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Background: Cardiovascular disease (CVD) is highly prevalent in patients with chronic kidney disease (CKD). Inhibition of the renin-angiotensinsystem (RAS) in hypertension causes differential effects on central and brachial blood pressure (BP), which has been translated into improved outcome. The objective was to examine if a more complete inhibition of RAS by combining an angiotensin converting enzyme inhibitor (ACEI) and an angiotensin receptor antagonist (ARB) compared to monotherapy has an additive effect on central BP and pulse-wave velocity (PWV), which are known markers of CVD., Methods: Sixty-seven CKD patients (mean GFR 30, range 13-59 ml/min/1.73 m(2)) participated in an open randomized study of 16 weeks of monotherapy with either enalapril or candesartan followed by 8 weeks of dual blockade aiming at a total dose of 16 mg candesartan and 20 mg enalapril o.d. Pulse-wave measurements were performed at week 0, 8, 16 and 24 by the SphygmoCor device., Results: Significant additive BP independent reductions were found after dual blockade in aortic PWV (-0.3 m/s, P<0.05) and in augmentation index (-2%, P<0.01) compared to monotherapy. Furthermore pulse pressure amplification was improved (P<0.05) and central systolic BP reduced (-6 mmHg, P<0.01)., Conclusions: Dual blockade of the RAS resulted in an additive BP independent reduction in pulse-wave reflection and arterial stiffness compared to monotherapy in CKD patients., Trial Registration: Clinical trial.gov NCT00235287.

Renal mechanisms, in particular the renin-angiotensin system and renal salt handling, are of major importance in blood pressure regulation. Co-existence of hypertension and decreased renal function may be due to nephrosclerosis secondary to hypertension, or primary renal disease with secondary hypertension. Mild degrees of chronic kidney disease (CKD) can be detected in around 10% of the population, and detection is important as CKD is an important risk factor for atherosclerotic cardiovascular disease. Conversely, heart failure may cause an impairment of renal function. In chronic progressive nephropathy, effective blood pressure lowering is of paramount importance, and angiotensin converting enzyme inhibitors and angiotensin receptor blockers are agents of choice.

Hypertension is a major and modifiable risk factor of stroke and dementia. Hypertension causes remodelling of the cerebral resistance vessels, impairing their tolerance to very low blood pressure. In primary prevention of stroke, the effect of beta-blockers is inferior to other classes of antihypertensives. In secondary prevention of stroke, ACE-inhibitors and angiotensin blockers may be recommended as first choice drugs. Lowering of the blood pressure is, however, more important than the choice of drug.

We reported impaired endothelium-derived relaxation factor/nitric oxide (EDRF/NO) responses and constitutive nitric oxide synthase (cNOS) activity in subcutaneous vessels dissected from patients with essential hypertension (n = 9) compared with normal controls (n = 10). We now test the hypothesis that the patients in this study have increased circulating levels of the cNOS inhibitor, asymmetric dimethylarginine (ADMA), or the lipid peroxidation product of linoleic acid, 13-hydroxyoctadecadienoic acid (HODE), which is a marker of reactive oxygen species. Patients had significantly (P < 0.001) elevated (means +/- SD) plasma levels of ADMA (P(ADMA), 766 +/- 217 vs. 393 +/- 57 nmol/l) and symmetric dimethylarginine (P(SDMA): 644 +/- 140 vs. 399 +/- 70 nmol/l) but similar levels of L-arginine accompanied by significantly (P < 0.015) increased rates of renal ADMA excretion (21 +/- 9 vs. 14 +/- 5 nmol/mumol creatinine) and decreased rates of renal ADMA clearance (18 +/- 3 vs. 28 +/- 5 ml/min). They had significantly increased plasma levels of HODE (P(HODE): 309 +/- 30 vs. 226 +/- 24 nmol/l) and renal HODE excretion (433 +/- 93 vs. 299 +/- 67 nmol/micromol creatinine). For the combined group of normal and hypertensive subjects, the individual values for plasma levels of ADMA and HODE were both significantly (P < 0.001) and inversely correlated with microvascular EDRF/NO and positively correlated with mean blood pressure. In conclusion, elevated levels of ADMA and oxidative stress in a group of hypertensive patients could contribute to the associated microvascular endothelial dysfunction and elevated blood pressure.

Objective. To determine the factors influencing treatment decisions in patients with hypertension. Methods. A postal questionnaire based on five constructed cases with hypertension was sent to 122 general practitioners (GPs) in the area around Herlev University Hospital and to 46 Danish hypertension specialists. The cases varied in gender, age, blood pressure, cholesterol, diabetes and smoking status and absolute risk for cardiovascular events. Results. Response rate was 46% for GPs and 59% for specialists. There were no significant differences in treatment decisions nor in drug choices for first-line monotherapy, which were diuretics, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists in both groups of physicians. Blood pressure alone was the most important factor for instituting drug therapy according to 59% of the GPs and 56% of the specialists. There was no association between pre-treatment risk assessment and instituting treatment in either group in four out of five cases. Conclusions. We found agreement with respect to all treatment decisions between GPs and hypertension specialists. The results from this study suggest that, in both GPs and specialists, a blood pressure threshold approach to treating hypertension is still dominating.

