Electromechanical alterations in the cerebrovasculature of stroke-prone rats.

BACKGROUND AND PURPOSE: Cerebrovascular pressure-dependent constriction (PDC) is associated with smooth muscle (SM) depolarization and Ca(2+) influx through voltage-gated channels. We studied the alterations in electromechanical contraction in the middle cerebral arteries (MCAs) of stroke-prone Wistar-Kyoto spontaneously hypertensive rats (SHRsp) in relation to the stroke-related loss of PDC. METHODS: Constriction to pressure, elevated [K(+)](o) and/or [Ca(2+)](o), and SM membrane potentials (E(m)) were measured in isolated pressurized MCAs of SHRsp and stroke-resistant SHR. RESULTS: MCAs of SHRsp exhibited an age-related decrease in PDC before hemorrhagic stroke and a loss of PDC after stroke. At 100 mm Hg, the MCAs of poststroke SHRsp maintained partial constriction that was not altered with pressure but was inhibited by nifedipine (1 micromol/L). The MCAs of poststroke SHRsp constricted to vasopressin (0.17 micromol/L) but not to elevated [K(+)](o). When pressure was reduced from 100 to 0 mm Hg, the MCAs from young prestroke SHRsp exhibited SM hyperpolarization (-38 to -46 mV), whereas those of poststroke SHRsp maintained a constant, depolarized E(m) (-34 mV). Alterations in E(m) with varying [K(+)](o) suggested that there was a decrease in SM K(+) conductance in the MCAs of poststroke SHRsp. CONCLUSIONS: The observation that the MCAs of poststroke SHRsp depolarize but do not constrict to elevated [K(+)](o) suggests the presence of dysfunctional voltage-gated Ca(2+) channels. The inability to alter E(m) with pressure or to constrict to depolarization could partially contribute to the loss of PDC in the MCAs of poststroke SHRsp.

Cerebrovascular alterations in protein kinase C-mediated constriction in stroke-prone rats.

BACKGROUND AND PURPOSE: Cerebrovascular pressure-dependent constriction may involve the smooth muscle production of diacylglycerol, which could facilitate constriction by activating protein kinase C (PKC). A dysfunctional PKC system could promote the loss of pressure-dependent constriction. We attempted to determine whether the alterations in pressure-dependent constriction in the middle cerebral arteries (MCAs) observed in relation to stroke development in Wistar-Kyoto stroke-prone spontaneously hypertensive rats (SHRsp) were associated with defects in the ability of the arteries to constrict in response to PKC activation. METHODS: MCAs were sampled from SHRsp before and after stroke development and in stroke-resistant Wistar-Kyoto spontaneously hypertensive rats. A pressure myograph was used to test the ability of the arteries to constrict in response to a 100 mm Hg pressure step and subsequently to contract in response to phorbol 12,13-dibutyrate in the presence of nifedipine (3 micromol/L). RESULTS: Pressure-dependent constriction and constriction in response to phorbol dibutyrate in the MCAs were inhibited by PKC inhibitors (staurosporine [40 nmol/L], chelerythrine [12 micromol/L], bisindolylmaleimide [5 micromol/L]), declined with age before stroke development in SHRsp, and were absent after stroke. There was a significant relationship between pressure- and phorbol dibutyrate-induced constriction (r=0.815, P<0. 05). CONCLUSIONS: Phorbol esters interact with the same activation site as diacylglycerol to stimulate PKC. An inability to constrict in response to phorbol dibutyrate may reflect unresponsiveness to diacylglycerol and may contribute to the loss of pressure-dependent constriction associated with stroke in the MCAs of SHRsp. The loss of this autoregulatory function before stroke could increase the risk of cerebral hemorrhage.

Stroke-prone spontaneously hypertensive rats lose their ability to auto-regulate cerebral blood flow prior to stroke.

