Effect of antihypertensive therapy on the vascular changes of spontaneously hypertensive rats

The effect of antihypertensive therapy on vascular morphologic characteristics was studied in spontaneously hypertensive rats (SHRs). Starting at either 7 or 22 weeks of age, SHRs were given a combination of hydralazine, chlorothiazide, and reserpine, which reduced the blood pressure significantly below the level of untreated animals. Rats were sacrificed at either the 22nd or the 42nd week of age along with age-matched untreated SHRs and normotensive Wistar-Kyoto controls. The following treatment groups were thus obtained: a) treated from the 7th to the 22nd or 42nd week, b) treated from the 22nd to the 42nd week, and c) treated from the 7th to the 22nd and left untreated until the 42nd week. Ultrastructural and morphometric studies were carried out on the aorta and intrarenal vessels. The expansion of the subendothelial space and medial thickening in the aorta as well as the increase in external to luminal diameter ratios and wall thickness of intrarenal vessels were prevented in SHRs treated continuously from the 7th week on. The severity of vascular lesions was markedly reduced in animals treated from the 22nd to 42nd week. Discontinuation of therapy resulted in rapid reestablishment and progression of both aortic and renal vascular disease to a degree identical to that of untreated SHRs. The results indicate that hypertensive vascular changes are preventable by early treatment and, depending on their nature, can be arrested or reversed by delayed treatment.     

Cardiovascular and sympathetic nervous system responses to an acute stressor in borderline hypertensive rats (BHR)

The present study examined cardiovascular and plasma catecholamine responses to acute footshock stress in adult male Wistar-Kyoto (WKY) normotensive, borderline hypertensive (BHR), and spontaneously hypertensive (SHR) rats. Basal mean arterial pressure and heart rate were equivalent for SHRs and BHRs, and levels for both groups were elevated compared to WKYs. Following transfer to the footshock chamber, blood pressure increased to a greater degree in SHRs than in WKYs or BHRs. However, the tachycardia was exaggerated in both BHRs and SHRs compared to WKYs. In response to intermittent footshock stress, all groups had comparable heart rate increases while maintaining blood pressure near baseline levels. SHRs demonstrated a sympathetic hyperresponsiveness to footshock stress, with greater increases in plasma norepinephrine and epinephrine levels than WKYs immediately following footshock. At 5 minutes postfootshock, plasma catecholamines remained elevated in SHRs over both WKYs and BHRs. Plasma catecholamine increases following footshock were comparable at all time points between WKYs and BHRs. The present results demonstrate that sympathetic responsiveness of BHRs to acute footshock stress is more similar to normotensive WKYs than to hypertensive SHRs.     

Acquisition of conditioned suppression and responsivity to thermal stimulation in spontaneously hypertensive,renal hypertensive and normotensive rats

The acquisition of conditioned suppression of instrumental responding and responsivity to thermal stimulation were assessed in spontaneously hypertensive rats of the Okamoto-Aoki strain (SHRs), renal hypertensive rats of the Wistar-Kyoto strain (WKYs), and normotensive WKY rats. Spontaneously hypertensive rats showed significantly faster acquisition of conditioned suppression than age-matched WKY normotensive rats. This acquisition difference between SHRs and normotensive WKYs was maintained even following chronic preexposure to shock alone; a treatment that retarded normal acquisition of conditioned suppression. In contrast, renal hypertensive WKYs acquired conditioned suppression at the same rate as age-matched normotensive WKYs. Spontaneously hypertensive rats and renal hypertensive WKYs both showed significantly longer latencies than normotensive WKYs to respond to thermal stimulation using a hot-plate assay. These outcomes suggest that the relationship between blood pressure and the acquisition of conditioned suppression in SHRs is either pleiotrophic or a consequence of random fixation, and that acquisition of conditioned suppression may serve as a valuable marker variable of hypertension in the SHR. The dissociation between acquisition of conditioned suppression and responsivity to thermal stimulation suggests that different mechanisms may mediate nociceptive responses to shock and thermal stimulation in these models of hypertension.     

