Effect of vasopressin and V1 receptors blockade on hypotensive action of ANP in normotensive (WKY) and spontaneously hypertensive rats.

The aim of the study was to find out whether vasopressin (AVP) modifies hypotensive and heart rate accelerating effects of atrial natriuretic peptide (ANP) in normotensive (WKY) and spontaneously hypertensive (SHR) conscious rats. The effect of i.v. administration of 1; 2 and 4 micrograms of ANP on blood pressure (MP) and heart rate (HR) was compared during i.v. infusion of 0.9% NaCl (NaCl), NaCl+AVP (1.2 ng kg-1 min-1) and NaCl+dEt2AVP (V1 receptors antagonist, 0.5 microgram kg-1 min-1). AVP increased MP in SHR and WKY and decreased HR in SHR. V1 antagonist decreased MP and increased HR only in SHR. In SHR ANP decreased MP and increased HR during NaCl, AVP and V1 antagonist infusion. In WKY these effects were observed only during AVP administration. In each experimental situation hypotension and tachycardia induced by ANP were greater in SHR than in WKY. In both strains ANP induced changes in MP and HR were enhanced during AVP in comparison to NaCl infusion. V1 antagonist did not modify effects of ANP in WKY and SHR. The results indicate that ANP abolishes hypertensive response induced by blood AVP elevation and that the basal levels of endogenous vasopressin acting through V1 receptors does not interfere with hypotensive action of ANP neither in WKY nor in SHR.     

Central cardiovascular effects of baclofen in spontaneously hypertensive rats

This study was conducted to investigate the effects of centrally administered baclofen on blood pressure and heart rate in conscious spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Administration of baclofen (1.0 microgram/kg) into the lateral cerebral ventricle (icv) produced an increase in mean arterial pressure (MAP) in both SHR and WKY rats. The increase in MAP was significantly lower in SHR (13 +/- 3 mmHg) when compared with WKY (27 +/- 5 mmHg). The changes in heart rate (HR) were variable, from no change to a very small increase and did not differ significantly between SHR and WKY rats. The ability of baclofen to interfere with baroreceptor reflexes was also tested in separate experiments. In SHR, icv injection of baclofen (1.0 microgram/kg) significantly suppressed the pressor response and bradycardia evoked by phenylephrine 3.0 micrograms/kg iv, whereas in WKY, the pressor and HR responses to similar injections of phenylephrine were not affected by icv baclofen. Similarly, baclofen treatment modified hypotensive response and reflex tachycardia induced by nitroprusside (10.0 micrograms/kg) iv in SHR but not in WKY rats. Administration of sympathetic ganglionic blocker hexamethonium (HEX; 25 mg/kg) iv produced an equivalent decrease in MAP between SHR and WKY following icv injection of baclofen (1.0 microgram/kg). These results suggest that the effects of baclofen on the baroreceptor reflexes in SHR may not be mediated by a change in peripheral sympathetic tone.     

Angiotensin restores atrial natriuretic factor-induced decrease of baroreceptor sensitivity in normotensive rats, but not in spontaneously hypertensive rats

The effect of atrial natriuretic factor (ANF) on baroreflex sensitivity was determined in unanesthetized normotensive (Wistar-Kyoto, WKY) or spontaneously hypertensive rats (SHR) during acute hypertensive stimuli (phenylephrine) or hypotensive stimuli (sodium nitroprusside). The i.v. dose of rat ANF [( Ser99,Tyr126]ANF) was 50 ng/min per rat, sufficient to decrease mean arterial blood pressure (ABP) by about 6 mmHg (1 mmHg = 133.3 Pa) in WKY. SHR showed no change in ABP with this ANF dose. During a control infusion of physiological saline, the mean heart rate (HR) response to increases in ABP was -1.30 +/- 0.27 beats/min (bpm)/mmHg in WKY and -0.37 +/- 0.22 in SHR (p less than 0.05). These values were not affected significantly by ANF. However, ANF blunted chronotropic responses to ABP decreases. The control values of the delta HR/delta ABP slope in WKY and SHR were -2.34 +/- 0.57 and -2.01 +/- 0.37 bpm/mmHg, respectively. In the presence of ANF, the slope changed to -0.36 +/- 0.43 (i.e., bradycardia in response to hypotension) in WKY and to +0.20 +/- 0.21 in SHR (p less than 0.005 for the difference from control for both). This ANF-induced loss of baroreflex sensitivity was reversed in WKY by the addition of angiotensin I (sufficient to increase ABP by 5 mmHg in control rats). Angiotensin did not restore baroreflex sensitivity in ANF-infused SHR, and ANF had no effect on the ABP increase caused by angiotensin in either group. The data suggest that ANF does not act on baroreceptor structures directly, but inhibits mechanisms involved in efferent sympathetic activation. Parasympathetic responses do not appear to be compromised.     