OBJECTIVES: We hypothesized that the loss of cerebral blood flow (CBF) auto-regulation under hypertensive conditions could promote cerebrovascular over-perfusion and haemorrhage formation. The possibility that CBF auto-regulation becomes defective prior to haemorrhagic stroke development was assessed in Wistar- Kyoto stroke-prone spontaneously hypertensive rats (SHRsp) and related to the myogenic responsiveness of the cerebrovasculature to pressure. METHODS: Laser Doppler techniques were used to measure relative CBF in relation to mean arterial pressure (MAP 130-260 mmHg) within the perfusion domains of the middle (MCA) and posterior (PCA) cerebral arteries. The ability of isolated MCAs and PCAs to constrict to a 120 mmHg pressure step (pressure-dependent constriction) was measured using a pressure myograph. RESULTS: Two weeks prior to stroke, 10-week-old pre-stroke SHRsp exhibited near-constant CBF regulation to a 200 mmHg MAP. Thirteen-week-old pre-stroke SHRsp and age-matched post-stroke SHRsp lost their ability to auto-regulate CBF in the MCA and PCA perfusion domains. CBF increased at a high rate and in a linear manner with MAP. A distinct upper limit to CBF auto-regulation was absent. Pressure-dependent constriction was attenuated prior to stroke, and lost after stroke in isolated MCAs, but not the PCAs, of SHRsp. CONCLUSIONS: The loss of CBF auto-regulation prior to stroke in SHRsp could enhance cerebral perfusion and facilitate the initiation of haemorrhage. Such dysfunction after stroke could produce secondary haemorrhages. Defects in pressure-dependent constriction cannot fully account for the pattern of CBF auto-regulation loss observed in post-stroke SHRsp.

Electrical conduction within the cerebrovasculature of stroke-prone spontaneously hypertensive rats.

Alterations in electrical conductivity between smooth muscle cells (SMCs) can alter the spread and effectiveness of electromechanical SMC contraction. We attempted to determine whether alterations in pressure-dependent constriction (PDC) occurring in relation to stroke development within the middle cerebral arteries (MCAs) of Wistar-Kyoto stroke-prone hypertensive rats (SHRsp) were associated with changes in electrical conductivity between the SMCs. Current was injected into nonpressurized MCAs, using a suction electrode. The conducting distance along the length of the MCA where the amplitude of the membrane potential deflection (electronic potential) produced by current injection declined to 1/e (length constant) was used to measure conductivity. PDC to a 100 mmHg pressure step was measured with a pressure myograph. A loss of PDC in the MCAs of SHRsp preceded stroke development. Heptanol (4 mM), a gap junction communication inhibitor, reversibly inhibited conductivity and PDC in the MCA of prestroke SHRsp. The ability of heptanol to reversibly inhibit PDC was likely not related to it's ability to alter electrical conduction. The length constant of electrical conduction in the MCAs was about 0.75 mm and didn't differ between MCA sampled from pre-versus post-stroke SHRsp or Sprague-Dawley rats. It was concluded that alterations in electrical conductivity along the MCA could modify the spread of PDC, but such changes do not contribute to the loss of PDC within the MCA of poststroke SHRsp.

Prevention of stroke and preservation of the functions of cerebral arteries by treatment with perindopril in stroke-prone spontaneously hypertensive rats.

The aim of this study was to determine whether the prevention of stroke with perindopril treatment in stroke-prone spontaneously hypertensive rats (SHRSP) is associated with the preservation of the myogenic properties of the cerebral arteries. After weaning at 4 weeks of age, male SHRSP were fed a Japanese-style rat diet with high salt to induce stroke development. Treatment with perindopril was given by gavage every morning beginning at 6 weeks of age. There were three experimental groups: two groups treated with 4 mg.kg-1.day-1 perindopril for different durations (8 or 12 weeks) and one control group consisting of littermates given distilled water. All the control animals developed stroke and died within 14 weeks of age, and myogenic response of the middle cerebral arteries (MCA) to pressure increase was lost in these animals. In contrast, all the treated SHRSP survived during the treatment period, and myogenic response of the MCA was preserved. After withdrawal of the treatment, SHRSP treated for a longer period (12 weeks) also survived longer than those treated for a shorter period (8 weeks). The subsequent development of stroke and death following treatment withdrawal after 8 or 12 weeks of treatment was associated with the loss of pressure-dependent constriction in MCA. A longer treatment duration also increased the stiffness of the MCA, MCA from SHRSP after 12 weeks of treatment had smaller external and lumen diameters, and thicker walls than those from the 8-week treatment group. In a separate study, we found that treatment of SHRSP with 1 or 4 mg.kg-1.day-1 of perindopril for 24 weeks beginning at 6 weeks of age also protected them against death related to stroke, because these rats survived up to 43 weeks of age, when the experiment was terminated. We conclude that there is an association between the absence of myogenic response in cerebral arteries and stroke development in SHRSP. Perindopril treatment preserves the myogenic response of MCA in SHRSP and prevents the stroke development in these animals. A prolonged treatment could increase the survival of SHRSP through a remodelling of the MCA and increasing the stiffness of the cerebral arteries.

