Tilt test in essential hypertension. Differential responses in heart rate and vascular resistance

Changes in hemodynamic parameters following 50-degree head-up tilt were studied in a population of 56 men, including 35 subjects with sustained essential hypertension and 21 age-matched normotensive controls. The increase in heart rate following tilt was similar in groups and exhibited the same reduction in response with age. The increase in vascular resistance following tilt was strongly and positively correlated with both age and baseline vascular resistance. The latter finding was observed mainly in hypertensive subjects. The study provided evidence that differentiated responses of heart rate and vascular resistance may be observed following orthostasis. In both normal and hypertensive subjects, the age dependence of heart rate response possibly reflected differences in baroreceptor reflex control of parasympathetic and sympathetic activity. In hypertensive subjects, the vascular response was amplified with age and baseline vascular resistance, suggesting a role for structural changes of the vessels in the increased vascular response.     

Reduced sympathoneural responses to the cold pressor test in individuals with essential hypertension and in those genetically predisposed to hypertension. No support for the "pressor reactor" hypothesis of hypertension development

BACKGROUND: The aim of this study was to examine the influences of genetic predisposition to hypertension and of age on the sympathetic nervous system response to the cold pressor test (CPT). METHODS: A total of 32 young subjects (aged 27 +/- 2 years) were studied: 11 normotensive subjects without a family history of hypertension (FH), 14 normotensive subjects with a strong family history of hypertension (FH+), and eight hypertensive subjects. In addition, 21 older subjects (aged 53 +/- 2 years) were studied: 13 hypertensive and eight normotensive subjects. Blood pressure (BP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were recorded at rest and during a 2-min period of a CPT. RESULTS: Both young and older hypertensive subjects had higher resting MSNA than did the normotensive ones (47 +/- 7 v 29 +/- 4 bursts per 100 heartbeats (P < .05) and 66 +/- 4 v 40 +/- 7 bursts per 100 heartbeats (P < .01), respectively). The CPT resulted in HR increases of similar magnitude in all groups of patients. The FH+ group displayed slightly less increase in systolic BP than that of the FH- group (P < .05). The MSNA increased to a far greater degree in FH- (103%) than in FH+ (32%) and in young hypertensive patients (12%) (P < .05). Similarly, MSNA change with the CPT was greater in older normotensive subjects than in older hypertensive patients (61% v 12%, P < .05). CONCLUSIONS: Our results show that a CPT induces sympathetic responses that are subnormal in hypertensive patients and those with a family history of hypertension, highlighting the importance of genetic factors in determining the sympathetic nervous reactivity to CPT.     

Dopaminergic modulation of pressor and hormonal responses in essential hypertension

Hormonal and mean arterial pressure (MAP) responses to posture, isometric handgrip, angiotensin II (AII), adrenocorticotrophic hormone (ACTH), and metoclopramide (MCP), a dopamine (DA) antagonist, were examined in nine men with essential hypertension and nine age- and weight-matched normotensive men on a constant 100 mEq sodium and 80 mEq potassium intake before and after 4 days of administration of the DA agonist, bromocriptine (BEC; 2.5 mg three times a day). BEC depressed supine basal MAP in the hypertensives, and decreased MAP response to posture and isometric exercise in both groups. Hypertensives displayed greater (p less than 0.01) NE responses to posture and exercise than the normotensives. BEC decreased the NE response to 10 minutes of upright posture and exercise more in hypertensives (p less than 0.01) than in normotensives, but following BEC, the responses were similar. BEC did not affect basal PRA or PRA responses to posture and exercise in the two groups. PA responses to ACTH and MCP were similar in both groups, but the hypertensives displayed greater (p less than 0.01) PA responses to AII. BEC suppressed PA responses to AII (p less than 0.01) and to high dose ACTH (p less than 0.05) to a similar extent in both groups. The prolactin as well as the PA response to DA antagonism with MCP was similar in the two groups. These results suggest that dopaminergic control of NE secretion may be altered in essential hypertension. Blood pressure lowering effects of BEC in patients with essential hypertension may be related, in part, to depression of sympathetic nervous system activity.     

