(1) receptors and that NK(1) receptors also have a prominent role in mediating the renal nerve and heart rate responses to SP. Quantitative autoradiography showed that NK(1) receptors are more abundant in the superior cervical ganglia of SHRs. RT-PCR showed increased abundance of NK(1) receptor mRNA in SHRs as well. These observations suggest that the greater ganglionic stimulation caused by SP in SHRs is due to upregulation of NK(1) receptors.     

Effect of neuromuscular blocking drugs on arterial pressure and heart rate in rats

The effects of neuromuscular blocking drugs on mean arterial pressure (MAP) and heart rate (HR) were studied in rats which were anaesthetised, tracheotomized and ventilated artificially. The arterial pressure was recorded from the carotid artery. Seven neuromuscular blocking drugs were injected intravenously at doses of 1, 5, and 25 mumol/kg. d-Tubocurarine, alcuronium and vecuronium lowered MAP in a dose dependent manner (maximum 40%). Succinylcholine, 1 mumol/kg, reduced MAP and HR, whereas the two larger doses increased them. Gallamine, 25 mumol/kg, or metocurine and pancuronium, 1 or 5 mumol/kg, each, induced short-lasting rises in MAP. Pancuronium, 25 mumol/kg, decreased MAP by 25%, while the largest dose of metocurine appeared to be toxic. The cardiovascular responses to neuromuscular blocking drugs were antagonized or abolished by pretreatment with the ganglionic blocking agent pentolinium. Pentolinium itself markedly reduced MAP and HR. After ganglionic blockade and restoration of MAP by noradrenaline infusion, all the neuromuscular blocking drugs induced short-lasting increases in MAP (10-30%), except d-tubocurarine which still reduced MAP by 30%, a fall which, in contrast to the effect in the absence of the pretreatments, was transient. This response to d-tubocurarine could not be abolished by a combined pretreatment with H1 and H2 antagonists showing that the hypotensive effect of this drug was not due to the liberation of histamine. These results suggest that the cardiovascular responses to neuromuscular blocking drugs in rats might be partly due to ganglionic effects. Other mechanisms are also involved since after the restoration of blood pressure by noradrenaline during the ganglionic blockade some cardiovascular responses to these drugs still occurred.     

ANG II in median preoptic nucleus and pressor responses to CSF sodium and high sodium intake in SHR

Pressor responses to increases in cerebrospinal fluid (CSF) sodium in Wistar rats and to high salt intake in spontaneously hypertensive rats (SHR) involve both brain ouabainlike activity ("ouabain") and the brain renin-angiotensin system (RAS). Because some of the effects of "ouabain" are mediated by the median preoptic nucleus (MnPO) and this nucleus contains all elements of the RAS, the present study assessed possible interactions of "ouabain" and ANG II in this nucleus. In conscious Wistar rats, injection of ANG II into the MnPO significantly increased mean arterial pressure (MAP) and heart rate (HR). This response was not affected by pretreatment with a subpressor dose of ouabain. MAP and HR increases by ouabain in the MnPO were significantly attenuated by MnPO pretreatment with losartan. In Wistar rats, losartan in the MnPO also abolished pressor and HR responses to intracerebroventricular 0.3 M NaCl and attenuated MAP and HR responses to intracerebroventricular ouabain. Five weeks of a high-salt diet in SHRs resulted in exacerbation of hypertension and increased responses to air-jet stress and intracerebroventricular guanabenz. Losartan injected into the MnPO reversed the salt-sensitive component of the hypertension and normalized the depressor response to guanabenz but did not change responses to air-jet stress. We conclude that in the MnPO, ANG II via AT(1) receptors mediates cardiovascular responses to an acute increase in CSF sodium as well as the chronic pressor responses to high sodium intake in SHR.     