alpha(2)-Adrenergic receptors in NTS facilitate baroreflex function in adult spontaneously hypertensive rats

We examined the effect of alpha(2)-adrenoreceptor blockade in the nucleus of the solitary tract (NTS) on baroreflex responses elicited by electrical stimulation of the left aortic depressor nerve (ADN) in urethane-anesthetized spontaneously hypertensive rats (SHR, n = 11) and normotensive Wistar-Kyoto rats (WKY, n = 11). ADN stimulation produced a frequency-dependent decrease in mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and heart rate (HR). In SHR, unilateral microinjection of idazoxan into the NTS markedly reduced baroreflex control of MAP, RSNA, and HR and had a disproportionately greater influence on baroreflex control of MAP than of RSNA. In WKY, idazoxan microinjections did not significantly alter baroreflex function relative to control vehicle injections. These results suggest that baroreflex regulation of arterial pressure in SHR is highly dependent on NTS adrenergic mechanisms. The reflex regulation of sympathetic outflow to the kidney is less influenced by the altered alpha(2)-adrenoreceptor mechanisms in SHR.     

Blood pressure responsiveness during the development of hypertension in the conscious spontaneously hypertensive rat

Blood pressure responsiveness to iv noradrenaline and angiotensin II was studied in conscious, freely moving, age-matched spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats from 4 to 16 weeks of age. At 4 and 6 weeks the SHR showed small, but nonsignificant increases in responsiveness compared with WKY to both noradrenaline and angiotensin II. At 8 weeks they exhibited similar responses to the WKY. Subsequently, at 12 and 16 weeks decreased responsiveness to noradrenaline (nonsignificant) and angiotensin II (p less than 0.05 at 12 and 16 weeks) was observed in SHR versus WKY. At 16 weeks of age, hexamethonium caused potentiation of the blood pressure response to noradrenaline and angiotensin II, but to the same degree in the two strains. Captopril at this age did not elicit potentiation to noradrenaline or angiotensin II in either strain. These results indicate that there is no rise in blood pressure responsiveness to circulating pressor agents, parallel to the development of hypertension in SHR. Increased receptor occupancy or more active attenuating reflexes in SHR versus WKY appear not to be involved in the absence of hyperresponsiveness in intact conscious SHR at 16 weeks of age.     

The mechanism of low susceptibility to stress in gastric lesions of spontaneously hypertensive rats.

The mechanism of low susceptibility to stress in gastric lesion formation in spontaneously hypertensive rats (SHR) was investigated focusing on the sympathetic and parasympathetic nervous systems. In the gastric tissues of SHR, norepinephrine (NE) and dopamine (DA) contents were higher, while acetylcholine content and choline acetyltransferase activity were lower than those of Wistar-Kyoto rats (WKY). Water-immersion restraint induced gastric lesions frequently in WKY (ulcer indices : 52 +/- 7mm2) but less frequently in SHR (ulcer indices : 3 +/- 1mm2). Although NE content decreased in both SHR and WKY as a result of water-immersion restraint, it remained higher in SHR than in WKY. ACh content decreased by the procedure in WKY but not in SHR. DA content was increased by the procedure in all gastric regions of SHR. The gastric lesions induced in SHR were aggravated by pretreatment with 6-hydroxydopamine, an agent for chemical sympathectomy, following decreases of NE and DA contents. These results indicate that the relative sympathetic hyperfunction, parasympathetic hypofunction and dopaminergic mechanism in the stomach contribute to the prevention of gastric lesion formation in SHR.     

