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.     

Body fluids and plasma atrial peptide after its chronic infusion in hypertensive rats

To determine the role of body fluid volume in the chronic hypotensive effect of atrial natriuretic factor (ANF), spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats were infused with the peptide (Arg 101-Tyr 126) at a rate of 100 ng/h/rat for 5 days. Blood pressure (BP) was decreased from 176 +/- 4 to 133 +/- 3 mmHg in the SHR group 4 days after ANF infusion was initiated, whereas no changes were observed in ANF-infused WKY animals. Starting 5 days after the infusion began, body fluid measurements revealed no differences in plasma, blood and extracellular fluid volumes or in interstitial spaces. BP and plasma ANF concentrations were determined in another set of experiments before, during and after chronic ANF infusion. BP declined from 169 +/- 3 to 133 +/- 5 mmHg in SHR 5 days after the infusion commenced, but returned to basal values by day 10 or 11. Plasma ANF was significantly higher in SHR than in WKY rats throughout the observation period. However, there were no discernible changes in this parameter in ANF-infused SHR compared to non-infused SHR. A 3-fold rise in plasma ANF was noted in infused WKY rats at day 3 only. It is concluded that the chronic hypotensive effect of ANF in hypertensive animals is not related to changes in either body fluid volume or distribution. Moreover, the finding that chronic ANF infusion reduces BP in SHR without altering its plasma levels suggests a rapid ANF turnover.     

Studies of arterial smooth muscle relaxation in younger (16-18 week) and older (28-31 week) spontaneously hypertensive rats

Both isometric and isotonic relaxation rates have previously been reported to be decreased in caudal arterial and mesenteric resistance arterial smooth muscle from 16- to 21-week-old spontaneously hypertensive rats (SHR) compared with muscle from age-matched normotensive Wistar-Kyoto rats (WKY). An increased maximum velocity of shortening (Vmax) and an increased shortening ability (delta Lmax) have also been reported for arterial smooth muscle from 16- to 21-week-old SHR. It has been suggested that both increased narrowing and prolonged narrowing of arteries contribute to the development of hypertension. However, SHR Vmax is not different from WKY Vmax when studying arterial muscle from older (28- to 31-week-old) rats. Thus increased arterial narrowing ability cannot be a contributing factor to the maintenance of hypertension. In this study the role of relaxation rate in the maintenance of hypertension was examined by comparing the relaxation rates of isometric and isotonic contractions of caudal arterial strips from 16- to 21-week-old SHR (n = 9) and WKY (n = 8) and from 28- to 31-week-old SHR (n = 7) and WKY (n = 5). While relaxation rates were lower for 16- to 21-week-old SHR compared with age-matched WKY preparations for both isometric and isotonic contractions, only isometric relaxation rates were found to be different in 28- to 31-week-old SHR compared with 28- to 31-week-old caudal arterial muscle (p less than 0.05). Vmax tended to normalize from a once-elevated velocity, while isometric relaxation rate remained decreased in SHR with ageing and (or) with progression of the hypertensive condition.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of salt loading and various therapies on cardiac hypertrophy and fibrosis in young spontaneously hypertensive rats

We investigated the effects of salt loading on blood pressure, cardiac hypertrophy and fibrosis as well as on the effectiveness of various antihypertensive therapies in young spontaneously hypertensive rats (SHR). Twenty-five male SHR were salt-stimulated by drinking 1% NaCl from 3 to 6 months of age. Eighteen of them were treated for the last 2 weeks of salt loading with either the angiotensin-converting enzyme inhibitor captopril, the beta-adrenergic receptor blocker propranolol or the calcium-channel antagonist verapamil. Age-matched male Wistar-Kyoto (WKY) rats and SHR drinking only water served as controls. At the age of 6 months, SHR had significantly elevated blood pressure that was unchanged by salt loading. Relative heart weight was increased in SHR without (3.3) and even more so with salt intake (3.6 vs. 2.4 in WKY). Left ventricular (LV) hypertrophy was accompanied by a 17-fold increase in the expression of mRNA for atrial natriuretic factor (ANF) both in untreated and salt-loaded SHR compared to WKY (p<0.001). Collagen I and III mRNA increased 1.7-1.8-fold in SHR without and with additional salt intake (p<0.01). None of the therapies significantly reduced blood pressure or hypertrophy. Although captopril had no antihypertensive effect, it reduced ANF, collagen I and III mRNA in LV to control level. Less pronounced effects were achieved with verapamil. These findings emphasize the cardioprotective role of captopril which may not be fully expressed in the presence of elevated salt intake.     