Cardiovascular and metabolic responses of hypertensive and normotensive rats to one week of cold exposure

Challenges to energy homeostasis, such as cold exposure, can have consequences for both metabolic and cardiovascular functioning. We hypothesized that 1-wk cold exposure (4 degrees C) would produce concurrent increases in metabolic rate (VO(2); indirect calorimetry), heart rate (HR), and mean arterial blood pressure (MAP) measured by telemetry. In the initial hours of change in ambient temperature (T(a)), both spontaneously hypertensive rats (SHRs) and normotensive Sprague-Dawley rats showed rapid increases (in cold) or decreases (in rewarming) of VO(2), HR, and MAP, although the initial changes in MAP and HR were more exaggerated in SHRs. Throughout cold exposure, HR, VO(2), food intake, and locomotor activity remained elevated but MAP decreased in both strains, particularly in the SHR. During rewarming, all measures normalized quickly in both strains except MAP, which fell below baseline (hypotension) for the first few days. The results indicate that variations of T(a) produce rapid changes in a suite of cardiovascular and behavioral responses that have many similarities in hypertensive and normotensive strains of rats. The findings are consistent with the general concept that the cardiovascular responses to cold exposure in rats are closely related to and perhaps a secondary consequence of the mechanisms responsible for increasing heat production.     

Longitudinal studies on the effect of hypertension on circadian hemodynamic and autonomic rhythms in telemetered rats

This study dealt with the long-term effects of hypertension on circadian rhythms of hemodynamic and cardiovascular autonomic functions in radiotelemetered rats. Blood pressure (BP), heart rate (HR), spontaneous locomotor activity, and respiration.were monitored in spontaneously hypertensive rats (SHRs), a model of human hypertension, from 14 to 27 weeks of age and in Wistar-Kyoto rats (WKY) as controls. Cardiovascular autonomic changes were determined by time-domain analysis of the variability of BP (standard deviation of mean arterial pressure, SDMAP) and HR (standard deviation of R-R intervals, SDRR, and the root mean square of successive differences in R-R intervals, rMSSD). Compared with WKY rats, the 24-hr MAP and SDMAP were higher at week 14 in SHRs and showed stepwise increases over the study duration, suggesting progressive increases in vasomotor sympathetic activity in hypertensive rats. Also, higher SDRR, rMSSD, and activity and lower HR and respiration were demonstrated in SHRs. Normal circadian rhythms (higher dark-time values) of MAP, HR, SDMAP, and SDRR were evident in WKY rats at week 20 and continued thereafter. Compared with WKY rats, the circadian BP and HR patterns were abolished and inverted, respectively, in SHRs. Lower dark-time, compared with light-time, SDMAP values were observed in SHRs that were associated with temporal increases in HR variability indices. These findings demonstrate that hypertension elicits significant alterations in circadian autonomic and hemodynamic profiles. Further, the steady increases in BP, average level and oscillations, in SHRs may explain the reported progressive age-related vascular and cardiac hypertrophy in these rats.     

Taste aversion involving central opioid antagonism is potentiated in morphine-dependent rats

A sensitive taste conditioning test was used to measure the aversive effect of a single intraventricular (i.c.v.) or subcutaneous (s.c) injection of an opioid antagonist that readily crosses the blood brain barrier (naltrexone), and one of two that do not (methylnaltrexone and diallylnormorphinium). This was done in drug-naive rats and in rats implanted 5 days earlier with a pellet containing 75 mg morphine. It was found that the morphine exposure had no significant effect on the dose-response curve of the taste aversion produced by s.c. methylnaltrexone and s.c. diallynormorphinium but reduced the lowest effective dose for the other antagonist treatments from three to more than 100 times. Consideration of the data, together with the pharmacokinetic properties of the drugs and the routes of administration used, supported a conclusion that only those aversions involving central antagonist activity show the potentiation effect of chronic morphine treatment. The findings were also discussed with regard to the location of receptors important for aversions produced by opioid antagonists in naive rats.     