Effects of oestrogen treatment and angiotensin-converting enzyme inhibition on the microvasculature of ovariectomized spontaneously hypertensive rats

We investigated the role of oestrogen in the function and structure of the microcirculation of female spontaneously hypertensive rats (SHRs), and evaluated the effect of 17beta-oestradiol on their cardiovascular response to pharmacological agents that block the formation of angiotensin II. Ten-week-old SHRs were randomly assigned to the following groups: intact, ovariectomized, and ovariectomized treated with 17beta-oestradiol (1.5 mg delivered over 60 days) and/or captopril (5 mg kg(-1) day(-1) for 8 weeks). Systolic blood pressure was determined from the time of ovariectomy up to 18 weeks of age, at which time endothelial function and microvascular density in skeletal muscle were evaluated. Both 17beta-oestradiol and captopril prevented development of hypertension in ovariectomized rats. Furthermore, coadministration of both drugs had a greater antihypertensive effect than either one alone. Acetylcholine-induced vasodilatation was impaired in ovariectomized SHRs, and the response was improved by treatment with 17beta-oestradiol and/or captopril. In addition, 17beta-oestradiol replacement in ovariectomized rats enhanced the effect of captopril on acetylcholine-induced vasodilatation. Ovariectomized rats also showed lower microvascular density than intact rats, an effect that was prevented by 17beta-oestradiol replacement or captopril treatment and, to a significantly larger extent, by coadministration of both. We concluded that both 17beta-oestradiol and captopril attenuated the development of hypertension and improved the impairment in microvascular density of ovariectomized SHRs. Moreover, when simultaneously administered, oestradiol and captopril had an additive effect on blood pressure and the microvasculature.     

Spontaneously hypertensive rats exhibit altered cardiovascular and neuronal responses to muscle contraction

We examined the cardiovascular and ventrolateral medullary neuronal responses to muscle contraction in the spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto rat (WKY) control. Cardiovascular, respiratory and ventrolateral medullary neuronal responses to muscle contraction evoked by tibial nerve stimulation were recorded. SHRs exhibited significantly larger drops in arterial pressure compared to WKYs in response to muscle contraction (P < 0.05). Basal ventrolateral medulla neuronal discharge rates were similar between the SHR and the WKY groups. A majority of neurons recorded responded to muscle contraction in both the WKY (77 %; n = 53) and the SHR groups (68 %; n = 62). There was no difference in the percentage of neurons that responded with an increase (approximately 60 %) or decrease (approximately 40 %) in firing rate between hypertensive and normotensive rats. Pulse wave-triggered averaging techniques showed that most neurons that responded to muscle contraction also possessed a basal firing rhythm temporally related to the cardiac cycle (85 % in WKYs, 83 % in SHRs). However, decreases in neuronal firing rates in response to muscle contraction were significantly greater in SHRs than WKYs. Therefore, we conclude that muscle contraction unmasks a hyperexcitability of neurons in the ventrolateral medulla of SHRs that parallels the heightened blood pressure responses.     

Early myocardial fibrosis is associated with depletion of vasoactive intestinal peptide in rat heart

In this study we sought to determine whether early myocardial fibrosis is associated with depletion of vasoactive intestinal peptide (VIP) in the heart, thereby suggesting a possible pathogenetic role for depletion of myocardial VIP levels in the development of fibrosis in the heart. Spontaneously hypertensive rats (SHRs) and normotensive control Wistar-Kyoto rats (WKYs) were assigned randomly to low, intermediate or high sodium diets and their blood pressure was recorded twice weekly for 4 weeks. At the end of this period the rats were anaesthetised, blood was sampled for plasma VIP concentration and the hearts were harvested for histology and determination of the concentration of VIP in the heart. The degree of myocardial fibrosis increased with increasing dietary sodium intake in both the WKYs (P < 0.001) and the SHRs (P < 0.01). Myocardial VIP concentration decreased with increasing dietary sodium intake in the WKYs (P < 0.01) and in the SHRs (P < 0.01). There was a negative correlation between myocardial VIP concentration and the degree of myocardial fibrosis in both the WKYs (P < 0.0005) and the SHRs (P < 0.005). Dietary sodium intake induces myocardial fibrosis in a dose-dependent manner. Further, in early myocardial fibrosis resulting from increasing dietary sodium intake in both normotensive and hypertensive rats the concentration of VIP in the heart was negatively correlated with the degree of fibrosis. This suggests a possible role for depletion of VIP in the myocardium in the pathogenesis of myocardial fibrosis.     