Aortic stiffness and pulse pressure amplification in Wistar-Kyoto and spontaneously hypertensive rats

In humans, increased body weight and arterial stiffness are significantly associated, independently of blood pressure (BP) level. The finding was never investigated in rodents devoid of metabolic disorders as spontaneously hypertensive rats (SHR). Using simultaneous catheterization of proximal and distal aorta, we measured body weight, intra-arterial BP, heart rate and their variability (spectral analysis), aortic pulse wave velocity (PWV), and systolic and pulse pressure (PP) amplifications in unrestrained conscious Wistar-Kyoto (WKY) rats and SHR between 6 and 24 wk of age. Aortic proximal systolic and diastolic pressure, PP, and mean BP were significantly higher in SHR than in WKY rats and increased significantly with age (with the exception of PP). PP amplification increased with age but did not differ between strains. PWV was significantly associated with heart rate variability. PWV was significantly higher (via two-way variance analysis) in SHR than in WKY rats (strain effect) and increased markedly with age in both strains (age effect). Adjustment of PWV to mean BP attenuated markedly both the age and the strain effects. After adjustment for body weight, either alone or associated with mean BP, the age effect was not more significant, but the strain effect was markedly enhanced. In conscious unanesthetized SHR and WKY rats, aortic stiffness is consistently associated with body weight independent of age and mean BP. An intervention study should consider in the objectives systolic BP and PP amplifications measured in conscious animals, central control of body weight, and autonomic nervous system.     

The effect of prolonged infusion and withdrawal of angiotensin II in the spontaneously hypertensive rat

In spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto controls (WKY), prolonged intravenous administration of angiotensin II (AII, 0.2 microgram X kg-1 X min-1 for 3h) resulted in similar increases in arterial blood pressure. Heart rate decreased in WKY and increased in SHR. At the end of the infusion, blood pressure dropped substantially in SHR, but not in WKY: at 5 h after AII withdrawal, blood pressure in SHR had fallen from a control value of 172 +/- 3.3 to 146 +/- 3.9 mmHg (p less than 0.01), whereas pressure in WKY had fallen from 116 +/- 3.0 to 107 +/- 4.2 mmHg (statistically non significant). Thus, pressure at 5 h after AII withdrawal was still substantially higher (p less than 0.01) in the SHR than in the WKY. The results demonstrate that the fall in blood pressure following withdrawal of a prolonged infusion of AII in SHR is much less than that reported to occur following withdrawal of a prolonged infusion of vasopressin (AVP) in SHR.     

Long-term effects of betamethasone on blood pressure and hypothalamo-pituitary-adrenocortical function in spontaneously hypertensive and normotensive rats

An enhanced hypothalamo-pituitary-adrenocortical (HPA) activity has been described during onset of elevated blood pressure in spontaneously hypertensive rats (SHR). An instability of the HPA axis could thus contribute to the development of hypertension in these animals. Glucocorticoid effects on blood pressure and HPA function were studied therefore in SHR and normotensive Wistar-Kyoto (WKY) and Wistar rats. Beginning at 4 weeks of age, the rats were treated with 0.1 and 0.5 microgram betamethasone per milliliter drinking water for 7 weeks. SHR and WKY responded with a significant elevation in average blood pressure. In SHR, mean blood pressure rose from 181.4 +/- 3.9 (mean +/- SEM) to 203.1 +/- 2.8 mm Hg in response to the lower dose of betamethasone and to 209.2 +/- 4.0 mm Hg in response to 0.5 microgram betamethasone per milliliter drinking water. In WKY, blood pressure increased from 134.4 +/- 3.3 to 148.2 +/- 3.0 and 157.9 +/- 4.5 mm Hg in response to the lower and higher dose of betamethasone, respectively. No significant effect was seen in Wistar rats, where the mean blood pressure values changed insignificantly from 133.8 +/- 2.1 to 136.3 +/- 3.2 and 135.6 +/- 2.4 mm Hg. Stress-induced secretion of corticosterone was significantly suppressed in a dose-dependent manner in all three strains. Stress-induced secretion of adrenocorticotropin was markedly reduced by 0.5 microgram betamethasone per milliliter in SHR and by both doses in WKY. No significant effect, however, was seen in Wistar rats. A predisposition to the hypertensiogenic actions of glucocorticoids was found therefore in SHR and WKY, but not in Wistar rats.     