Objective: In chronic renal failure, clearance of enalapril is reduced. Hence, a renoprotective effect may be achieved with lower doses than conventionally used. Since marked inter-patient variation in concentrations of enalaprilat has been shown in patients with renal failure despite equivalent dosage of enalapril, a direct comparison of the effect of high versus low plasma concentrations of enalaprilat on the progression of renal failure was undertaken., Methods: Forty patients with a median glomerular filtration rate (GFR) of 17 (6-35) ml/min/1.73 m2 were studied in an open-label, randomised trial comparing patients with a high (>50 ng/ml) with patients with a low (<10 ng/ml) target trough plasma concentration of enalaprilat. The dose of enalapril was titrated accordingly. The patients were followed for 12 months or until they needed renal replacement therapy. GFR was measured at 3-month intervals by the plasma clearance of 51Cr-EDTA, and the individual rates of progression of renal failure were calculated as the slope of GFR versus time plot., Results: In the high-concentration group, the median enalaprilat trough concentration was 92.9 ng/ml (21.8-371.0 ng/ml) and in the low-concentration group it was 9.1 ng/ml (2.5-74.8 ng/ml) at 3 months follow-up (P<0.001). The median daily doses of enalapril were 10 mg (2.5-30 mg) and 1.88 mg (1.25-5 mg) in the high and low groups, respectively (P<0.001). In the high-concentration group, the mean+/-SE decline in renal function was 6.1+/-1.5 ml/min/1.73 m2 per year and in the low-concentration group it was 4.3+/-14.4 ml/min/1.73 m2 per year (P=0.48). Five patients in the high-concentration group reached end-stage renal failure whereas none in the low-concentration group did (P=0.04). There were no statistically significant differences in blood pressure level, concomitant antihypertensive therapy or urinary albumin excretion. However, the high-enalaprilat concentration group had an overall higher plasma potassium concentration of 0.42 mmol/l than the low group (P<0.001)., Conclusion: In patients with moderate to severe renal insufficiency, a low concentration of enalaprilat afforded the same degree of renoprotection, blood pressure control and minimisation of proteinuria as a high concentration, during 12 months of follow-up. The high-dosage treatment was associated with a more pronounced tendency to hyperkalaemia. Thus, there seems to be no indication for increasing the daily dose of enalapril beyond what achieves adequate blood pressure control in this group of patients.

Introduction: The urinary excretion of albumin is positively correlated to the presence of ischaemic heart disease and atherosclerotic risk factors in subjects with arterial hypertension. The aim of this population-based, follow-up study of hypertensive patients was to assess the predictive impact of a slightly elevated urinary excretion of albumin, i.e. microalbuminuria, on ischaemic heart disease., Material and Methods: In 1983-1984, blood pressure, the albumin/creatinine concentration ratio in a morning urine sample, total and HDL cholesterol in plasma, body mass index, and smoking habits were measured in a population of 2085 men and women aged 30-60 years. Exclusion criteria were ischaemic heart disease, diabetes mellitus, and renal or urinary tract disease. Untreated hypertension or borderline hypertension (a systolic blood pressure above 140 mmHg and/or a diastolic blood pressure above 90 mmHg) were found in 204 of the participants, who were followed up until 1993 with respect to the development of ischaemic heart disease through the Danish Hospital Register and Death Certificate Register., Results: Over 1978 person-years, 18 participants (9%) developed ischaemic heart disease. Microalbuminuria, defined as a urinary albumin/creatinine ratio above the upper decile in the hypertensive population under study (1.07 mg/mmol), was the strongest predictor of ischaemic heart disease with a relative risk (95% confidence interval) of 4.2 (1.5-11.9) (p = 0.006). When adjusted for all other variables, including age and sex, the relative risk was 3.5 (1.0-12.1) (p = 0.05)., Discussion: Microalbuminuria is associated with a fourfold increased risk of ischaemic heart disease in subjects with untreated hypertension or borderline hypertension. Urinary excretion of albumin should perhaps be monitored regularly in the hypertension clinic, and rigorous control of blood pressure and other modifiable atherosclerotic risk factors is to be recommended in hypertensive patients with microalbuminuria.

Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral circulation is uncertain. Hence, the present study investigated the effect on CBF autoregulation of blocking of angiotensin AT2-receptors with PD 123319 in spontaneously hypertensive rats (SHR). Anaesthetised and ventilated SHR were given PD 123319, 0.36 mg/kg/min, intravenously, and compared with a control group. CBF was measured by the intracarotid 133xenon injection method and BP was raised by noradrenaline infusion and lowered by controlled haemorrhage in separate groups of rats. The limits of autoregulation were determined by computed least-sum-of-squares analysis. PD 123319 did not influence baseline CBF, but resulted in a minor BP decrease (10 control and 10 treated rats). The lower limit of CBF autoregulation (eight treated and eight control) as well as the upper limit of CBF autoregulation (eight treated and eight control) were not significantly different in PD 123319 and control animals (lower limit treated 102+/-4 mmHg and control 94+/-4; NS, and upper limit treated 171 +/- 10 mmHg and control 162+/-7; NS). These findings indicate that acute AT2-receptor blockade does not influence CBF autoregularion.