Prolonged tissue PO2 reduction after contraction in spinotrapezius muscle of spontaneously hypertensive rats

We tested the hypothesis that a deficit in oxygen extraction or an increase in oxygen demand after skeletal muscle contraction leads to delayed recovery of tissue oxygen tension (Po(2)) in the skeletal muscle of hypertensive rats compared with normotensive rats. Blood flow and Po(2) recovery at various sites in the spinotrapezius muscle of spontaneously hypertensive rats (SHRs) were evaluated after a 3-min period of muscle contraction and were compared with corresponding values in Wistar-Kyoto rats (WKYs). The recovery of tissue Po(2) [75 +/- 7 (SHRs) vs. 99 +/- 12% (WKYs) of resting values] and venular Po(2) [72 +/- 13 (SHRs) vs. 104 +/- 10% (WKYs) of resting values] were significantly depressed in the SHRs 30 s postcontraction. The delayed recovery persisted for 120 s postcontraction for both tissue [86 +/- 11 (SHRs) vs. 119 +/- 13% (WKYs) of resting values] and venular [74 +/- 2 (SHRs) vs. 100 +/- 9% (WKYs) of resting values] Po(2) levels. There was no significant difference in the recovery of arteriolar Po(2) between the two groups 30 s postcontraction [95 +/- 7 (SHRs) vs. 84 +/- 8% (WKYs) of resting values]. Values for resting diameter of arcade arterioles in the two groups were not different [52 +/- 3 (SHRs) vs. 51 +/- 3 microm (WKYs)], but the arteriolar diameter after the 3-min contraction period was greater in the SHRs (71 +/- 4 microm) than the WKYs (66 +/- 4). Likewise, red blood cell (RBC) velocity [5.8 +/- 0.3 (SHRs) vs. 4.7 +/- 0.2 mm/s (WKYs)] and blood flow [23.0 +/- 0.8 (SHRs) vs. 16.0 +/- 1.0 nl/s (WKYs)] measurements were significantly greater in the SHRs at 30 s postcontraction. The delayed recovery of tissue Po(2) in the SHRs compared with the WKYs can be explained by a decrease in oxygen diffusion from the rarefied microvascular network due to the increased RBC velocity and the shorter residence time in the microcirculation and the consequent disequilibrium for oxygen between plasma and RBCs. The delayed recovery of venular Po(2) in the SHRs is consistent with this explanation, as venular Po(2) is slowly restored to baseline by release of oxygen from the RBCs. This leaves the arterioles in the primary role as oxygen suppliers to restore Po(2) in the tissue after muscle contraction.     

Possible role of brain salt-inducible kinase 1 in responses to central sodium in Dahl rats

In Dahl salt-sensitive (S) rats, Na(+) entry into the cerebrospinal fluid (CSF) and sympathoexcitatory and pressor responses to CSF Na(+) are enhanced. Salt-inducible kinase 1 (SIK1) increases Na(+)/K(+)-ATPase activity in kidney cells. We tested the possible role of SIK1 in regulation of CSF [Na(+)] and responses to Na(+) in the brain. SIK1 protein and activity were lower in hypothalamic tissue of Dahl S (SS/Mcw) compared with salt-resistant SS.BN13 rats. Intracerebroventricular infusion of the protein kinase inhibitor staurosporine at 25 ng/day, to inhibit SIK1 further increased mean arterial pressure (MAP) and HR but did not affect the increase in CSF [Na(+)] or hypothalamic aldosterone in Dahl S on a high-salt diet. Intracerebroventricular infusion of Na(+)-rich artificial CSF caused significantly larger increases in renal sympathetic nerve activity, MAP, and HR in Dahl S vs. SS.BN13 or Wistar rats on a normal-salt diet. Intracerebroventricular injection of 5 ng staurosporine enhanced these responses, but the enhancement in Dahl S rats was only one-third that in SS.BN13 and Wistar rats. Staurosporine had no effect on MAP and HR responses to intracerebroventricular ANG II or carbachol, whereas the specific protein kinase C inhibitor GF109203X inhibited pressor responses to intracerebroventricular Na(+)-rich artificial CSF or ANG II. These results suggest that the SIK1-Na(+)/K(+)-ATPase network in neurons acts to attenuate sympathoexcitatory and pressor responses to increases in brain [Na(+)]. The lower hypothalamic SIK1 activity and smaller effect of staurosporine in Dahl S rats suggest that impaired activation of neuronal SIK1 by Na(+) may contribute to their enhanced central responses to sodium.     