Endogenous opioids and opiate antagonists modulate the blood pressure of the spontaneously hypertensive rat

Endogenous opioids have been implicated as modulators of the central nervous system regulation of blood pressure and heart rate. Whether these neuropeptides participate in blood pressure regulation in hypertension is unknown. To begin to study this question, we examined the response to opiate antagonists and agonists in the spontaneously hypertensive rat (SHR) and the normotensive Wistar-Kyoto (WKY) rat. The long-acting opiate antagonist naltrexone, 2.5 micrograms/kg, was injected into the lateral ventricle of the brain in awake, freely-moving SHR and produced a significant 19 mmHg decrease in mean arterial blood pressure compared to basal blood pressure (p less than 0.01); a decrease was not observed at a two logarithm lower dose. In contrast, naltrexone had no effect on the blood pressure of normotensive Wistar-Kyoto (WKY) rats. To evaluate a possible regulatory role for the predominantly kappa receptor active opioids, alpha- and beta-neo-endorphin, 10 micrograms each, was administered to SHR on separate days by intracerebroventricular injection. alpha- and beta-neo-endorphin caused significant decreases in mean arterial blood pressure of 11 and 9 mmHg respectively, effects reversed by pre-treatment with the opiate antagonist, naloxone. Heart rate was unaffected by any of the injected opioids or antagonists. Our naltrexone results support the hypothesis that an endogenous opioid(s) contributes to the hypertensive state of the SHR. Additionally, alpha- and beta-neo-endorphin can lower blood pressure in this model.     

Noradrenergic content and turnover rate in kidney and heart shows gender and strain differences.

The objective of this study was to compare strain and gender differences in kidney and heart norepinephrine (NE) content and turnover rate in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR, SHR/a, and SHR/y). Our laboratory has shown that the Y chromosome has a significant effect on blood pressure in the SHR model of hypertension through the use of two new rat stains, SHR/a and SHR/y, to study the Y chromosome. SHR/a have a SHR autosomal genetic background with a WKY Y chromosome, whereas the SHR/y rats have a WKY autosomal genetic background with a SHR Y chromosome. Tissues were homogenized after alpha-methyl-DL-p-tyrosine injection and analyzed for NE. The male kidney NE content was significantly lower in the WKY compared with the SHR, SHR/y, and SHR/a. Kidney and heart NE content was significantly higher in females compared with males in all strains except the SHR/y. The WKY and SHR/y females had significantly lower kidney NE turnover rates, and the SHR and SHR/a females had significantly higher kidney NE turnover rates than strain-matched males. This study suggests both a strain and gender difference in sympathetic nervous system activity through noradrenergic neurotransmission.     

Changes in the content of atrial natriuretic factor with the progression of hypertension in spontaneously hypertensive rats

In order to assess possible roles of atrial natriuretic factor (ANF) in spontaneously hypertensive rats (SHR), we examined the content of immunoreactive-ANF in plasma, the atria, hypothalamus and pons of SHR and Wister Kyoto (WKY) rats by radioimmunoassay at different stages of age. With the progression of hypertension, plasma concentration of ANF increased whereas it decreased in the atria in SHR. This suggests ANF is secreted in response to hypertension. On the other hand, at hypothalamus and pons, ANF content was significantly higher in SHR than in WKY rats. This finding suggests possible involvement of ANF in the central regulation of blood pressure.     