Albumin excretion in urine is positively correlated with the presence of ischemic heart disease and atherosclerotic risk factors. We studied prospectively whether a slight increase of urinary albumin excretion, ie, microalbuminuria, adds to the increased risk of ischemic heart disease among hypertensive subjects. In 1983 and 1984, blood pressure, urinary albumin/creatinine concentration ratio, plasma total and HDL cholesterol levels, body mass index, and smoking status were obtained in a population-based sample of 2085 subjects, aged 30 to 60 years, who were free from ischemic heart disease, diabetes mellitus, and renal or urinary tract disease. Untreated arterial hypertension or borderline hypertension was present in 204 subjects, who were followed until 1993 by the National Hospital and Death Certificate Registers with respect to development of ischemic heart disease. During 1978 person-years, 18 (9%) of the hypertensive subjects developed ischemic heart disease. Microalbuminuria, defined as a urinary albumin/creatinine ratio above the upper decile (1.07 mg/mmol), was the strongest predictor of ischemic heart disease, with an unadjusted relative risk of 4.2 (95% CI 1.5 to 11.9, P=0.006) and a relative risk of 3.5 (95% CI 1.0 to 12.1, P=0.05) when adjusted for all other atherosclerotic risk factors, including age and gender. In conclusion, microalbuminuria confers a 4-fold increased risk of ischemic heart disease among hypertensive or borderline hypertensive subjects. Urinary albumin excretion should be measured regularly in a hypertension clinic, and a rigorous control of blood pressure and of other atherosclerotic risk factors is recommended in hypertensive patients with microalbuminuria.

Background: Hypertension is a common and serious complication of autosomal dominant polycystic kidney disease (ADPKD), often occurring early in the disease before the renal function starts to decrease. The pathogenesis of this early hypertension is controversial., Objective: To review studies on the pathogenesis of early and late hypertension in ADPKD., Study Selection: Studies on ADPKD and hypertension were retrieved from Medline from the last 20 years, with an emphasis on the last 10 years. These studies, together with selected published abstracts from recent hypertension and nephrology meetings, were reviewed critically., Results: Cyst growth, renal handling of sodium, activation of the renin-angiotensin-aldosterone system, volume expansion, an elevated plasma volume, and increased plasma atrial natriuretic peptide and plasma endothelin levels have all been found to be associated with hypertension in ADPKD. In some studies an inappropriate activity of the renin-angiotensin-aldosterone system that could be related to cyst growth and intrarenal ischemia was found. An increase in renal vascular resistance has been demonstrated and might be caused by intrarenal release of angiotensin II. Interestingly, the protective effect of angiotensin converting enzyme inhibitors on the renal function could not be demonstrated in ADPKD patients with a moderately decreased renal function. The importance, if any, of endothelial vasodilatory factors is not known. Sympathetic nervous activity seems to be increased in ADPKD, but the importance of this for the blood pressure level is not known., Conclusion: The pathogenesis of hypertension in ADPKD is complex and likely to be dependent on the interaction of hemodynamic, endocrine and neurogenic factors.

One hundred and eighteen consecutive cases of spontaneous subarachnoid haemorrhage seen at one hospital during a three-year period were examined to assess the prevalence of hypertension and the correlation between the presence of hypertension and the risk of early death. Eighty-seven of the patients had intracranial aneurysms. The diagnosis of hypertension was determined by means of three complementary criteria: a history of treatment with antihypertensive drugs; systolic and/or diastolic blood pressure levels > or = 160 and 95 mmHg, respectively, measured by the general practitioners of the patients before the onset of the subarachnoid haemorrhage; and the presence of left ventricular hypertrophy determined by echocardiography and/or necropsy. The major findings were as follows: 1) hypertension was present in at least 41% of the patients; 2) in 37% of 51 patients with no history of hypertension before the haemorrhage, left ventricular hypertrophy was diagnosed; and 3) the frequency of hypertension was significantly higher in patients who died within 14 days after the bleeding episode compared with patients surviving this period.