Prevention of stroke with perindopril treatment in stroke-prone spontaneously hypertensive rats.

OBJECTIVE: To determine the protective effects of perindopril treatment in the prevention of stroke and the relation between preventive effects and the histopathology of the brain and kidneys in male stroke-prone spontaneously hypertensive rats (SHRSP). DESIGN: Prospective animal study. INTERVENTIONS: Beginning at 6 weeks of age, SHRSP were treated with either distilled water (control) or perindopril for different periods (8, 12 or 24 weeks) and at different dosages (1 or 4 mg/kg per day). OUTCOME MEASURES: Regular determination of systolic blood pressure, heart rate and body weight until death; at necropsy, macroscopic and microscopic examinations of the brain and kidneys. RESULTS: Control SHRSP developed severe hypertension (up to 250 mm Hg) by 11 weeks of age and died of stroke within 14 weeks of age. Treatment with perindopril (4 mg/kg per day for 8 or 12 weeks or either 1 or 4 mg/kg per day for 24 weeks) attenuated the blood pressure rise and prevented stroke. In untreated SHRSP, the last blood pressure measurement before the first stroke sign was significantly higher than in SHRSP of the same age treated with perindopril. Withdrawal of the treatment resulted in a rise in blood pressure in all the treatment groups, to approximately 260 mm Hg within 4 weeks. Most of the rats treated for 8 or 12 weeks died within 10 weeks after withdrawal of treatment, whereas those treated for 24 weeks survived up to 43 weeks of age. Treatment also prevented damage to the brain and kidneys and reduced the severity of lesions in the brain and kidneys after treatment withdrawal. CONCLUSION: Treatment of SHRSP with perindopril prevents stroke through the suppression of blood pressure rise and prevention of tissue damage in the brain and the kidneys. Longer treatment decreased the rate of mortality due to stroke after the withdrawal of treatment as well as the severity of lesions in the brain and kidneys.

The role of blood pressure and aldosterone in the production of hemorrhagic stroke in captopril-treated hypertensive rats.

BACKGROUND AND PURPOSE: We tested the hypothesis that the lowering of plasma aldosterone levels contributed to the antistroke effects of captopril treatment in Wistar Kyoto stroke-prone spontaneously hypertensive rats (SHRSP). METHODS: The suppression of plasma aldosterone by captopril treatment (50 mg.kg-1.d-1) was prevented by the subcutaneous infusion of aldosterone into captopril-treated SHRSP. We studied the effect this had on blood pressure (BP) and stroke development. RESULTS: SHRSP fed a Japanese-style diet containing 4% NaCl developed hypertension and a 100% mortality associated with intracerebral hemorrhage by 14 weeks of age. Captopril treatment from 6 weeks of age did not lower the BP but increased survival past 35 weeks of age. Hydralazine treatment (40 to 80 mg/L of drinking water) lowered BP in SHRSP but was less effective than captopril in retarding stroke. Plasma aldosterone levels were elevated with age in SHRSP after 10 weeks and were higher in poststroke versus prestroke SHRSP. Captopril treatment suppressed plasma aldosterone. When we elevated plasma aldosterone in captopril-treated SHRSP to levels between those present in untreated pre- and poststroke SHRSP, the ability of captopril to retard stroke development was negated. The effects of aldosterone were mimicked by deoxycorticosterone (40 mg/kg, SC2 times/wk) but not by dexamethasone (0.1 mg.kg-1.d-1, SC). Spironolactone treatment (20 mg.kg-1.d-1, SC) of SHRSP reduced BP but had little effect on stroke development. CONCLUSION: Elevations in plasma aldosterone enhance stroke development within captopril-treated SHRSP through mechanisms that do not involve stimulation of mineralocorticoid receptors or the enhancement of hypertension. The antistroke effects of captopril treatment may be partially mediated through the suppression of plasma aldosterone.