Effects of acute and subacute cocaine administration on the CNS dopaminergic system in Wistar-Kyoto and spontaneously hypertensive rats: I. Levels of dopamine and metabolites

Effects of acute and subacute cocaine administration on dopamine (DA) and its metabolites in striata and nucleus accumbens of nine week-old Wistar-Kyoto and spontaneously hypertensive rats were studied. Levels of DA,3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined by HPLC-EC. There were no differences in DA levels in striata and nucleus accumbens between control WKY and SHR. Levels of DA in two brain regions were unaffected in groups treated acutely with cocaine. Both strains showed a significant increase in striatal HVA 2 hr after cocaine injection. Seven day treatment declined DA levels in striatum of WKY and in nucleus accumbens of SHR. However, only WKY treated subacutely with cocaine showed significantly increased HVA either with or without changes in DOPAC in nucleus accumbens and striatum, respectively. Increased DOPAC/DA and HVA/DA ratios appeared only in striatum of WKY and in nucleus accumbens of SHR following subacute treatment. These results suggest that subacute cocaine administration affects DA levels in striata and nucleus accumbens differently between WKY and SHR.     

Effects of Music Composed by Mozart and Ligeti on Blood Pressure and Heart Rate Circadian Rhythms in Normotensive and Hypertensive Rats

There is continuing discussion on the effect of music (“Mozart effect”) on numerous functions in man and experimental animals. Radiotelemetry now allows one to monitor cardiovascular functions in freely‐moving unrestrained experimental animals. Radiotelemetry was used to monitor systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), and motor activity (MA) in male normotensive WKY and hypertensive SHR animals. Rats were synchronized to a 12 h light (L): 12 h dark (D) regimen in an isolated, ventilated, light‐controlled, sound‐isolated animal container. Music (Mozart, Symphony # 40; Ligeti, String Quartet # 2) were played for 2 h at 75 dB in the animal cabin starting at the onset of L or D in a cross‐over design. Data were collected every 5 min for 24 h under control conditions and during and after music. In addition, plasma concentrations of norepinephrine (NE) were determined in unrestrained animals at 3 h intervals over 24 h. In both WKY and SHR, highly significant circadian rhythms were obtained in SBP, DBP, HR, and MA under control conditions; HR was lower and BP higher in SHR than in WKY. NE was circadian rhythmic in both strains with higher values in D; the increase in NE with immobilization was much more pronounced in SHR than in WKY. The music of Mozart had no effect on either parameter in WKY, neither in L nor in D. In contrast, in SHR, the music of Mozart presented in L significantly decreased HR and left BP unaffected, leading to a small decrease in cardiac output. The music of Ligeti significantly increased BP both in L and in D and reflexively reduced HR in L, the effects being long‐lasting over 24 h. Interestingly, white noise at 75 dB had no effect at all on either function in both strains. The effects of both Mozart and Ligeti cannot be attributed to a stress reaction, as stress due to cage switch increased HR and BP both in WKY and SHR. The study clearly demonstrates that music of different character (tempo, rhythm, pitch, tonality) can modify cardiovascular functions in freely‐moving rats, with SHR being more sensitive than normotensive animals. The relative contribution of the characteristics of the two pieces of music, however, needs further evaluation.     