Objective: To investigate the effect of cyclosporine A (CsA; Sandimmun Neoral) on systemic and renal hemodynamics, tubular function, and sodium excretion in healthy volunteers. Furthermore, we studied whether CsA enhances the systemic and renal hemodynamic sensitivity to norepinephrine., Methods: Eighteen healthy volunteers were administered 10 mg/kg CsA or placebo capsules in a double-blind fashion. The mean arterial blood pressure (MAP), renal vascular resistance (RVR), glomerular filtration rate (GFR), and renal clearances of lithium (CLi) and sodium (CNa) were measured for 8 h after ingestion of the capsules. Norepinephrine (2 microg/kg per h) was infused intravenously for 1.5 h into nine subjects., Results: CsA increased the MAP by 17+/-2 mmHg. The GFR decreased by 18+/-2% (P < 0.001) and the RVR increased by 37+/-4% (P< 0.001) after ingestion of CsA. The CsA-induced increase in MAP preceded the CsA-induced fall in GFR. The rise in MAP was followed by an early 35+/-8/0 increase in CNa (P < 0.001). At the end of the 8 h study period, CNa decreased by 25+/-7% (P < 0.001). Using CLi, it was found that the initial natriuresis had been caused by a relative decrease both in proximal and in distal tubular reabsorption of sodium, whereas the late sodium retention was secondary to the CsA-induced fall in GFR. Infusion of norepinephrine increased the MAP, RVR, and filtration fraction, and decreased the renal plasma flow, without CsA having any additional effect., Conclusion: It was demonstrated that a single oral dose of CsA caused a rise in blood pressure and transient natriuresis, followed by a fall in GFR and antinatriuresis. Thus, the present study confirms and extends earlier observations that renal dysfunction and sodium retention are not the initiating events in CsA-induced hypertension. The study also affords evidence suggesting that such rises in blood pressure are not mediated by an increased sensitivity to norepinephrine.

HYPERTENSION AND STROKE: Hypertension is a major risk factor for stroke, and stroke prevention is the most important achievement of modern antihypertensive treatment. In controlled trials, a few years of this treatment can eliminate the entire excess stroke risk associated with hypertension. In observational studies, stroke risk appears to be not always fully reversible when the blood pressure is lowered with drugs. Hypertension is associated with an increased incidence of both haemorrhagic, ischaemic and lacunar stroke. It is likely that antihypertensive treatment prevents all these types of strokes as well as transient ischaemic attacks., Acute Stroke: In acute stroke, a transient rise in blood pressure is common, in some cases superimposed on chronic hypertension. No major controlled trials have reported findings on whether blood pressure should be lowered acutely in such patients. On the basis of observational studies and haemodynamic considerations, it seems prudent to leave all but the highest blood pressures in acute stroke to settle spontaneously. ISCHAEMIC STROKE: Ischaemic stroke may occasionally be precipitated by overzealous blood pressure reduction. This has been reported in particular in the initial treatment of very severe hypertension, and occasionally in the elderly hypertensive. It may also occur in the rare cases where transient cerebral ischaemia is haemodynamically induced.

Cerebral blood flow (CBF) is the same in hypertensive and normotensive man without neurological deficit. Chronic hypertension shifts the lower and upper blood pressure limits of CBF autoregulation towards higher pressure. Acute blood pressure reduction will lower CBF only if the pressure is taken below the lower limit of autoregulation. Added to this, some drugs are cerebral vasodilatators and have the potential for paralysing autoregulation and raising intracranial pressure, an effect also seen with at least some calcium antagonists. Converting enzyme inhibitors improve autoregulation during hypotension, probably by releasing angiotensin II dependent tone in the larger cerebral resistance vessels. With chronic antihypertensive treatment, CBF autoregulation may re-adapt towards normal. Converting enzyme inhibitors when given chronically probably retain their beneficial effect on the lower limit of autoregulation. Apart from this, it is uncertain whether there are chronic pharmacological effects of antihypertensive drugs directly on the cerebral circulation.

One hundred eighteen consecutive cases of spontaneous subarachnoid hemorrhage seen at one hospital during a 3-year period were examined to assess the prevalence of hypertension and the correlation between the presence of hypertension and the risk of early death. Eighty-seven of the patients had intracerebral aneurysms. The diagnosis of hypertension was determined by means of three complementary criteria: a history of treatment with antihypertensive drugs; systolic and/or diastolic blood pressure levels > or = 160 and 95 mm Hg, respectively, measured by the general practitioners of the patients before the onset of the subarachnoid hemorrhage; and the presence of left ventricular hypertrophy determined by echocardiography and/or necropsy. The major findings were as follows: 1) hypertension was present in at least 41% of the patients; 2) in 37% of 51 patients with no history of hypertension before the hemorrhage, left ventricular hypertrophy was diagnosed; and 3) the frequency of hypertension and left ventricular hypertrophy was significantly higher in patients who died within 14 days after the bleeding episode compared with patients surviving this period.