Cardiovascular reactivity to the cold pressor test as a predictor of hypertension

Cardiovascular reactivity to stress is hypothesized to be a marker for subsequent neurogenic cardiovascular disease, but few prospective studies of this hypothesis are available. We studied 910 white male medical students who had their blood pressure and pulse rate measured before and during a cold pressor test in the years 1948-1964. Hypertensive status (requiring drug treatment) was ascertained by annual questionnaires in the 20- to 36-year follow-up period. An association was observed between maximum change in systolic blood pressure and later hypertension, with a cumulative incidence of hypertension by age 44 of 6.7%, 3.0%, and 2.4% for a change in systolic blood pressure in the upper, middle two, and lowest quartiles, respectively (Kaplan-Meier, p less than 0.02). After adjustment for study entry age, Quetelet Index, cigarette smoking, pretest systolic blood pressure, and paternal or maternal history of hypertension in a Cox model, the association persisted. The excess risk associated with systolic blood pressure reactivity was not apparent until the population aged some 20 years and was most apparent among those in whom hypertension developed before age 45 (relative risk = 2.5, 95% confidence intervals = 1.47, 4.71 for a 20 mm Hg change). Diastolic blood pressure and heart rate changes were not associated with later hypertension. These data suggest that persons prone to later hypertension manifest an altered physiology at a young age.     

Alpha 1-adrenergic blockade and cardiovascular pressor responses in essential hypertension

The effects of selective alpha 1-adrenergic blockade with terazosin on blood pressure and cardiovascular pressor responsiveness were assessed in 17 subjects with mild to moderate essential hypertension (mean age, 48 +/- 2 [SEM] years). As compared with a 2-week placebo period, 8 weeks of terazosin treatment (mean dose, 10.5 +/- 1.7 mg/day) caused a fall of supine (from 153/103 +/- 3/2 to 143/96 +/- 4/2 mm Hg; p less than 0.025) and upright (from 145/106 +/- 4/2 to 131/94 +/- 5/3 mm Hg; p less than 0.01) arterial pressure; a marked blunting of cardiovascular pressor responsiveness to norepinephrine, as judged from the pressor dose (from 73 +/- 9 to 2156 +/- 496 ng/kg/min; p less than 0.02) and from the rightward shift (p less than 0.01) of the plasma concentration-blood pressure response curve; and a slight increase in plasma norepinephrine concentration (from 37.7 +/- 3.3 to 52.2 +/- 7.8 ng/dl; p less than 0.01). Heart rate, body weight, exchangeable sodium, blood volume, and norepinephrine plasma clearance; plasma epinephrine, renin, angiotensin II, and aldosterone levels; the relationships between angiotensin II-induced increases in arterial pressure or plasma aldosterone and the concomitant increments of plasma angiotensin II; and heart rate responsiveness to isoproterenol did not change significantly after terazosin treatment. These findings suggest that the fall of arterial pressure induced by selective alpha 1-adrenergic blockade in subjects with essential hypertension is associated with, and probably explained by, inhibition of alpha 1-mediated, noradrenergic-dependent vasoconstriction. alpha 1-Adrenergic receptor antagonism did not modify body sodium concentration, the adrenomedullary component of the sympathetic nervous system, angiotensin II levels, or beta-adrenergic dependent mechanisms.     

Left and right ventricular diastolic properties in essential hypertension during cold pressor test: noninvasive assessment by pulsed Doppler echocardiography

The diastolic properties of the left and right ventricles of 17 essential hypertensive patients (HT) without left ventricular hypertrophy and of 12 normotensive subjects were assessed by pulsed Doppler echocardiography during the cold pressor test (CPT) and after administration of nifedipine (10 mg). The results were as follows: 1. The peak blood flow velocities due to the left and right atrial contractions (ALV, ARV) at rest in the HT group were significantly greater (p less than 0.001) than those in the control group. The ratios of peak velocities due to atrial contraction and rapid filling of each ventricle (A/R) in the HT group were significantly increased (p less than 0.001) compared with those of the controls. 2. The peak rapid filling flow velocity of each ventricle during cold pressor test in the HT group was significantly less and the A/R of each ventricle was significantly (p less than 0.001) greater compared to those at rest. 3. Diastolic indices and systolic blood pressure did not change significantly after administration of nifedipine at rest or during cold pressor test. These results indicate that abnormal diastolic properties of the left and right ventricles are further deteriorated by increasing afterload.     