自发性高血压大鼠颈总动脉的平均壁面切应力和周向应力

目的确定自发性高血压大鼠(SHR)颈总动脉的平均壁面切应力(WSS)和周向应力(CS),并与同龄正常血压大鼠(WKY)相对比,观察SHR和WKY大鼠颈总动脉平均WSS和CS的特征。方法选取12周龄SHR作为动物模型,同龄WKY为对照组;通过在体测定颈总动脉的平均血流量与平均血压,离体测量颈总动脉的无载荷状态形态学数据,以及在体轴向伸长比条件下颈总动脉段的压力(p)-容积(V)关系,确定颈总动脉平均WSS和CS;同时比较SHR和WKY颈总动脉的平均血压和血流量、无载荷和载荷状态几何尺寸以及平均WSS和CS的特征。结果与正常血压的WKY组相比,SHR组颈总动脉血压明显增高、流量明显降低;无载荷和载荷状态下SHR组动脉的内外半径均增大,载荷状态下SHR组动脉壁厚减小;SHR颈总动脉平均WSS明显降低,而CS明显增高。结论高血压和低流量引起了SHR颈总动脉重建;低WSS和高CS是SHR颈总动脉血液动力学参数的重要特征;WSS和CS的协同作用可能是反映动脉重建的敏感指标之一。     

Pharmacological blockade of blood pressure and heart rate increases following milk ingestion in 15-day-old SHR and WKY rat pups.

The effects of hexamethonium, a ganglionic blocker, on blood pressure (BP) and heart rate (HR) responses to milk ingestion were assessed in awake, 15-day-old spontaneously hypertensive rats (SHR) and their normotensive progenitor strain, Wistar-Kyoto rats (WKY) using two methods of milk delivery. SHRs had larger increases in BP compared to WKYs, but WKYs exhibited larger increases in HR following milk ingestion from an anesthetized dam. BP responses to milk ingestion from a tongue cannula were also larger in SHRs. Administration of hexamethonium prior to milk delivery resulted in a drop in BP following milk ingestion in both milk delivery situations for each strain. The results suggest that SHRs exhibit exaggerated sympathetic activation to milk ingestion compared to WKYs, and that in both strains, cardiovascular responses to feeding are modulated by the presence of the dam.     

The renal medulla and mechanisms of hypertension in the spontaneously hypertensive rat.

A significant number of offspring from brother-sister matings of NIH-Okamoto-Aoki spontaneously hypertensive rats (SHRs) were found to be normotensive at 20 weeks of age. Over 20% of the animals that were hypertensive at this age had mild-to-moderate unilateral hydronephrosis at the time of sacrifice. In over 90% of the rats that did not develop hypertension spontaneously, ligation of one ureter raised blood pressure above 150 mm Hg within 2 weeks. In those rats made hypertensive by obstructing one ureter and in those that developed hypertension with accompanying naturally occurring hydronephrosis, subcutaneous implants of fragmented renal medulla from unrelated normal rats decreased blood pressure to normotensive levels. In contrast, medullary implants had no significant effect in rats developing hypertension spontaneously without hydronephrosis. Renal inner medullary plasma flow was low in the obstructed kidneys of hydronephrotic hypertensive SHRs but was elevated in the kidneys of nonhydronephrotic hypertensive SHRs. The hypertension in hydronephrotic SHRs appears to be related to an impairment of the antihypertensive function of the renal medulla. Such an impairment of medullary antihypertensive function does not appear to play a significant role in the hypertension in SHRs without hydronephrosis.     

Gamma-interferon corrects aberrant protein kinase C levels and immunosuppression in the spontaneously hypertensive rat.

The effects of gamma-interferon (gamma-IFN) on protein kinase C (PKC) levels and immunosuppression in the spontaneously hypertensive rat (SHR) were examined. First, an abnormal PKC distribution was found in spleen, thymus and aorta from SHRs relative to normotensive controls. Biweekly injections of rat recombinant gamma-IFN (1000 U/kg) restored basal or resting PKC levels to those found in normotensive Wistar-Kyoto (WKY) rats. We also examined the effects of in vivo gamma-IFN treatment on nuclear PKC (nPKC) activation in purified, isolated splenocyte nuclei. It was found that basal nPKC levels were higher in untreated SHRs than gamma-IFN SHRs or WKYs. Also, while nuclei from untreated SHRs were relatively unresponsive to various immunoreactive substances and PKC activators, gamma-IFN treatment significantly restored activity. Last, the proliferative response to mitogen challenge of isolated splenocytes from untreated SHRs, gamma-IFN-treated SHRs and WKYs was studied. Although gamma-IFN treatment did not restore the proliferative response to that of WKYs, the mitogen response was significantly enhanced by treatment with gamma-IFN. The data show that gamma-IFN acts to restore normal immune function and corrects aberrant PKC levels and adds to the growing body of knowledge suggesting a role for immune dysfunction in the etiology of hypertension.     