Formation of biogenic amines by isolated kidneys of spontaneously hypertensive rats

Kidneys form dopamine (DA) from L-dopa and serotonin from L-5-hydroxytryptophan (L-5-HTP) via aromatic L-amino acid decarboxylase. We compared the ability of isolated perfused kidneys from adult (20-week-old) spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) to form these biogenic amines. Renal vascular resistance (RVR) was greater in perfused kidneys from SHR (n = 10) than WKY (n = 8) (p less than 0.01). Slight decreases in RVR were observed during L-dopa infusion but these were unrelated to DA formation. L-Dopa infusion was associated with greater DA output in SHR than WKY in both the renal venous and urinary effluents although the latter did not achieve statistical significance. L-5-HTP increased RVR to a greater degree in SHR than WKY kidneys. This was associated with larger quantities of serotonin in the urinary and venous effluents and greater pressor responses to exogenous serotonin in SHR than WKY kidneys; however, either parameter alone was not significantly increased. Our findings do not support a deficiency of intrarenal DA formation as a pathogenic factor for hypertension in SHR. Biogenic amine formation is as great if not greater in SHR than WKY kidneys and appears to contribute largely to the greater increases in renal resistance seen in SHR kidneys on infusion of L-5-HTP. Enhanced renal serotonin formation may elevate blood pressure, whereas enhanced renal DA formation would favor blood pressure lowering, perhaps as a compensatory mechanism.     

Effects of angiotensins on day-night fluctuations and stress-induced changes in blood pressure

In this study we evaluated by telemetry the effects of ANG II and ANG-(1-7) infusion on the circadian rhythms of blood pressure (BP) and heart rate (HR) and on the cardiovascular adjustment resulting from restraint stress in rats. ANG II or ANG-(1-7) or vehicle were infused subcutaneously for 7 days. Restraint stress was carried out before, during, and after infusion at 7-day intervals. Parallel with an increase in MAP, ANG II infusion produced an inversion of MAP circadian rhythm with a significant MAP acrophase inversion. It also produced bradycardia during the first 3 days of infusion. Thereafter, HR progressively increased, reaching values similar to or above those of the control period at the end of the infusion period. HR circadian variation was not changed by ANG II infusion. Strikingly, ANG II significantly attenuated the increase in MAP induced by restraint stress without altering the HR response. ANG-(1-7) infusion produced a slight but significant decrease in MAP restricted to the daytime period. No significant changes in the MAP acrophase were observed. In addition, ANG-(1-7) infusion produced a small but significant sustained bradycardia. ANG-(1-7) did not change cardiovascular responses to restraint stress. These data indicate that ANG II can influence the activity of brain areas involved in the determination of stress-induced or circadian-dependent variations of blood pressure without changing HR fluctuations. A significant modulatory influence of ANG-(1-7) on basal MAP and HR is also suggested.     

Altered frequency characteristic of central vasomotor control in SHR

Previous work from our laboratory has demonstrated that the very low-frequency (VLF: 0-0.25 Hz) and low-frequency (LF: 0.25-0.8 Hz) power of arterial pressure variability (APV) are related to vasomotor reactivity in response to control signals from the rostral ventrolateral medulla (RVLM) via the sympathetic system in the rat. The present study evaluated the differences in the dynamic property of central vasomotor control between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Experiments were carried out in 10- to 12-wk-old rats that were anesthetized with continuous infusion of pentobarbital sodium, paralyzed with pancuronium, and maintained on mechanical ventilation. We found that SHR exhibited significantly higher arterial pressure (AP), heart rate (HR), and VLF, LF, and high-frequency (0.8-2.4 Hz) power of APV than WKY under resting state. Broad-band electrical stimulation of the RVLM elicited parallel APV in the VLF and LF ranges in both rat strains. The evoked APV and transfer magnitude of the APV to stimulus spike rate variability (RVLM-AP magnitude) were significantly higher in SHR, especially in the LF range. The response frequency of central vasomotor control, represented by the high-cut frequency of RVLM-AP magnitude, was also extended in SHR. The disparity in RVLM-AP transfer magnitude between SHR and WKY became virtually absent after combined alpha- and beta-adrenoceptor blockade by phentolamine and propranolol. These results suggest that the dynamic control of RVLM on AP reactivity is enhanced in SHR, in which the adrenergic system may play a major role.     