Comparison of the effects of four ACE inhibitors on sympathetic reactivity to cold pressor test in essential hypertensive patients

Background. We compared the effects of four different structural angiotensin-converting enzyme (ACE) inhibitors on the hemodynamic profile and catecholamine response to the cold pressor test (CPT) in hypertensive patients. Methods. We studied 44 patients with mild to moderate essential hypertension. The patients were divided into four groups according to the ACE inhibitor [enalapril (E), fosinopril (F), captopril (C), or ramipril (R)]. They were given for 8 weeks. Sympathetic reactivity was evaluated by a CPT at baseline and at the end of therapy. Blood pressure (BP), heart rate (HR), and plasma norepinephrine (NE, pg ml⁻¹) were measured at the times 0, 2, 4, 6, 8, 10, and 15 min. The delta (subtracting the basal values from the min 2 values) and the area under the curve (AUC) of the response during the CPT were studied. Results. The rise in diastolic blood pressure (DBP) (AUC) during the cold stimulus was significantly attenuated by all inhibitors studied (P<0.01): E, 17±22 to 0±20; F, 23±41 to −4±40; C, 34±33 to 7±28; R, 32±28 to −1±25. Drug therapy also blunted the response of HR to cold stress (delta HR, bpm): E, 2±2 to 0±2, P<0.05; F, 2±2 to 0±2, P<0.05; C, 3±3 to −1±3, P<0.01; R, 2±4 to −2±3, P<0.05. The rise in plasma NE (AUC) during CPT was decreased by all ACE inhibitors: E, 198±405 to 24±148, P<0.05; F, 353±436 to 51±412, P<0.05; C, 315±318 to 124±516, P<0.05; R, 677±398 to 251±307, P<0.01. Conclusions. The results in our study suggest that the blunting effects of ACE inhibitors on adrenergic tone seem to be class-dependent.     

Functional versus structural changes of forearm vascular resistance in hypertension

Structural changes in resistance vessels have been considered an important factor in triggering and maintaining chronic hypertension in humans and in experimental animals. To determine whether the increased forearm vascular resistance observed following vasodilator maneuvers in hypertensive patients is predominantly due to structural or to functional changes, we examined the influence of different vasodilator stimuli on forearm blood flow and blood pressure in 22 male patients with established essential hypertension and in 22 age-matched normotensive men (age range, 28-52 years). Blood pressure was measured directly, and blood flow was measured by venous occlusion plethysmography. The maneuvers applied were 1) arterial occlusion combined with handgrip exercise and local heating, 2) intra-arterial infusion of the calcium entry blocker nifedipine, 3) intra-arterial infusion of the nonspecific vasodilator sodium nitroprusside, 4) arterial occlusion initiated after intra-arterial infusion of nifedipine. Vascular resistance during vasodilation induced by arterial occlusion or infusion of nifedipine or sodium nitroprusside remained significantly higher in the hypertensive than in the normotensive subjects. However, the maximal vasodilation achieved by the combination of arterial occlusion and nifedipine resulted in a similar resistance in both groups (1.6 +/- 0.2 in the hypertensive vs 1.4 +/- 0.2 mm Hg/ml/min/100 ml tissue in the normotensive subjects. These data suggest that there is an important functional component of the elevated resistance in patients with essential hypertension.     

Consequences of impaired arterial baroreflexes in essential hypertension: effects on pressor responses, plasma noradrenaline and blood pressure variability