Regression of ventricular hypertrophy abolishes cardiocyte vulnerability to acute hypoxia

Left ventricular hypertrophy (LVH) secondary to a pressure overload commonly leads to perfusion abnormalities that may limit oxygen delivery to the myocardium and, therefore, result in cardiocyte intracellular damage. We initiated this study to test the hypothesis that the increased vulnerability of the hypertrophied left ventricle to acute hypoxia is minimized when LVH regresses and maximal coronary flow returns to normal. Six-month-old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were divided into control or one of two antihypertensive treatment groups. A 3-month treatment consisted of captopril (75-100 mg/kg) or hydralazine (80-160 mg/L) with hydrochlorothiazide (500 mg/L) added to each therapy. At the conclusion of the treatment period, the rats were administered a 7% O2-93% N2 gas mixture for 20 minutes to induce acute hypoxic stress during which time hemodynamics, blood gases, and pH were monitored. The heart was then rapidly fixed by vascular perfusion and prepared for electron microscopy. Captopril and hydralazine were equally effective in lowering arterial pressure in both strains, but only captopril was efficacious in reducing heart mass. Hypoxia-induced changes in hemodynamics, blood gases, and pH were similar in all of the groups; PO2 was decreased by about 70%. The electron micrographs revealed that the hypertrophied left ventricle consistently showed morphologic evidence of hypoxic damage (as indicated by T-tubular swelling, intracellular edema, and mitochondrial alterations); in contrast hypoxia had little effect on the non-hypertrophied ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term effects of captopril and atenolol in essential hypertension

Fifty patients with mild or moderate essential hypertension were randomized (double-blindly) to treatment with either captopril (n = 26) or atenolol (n = 24). Their mean supine diastolic blood pressure after placebo was 100-125 mmHg. The study included an initial dose finding phase (12 weeks) during which the dosages of captopril and atenolol were increased stepwise every second week in order to obtain normotension (supine diastolic blood pressure less than 95 mmHg). Hydrochlorothiazide was added when necessary. During the second phase of the study the patients were followed on active treatment for 2 years. After the initial 12 weeks of active treatment, recumbent and standing blood pressures had fallen significantly both in the captopril group (by 31/20 and 33/19 mmHg, p less than 0.001) and in the atenolol group (by 24/18 and 30/20 mmHg, p less than 0.01 (systolic), p less than 0.001 (diastolic)). The antihypertensive effect was maintained in both groups during long-term treatment. The antihypertensive effect of both agents was potentiated to the same extent by addition of hydrochlorothiazide. Side-effects were few and mild. It can be concluded that both captopril and atenolol are safe and effective antihypertensive drugs.     

Early onset of a decreased intracellular magnesium and phosphate concentration in smooth muscle cell of SHR.

A decrease in total magnesium content is not a direct proof of a decreased magnesium ion concentration. It could reflect a phosphate alteration or an ATP metabolism disorder. Plasma phosphate levels are lower in spontaneously hypertensive rats (SHRs) than in Wistar-Kyoto rats (WKYs), and defects in membrane regulation or mitochondrial ATP synthase occur. Only sparse data exist concerning cellular magnesium and phosphate concentrations in hypertensive cells. In aortic smooth muscle cells from 10 SHRs of the Münster strain and 10 age-matched normotensive WKY rats, the intracellular phosphate and magnesium content was measured by electron probe X-ray microanalysis (Camscan CS 24 apparatus, Cambridge, U.K.). The Mg++ content was 0.09 +/- 0.15 g/kg dry weight in SHRs versus 1.15 +/- 0.10 g/kg dry weight in WKY rats (p < 0.01). Vascular smooth muscle phosphate content was 23.6 +/- 0.79 g/kg dry weight in WKY rats versus 15.81 +/- 1.22 g/kg dry weight in SHRs (p < 0.01). In aortic smooth muscle cells of one month old SHRs intracellular magnesium was measured as 1.05 +/- 0.08 versus 1.09 +/- 0.09 g/kg dry weight in WKYs. Intracellular phosphate concentration in one month old SHRs was 18.71 +/- 2.41 versus 21.36 +/- 1.25 g/kg dry weight in WKYs (eight animals in each group). Aortic smooth muscle cells of SHRs are caracterized by markedly lowered intracellular phosphate and magnesium concentrations, resulting in an altered ATP-metabolism, as described earlier. Possibly a membrane defect or a magnesium deficiency or disturbed magnesium channels are responsible for the early onset in the pathogenesis of primary hypertension.     