Renal function in stroke-prone rats fed a high-K+ diet.

Renal function was assessed in prestroke and poststroke Kyoto-Wistar stroke-prone spontaneously hypertensive rats (SHRsp) fed high-K+ (2.11%) and low-K+ (0.75%) diets containing 4% NaCl and in stroke-resistant SHR (srSHR) fed a low-K+ diet. Elevations in dietary K+ retarded the onset of stroke development in SHRsp, but did not alter the life-span of SHRsp between the onset of stroke and death. At ages < 12 weeks, renal function, measured by serum urea and creatinine levels and urinary protein loss, was comparable in high and low K+ fed prestroke SHRsp, and age-matched srSHR. At ages > 12 weeks, hemorrhagic stroke rapidly developed in SHRsp. When compared with srSHR, prestroke SHRsp exhibited higher serum creatinine and urea levels, a greater excretion of protein into the urine, and lower serum albumin levels. The severity of the above indices of renal failure was amplified in similar-aged poststroke SHRsp. Poststroke SHRsp also had elevated levels of hemoglobin in the urine. Increases in dietary K+ did not significantly decrease the severity of uremia and proteinuria in age-matched prestroke or poststroke SHRsp. It was concluded that a decrease in glomerular filtration, uremia, and proteinuria preceded stroke development in SHRsp. The onset of proteinuria and uremia in SHRsp could potentiate stroke development. The latter indices of renal function were not altered by modifications in dietary K+ that retard stroke development in SHRsp.

Perindopril treatment in the prevention of stroke in experimental animals.

OBJECTIVE: To determine the effect of perindopril treatment and treatment withdrawal in the prevention of stroke in male stroke-prone spontaneously hypertensive rats (SPSHR). DESIGN: After weaning at 4 weeks of age, male SPSHR were given a Japanese-style rat diet which induces stroke in these animals. Beginning at 6 weeks of age, SPSHR were treated with either distilled water (control) or different daily dosages of perindopril (1 or 4 mg/kg) by gavage for 24 weeks followed by treatment withdrawal. Additional subgroups were treated with the 4 mg/kg dose for different durations (B, 12 or 24 weeks) before treatment withdrawal. Treatment effects on blood pressure, heart rate and body weight were studied during the treatment period and after the withdrawal of the treatment. Myogenic and mechanical properties of the middle cerebral arteries were studied in control SPSHR that had developed stroke, in treated SPSHR at the end of the treatment period, and at certain intervals after the withdrawal of the treatment. METHODS: Systolic blood pressure, heart rate and body weight of control and treated SPSHR were determined at regular intervals before, during and after the treatment withdrawal periods until they died from stroke, or until 42 or 43 weeks of age when the study was terminated. Functional studies of the cerebral arteries were carried out using a pressurized artery system. At necropsy, macroscopic and microscopic examinations were made of the kidneys and brain. RESULTS: Untreated SPSHR usually died of stroke-related complications by 14 weeks of age. The middle cerebral arteries from these animals had lost their ability to contract in response to pressure increase. Chronic treatment of SPSHR with perindopril when initiated at 6 weeks of age attenuated the sharp blood pressure rise, and prevented the development of stroke during the treatment period. This was associated with the preservation of the myogenic response of the middle cerebral arteries to pressure increase, and the prevention of tissue damage in the kidneys and brain. After withdrawal of the treatment, SPSHR treated for a longer period (12 or 24 weeks) also survived longer than those treated for a shorter period (8 weeks). The subsequent loss of myogenic response in the middle cerebral arteries was associated with the development of stroke and death in these treatment withdrawal groups. CONCLUSION: Chronic treatment with perindopril is beneficial for the prevention of stroke in SPSHR, through the preservation of the myogenic response properties of the cerebral arteries, and the attenuation of tissue damage in the brain and kidneys.