In 62 untreated patients with essential hypertension, arterial baroreflex sensitivity (BRS) for heart rate, i.e. the change in pulse interval in response to a phenylephrine-induced increase in blood pressure, was compared with (1) haemodynamic changes during mental arithmetic, a reaction time test, isometric and bicycle exercise; (2) plasma noradrenaline (PNA) concentrations at rest, and during bicycle exercise and; (3) the variability of ambulatory intra-arterial blood pressure. Subjects with diminished BRS showed the following responses: (1) higher mean arterial blood pressure (MAP) during all four stimuli; (2) a greater pressor response to cycling; (3) tended to have higher PNA concentrations during bicycle exercise and; (4) greater variation in ambulatory blood pressure. Furthermore, an increased pressor response to the reaction time test and increased ambulatory blood pressure variability was seen in younger subjects with reduced BRS. When subjects were subgrouped according to their WHO stage of hypertension, there were significant inverse relationships between BRS and the pressor responses to mental arithmetic, the reaction time test and cycling, and with ambulatory blood pressure variability only in those subjects without ECG or radiographic evidence of left ventricular enlargement (WHO stage I hypertension; n = 42). None of these correlations were present in subjects with one or both of these clinical findings (WHO stage II; n = 20). Pressor responses to the four laboratory stimuli and ambulatory blood pressure variability were similar in both groups, despite significantly higher arterial pressure and significantly lower BRS in WHO stage II subjects. These results suggest that differing mechanisms may be responsible for the regulation of blood pressure variation in these two groups. The arterial baroreflex can buffer acute changes in blood pressure in subjects with WHO stage I hypertension, but this ability is attenuated with progressive reduction of BRS. With the development of clinically evident cardiac adaptation to hypertension (WHO stage II), the contribution of the arterial baroreflex to the regulation of blood pressure is no longer detectable and the influence of cardiac and somatic afferents to reflex circulatory adjustments to activity may predominate.     

Renal vascular resistance in essential hypertension: duplex-Doppler ultrasonographic evaluation

Duplex Doppler ultrasonography has been validated as a noninvasive method to evaluate hemodynamic features of renal blood flow in renal and intrarenal arteries in patients with various renal diseases. The significance of duplex Doppler sonography in the evaluation of renal vascular resistance in essential hypertension has not yet been clearly determined. The aim of the present study was to evaluate the renal vascular resistance in patients with essential hypertension by measuring intrarenal arterial resistance (RI) and to correlate RI with renal functional tests and other clinical and laboratory data. Duplex Doppler ultrasonography was used to measure RIs in intrarenal arteries in 128 patients with essential hypertension and 61 age-matched normotensive control examinees. The renal vascular resistance index (RI) was determined by use of Doppler ultrasound. Hypertension was classified according to the 1997 Joint National Committee Guidelines (JNC-VI). Mean RI in hypertensive patients was 0.66 +/- 0.05 (+/- sd) and in healthy controls 0.60 +/- 0.03 (+/- sd) (p = 0.0001). RI correlated significantly with patient's age (r = 0.577, p = 0.001), duration of hypertension (r = 0.335, p= 0.001), stage of hypertension according to the JNC-VI classification (r = 0.315, p = 0.006), creatinine clearance (r = -0.383, p = 0.001), systolic blood pressure (SBP, r = 0.41, p = 0.001) and mean blood pressure (MBP, r = 0.30, p = 0.002). RI values did not correlate significantly with plasma renin concentration (r = -0.198 NS), diastolic blood pressure (DBP, r = 0.17, p = 0.06), and cardiac pulse (r = -0.10, p = 0.16). Multiple regression analysis showed that independent variables for RI were the patient's age (multiple R = 0.53, signif. F = 0.001) and systolic blood pressure (multiple R = 0.57, signif. F = 0.03). The renal Doppler resistance index (RI) is increased in essential hypertension and it correlates with renal functional tests as well as with patient's age, duration of hypertension, with a stage of hypertension according to the JNC-VI classification, and with systolic and mean blood pressure. The increased renal vascular resistance (RI) in hypertensive patients could be a sign of developing hypertensive nephrosclerosis and consequently renal failure. The utilization of the renal vascular resistance index (RI), provides a new noninvasive parameter in the followup of patients with essential hypertension.     

Chronology versus biology: telomeres,essential hypertension,and vascular aging

There is considerable evidence that essential hypertension is closely linked to the growth, development, and aging of human beings. It is imperative, therefore, to introduce biological indicators of growth and aging into models developed to provide a better understanding of the etiology of essential hypertension. One of these indicators may well be the age-dependent telomere attrition rate in somatic cells. Telomere attrition registers the replicative history of somatic cells. As such, it chronicles not only the growth that results from the replication of somatic cells but also their turnover-a process that is strongly linked to inflammation and oxidative stress, which are key factors in the biology of human aging.     

Renal vascular tone in essential and secondary hypertension: hemodynamic and angiographic responses to vasodilators.