Temporal characteristics of cardiomyocyte hypertrophy in the spontaneously hypertensive rat.

BACKGROUND: The spontaneously hypertensive rat (SHR) is frequently used as model of cardiovascular disease, with considerable disparity in reported parameters of hypertrophy. The aim of this study was to assess the temporal changes occurring during the development and progression of cardiomyocyte hypertrophy in SHR, subsequent to pressure overload, compared to changes associated with normal aging using the normotensive Wistar-Kyoto (WKY) rat. METHODS: Ventricular cardiomyocytes were isolated from rats at 8, 12, 16, 20 and 24 weeks, and parameters of hypertrophy (cell dimensions, protein mass, de novo protein synthesis, and gene expression) and function (contraction and hypertrophic responsiveness in vitro) were assessed. RESULTS: Hypertension was evident at > or =7 weeks in SHRs. Heart:body mass ratio, cardiomyocyte protein mass and width were elevated (P<.05) in SHRs at 16-20 weeks compared to WKYs. In SHRs compared to WKYs at 16 weeks, there was a transient increase (P<.05) in protein synthesis, enhanced hypertrophic responsiveness to phorbol-12-myristate-13-acetate, and induced hypertrophic responsiveness to isoprenaline. Skeletal-alpha-actin mRNA was detected in SHR but not WKY cells at all ages. ANP mRNA was lower in SHR than in WKY cells at 8-20, but progressively increased (P<.05) from 12 to 24 weeks within SHRs. Contractile function increased (P<.05) at 20 weeks in SHR compared to WKY rats. CONCLUSION: Structural and functional changes occurring at the cellular level in the myocardium of SHR follow a distinct pattern, such that pressure overload was initially accompanied by expressional changes (8-12 weeks), followed by active hypertrophic growth and enhanced function (16-20 weeks), which subsequently decelerated as stable compensation was attained.     

Locomotor activity, auditory startle and shock thresholds in spontaneously hypertensive rats

A group of SHRs and a group of WKY normotensive controls were compared sequentially on open-field behavior, Y-maze activity, responsiveness and habituation of the auditory startle response, and shock thresholds. In the open field and Y maze the SHRs were more active than the WKYs, but the locomotor activity of the SHRs decreased more within sessions. However, the SHRs could be described as showing more, less or the same between-session habituation depending upon the apparatus and the portion of the session analyzed. The SHRs were less responsive than controls on the auditory startle response measure, and they did not differ from controls on startle-response habituation. The SHRs were less responsive than controls at low shock levels but more responsive at high shock levels. The relationship between SHRs and WKYs on the responsiveness dimension depended upon the modality and intensity of the stimulus, the response characteristics of the test situation, and the time sample of behavior taken.     

自发性高血压大鼠中脑导水管周围灰质nNOS阳性神经元的变化

目的观察自发性高血压大鼠(spontaneously hypertensiverats,SHR)中脑导水管周围灰质内神经元型一氧化氮合酶(neuronal nitric oxide synthase,nNOS)阳性神经元的变化。方法取SHR和京都种威斯特大鼠(Wistar-Koytorats,WKY)大鼠各30只,分别于3月(14周)龄,6月龄和12月龄测血压并处死,ABC免疫细胞化学方法显示nNOS阳性神经元。结果SHR血压随鼠龄的增长逐渐升高,于12～14周龄时血压在高位稳定,且均高于WKY大鼠(P<0.05)维持在[(20.8±1.1)～(26.3±1.0)]kPa(P<0.05);WKY大鼠各时期血压无明显差异,维持在[(13.7±1.6)～(15.1±1.7)]kPa。中脑导水管周围灰质nNOS阳性神经元以小细胞为主,突起有2-4个,许多朝中脑水管方向延伸。定量结果显示,SHR大鼠nNOS阳性神经元随着血压升高呈逐渐减少的趋势,12月龄与3月龄和6月龄相比均有显著差异(P<0.01),而各个时期WKY大鼠PAGnNOS阳性神经元均无明显变化。结论SHR中脑导水管周围灰质nNOS阳性神经元的减少可能通过影响延髓的血压调节中枢调控高血压的发生,并有可能与高血压的痛觉过敏有关。     