Effects of perindopril on hypertension and stroke prevention in experimental animals.

BACKGROUND: Among the antihypertensive agents available for the treatment of hypertension, only angiotensin-converting enzyme (ACE) inhibitors have been shown to modify cardiovascular changes in structure and function. OBJECTIVE: To study the effect of perindopril treatment on hypertension and stroke prevention in two genetic models of hypertensive rats. DESIGN: Adult (15 weeks old) spontaneously hypertensive rats (SHR) were treated with perindopril to determine the dose- and duration-dependent effects of treatment on systolic blood pressure, and the effect of withdrawal of this treatment on blood pressure and survival. In stroke-prone SHR, treatment was initiated in young animals (six weeks), and dose- and duration-dependent effects of perindopril treatment on stroke prevention were assessed. RESULTS: In adult SHR, perindopril caused a dose-dependent lowering of blood pressure. Blood pressure was controlled for a 24 h period with a single daily dose. The magnitude of rebound hypertension after withdrawal of treatment was negatively correlated with duration of treatment. After 12 weeks of treatment, the blood pressure of treated SHR remained normotensive without further treatment, and the life span of treated SHR was also extended. Treatment of young, stroke-prone SHR with perindopril prevented stroke in these animals during the treatment period. After withdrawal of treatment, survival of the rats was increased in animals given a longer treatment period (24 weeks versus eight or 12 weeks). CONCLUSION: Treatment with the ACE inhibitor perindopril is effective in the prevention of hypertension and stroke in experimental animals.

Cerebral vascular changes associated with hemorrhagic stroke in hypertension.

There are a number of alterations that protect the cerebrovasculature from hemorrhagic stroke development during hypertension. The upper limit of cerebral blood flow autoregulation is shifted to higher blood pressure levels; this allows a constant blood flow to be maintained during hypertension. Studies we have performed have indicated that the middle cerebral arteries (MCA) of Wistar-Kyoto stroke-prone spontaneously hypertensive rats (spSHR) lose their ability to constrict in response to elevations in transmural pressure. The decline in such function precedes stroke development and totally disappears at an age where there is a 100% mortality from stroke. Prior to stroke development, spSHR also develop uremic conditions and signs of renal failure. The induction of uremia in stroke-resistant SHR (srSHR) via nephrectomy induces these animals to develop stroke. Like prestroke spSHR, prestroke uremic srSHR also have MCA with attenuated pressure-dependent myogenic function. It is hypothesized that the inability to increase vascular resistance in response to elevations in pressure might promote overperfusion of the more distal vasculature leading to cerebral hemorrhage formation. Since uremia promotes bleeding tendencies, such alterations along with the loss of cerebrovascular myogenic function could initiate or aggravate hemorrhage formation.

Effects of diuretics on stroke development in Kyoto-Wistar stroke-prone spontaneously hypertensive rats.