The renal vascular response to graded doses of acetylcholine, dopamine and phentolamine, assessed by xenon washout and selective arteriography was used to define the relative contribution of fixed and reversible vascular abnormalities to increased renal vascular resistance in patients with essential or secondary hypertension. The increase in blood flow induced by acetylcholine and dopamine was blunted strikingly in patients with advanced nephrosclerosis, chronic pyelonephritis and polycystic kidney disease and was normal in the kidney contralateral to a significant renal artery stenosis. Conversely, the response to both was potentiated in 9 of 13 (69%) patients with mild essential hypertension. Equivalent potentiation of the response to acetylcholine was induced in normal subjects by increasing renal vascular tone pharmacologically with angiotensin. Phentolamine infused into the renal artery also increased renal blood flow significantly in 6 of 9 (67%) patients with mild essential hypertension, but in none of 15 normal subjects, over a dose reange that paralleled that for alpha-adrenergic blockade. Changes in the selective renal arteriogram were in excellent accord: potentiated response to acetylcholine, phentolamine or dopamine was associated with reversal of the small vessel abnormalities visualized in the arteriogram. The reduced blood flow response in advanced nephrosclerosis or parenchymal disease was associated with a reduced angiographic change during dilator infusion. The results suggest a quantitatively important, functional renal vascular abnormality--perhaps mediated by the sympathetic nervous system--in many patients with mild essential hypertension. Conversely the renal vascular abnormality associated with advanced nephrosclerosis or renal parenchymal disease is largely fixed and is probably due to organic changes.     

Beta-endorphin and cold pressor test in the aged

In 8 young and 8 elderly subjects mean values of plasma beta-endorphin were nearly equal under basal conditions. In all subjects the cold pressor test provoked a marked increase of beta-endorphin, which was more evident in young subjects. Mean values of the areas of endorphin modifications were the same in both young and elderly subjects. These results may suggest that after a short-term stimulus, such as the cold pressor test, no marked differences in pituitary secretion between young and elderly subjects may be evidenced.     

Regional coronary hemodynamic responses during the cold pressor test: lack of effect of nitroglycerin

The effects of large coronary vessel dilation on responses to immersion of a hand and forearm in ice water for 1 minute (that is, the cold pressor test) were calculated for 17 patients. Regional coronary blood flow and aortic and left ventricular pressures were continuously measured before and during two cold pressor tests, each performed before and after administration of sublingual (0.4 mg) or low dose intracoronary (0.01 mg) nitroglycerin. During the initial cold pressor test, heart rate and coronary pressures increased in all patients; total and regional coronary resistance usually increased in patients with severe coronary artery disease and usually decreased in patients with a normal coronary angiogram. Sublingual nitroglycerin induced important systemic effects, but intracoronary nitroglycerin did not; both induced dilation of coronary arteries viewed angiographically. Regardless of the route of nitroglycerin administration, coronary hemodynamic responses were directionally similar during the repeat cold pressor test compared with the initial one. These data support the concept that changes in tone of the large coronary arteries are not important in producing the cardiac responses observed during the cold pressor test.     

Ventricular response to dynamic exercise and the cold pressor test

The ventricular response to stress has been used to identifypatients with coronary artery disease, but the most suitablestress test remains in dispute. We compared the ventricularresponse to supine exercise and the cold pressor test in 10control subjects and in 12 patients with coronary artery disease.We did not find the previously reported increase of ejectionfraction in normal subjects during the cold pressor test, althoughthere was a significant decrease in ejection fraction in patientswith coronary artery disease. On supine exercise, normal subjectssteadily increased ejection fraction and decreased end-systolicleft ventricular volume; patients with coronary artery diseasefailed to increase ejection fraction and to decrease end-systolicvolume. In this study the failure to decrease end-systolic volumeduring supine exercise appeared the most reliable indicatorof impairment of coronary circulation.     

Haemodynamic resistance of forearm vessels during prolonged drug treatment of essential hypertension

In 40 patients with essential hypertension, the authors studied the haemodynamic resistance in forearm vessels before and after 15-min arterial occlusion, and changes in this parameter during a three-year combined antihypertensive treatment. The study revealed that the 15-min occlusion did not entirely suppress the contractile activity of vascular smooth muscles. Under these conditions, the minimum vascular resistance reflects the sum of structural and functional alterations. The character of change in minimal haemodynamic vascular resistance depends on the mechanism of action of the antihypertensive drugs. Administration of the post-synaptic alpha-adrenergic blocker Pratsiol produces a decrease in the minimal haemodynamic vascular resistance.