Inhibition of neurons in commissural nucleus of solitary tract reduces sympathetic nerve activity in SHR

Neurons in the commissural nucleus of the solitary tract (commNTS) play an important role in certain cardiovascular responses dependent on sympathetic vasoconstrictor activation, including the arterial chemoreceptor reflex. Electrolytic lesions of the commNTS elicit a fall in arterial pressure (AP) in spontaneously hypertensive rats (SHR). To determine whether the latter result 1) arose from elimination of commNTS neuronal activity rather than en passant axons and 2) was accompanied by a reduction in sympathetic nerve activity, we evaluated the effect of inhibition of neurons in the commNTS on basal splanchnic sympathetic nerve activity (SNA), AP, and heart rate (HR) in SHR, Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats. In chloralose-anesthetized, paralyzed, and artificially ventilated SHR, microinjection of GABA into the commNTS markedly decreased splanchnic SNA, AP, and HR. The reductions in SNA and AP following similar microinjections in WKY and SD rats were significantly less than those in SHR. Our findings suggest that tonically active neurons in the commNTS contribute to the maintenance of SNA and the hypertension in SHR. The level of tonic discharge of these commNTS neurons in normotensive WKY and SD rats may be lower than in SHR.     

Effects of subacute treatment with cocaine on activities of N-demethylase, UDP-glucuronyltransferase and sulfotransferase in WKY and SHR rat liver--sex and strain differences

The effects of subacute treatment with cocaine on activities of cocaine N-demethylase, UDP-glucuronyltransferase (GT) toward 4-nitrophenol and phenolphthalein and sulfotransferase (ST) toward androsterone and 4-nitrophenol in livers from Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were investigated. Hepatic metabolism of cocaine was different between the sexes (with males having higher N-demethylase activity) and the strains (with WKY rats having higher activity). The effects of subacute cocaine administration on the activity of cocaine N-demethylase were also sex- and strain-related. Whereas cocaine administration increased activity of hepatic N-demethylase in both female strains, it decreased activity in male WKY and had no effect on activity in male SHR. Sex and strain-related as well as cocaine-induced differences were also found in activities of hepatic GT toward 4-nitrophenol and phenolphthalein as well as in activity of hepatic ST towards andersterone and 4-nitrophenol. These results suggest that some of the individual variation in the effects of cocaine may be due to sex and genetic differences in the hepatic metabolism of cocaine and/or in sexually and/or/genetically-determined differences in how cocaine affects hepatic metabolism of other xenobiotics.     

Aging and prostacyclin responses in aorta and platelets from WKY and SHR rats

In spontaneously hypertensive rat (SHR) aorta, prostacyclin is an endothelium-derived contracting factor contributing to the endothelial dysfunction. This study was designed to determine whether the impairment of the prostacyclin response is influenced by aging and whether such a dysfunction is observed in platelets. Isometric tension was measured in aortic rings, and aggregation was studied in platelet-rich plasma taken from 3-, 6-, and 15-mo-old Wistar-Kyoto rats (WKY) and SHR. In aorta from 3- and 6-mo-old WKY, prostacyclin and beraprost [prostacyclin receptor (IP) agonists] produced relaxations that were enhanced by Triplion (thromboxane-prostanoid receptor antagonist). In 15-mo-old WKY, the relaxations to beraprost were maintained, but not those to prostacyclin. In SHR aorta, prostacyclin or beraprost produced no or minor relaxations, which, in younger SHR, were enhanced by Triplion. In both strains, the relaxations were inhibited by CAY-10441 (IP receptor antagonist). The relaxations to forskolin and isoproterenol were reduced with aging. When compared with those of WKY, the relaxations to isoproterenol were reduced in 3- but not in 6- or 15-mo-old SHR, whereas those to forskolin were consistently diminished at any given age. Whatever the age, prostacyclin and beraprost produced CAY-10441-sensitive inhibitions of ADP-induced platelet aggregation. Both agonists were more potent in SHR than in WKY. Therefore, in platelets from WKY and SHR, the IP receptor-dependent antiaggregant response is functional and maintained during aging. In aorta from WKY those responses are reduced by aging and, in SHR, are already compromised at 3 mo. This dysfunction of the IP receptor is only partially explained by a general dysfunction of the adenylate cyclase pathway.     