Objective: To investigate whether the angiotensin II (Ang II) subtype 1 receptor (AT1) antagonist CV-11974 had a similar effect to angiotensin converting enzyme inhibitors on cerebral blood flow autoregulation in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR)., Methods: Sixteen WKY rats and 16 SHR were given CV-11974 0.1 mg/kg intravenously and compared with two control groups (n = 16). Their cerebral blood flow was measured with the intracarotid xenon-133 injection method and blood pressure was raised by noradrenaline infusion and lowered by controlled haemorrhage in separate groups of rats. The limits of autoregulation were determined by computed least-sum-of-squares analysis., Results: The dose of CV-11974 given lowered blood pressure but did not influence baseline cerebral blood flow. In WKY rats the lower limit of autoregulation in control rats was 60 +/- 3 mmHg, whereas after CV-11974 administration it was 48 +/- 2 mmHg (P < 0.01). In SHR the corresponding values were 85 +/- 2 and 78 +/- 2 mmHg, respectively (P < 0.05). In WKY rats the upper limit of autoregulation in control rats was 144 +/- 5 mmHg, whereas after CV-11974 administration it was 126 +/- 7 mmHg (P < 0.05). In SHR the corresponding figures were 174 +/- 8 and 144 +/- 6 mmHg, respectively (P < 0.01)., Conclusion: Thus, the AT1 receptor antagonist, although it did not influence baseline cerebral blood flow, shifted the autoregulation curve towards lower blood pressure. This effect is similar to that of angiotensin converting enzyme inhibitors, and might be due to release of Ang II-dependent tone in the larger cerebral resistance vessels.

Hypertension causes marked adaptive changes in the cerebral circulation. The excess risk of stroke associated with hypertension is eliminated in controlled trials of antihypertensive treatment. Such treatment may even prevent transient ischaemic attacks in the elderly. In rare cases, overzealous antihypertensive treatment may cause cerebral ischaemia, especially in the initial treatment of very severe hypertension. Headache may occasionally be caused by severe hypertension, which may also lead to the rare syndrome of acute hypertensive encephalopathy. Finally, the importance of white-matter lesions, or leukoaraiosis, in hypertension is not yet fully established.

A review is given of the normal regulation of cerebral blood flow (CBF) and its pathophysiology in hypertension and stroke. In otherwise healthy hypertensive patients, the absolute level of CBF is the same as in normal subjects. CBF autoregulation, however, is shifted towards higher pressure, thus impairing the tolerance to hypotension. In most patients, this does not interfere with the beneficial effect of treatment, i.e., stroke prevention. Cerebral ischemia, however, may be provoked by overzealous pressure lowering in selected clinical settings: initial or intensified treatment of very severe hypertension, treatment of hypertension in the elderly, and treatment of hypertension in acute stroke. In the latter, a complicated sequence of brain ischemia and hyperemia makes antihypertensive intervention difficult in the early phase, when blood pressure is probably best allowed to decrease spontaneously.

The subject of the cerebral circulation in the elderly is reviewed. In old age, cerebral blood flow (CBF), which is closely coupled to cerebral oxidative metabolism, decreases along with the amount of brain tissue. In healthy old people, the cerebral circulation is regulated as earlier in life, by autoregulation, metabolic regulation, and chemical and other factors. CBF and its regulation is influenced by disease processes prevailing in old age, such as dementia, atherosclerosis, diabetes mellitus, stroke, and hypertension. Hypertension, apart from being a risk factor for stroke, causes adaptive cerebral vascular changes, leading to a shift of the lower limit of autoregulation towards high pressure, with an impaired tolerance to pressure decrease. In old age, this adaptation may not be reversible. With this background, a conservative approach to elderly hypertensive patients is suggested, aimed at some reduction of pressure but carefully avoiding overtreatment.

The effect of the angiotensin converting enzyme (ACE) inhibitor fosinopril sodium on regional cerebral blood flow (rCBF) was investigated in 8 patients with moderate essential hypertension. A constant dose of chlorthalidone (25 mg/day) was given to stimulate the renin angiotensin system, and fosinopril sodium was given in incremental doses (10 to 40 mg/day) with the aim of obtaining a diastolic blood pressure at or below 90 mm Hg. Regional CBF was measured with xenon-133 inhalation tomography. Repetitive measurements were made at the start of treatment and again after 4 to 12 weeks treatment in the resting supine position, and during lower body negative pressure (LBNP) as a substitute for the upright position. Four hours after the first 10 mg dose of fosinopril the mean arterial pressure (MAP) had been reduced from 127 +/- 13 mm Hg to 105 +/- 9 mm Hg (P less than .01) without any significant change in mean CBF (55 +/- 9 mL/(100 g X min) at baseline versus 52 +/- 9 mL/(100 g X min) after fosinopril). After prolonged treatment with chlorthalidone and fosinopril, mean CBF was still unchanged from baseline levels, when measured 4 and 24 h after a single dose of fosinopril, despite a 10% reduction in MAP (P less than .01). LBNP did not lead to any significant change in rCBF. The regional distribution of CBF was normal in all patients throughout the study. We conclude that treatment with fosinopril sodium causes a moderate fall in blood pressure without any adverse effects on rCBF.

The upper limit autoregulation of cerebral blood flow was investigated in eight young baboons with the intracarotid 133xenon clearance method. Blood pressure was increased by intravenous angiotensin infusion. Autoregulation was effective during blood pressure increase from normotensive levels to a mean pressure of 130 to 139 mm Hg. At this pressure, cerebrovascular resistance reached a maximum. With further blood pressure increase, autoregulation was broken, and the vascular resistance dropped significantly. This flow increase was restricted to the fast component of the 133xenon clearance curve, leaving slow component unchanged.