Vascular reactivity, tissue levels, and binding sites for endothelin: a comparison in the spontaneously hypertensive and Wistar-Kyoto rats.

The role of endothelin (ET-1) in mediating the development of blood pressure was investigated in the spontaneously hypertensive (SHR) rat using the Wistar-Kyoto (WKY) rat as the normotensive control. The following were characterized in both rat strains: age-dependent changes in mean arterial blood pressure (MAP), tissue (blood, lung, heart, and kidney) levels of immunoreactive ET-1 like related peptides (ET-1RP), aortic ring responses to ET-1, and specific high-affinity tissue (lung, atrium, ventricle, aorta, and kidney) binding sites for 125I-labelled ET-1. Commencing at age 10 weeks through to 12 weeks, SHR rats but not WKY rats developed a significant increase in MAP (from 152 +/- 7 to 189 +/- 3 mmHg) (1 mmHg = 133.32 Pa). However, in both WKY and SHR rats immunoreactive levels of ET-1RP increased (100 and 80%, respectively) throughout the same measurement period. The potency of ET-1 to contract aortic rings from SHR rats was slightly but not significantly greater than that for aortic rings from WKY rats, although aortic rings from SHR rats contracted in the presence of 0.5 nM ET-1, while those from WKY rats did not. The levels of immunoreactive ET-1RP were significantly reduced (32%) in the kidney and unchanged in the heart and lung of SHR rats compared with WKY rats. Specific 125I-labelled ET-1 binding sites displayed an increase and a significant decrease (24%) of density in the atrium and ventricle, respectively, a significant increase (31%) of affinity in the lung, and were unchanged in the kidney and aorta of SHR rats compared with WKY rats following the development of hypertension. The lack of a correlation between circulating levels of immunoreactive ET-1RP and the development of hypertension coupled with a lack of significant differences in vascular reactivity suggest that ET-1 is not the sole mediator of hypertension in this animal model. However, the tissue-specific changes in immunoreactive ET-1RP and 125I-labelled ET-1 binding sites suggest that ET-1 may be a partial mediator of hypertension and is subject to compensatory changes in response to the increased total peripheral resistance in SHR rats.     

LVV-hemorphin-7 lowers blood pressure in spontaneously hypertensive rats: radiotelemetry study

Cardiovascular effects of LVV-hemorphin-7, a member of the family of fragments from beta-chain of human or bovine hemoglobin, were studied in conscious spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats by radiotelemetry. Intraperitoneal injection of hemorphin in a dose of 100 microg/kg significantly decreased blood pressure in SHR, whereas negligible effect was seen in normotensive WKY rats. Blood pressure changes were accompanied by reduction of heart rate. In conclusion, a direct effect of LVV-hemorphin-7 on blood pressure was demonstrated in SHR. These biologically active peptides could be involved in blood pressure regulation especially in hypertensive rats, but the precise mechanism should be elucidated.     

Clonidine fails to reduce pressor responsiveness of conscious spontaneously hypertensive rats to vasopressin

Pressor responses and heart rate responses to intravenous injections (3.5-50.0 pmol/kg) of arginine vasopressin (AVP) were recorded in saline- and clonidine-treated spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Clonidine (20 micrograms/kg, i.v.) caused a marked fall of arterial pressure in SHR but not in WKY rats so that, 20 min after the injection of the alpha 2-adrenoceptor agonist, arterial pressure was similar in the two strains of rats. The curve expressing the relationship between the dose of AVP and the increase of arterial pressure for saline-treated SHR was positioned to the left of that for saline-treated WKY rats. This enhanced pressor responsiveness of SHR to AVP may have been related to impaired reflex activity since heart rate fell much less in SHR than in WKY rats for a given elevation in pressure. Pressure responses to AVP were augmented by clonidine in both SHR and WKY rats so that, similar to saline-treated rats, pressor responsiveness to the peptide was still greater in SHR. Heart rate responses to AVP were not altered significantly by clonidine. The results indicate that clonidine fails to enhance reflex activity and reduce pressor responsiveness of SHR to AVP. The increased pressor responsiveness of both SHR and WKY rats to AVP following clonidine was an unexpected finding and may be related to a peripheral interaction between alpha-adrenergic agonists and AVP.     