Stereospecific aversive property of narcotic antagonists in morphine-free rats

If endogenous, morphine-like substances have physiological functions, narcotic antagonists should have effects $\text{in vivo}$ even in the absence of exogenous, narcotic agonists. This hypothesis was supported by studies of taste aversions conditioned with narcotic antagonists; rats drank smaller amounts of distinctively flavoured solutions when their consumption on previous occasions preceded injections of naloxone (1–10 mg/kg), naltrexone (3.2 mg/kg), Mr 1452 (10 mg/kg) or (-)-BC-2860 (10 mg/kg). Stereoisomers (i.e. Mr 1453, (+)-BC-2860) which were inactive as narcotic antagonists did not induce significant taste aversions. It was suggested that the consistency and stereospecificity of aversion with the antagonists gave some support to interpretations in terms of antagonist actions at receptors for endogenous opioids.     

Nifedipine-resistant Ca(++)-induced contraction in tail artery of spontaneously hypertensive rats.

Nifedipine-resistant Ca(++)-induced contractions (NR-Ca(++)-contraction) were compared in the tail arteries from SHRs and WKYs (5 and 13 week old). NR-Ca(++)-contraction of tail artery was defined as follows: Ca(++)-induced contraction in the presence of norepinephrine (NE) (10(-5) M) or 5-hydroxytryptamine (5-HT) (10(-5) M) in Ca(++)-free medium containing EGTA (0.1 mM) and nifedipine (10(-6) M). NR-Ca(++)-contractions in arteries from 5 week old SHRs and WKYs were not different. In contrast, NR-Ca(++)-contractions in arteries from 13 week old SHRs were about 2-fold greater than in arteries from 13 week old WKYs. In arteries from 13 week old WKYs and SHRs, nitroglycerin (10(-5) M) significantly reduced the NR-Ca(++)-contraction in the presence of 5-HT but not in the presence of NE. The reduction was inhibited by the presence of methylene blue (3 x 10(-6) M). 8-Bromo-cGMP (10(-4) M) reduced significantly the NR-Ca(++)-contraction in the presence of 5-HT in arteries from 13 week old SHRs and WKYs. The present experiments clearly demonstrated that the NR-Ca(++)-contractions (both in the presence of NE and 5-HT) in 13 week old SHRs were significantly greater than those in arteries from 13 week old WKYs. These results suggest that in addition to an increase in voltage-operated Ca++ mobilization reported by others, an increase in NR-Ca++ mobilization may contribute to the development of hypertension in SHR.     

Cold pressor test in the rat: medullary and spinal pathways and neurotransmitters