Autoregulation of the cerebral circulation is the regulating mechanism that keeps cerebral blood flow (CBF) constant within wide limits of arterial pressure. The lower limit is defined as the value of mean arterial pressure below which CBF decreases below the plateau, and the upper limit as the value of mean arterial pressure above which CBF increases above the plateau (60 and 150 mm Hg, respectively). Two possible mechanisms for autoregulation are discussed, myogenic response and metabolic regulation. Stimulation of the sympathetic nervous system and antagonism of the renin-angiotensin system modulate CBF autoregulation by shifting the entire curve toward higher or lower values of arterial pressure, respectively. The autoregulatory curve is shifted toward higher arterial pressures in chronic hypertension. Therefore, the tolerance to acute decreases in arterial pressure is impaired. Concomitantly, the tolerance of the brain to acute increases in arterial pressure is improved. This shift in the limits of autoregulation is due to structural and functional (hemodynamic) changes in the cerebral resistance vessels. These adaptive changes are partly reversible after chronic treatment with antihypertensive agents. The pathophysiology of autoregulation should be taken into consideration before drugs are used to decrease arterial pressure acutely.

The effect on cerebral blood flow of acute diazoxide-induced hypotension was studied in rats with renal and spontaneous hypertension. Diazoxide (5 mg/kg, i.v. bolus), caused arterial pressure to fall rapidly to that of normotensive rats, i.e. c. 75 mmHg. There was a concomitant fall in cerebral blood flow of about 35% (P less than 0.01) in renal hypertensive rats and 25% (P less than 0.05) in spontaneously hypertensive rats; the greater fall in flow in the former corresponded to a greater drop in pressure. Flow remained at these reduced levels during a 2 h observation period. Histological examination revealed small areas of ischaemic damage in the brains of five of the twelve animals. In control hypertensive rats not given diazoxide, cerebral blood flow and blood pressure were stable during a 2 1/2 h period and there was no evidence of ischaemic damage to the brains. The diazoxide-induced reduction in cerebral blood flow was interpreted as being secondary to a blood pressure fall to below the lower limit of cerebral blood flow autoregulation. No evidence was found of direct effects on the cerebral circulation such as seen with ganglionic blockers, alpha-blockers and cerebral vasodilators.

The effect of chronic hypertension on cerebral blood flow (CBF) was studied in anaesthetised rats. CBF was measured with the intracarotid 133Xe injection method. Rats with spontaneous and renal hypertension were compared with normotensive controls. The lower limit of autoregulation was determined during controlled haemorrhage. In the normotensive rats, CBF remained constant until mean arterial pressure (MAP) had decreased to the range of 50-69 mm Hg. Thereafter, CBF decreased with each further decrease in MAP. In both types of hypertensive rats, CBF remained constant until MAP had decreased to the range of 70-89 mm Hg. Thus, a 20-mm Hg shift of the lower limit of CBF autoregulation was found in both spontaneous and renal hypertensive rats. A neuropathological study revealed ischaemic brains lesions in half of the hypertensive rats following hypotension, whereas only a single lesion was found in one of six normotensive rats. No ischaemic brain lesions were found in a control study in which CBF was shown to be stable over a 21/2-h period. In conclusion, hypertensive rats showed a shift of the lower limit of CBF autoregulation as well as an increased susceptibility to ischaemic brain damage during hypotension. These findings presumably reflect hypertensive structural changes in the cerebral circulation.

Cerebrovascular reactivity to CO2 inhalation and voluntary hyperventilation was studied in seven normotensive subjects and nine hypertensive patients without clinical or angiographical signs of arteriosclerosis. Cerebral blood flow (CBF) was measured by the intracarotid 133Xe clearance method and calculated as the initial slope index. Three to five CBF measurements were made in each patient in the PaCO2 range of 20 to 55 mm Hg. No difference was observed in reactivity between hypertensive and normotensive patients, either during CO2 inhalation or during hyperventilation. The shape of the CBF:PaCO2 curve suggested a decrease in reactivity below a PaCO2 of 30 to 35 mm Hg in both groups. Above a PaCO2 of 35 mm Hg, exponential regression analysis yielded a mean reactivity of 6 +/- 2%, whereas below a PaCO2 of 30 mm Hg it was about 2%. The rise in CBF during CO2 inhalation was not influenced by the intravenous infusion of a small dose of trimethaphan which blocked the concomitant rise in blood pressure.

The cerebrovascular effects of the converting enzyme inhibitor captopril were examined after intravenous or intracerebroventricular administration in normotensive and hypertensive rats. Cerebral blood flow (CBF) was measured using the intracarotid 133xenom method in halothane/nitrous oxide anaesthetised animals. Captopril given either way did not influence the absolute value of CBF. The main finding, however, was that following intravenous administration of captopril at a dose of 10 mg/kg, both the lower pressure limit of CBF autoregulation were shifted to lower pressure and the autoregulatory plateau shortened. The lower limit was shifted 20-30 mm Hg, the upper limit 50-60 mm Hg, and the autoregulatory plateau consequently shortened by 20-30 mm Hg. In contrast to the marked effects of intravenous captopril, intracerebroventricular captopril was without effect on CBF autoregulation. The effect of intravenous captopril was thus probably mediated by converting enzyme in the cerebrovascular endothelium.