1. Previous studies have indicated that increases in dietary K+ promote diuresis and retard stroke development in stroke-prone spontaneously hypertensive rats (spSHR) fed a Japanese-style diet containing 4% NaCl. 2. It is possible that elevations in dietary K+ retard stroke development by inducing natriuresis and facilitating the clearance of Na+, and that diuretics associated with natriuresis might also be capable of retarding stroke development in spSHR. To test if this was the case, the onset of stroke development in spSHR fed a low (0.75%) K+ diet containing 4% NaCl (controls) was monitored and compared with that in spSHR treated with (a) frusemide, (b) chlorothiazide, (c) amiloride or (d) acetazolamide, and with (e) untreated spSHR fed a high (2.11%) K+ diet. 3. The onset of stroke, as well as death resulting from stroke, occurred at a significantly later age in spSHR fed a high K+ diet than in spSHR fed a low-K+ diet, despite the fact that both groups of spSHR rats had comparable blood pressures. 4. Treatment of spSHR with the above-named diuretics before stroke development did not alter the blood pressure of the rats. The onset of stroke development and death in spSHR treated with chlorothiazide, amiloride or acetazolamide was comparable with that observed in untreated control spSHR. In spSHR treated with frusemide, the onset of stroke was comparable with that of untreated control spSHR, whereas the onset of death after stroke development was accelerated. 5. Post mortems performed on spSHR that developed stroke indicated the presence of haemorrhagic stroke of comparable severity in the six groups of spSHR studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hydralazine on the mesenteric vasculature of hypertensive rats.

To test whether structural alterations observed in the mesenteric vasculature of Wistar-Kyoto spontaneously hypertensive rats (SHR) were dependent on the presence of hypertension, male SHR and Wistar-Kyoto normotensive (WKY) rats were treated in utero and postnatally with hydralazine up to 28 weeks of age. Treated SHR, WKY, and untreated WKY rats had comparable blood pressures that were less than those of untreated SHR. Treatment altered the dimensions of the superior mesenteric, intermediate-sized, and small arteries of the mesenteric vasculature. In the case of the superior mesenteric artery and intermediate vessels, hydralazine treatment increased the lumen and medial cross-sectional areas of the arteries in WKY rats and slightly decreased both parameters in SHR. Within the small arteries, treatment significantly increased the lumen size in SHR but not WKY rats and had no significant effect on the media of the vessels. Despite the above alterations, the media-to-lumen cross-sectional area ratios remained significantly elevated in SHR over WKY rats in both the treated and control groups of animals within all classes of arteries. The results indicate that there is an inherent increase in the quantity of media surrounding the arteries of SHR when compared with WKY rats that cannot be abolished by normalizing the blood pressure in utero and postnatally with hydralazine treatment. In SHR, such changes persist not only in arteries that exhibit an increase in the media-to-lumen ratio before hypertension but also in the superior mesenteric artery in which an increase in the ratio occurs after hypertension development.

Analysis of cerebrovascular sympathetic nerve density in relation to stroke development in spontaneously hypertensive rats.

Previous studies have shown that elevating the K+ levels from 0.75% to 2.11% in the diet of stroke-prone spontaneously hypertensive rats significantly retards the development of stroke and increases their lifespan. On the other hand, stroke-resistant spontaneously hypertensive rats fail to develop stroke even if they are fed the low-K+ version of this diet. Since sympathetic nerves surrounding the cerebral vasculature play an important role in protecting the brain from stroke during hypertension, I studied whether changes in sympathetic nerve density accounted for the differing incidences of stroke in stroke-prone spontaneously hypertensive rats fed high- and low-K+ diets and in stroke-resistant and stroke-prone spontaneously hypertensive rats fed a low-K+ diet. At 14 weeks of age, all 11 stroke-prone rats fed the low-K+ diet had evidence of cerebral hemorrhage while such lesions were virtually absent in the 11 littermates fed the high-K+ diet and totally absent in the eight stroke-resistant rats fed the low-K+ diet. Stroke-prone (regardless of diet) but not stroke-resistant rats exhibited greater sympathetic nerve densities in the left hemisphere than in the right. When stroke-prone rats were compared, in some areas of the cerebrovasculature, rats fed the high-K+ diet had greater mean sympathetic nerve densities than those fed the low-K+ diet. On the other hand, stroke-resistant and stroke-prone rats fed the low-K+ diet exhibited comparable sympathetic nerve densities in most cerebral arteries studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemorrhagic stroke development in spontaneously hypertensive rats fed a North American, Japanese-style diet.