Effects of Aqueous Extract of Lycopersicum esculentum L. var. “Camone” Tomato on Blood Pressure,Behavior and Brain Susceptibility to Oxidative Stress in Spontaneously Hypertensive Rats

Behavioral disorders affect millions of people worldwide. Hypertension contributes to both the development and progression of brain damage and cognitive dysfunction and could represent the most powerful modifiable risk factor for cerebral vessel dysfunction and consequent behavioral impairment. Tomato contains antioxidants and bioactive molecules that might play an important role in the prevention of cardiovascular and brain diseases. The effects of the combined gel and serum from Lycopersicum esculentum L. var. “Camone” tomatoes and those of purified tomato glycoalkaloids (tomatine) and an antihypertensive drug (captopril) were investigated in male spontaneously hypertensive rats (SHRs) and compared with normotensive Wistar Kyoto (WKY) rats. Body weight, systolic blood pressure, behavioral parameters, as well as brain susceptibility to oxidative stress and brain cytokine contents, were assessed. Treating hypertensive rats with tomato gel/serum or captopril for four weeks caused a significant reduction in blood pressure, decreased locomotor activity and increased grooming behavior; the last two parameters were also significantly affected by tomatine treatment. Brain slices obtained from hypertensive rats treated with tomato gel/serum were more resistant to oxidative stress and contained lower levels of inflammatory cytokines than vehicle-treated ones. In contrast, tomatine treatment had no effect. In conclusion, the tomato-derived gel/serum can be considered a dietary supplement able to drive in vivo blood pressure towards healthier values and also control some central effects such as behavior and brain oxidative stress.     

Structure of renal afferent arterioles in the pathogenesis of hypertension

Renal vascular resistance is increased in essential hypertension, as in genetic models of hypertension. Here we review the evidence that this is at least in part due to structural changes in the afferent arterioles. Rat studies show that the renal afferent arteriole is structurally narrowed in young and adult spontaneously hypertensive rats (SHR). Furthermore, in the second generation of crossbred SHRs/normotensive rats (SHR/WKY F(2)-hybrids), a narrowed afferent arteriole lumen diameter at 7 weeks is a predictor of later development of high blood pressure. The reduced lumen diameter of resistance vessels is accompanied by a decrease in media cross-sectional area in SHR and could therefore be due to inhibited growth. Evidence from a primate model of hypertension has shown a negative correlation between left ventricular hypertrophy and afferent arteriole diameter, but apparently no relation to blood pressure. In SHR, the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors is mediated through renal vascular mechanisms, while ACE inhibitors (like AT(1) antagonists) have a more persistent effect on blood pressure after treatment withdrawal compared with other antihypertensive drugs. Taken together, the evidence suggests that structural narrowing of the renal afferent arteriole could be an important link in the pathogenesis of primary hypertension, at least in the SHR.     

Differential cardiovascular responses to stressors in hypertensive and normotensive rats

The aim of this study was to determine to what extent stress-induced cardiovascular responses depend upon rat strain and/or stressor. Spontaneously hypertensive rats (SHRs), Wistar-Kyoto rats (WKYs) and Sprague-Dawley (SD) rats were implanted with telemetry probes in order to measure heart rate and blood pressure changes when exposed to a stressor. The stress protocols employed included handling, air-jet and restraint, where each stressor was repeated over 10 consecutive days. In addition, a heterologous protocol was established whereby the experimental groups having experienced 10 days of air-jet stress were then immediately exposed to 10 consecutive days of restraint. Each stressor caused graded tachycardic and pressor responses in all strains. For all strains, the magnitude and duration of heart rate and blood pressure increases were greatest in the restraint-based protocols while handling and air-jet caused submaximal changes. A comparison between strains indicated that SHRs exhibited prolonged pressor responses to each of the stressor types tested as compared to the normotensive strains. In addition, repeated exposure over 10 days to handling and air-jet in SHRs caused tachycardic and/or pressor responses to adapt to 'normotensive-like' levels. Heterologous restraint stress caused sensitization of cardiovascular responses upon first exposure, predominantly in normotensive strains. Collectively these data show that the magnitude and duration of the tachycardia and pressor responses evoked by the stressors were different within the strains and were also modified by prior experience. In addition, the cardiovascular profiles presented in this study demonstrate that, within each strain, the heart rate response during stress is graded according to the type of stressor encountered.