Acute hypertension was induced in 19 anesthetized cats by the intravenous administration of angiotensin. The caliber of pial arteries was measured by a television image-splitting technique and local cerebral blood flow by the hydrogen clearance technique. As the blood pressure was increased, pail arterioles constricted and cerebral blood flow remained relatively constant, showing that autoregulation of cerebral blood flow was intact. At mean arterial pressures of more than 170 mm Hg arteriolar dilation appeared. In smaller arterioles (initial diameter less than 100 mum) a segmental dilation (the "sausage'string" phenomenon) frequently preceded uniform dilation. This arteriolar dilation was associated with a marked increase in local cerebral blood flow indicating that the upper level of autoregulation had been breached. In no cat was vasospasm or a decrease in blood flow observed during induced hypertension. Hypertension also caused dysfunction of the bloodbrain barrier since, in 17 out of 19 of the cats examined, there was extravasation of protein-bound Evans blue into brain tissue. In only one of the 19 cats subjected to neuropathological analysis was ischemic brain damage identified and this was restricted to minimal ischemic cell change. The results indicate that severe, induced hypertension in cats produces cerebral arteriolar dilation, an increase of cerebral blood flow, and dysfunction of the blood-brain barrier. These observations may be of importance in understanding the pathogenesis of hypertensive encephalopathy.

The cerebrovascular effects of graded, controlled dihydralazine-induced hypotension were studied in rats with renal hypertension (RHR) and spontaneous hypertension (SHR). Repeated measurements of cerebral blood flow (CBF) were made using the intraarterial 133Xenon injection technique in anaesthetised normocapnic animals. Dihydralazine was administered in single increasing i.v. doses (0.1 to 2 mg/kg), and CBF measured after each dose when a stable blood pressure had been reached. From a resting level of 145 +/- 7 mm Hg in RHR and 138 +/- 11 mm Hg in SHR, mean arterial pressure (MAP) fell stepwise to a minimum of around 50 mm Hg. CBF was preserved during dihydralazine induced hypotension, and remained at the resting level of 79 +/- 13 ml/100 g . min in RHR and 88 +/- 16 ml/100 g . min in SHR. Following 2 hours hypotension at the lowest pressure reached, the rats were sacrificed by perfusion fixation and the brains processed for light microscopy. Evidence of regional ischaemic brain damage was found in 4 of 11 animals: in 2 cases the damage appeared to be accentuated in the arterial boundary zones. Although the lower limit of CBF autoregulation in these rats is around 100 mm Hg during haemorrhagic hypotension, dihydralazine brought MAP to around 50 mm Hg without any concomitant fall in CBF. This was interpreted as being due to direct dilatation of cerebral resistance vessels. The combination of low pressure and direct dilatation may have resulted in uneven perfusion, thus accounting for the regional ischaemic lesions.

Cerebrovascular effects of the angiotensin converting enzyme inhibitor captopril were examined in normotensive and hypertensive rats. Cerebral blood flow was measured with the intracarotid 133xenon injection method in halothane-anesthetized animals. The blood-brain barrier permeability of captopril (determined with an integral-uptake method) was negligible, the permeability-surface area product in most brain regions being 1 X 10(-5) cm3/g per second, that is, three to four times lower than that of sodium ion. When administered into the cerebral ventricles to bypass the blood-brain barrier, captopril had no effect on cerebral blood flow: furthermore, cerebral blood flow autoregulation (studied by raising and lowering blood pressure) was identical to that in controls. In contrast, when given intravenously, captopril had a marked effect on cerebral blood flow autoregulation--both the lower and upper limits of autoregulation being shifted to a lower pressure (by about 20 to 30 and 50 to 60 mm Hg, respectively), and the autoregulatory range was shortened by about 40 mm Hg. This effect may be ascribed to inhibition of converting enzyme in the cerebral blood vessels rather than within the brain.

Evidence for hypertension was sought retrospectively in the necropsy records of 37 cadaveric kidney donors who had died of subarachnoid haemorrhage and 41 donors who had died of head injury, cerebral tumour, or (in a few instances) other causes. Mean relative heart weight in the donors with subarachnoid haemorrhage was 0.58 (1 SD = 0.09)% and in the other donors 0.52 (0.09)% (p less than 0.01), a difference unexplained by any factor other than a comparatively higher blood pressure in the donors who had died of subarachnoid haemorrhage. Blood pressure was analysed over 72 months after renal transplantation in 23 recipients with normal or near normal graft function and no evidence of chronic rejection or graft artery stenosis. Twelve patients who had received kidneys from donors with subarachnoid haemorrhage had consistently higher systolic blood pressures (p less than 0.004) and needed more antihypertensive treatment (p less than 0.0004) than the 11 recipients of kidneys from donors who had died of head injury or cerebral tumour. These observations suggest that cadaveric kidneys from donors dying of subarachnoid haemorrhage may induce or sustain hypertension after transplantation.