GABA receptor binding and hemodynamic responses to ICV GABA in adult spontaneously hypertensive rats

Blood pressure and heart rate responses after central administration of GABA (100-1000 micrograms, ICV) and after ganglionic blockade with hexamethonium (25 mg/kg, i.a.) were compared in conscious 12 week-old spontaneously hypertensive (SH) and age-matched Wistar-Kyoto (WKY) rats. Ganglionic blockade produced an equivalent change in mean arterial pressure between SH and WKY rats. Thus, the total functional sympathetic nervous system contribution to blood pressure is equivalent in these two strains. Intraventricularly-administered GABA produced a greater absolute decrease in mean arterial pressure in the SHR compared to the WKY. However, the percent changes in arterial pressure produced by GABA were not different between these strains. This greater absolute depressor effect of GABA does not appear to be due to differences in GABA receptor binding constants since GABA receptor affinity and number of binding sites were not significantly different in the forebrain, cerebellum or pons-medulla between SH and WKY rats.     

Chronic infusion of low doses of atrial natriuretic factor (ANF Arg 101-Tyr 126) reduces blood pressure in conscious SHR without apparent changes in sodium excretion

Conscious SHR and WKY rats were infused during 7 days with synthetic ANF (Arg 101-Tyr 126), 100 ng/hr/rat (35 pmol/hr/rat) by means of miniosmotic pumps. The SHR initial blood pressure of 177 +/- 5 mmHg gradually dropped to 133 +/- 3 and 142 +/- 4 mmHg the last two days of infusion. No significant change in blood pressure was observed in the ANF-infused WKY group. No apparent difference in natriuresis or diuresis was observed in ANF-infused SHR and WKY when compared with non-infused control groups. A slight but significant lower immunoreactive ANF concentration was found in the atria of SHR than in their normotensive controls. No difference in cardiac weight was found between infused and non-infused rats. It is suggested that the hypotensive response observed in SHR and not in WKY is due to a decrease in vascular peripheral resistance. Whether ANF is involved in the development and maintenance of high blood pressure in SHR remains to be elucidated.     

Pressor responsiveness to vasopressin in spontaneously hypertensive rats

The present study was designed to find out whether pressor responsiveness to vasopressin (AVP) is altered in spontaneously hypertensive rats (SHR) in comparison with their normotensive controls (WKY). Blood pressure and heart rate changes after injection of graded doses of 2.5, 5.0 and 10.0 ng of AVP (Calbiochem) i.v. were compared in 9 conscious, unrestrained spontaneously hypertensive (SHR) and 11 normotensive Wistar Kyoto (WKY) rats, chronically instrumented with venous and arterial catheters. The threshold dose necessary to elicit a significant increase in blood pressure and reduction of heart rate was lower in WKY than in SHR. At each dose level the blood pressure elevation persisted for a longer period in WKY than in SHR. Bradycardia was greater in WKY than in SHR both in absolute terms and in relation to the blood pressure increase. Thus, the results reveal diminished pressor responsiveness to moderate doses of AVP in SHR in spite of suppressed reflex bradycardia. It is suggested that the peripheral action of AVP on the vascular system is attenuated in SHR.     

Increased sympathetic innervation in the cerebral and mesenteric arteries of hypertensive rats

The density of catecholamine-containing nerve fibers was studied in the cerebral and mesenteric arteries from normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and stroke-prone SHR (SHRSP) in the growing (SHR, WKY) and adult (SHR, SHRSP, WKY) animals. Cerebral arteries from SHR showed an increased adrenergic innervation from day 1. The nerve plexuses reached an adult pattern earlier in SHR than in WKY. The arteries from adult SHR and SHRSP (22 weeks old) showed a markedly higher nerve density than WKY. There was a positive linear correlation between blood pressure and nerve density for four cerebral arteries. The mesenteric arteries were not innervated at birth. However, hyperinnervation of these arteries in the SHR was already present at 10 days of age as compared with WKY. Sympathectomy with anti-nerve growth factor and guanethidine caused a complete disappearance of fluorescent fibers in the mesenteric arteries from SHR and WKY, and in the cerebral arteries of WKY. The same procedure caused only partial denervation of the cerebral arteries from hypertensive animals. We postulate that the increase in nerve density in the cerebral arteries from the hypertensive rats may contribute to the development of arterial hypertrophy in chronic hypertension through the trophic effect of the sympathetic innervation on vascular structure.     