Placentas from spontaneously hypertensive rats and control strain Wistar-Kyoto rats

Placentas from spontaneously hypertensive rats (SHR) were compared to those of control strain Wistar-Kyoto rats (WKY) at 15, 18 and 20 days of gestation using light microscopic techniques. Placental lesions similar to those in pregnant hypertensive women were absent in both strains; however, other abnormalities were noted. Hemorrhage at the lateral edges of the decidua basalis appeared to be more extensive in the SHR than WKY at 15 days. At the same time, bloody vaginal discharges were noted in 18% of the SHR. Leukocytic encapsulation of 20-day placentas with viable fetuses was noted in two SHR dams but not in any WKY. It is thought that these differences may be related to the high maternal blood pressure in the SHR or to hormonal imbalance associated with the stress response in the SHR due to frequent monitoring of blood pressure.     

Spontaneously hypertensive rats exhibit supersensitivity to the hypertensive and hyperthermic effects of thyrotropin releasing hormone

The effect of thyrotropin releasing hormone (TRH) on colonic temperature and systolic blood pressure of age-matched spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats was determined. Administration of TRH produced dose-dependent increases in body temperature and systolic blood pressure. TRH-induced changes in both responses were of greater magnitude in SHR rats compared to WKY rats. The results provide the first evidence that SHR rats exhibit supersensitivity to non-neuroendocrinological effects of TRH and that TRH may play a role in the pathophysiology of elevated blood pressure.     

Role of sodium and water excretion in the antihypertensive effect of vasopressin in the spontaneously hypertensive rat.

Mean arterial pressure (mmHg (1 mmHg = 133.322 Pa)), sodium excretion rate (mumol.kg-1.min-1), and urine flow (microL.kg-1.min-1) were measured in conscious unrestrained spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) before, during, and after a 3-h intravenous infusion of arginine vasopressin (20 ng.kg-1.min-1), an equipressor dose of phenylephrine, or an infusion of the vehicle. Cessation of the phenylephrine infusion was associated with a return of arterial pressure to preinfusion control values in both SHR and WKY. Cessation of the vasopressin infusion was also associated with a return of arterial pressure to preinfusion values in WKY. In contrast, in the SHR, arterial pressure fell from a preinfusion control level of 164 +/- 6.2 to 137 +/- 4 mmHg within 1 h of stopping the vasopressin infusion. Five hours after stopping the infusion, pressure was 134 +/- 3 mmHg (29 +/- 5 mmHg below preinfusion levels). Similar to the WKY, cessation of a vasopressin infusion was associated with a return of arterial pressure to preinfusion values in Sprague-Dawley rats. Thus, the failure to observe a hypotensive response in normotensive rats was not a peculiarity of the WKY strain. Sodium excretion rates increased during the infusions of vasopressin to a greater extent in SHR than in WKY. However, the natriuresis induced by phenylephrine was not significantly different from that generated by vasopressin in SHR, and in WKY, the natriuresis was greater for phenylephrine than for vasopressin. Urine output increased to a greater extent during the infusions of phenylephrine in both SHR and WKY than during vasopressin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

SHR Y chromosome enhances the nocturnal blood pressure in socially interacting rats

Our objective was to test the hypothesis that nocturnal mean arterial pressure (MAP), heart rate (HR), and activity would be increased in 1) colony over individually caged rats and 2) the spontaneously hypertensive rat (SHR) Y chromosome strain (SHR/y colony) compared with Wistar-Kyoto (WKY) rats. MAP, HR, and activity were monitored using radiotelemetry. The nocturnal MAP rise expressed as the percentage change in MAP from light to dark was increased (P < 0.05) in the SHR/y colony. The SHR Y chromosome increased MAP in both the colony and caged groups compared with WKY (P < 0.001). The SHR/y colony animals spent 23% of a 24-h period at a MAP >120 mmHg, whereas the WKY colony animals spent 2% of a 24-h period in this range. The MAP of the SHR/y colony on clonidine was reduced (P < 0.001) to WKY baseline values. Activity but not HR was increased (P < 0.01) in the WKY and SHR/y colonies compared with caged animals. In conclusion, colony housing and the SHR Y chromosome increased MAP compared with individually caged housing.     