It is proposed that the failure of current antihypertensive treatment to reduce the incidence of coronary heart disease in patients with hypertension is due to severe, possibly irreversible restriction of coronary vascular reserve in the deeper layers of the left ventricle. Contrary to the heart, the brain can maintain a normal oxidative metabolism when the blood pressure is lowered, by extracting more oxygen from the blood. The brain is thus better suited than the heart to take advantage of the beneficial effect of antihypertensive treatment in terms of protection against hypertensive organ damage. This hypothesis is supported by studies of cerebral and coronary autoregulation and the J-shaped relation between death from myocardial infarction and treated diastolic blood pressure now reported from a number of studies.

Autoregulation of cerebral blood flow (CBF) was studied by the arteriovenous oxygen difference method in 13 patients with untreated or ineffectively treated severe hypertension, nine patients with effectively treated, formerly severe hypertension, and ten normotensive controls. Resting mean blood pressure in these three groups was 145 +/- 17 (1 SD) mm Hg, 116 +/- 18 mm Hg, and 98 +/- 10 mm Hg, respectively. Blood pressure was decreased by trimethaphan infusion combined with head-up tilt. The lower limit of CBF autoregulation in the three groups was 113 +/- 17 mm Hg, 96 +/- 17 mm Hg, and 73 +/- 9 mm Hg, and the lowest tolerated blood pressure where mild symptoms of brain hypoperfusion were encountered was 65 +/- 10 mm Hg, 53 +/- 18 mm Hg, and 43 +/- 8 mm Hg. These pressures were all significantly higher (P less than 0.01) in the group of untreated or ineffectively treated hypertensive patients than in the normotensive group demonstrating a shift of CBF autoregulation in the former. The observations in effectively treated hypertensive patients strongly suggested a readaptation of CBF autoregulation toward normal in some cases. In four hypertensive patients studied twice it was found that 8-12 months of antihypertensive treatment on average did not influence the lower limit of CBF autoregulation.

In chronic hypertension, the lower limit of autoregulation of cerebral blood flow (CBF) is shifted towards high blood pressure with a consequent impairment of the tolerance to acute hypotension. Despite this, antihypertensive treatment in the great majority of patients prevents stroke and the risk for treatment-induced cerebral ischemia is only real in a limited number of clinical settings such as malignant hypertension, hypertension in the elderly, and hypertension associated with acute stroke. During long-term treatment adaptive hypertensive changes in CBF autoregulation may be reversible, especially in young patients. Drugs used for emergency lowering of blood pressure may be classified into four groups according to their effect on CBF and intracranial pressure: (1) drugs with no pharmacological action in the cerebral circulation; (2) cerebral vasodilators; (3) alpha-adrenergic and ganglionic blockers; and (4) angiotensin-converting enzyme (ACE) inhibitors. Oxygen saturation in the jugular venous blood is of the order of 60% to 70% and is considerably higher than in the coronary sinus. It is hypothesized that this oxygen reserve enables the brain better than the heart to take hemodynamic advantage of pressure lowering without risking tissue ischemia. This may explain why antihypertensive treatment prevents stroke but not myocardial infarction. Acute hypertensive encephalopathy is probably caused by failure of autoregulatory vasoconstriction with focal or generalized dilatation of small arteries and arterioles. This is associated with a high CBF, dysfunction of the blood-brain barrier, and the formation of brain edema that is thought to cause the clinical symptoms.

In four hypertensive patients, acute lowering of blood pressure by therapeutic or diagnostic procedures caused visual disturbances ranging from transient visual hallucinations to severe, long-lasting visual impairment. These symptoms were associated with occipital lobe cerebral infarcts that tended to occur in the border zones between the major cerebral arteries. The infarcts may be seen as the combined result of a "watershed" effect during acute hypotension and the presence of structural hypertensive vascular adaptation. When a hypertensive patient complains of visual disturbances during acute blood pressure lowering, the pressure should be allowed to settle at a level somewhat above normal.

The cerebrovascular effects of converting enzyme inhibition were examined in normotensive and hypertensive rats. Cerebral blood flow was measured using the intracarotid 133xenon injection method in halothane/nitrous oxide anaesthetized animals. The main finding was that following intravenous administration of captopril (10 mg/kg), cerebral blood flow autoregulation was markedly altered. Although cerebral blood flow was unchanged from baseline levels, both the lower and upper limits of autoregulation were reset to lower mean arterial pressure and the autoregulatory plateau shortened. The lower limit was shifted 20-30 mmHg, the upper limit 50-60 mmHg, and the plateau shortened by 20-40 mmHg. The effect was interpreted as being a consequence of compensatory autoregulatory constriction of small resistance vessels in the brain following captopril-induced dilatation of large resistance vessels. It was inferred that locally produced angiotensin II might play a role in the resistance of large cerebral arteries.