This study was designed to delineate the medullary and spinal pathways mediating the cardiovascular responses to cold pressor test (CPT) and to identify neurotransmitters in these pathways. Experiments were done in barodenervated, urethane-anesthetized, male Wistar rats. The CPT was performed by immersing the limbs and ventral half of the body of the rat in ice-cold water (0.5 degrees C) for 2 min. CPT elicited an immediate increase in mean arterial pressure (MAP), heart rate (HR), and greater splanchnic nerve activity (GSNA). Bilateral blockade of ionotropic glutamate receptors (iGLURs) in the rostral ventrolateral medullary pressor area (RVLM) significantly attenuated the CPT-induced responses. Bilateral blockade of gamma-aminobutyric acid (GABA) receptors, but not iGLURs, in the nucleus ambiguus (nAmb) significantly reduced the CPT-induced increases in HR, but not MAP. Blockade of spinal iGLURs caused a significant reduction in CPT-induced increases in MAP and GSNA, whereas the increases in HR were reduced to a lesser extent. Combination of the blockade of spinal iGLURs and bilateral vagotomy or intravenous atropine almost completely blocked CPT-induced tachycardia. Midcollicular decerebration significantly reduced CPT-induced increases in MAP and HR. These results indicated that: 1) CPT-induced increases in MAP, HR, and GSNA were mediated by activation of iGLURs in the RVLM and spinal cord, 2) activation of GABA receptors in the nAmb also contributed to the CPT-induced tachycardic responses, and 3) brain areas rostral to the brain stem also participated in the CPT-induced pressor and tachycardic responses.     

Microinjection of muscimol into the periaqueductal gray suppresses cardiovascular and neuroendocrine response to air jet stress in conscious rats

Microinjection of the neuronal inhibitor muscimol into the dorsomedial hypothalamus (DMH) suppresses increases in heart rate (HR), mean arterial pressure (MAP), and circulating levels of adrenocorticotropic hormone (ACTH) evoked in air jet stress in conscious rats. Similar injection of muscimol into the caudal region of the lateral/dorsolateral periaqueductal gray (l/dlPAG) reduces autonomic responses evoked from the DMH, leading to the suggestion that neurons in the l/dlPAG may represent a descending relay for DMH-induced increases in HR and MAP. Here, we examined the role of neuronal activity in the caudal l/dlPAG on the increases in MAP, HR, and plasma ACTH seen in air jet stress in rats. Microinjection of muscimol into the caudal l/dlPAG reduced stress-induced increases in HR and MAP, while identical injections into sites just dorsal or into the rostral l/dlPAG had no effect. Microinjection of a combination of the glutamate receptor antagonists 2-amino-5-phosphonopentanoate (AP5) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) into the caudal l/dlPAG decreased stress-induced increases in HR alone only at the end of the 20-min stress period but significantly accelerated return to baseline. Surprisingly, microinjection of muscimol into the caudal l/dlPAG also reduced the stress-induced increase in plasma ACTH by 51%. Compared with unstressed control rats, rats exposed to air jet stress exhibited approximately 3 times the number of Fos-positive neurons in the l/dlPAG. These findings suggest that neurons in the l/dlPAG are activated in air jet stress and that this activity contributes to increases in HR, MAP, and plasma ACTH.     

Quaternary narcotic antagonists' relative ability to prevent antinociception and gastrointestinal transit inhibition in morphine-treated rats as an index of peripheral selectivity

Single doses of naloxone (0.025 to 0.5 mg/kg) or of one of four quaternary narcotic antagonists (i.e. nalorphine allobromide, nalorphine methobromide, naloxone methobromide or naltrexone methobromide, 1 to 60 mg/kg) were given s.c. to rats before morphine, 5 mg/kg i.v. In the absence of antagonists morphine reduced G.I. transit of a charcoal meal to about 15% of drug-free controls and consistently delayed nociceptive reactions (55°C hot plate) in all animals. Doses of antagonists slightly reducing morphine antinociception (centrally effective = A) and restoring G.I. transit to about 50% of drug-free rats (peripherally effective = B) were estimated. The A:B ratio, indicating peripheral selectivity, was at least 8 for any of the quaternary antagonists given 10 min before morphine, but prolonging this interval may have resulted in a lower figure (i.e. less peripheral selectivity) because of reduced A and increased B. This was definitely so for naltrexone methobromide (A:B, > 60 at 10 min, about 1 at 80 min) and was not apparent for nalorphine methobromide according to available data, which for nalorphine allobromide and to a lesser extent for naloxone methobromide showed only an increase in B at intervals longer than 10 min. Both morphine-induced antinociception and inhibition of G.I. transit were reduced by naloxone at the lower doses tested and were fully prevented at the higher. These findings indicate that, unlike naloxone, the investigated quaternary narcotic antagonists are interesting prototype drugs for selective blockade of opiate receptors outside the CNS, although certain critical aspects, possibly biological N-dealkylation to the corresponding tertiary antagonists, condition peripheral selectivity.     