Cocaine-induced changes in 3H-naloxone binding in brain membranes isolated from spontaneously hypertensive and Wistar-Kyoto rats

Effects of sub-acute cocaine treatment on 3H-naloxone binding to 6 brain regions were examined in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Cocaine hydrochloride (3 mg/kg, i.v.) was given by bolus injection daily for five days. Rats were decapitated 24 hr following the final injection and crude membrane fractions prepared from the cortex (CT), hippocampus (HI), striatum (ST), hypothalamus (HY), midbrain (MB) and medulla/pons (MD). Binding of 3H-naloxone was consistent with a single site model in CT, HI, HY, MB and MD from vehicle-treated SHR and WKY. Cocaine treatment of SHR significantly decreased the maximal binding capacity (Bmax) of 3H-naloxone in the HI, ST and HY and the binding affinity was increased in HI. In contrast, a significant increase in Bmax was noted in CT and HI membranes isolated from cocaine-treated WKY. The binding affinity of 3H-naloxone to MB membranes of WKY was significantly decreased by cocaine treatment. The binding characteristics of 3H-naloxone in MD membranes were not different following cocaine treatment or between strains. Scatchard analysis indicated biphasic binding of 3H-naloxone binding to ST membranes from both SHR and WKY. Our results indicate that cocaine produces complex and differential changes in opiate receptors and, presumably, opioid peptide neuronal function in SHR and WKY.     

Increases in CSF [Na+] precede the increases in blood pressure in Dahl S rats and SHR on a high-salt diet

In Dahl salt-sensitive (S) and salt-resistant (R) rats, and spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, at 5-6 wk of age, a cannula was placed in the cisterna magna, and cerebrospinal fluid (CSF) was withdrawn continuously at 75 microl/12 h. CSF was collected as day- and nighttime samples from rats on a regular salt intake (0.6% Na+; R-Na) and then on a high salt intake (8% Na+; H-Na). In separate groups of rats, the abdominal aorta was cannulated and blood pressure (BP) and heart rate (HR) measured at 10 AM and 10 PM, with rats first on R-Na and then on H-Na. On H-Na, CSF [Na+] started to increase in the daytime of day 2 in Dahl S rats and of day 3 in SHR. BP and HR did not rise until day 3 in Dahl S rats and day 4 in SHR. In Dahl R and WKY rats, high salt did not change CSF [Na+], BP, or HR. In a third set of Dahl S rats, sampling of both CSF and BP was performed in each individual rat. Again, significant increases in CSF [Na+] were observed 1-2 days earlier than the increases in BP and HR. In a fourth set of Dahl S rats, BP and HR were recorded continuously by means of radiotelemetry for 5 days on R-Na and 8 days on H-Na. On H-Na, BP (but not HR) increased first in the nighttime of day 2. In another set of Dahl S rats, intracerebroventricular infusion of antibody Fab fragments binding ouabain-like compounds (OLC) with high affinity prevented the increase in BP and HR by H-Na but further increased CSF [Na+]. Finally, in Wistar rats on H-Na, intracerebroventricular infusion of ouabain increased BP and HR but decreased CSF [Na+]. Thus, in both Dahl S and SHR on H-Na, increases in CSF [Na+] preceded the increases in BP and HR, consistent with a primary role of increased CSF [Na+] in the salt-induced hypertension. An increase in brain OLC in response to the initial increase in CSF [Na+] appears to attenuate further increases in CSF [Na+] but at the "expense" of sympathoexcitation and hypertension.