The purpose of my study was to assess a North American, Japanese-style diet commercially available from Zeigler Brothers (Gardners, Pennsylvania) with respect to the initiation of stroke development in 34 stroke-prone spontaneously hypertensive rats (spSHR) and in 14 stroke-resistant spontaneously hypertensive rats (srSHR). Nineteen spSHR fed the diet containing 4% NaCl and 0.75% K+ (low-K+ diet) from weaning had an accelerated rate of stroke development (mean +/- SEM age at death 15.3 +/- 0.5 weeks). The same diet containing 2.11% K+ (high-K+ diet) increased the mean lifespan of 15 spSHR by 39% but did not prevent stroke. The locations of hemorrhagic lesions were similar in the groups of spSHR fed high- and low-K+ diets, being nearly equally divided between the territories of the anterior, posterior, and middle cerebral arteries. The 14 srSHR fed the low-K+ diet exhibited 50% mortality at 66 weeks of age. However, in the srSHR fed the low-K+ diet, death did not result from hemorrhagic stroke. The differing incidence of stroke between the spSHR fed high- and low-K+ diets and between spSHR and srSHR fed the low-K+ diet could not be explained on the basis of differing blood pressures. Compared with spSHR fed the low-K+ diet, both srSHR fed the low-K+ diet and spSHR fed the high-K+ diet exhibited higher drinking and urine excretion rates and elevated plasma K+ levels. My study indicates the availability of a commercial North American diet that produces a predictable high incidence of stroke within a compressed time period in spSHR but not in srSHR. This diet would be useful in studies attempting to determine the events preceding and leading to the development of stroke and in determining the genetic factors responsible for stroke resistance.

Structural and reactivity alterations of the renal vasculature of spontaneously hypertensive rats prior to and during established hypertension.

The renal vasculature of Wistar Kyoto spontaneously hypertensive rats (SHR), prior to (4-5 week) and during established hypertension (21 week) and those of age-matched Wistar Kyoto normotensive rats (WKY) were morphometrically and pharmacologically studied. Under dilated conditions, the vascular resistances (RVR) of the isolated kidneys of young and adult SHR were similar to WKY. Morphometric measurements of renal vasculature indicated that the cross-sectional area of the intima and adventitia and its subcomponents were similar in adult SHR and WKY. With the exception of the preglomerular arterioles, all the renal arteries of adult SHR exhibited elevated cross-sectional quantities of total media, medial smooth muscle cells (SMCs), and extracellular space. Analysis of the SMCs indicated the presence of increased numbers of SMC layers and/or an increase in the SMC volume-to-surface area ratio in arteries sampled from adult SHR. Vascular contraction produced by infusing norepinephrine, BaCl2, angiotensin II, or by stimulating the renal nerves elevated the RVR to a greater degree in adult SHR than in WKY. The sensitivity of the renal vasculature to the various contractile agents was similar in adult SHR and WKY. When compared with WKY, prehypertensive SHR also exhibited increased cross-sectional quantities of arterial media and elevated amplitudes of RVR change in response to norepinephrine and renal nerve stimulation. However, the vascular contractile sensitivity to norepinephrine was reduced. Our results indicate that renovascular wall thickening and the hypercontractile reactivity associated with such a change precedes hypertension in SHR. In prehypertensive SHR, elevations in RVR might be counterbalanced by a decreased norepinephrine sensitivity. An increase in the norepinephrine contractile sensitivity and further vascular thickening with age could elevate the RVR and establish hypertension.

Prenatal and postnatal hydralazine treatment does not prevent renal vessel wall thickening in SHR despite the absence of hypertension.