In spontaneously hypertensive rats alterations in aortic wall properties precede development of hypertension

In hypertension arterial wall properties do not necessarily depend on increased blood pressure alone. The present study investigates the relationship between the development of hypertension and thoracic aortic wall properties in 1.5-, 3-, and 6-mo-old spontaneously hypertensive rats (SHR); Wistar-Kyoto rats (WKY) served as controls. During ketamine-xylazine anesthesia, compliance and distensibility were assessed by means of a noninvasive ultrasound technique combined with invasive blood pressure measurements. Morphometric measurements provided in vivo media cross-sectional area and thickness, allowing the calculation of the incremental elastic modulus. Extracellular matrix protein contents were determined as well. Blood pressure was not significantly different in 1.5-mo-old SHR and WKY, but compliance and distensibility were significantly lower in SHR. Incremental elastic modulus was not significantly different between SHR and WKY at this age. Media thickness and media cross-sectional area were significantly larger in SHR than in WKY, but there was no consistent difference in collagen density and content between the strains. Blood pressure was significantly higher in 3- and 6-mo-old SHR than in WKY, and compliance was significantly lower in SHR. The findings in this study show that in SHR, in which hypertension develops over weeks, alterations in functional aortic wall properties precede the development of hypertension. The decrease in compliance and distensibility at a young age most likely results from media hypertrophy rather than a change in intrinsic elastic properties.     

Differential sensitivity to cocaine in spontaneously hypertensive and Wistar-Kyoto rats

Physiological, pharmacological and toxicological responses to two regimens of cocaine administration were compared between spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. An initial experiment examined renal excretory and hemodynamic function in response to an acute volume load in anesthetized SHR and WKY following subacute cocaine treatment (20 mg/kg, s.c., twice a day for 9 days). Anticipated renal responses to volume loading were obtained but the responses of cocaine-treated SHR and WKY did not differ from vehicle-treated rats. A second group of experiments compared responses to continuous i.v. infusions of cocaine (1.25 mg/kg.min). In freely moving animals, no differences were noted between SHR and WKY in the increases in mean blood pressure (MBP) and heart rate (HR) produced during cocaine infusion. The elapsed time-to-onset of convulsions (Tc) elicited by cocaine was similar in both strains. However, when rats were subjected to restraint during the infusion period, pressor and tachycardic responses were observed to be significantly less in WKY than in SHR or in freely moving rats of either strain. Restraint also differentially affected rectal temperature (RT) responses to cocaine. Hypothermic responses to cocaine were observed in all WKY. Both hypothermic and hyperthermic responses were observed in SHR. A significant correlation was demonstrated between the Tc and the maximal change in RT produced during cocaine infusion. Division of SHR into two arbitrary groups was made, based on the direction of cocaine-induced change in RT. A significant (p less than 0.01) shortening of the Tc was obvious in SHR (8 of 15) in whom cocaine produced a hyperthermia. These animals were designated SHRH. The mean value for Tc in those SHR which demonstrated a lowering in RT (SHRL; 7 of 15) in response to cocaine was similar to that for WKY. Moreover, the SHRH evidenced significantly greater increases in HR, but not MBP, to cocaine infusion than did SHRL. The results indicate that restraint stress causes expression of a significant heterogeneity in the RT response of SHR to cocaine. The magnitude and direction of the RT responses are negatively correlated with sensitivity to the convulsive effects of cocaine in SHR. Stress may modify toxic responses to cocaine by interactions with body temperature homeostasis.