Bimodal effects of chronically administered neurokinin B (NKB) on in vivo and in vitro cardiovascular responses in female rats

The in vivo cardiovascular effects of acutely administered neurokinin B (NKB) have been attributed both to direct effects on vascular tone and to indirect effects on central neuroendocrine control of the circulation. We proposed: 1) that a modest long-term increase in plasma NKB levels would decrease mean arterial pressure (MAP) due to attenuated peripheral vascular tone, and 2) that chronic high-dose NKB would increase MAP, due to increased sympathetic outflow which would override the peripheral vasodilation. We examined the in vivo and in vitro cardiovascular effects of chronic peripheral NKB. Low- (1.8 nmol/h) or high- (20 nmol/h) dose NKB was infused into conscious female rats bearing telemetric pressure transducers. MAP, heart rate (HR) and the pressor responses to I.V. phenylephrine (PE, 8 microg) and angiotensin II (Ang II, 150 ng) were measured. Concentration-response curves of small mesenteric arteries were constructed to PE using wire myography. Low-dose NKB reduced basal MAP (88+/-2 mm Hg to 83+/-2 mm Hg), did not affect resting HR, reduced the pressor responses to PE, and attenuated the maximal constriction of mesenteric arteries to PE and KCl. By contrast, high-dose NKB increased basal MAP (86+/-1 mm Hg to 89+/-1 mm Hg), increased HR (350+/-3 beats/min to 371+/-3 beats/min), increased the pressor responses to Ang II and, contrary to our hypothesis, increased the maximum contractile responses of mesenteric arteries to PE and KCl. The cardiovascular effects of NKB are thus dose-dependent: whereas chronic low-dose NKB directly modulates vascular tone to reduce blood pressure, chronic high-dose NKB induces an increase in blood pressure through both central (indirect) and peripheral (direct) pathways.     

Hindlimb unloading alters nitric oxide and autonomic control of resting arterial pressure in conscious rats

After periods of microgravity or bed rest, individuals often exhibit reduced Vo(2 max), hypovolemia, cardiac and vascular effects, and autonomic dysfunction. Recently, alterations in expression of vascular and central nervous system NO synthase (NOS) have been observed in hindlimb-unloaded (HU) rats, a model used to simulate physiological effects of microgravity or bed rest. We examined the effects of 14 days of hindlimb unloading on hemodynamic responses to systemic NOS inhibition in conscious control and HU rats. Because differences in NO and autonomic regulation might occur after hindlimb unloading, we also evaluated potential differences in resting autonomic tone and effects of NOS inhibition after autonomic blockade. Administration of nitro-L-arginine methyl ester (L-NAME; 20 mg/kg iv) increased mean arterial pressure (MAP) to similar levels in control and HU rats. However, the change in MAP in response to L-NAME was less in HU rats, that had an elevated baseline MAP. In separate experiments, atropine (1 mg/kg iv) increased heart rate (HR) in control but not HU rats. Subsequent administration of the ganglionic blocker hexamethonium (30 mg/kg iv) decreased MAP and HR to a greater extent in HU rats. Administration of L-NAME after autonomic blockade increased MAP in both groups to a greater extent compared with intact conditions. However, the pressor response to L-NAME was still reduced in HU rats. These data suggest that hindlimb unloading in rats reduces peripheral NO as well as cardiac parasympathetic tone. Along with elevations in sympathetic tone, these effects likely contribute to alterations in vascular control and changes in autonomic reflex function following spaceflight or bed rest.     