Previous studies in our laboratory have shown that the renal blood vessels of 21-week-old Wistar-Kyoto spontaneously hypertensive rats exhibited thicker vascular walls than age matched Wistar-Kyoto normotensive rats. Morphometric analysis of the relaxed renovasculature revealed an increase in the cross-sectional area of the media, which in most cases was associated with an increase in the number of smooth muscle cell layers. To test if these structural changes occur in the absence of raised blood pressure, hydralazine was administered to spontaneously hypertensive rats and normotensive controls prior to and during pregnancy (100 ml/l drinking water), and to the newborn males up to 21 weeks of age (16.9 mg/kg/day by gavage until weaning followed by 100 mg/l in the drinking water). Treated animals were compared with untreated rats. Treatment prevented hypertension development in spontaneously hypertensive rats but did not alter the structural changes found in untreated animals with hypertension. At 21 weeks of age, hydralazine-treated spontaneously hypertensive rats had similar wall-to-lumen area ratios, medial cross-sectional areas and numbers of medial smooth muscle layers as untreated hypertensive rats while these parameters were greater in treated and untreated spontaneously hypertensive rats than in either treated or untreated normotensive controls. Withdrawal of hydralazine from 26-week-old spontaneously hypertensive rats that had been treated in utero and postnatally and had normal blood pressures throughout life resulted in the rapid onset of hypertension. Our results show that renal vascular wall thickening in spontaneously hypertensive rats occurs in the absence of high blood pressure and therefore is not a secondary effect of raised blood pressure.

Elevations in arterial pressure induce the formation of spontaneous action potentials and alter neurotransmission in canine ileum arteries.

Arterial segments (less than 250 micron o.d.) excised from canine ileum were mounted in a chamber that permitted arterial transmural pressure (TMP) to be altered and measured. Subsequently, the periarterial nerves were field stimulated with single pulses (0.1 msec, 70 V), and the resting membrane potential (Em) as well as the nerve-mediated alterations in smooth muscle Em were measured using intracellular microelectrodes at TMPs between 0 and 160 mm Hg. The resting Em was greatest at TMPs of 40 mm Hg (-54.7 +/- 2.6 mV) and depolarized as the TMP was increased, reaching a value of -44.8 +/- 3.1 mV at 160 mm Hg. At TMP greater than or equal to 60 mm Hg, a proportion of the preparations exhibited spontaneous electrical activity (SA) consisting of constant rhythmic oscillations in Em or action potentials (APs) or of trains of rhythmic APs that progressively decreased in amplitude, interrupted by periods of hyperpolarization. SA stopped when the TMP was lowered to 40 mm Hg and was reestablished when the TMP was reelevated to TMPs above 60 mm Hg. Nerve stimulation evoked excitatory junction potentials (ejps) or APs. At constant stimulus parameters, ejps of maximum amplitude having the greatest rate of potential rise and fall were produced at TMP of 100 mm Hg. At TMPs greater than 100 mm Hg or less than 100 mm Hg, the amplitude and the rate of rise and fall of the ejps decreased. Ejps formed in response to a constant single pulse stimulus (0.1 msec, 70 V) elicited APs only at TMPs greater than or equal to 60 mm Hg. Neither ejps nor APs were inhibited by alpha-receptor-blocking agents. These studies indicate that the TMP at which an artery is maintained plays an important role in determining the resting Em, the occurrence of spontaneous action potentials, and the alterations in Em associated with nerve stimulation.

The effect of alkaline pH and transmural pressure on arterial constriction and membrane potential of hypertensive cerebral arteries.

These studies were undertaken to examine the effect of alkalosis to modify "pressure-induced" activation of isolated cerebral arteries from spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WKY) controls. At pH 7.4 and PCO2 of 34 torr elevation of transmural pressure from 0-140 mm Hg resulted in myogenic activation preceded by membrane depolarization in both SHR and WKY. The degree of developed myogenic tone in SHR was elevated above WKY. Alkalosis (pH 7.4-7.7) depolarized and activated SHR cerebral arteries to a greater extent than WKY. Furthermore, both the electrical and mechanical responses to elevation in transmural pressure were exaggerated in SHR compared to WKY at pH 7.7 (PCO2 constant at 34 torr). Manipulation of PCO2 at constant pH of 7.4 had similar effects on "pressure-induced" myogenic tone in both SHR and WKY. Thus, cerebral arteries from both SHR and WKY depolarize and develop myogenic tone in response to increasing transmural pressure. This response is augmented in SHR, but to a much greater extent upon elevation of extracellular pH, while PCO2 is maintained within normal limits. The implications of these findings are discussed.