Central, stereoselective receptors mediate the acute effects of opiate antagonists on luteinizing hormone secretion

Although a central site of acute opiate action in regulating luteinizing hormone (LH) secretion has been suggested by the ability of centrally implanted opiate antagonists to increase LH levels, opiate antagonists are lipophilic and could influence the pituitary in situ. Also, the physiological significance of opiate receptor blockade with antagonists rests on the assumed, but untested, stereoselectivity of these receptors. Therefore, a lipophobic quaternized derivative of naltrexone (MRZ 2663-Naltrexone methobromide) and dextro- (+) and levo- (-) stereoisomers of naloxone were used to study the site- and stereoselectivity of gonadotropin responses to opiate antagonists in vivo. Male rats were injected intracerebroventricularly (icv) or intravenously (iv) with the quaternary or tertiary congeners of naltrexone and subcutaneously (sc) with (-) or (+)-naloxone. Rats injected icv with 20 ug of quaternary naltrexone displayed significant increases in serum luteinizing hormone (LH). The onset of the response was rapid with serum LH levels being significantly elevated 15 minutes after the injection and returning to basal levels 30 minutes later. Rats injected iv with 10 mg/kg of quaternary naltrexone failed to show significant LH responses. Rats injected either centrally or periphally with equivalent doses of tertiary naltrexone showed LH responses that were similar to those found in animals injected icv with quaternary naltrexone. As little as 0.5 mg/kg of (-)-naloxone resulted in significant elevations in serum LH that were higher than those elicited by up to 10 mg/kg of (+)-naloxone, indicating that this effect of naloxone is stereoselective. These data support the argument that opioids can acutely modulate LH secretion through actions at stereoselective opioid receptors in the central nervous system.     

Nitric oxide-independent effects of tempol on sympathetic nerve activity and blood pressure in DOCA-salt rats

The role of sympathetic nerves and nitric oxide (NO) in tempol-induced cardiovascular responses was evaluated in urethane-anesthetized sham and deoxycorticosterone acetate (DOCA)-salt-treated (DOCA-salt) rats. Tempol (30-300 micromol/kg iv), a superoxide (O) scavenger, decreased renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) in DOCA-salt and sham rats. The antioxidants tiron and ascorbate did not alter MAP, HR, or RSNA in any rat. Tempol responses were unaffected after sham rats were treated with N(G)-nitro-L-arginine (L-NNA, 13 mg/kg). In DOCA-salt rats, L-NNA reduced tempol-induced depressor responses but not the inhibition of HR or RSNA. Tempol did not significantly decrease MAP, HR, or RSNA after hexamethonium (30 mg/kg iv) treatment in any rat. Dihydroethidine histochemistry revealed increased O levels in arteries and veins from DOCA-salt rats. Tempol treatment in vitro reduced O levels in arteries and veins from DOCA-salt rats. In conclusion, tempol-induced depressor responses are mediated largely by NO-independent sympathoinhibition in sham and DOCA-salt rats. There is an additional interaction between NO and tempol that contributes to depressor responses in DOCA-salt rats.     

Naloxone potentiation of apomorphine-induced stereotypic climbing in mice and interaction with mu-, sigma- and kappa-opiate drugs

Pretreatment with the narcotic antagonist naloxone produced a dose-related potentiation of mouse stereotypic climbing behavior induced by the dopaminergic agonist apomorphine. In further experiments, mice were also pretreated with various drugs specific for mu-opiate receptors (morphine), sigma-opiate receptors (N-allylnormetazocine) and kappa-opiate receptors (ketocyclazocine). Doses of morphine that alone did not affect apomorphine-induced climbing antagonized naloxone potentiation of apomorphine. Doses of N-allylnormetazocine that did not influence apomorphine stereotypy also reversed naloxone potentiation of apomorphine. On the other hand, ketocyclazocine alone exerted a behavioral suppressant effect upon apomorphine- induced stereotypic climbing, however, these same doses failed to prevent naloxone potentiation of apomorphine.