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.     

Metabolic and hormonal studies in patients with essential hypertension

In 106 patients with essential hypertension and different plasma renin activity several hormonal and metabolic factors were studied: urinary excretion of catecholamines, blood levels of cholesterol and triglycerides, levels of glycaemia and insulinaemia after glucose load and plasma fibrinolytic activity. The plasma renin activity in 46.2 percent of patients was normal, whereas in 25.5 percent it was low, and in 28.3 percent it was high. In patients with high plasma renin activity the excretion of noradrenaline and adrenaline was relatively high while that of dopamine was low. Significantly lower triglyceride levels were found in patients with low plasma renin activity in comparison with those with high and normal plasma renin activity. There was also a statistically significant difference in the euglobulin lysis time which was shorter in patients with low and longest in patients with normal plasma renin activity. The results of the study show that patients with different plasma renin activity may also differ in some hormonal and metabolic values.     

Norepinephrine and forearm vascular resistance responses to tilt and cold pressor test in essential hypertension: effects of aging

Heart rate, blood pressure, forearm vascular resistance (FVR), and catecholamine and renin responses to head-up tilt at 80 degrees and cold pressor test were investigated in 15 hypertensive men aged less than fifty-five (mean 44 +/- 7 years; M +/- SD) and 13 similarly hypertensive men aged more than fifty-five (mean 62 +/- 4 years; M +/- SD). Baseline plasma norepinephrine levels, as well as norepinephrine responses to tilt and cold pressor stress, were similar in the two groups, suggesting a lack of age-related increase in plasma norepinephrine (NE) responses in patients with essential hypertension. Normalized FVR responses (% change) to tilting (28 +/- 21 vs 95 +/- 36; M +/- SE) and cold pressor test (33 +/- 12 vs 64 +/- 21; M +/- SE) were significantly less (p less than 0.01) in older hypertensives. These results, but not the plasma NE responses to reflex sympathetic activation by tilt and cold pressor testing in older hypertensives, suggest an impaired forearm vasoconstriction.     

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.     

Atrial natriuretic peptide in patients with essential hypertension. Hemodynamic, renal, and hormonal responses.

In six patients with essential hypertension (EH) and in six healthy volunteers (C) the effects of a 60-min intravenous (iv) infusion of human atrial natriuretic peptide (alpha-hANP) (24 ng/min/kg) on systemic and renal hemodynamics and renal excretory function were evaluated. Basal plasma ANP concentrations in patients with EH were higher (P less than .05) than in C (30.9 +/- 4.5 v14.0 +/- 1.7 pmol/L). Maximal effects of alpha-hANP infusion occurred after 30 to 60 min. Blood pressure (BP) declined from 154 +/- 5/109 +/- 4 to 139 +/- 7/94 +/- 4 in EH and from 117 +/- 1/72 +/- 2 to 106 +/- 1/65 +/- 3 mm Hg in C (P less than .05). Cardiac output (CO) increased transiently from 6.1 +/- 0.3 to 6.5 +/- 0.4 L/min in EH and from 6.8 +/- 0.3 to 7.2 +/- 0.5 L/min in C, whereas heart rate (HR) remained constant both in patients with EH and in C (69 +/- 3 to 72 +/- 5 and 60 +/- 3 to 63 +/- 3/min). The increases in urine flow and in urinary sodium excretion from 3.6 +/- 0.2 to 16.0 +/- 2.0 mL/min and from 230 +/- 33 to 1004 +/- 137 mumol/min, respectively, in EH were more pronounced than in C (from 3.9 +/- 1.0 to 8.4 +/- 0.8 mL/min and from 211 +/- 37 to 451 +/- 84 mumol/min); (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic and hormonal studies in patients with essential hypertension.

In 106 patients with essential hypertension and different plasma renin activity several hormonal and metabolic factors were studied: urinary excretion of catecholamines, blood levels of cholesterol and triglycerides, levels of glycaemia and insulinaemia after glucose load and plasma fibrinolytic activity. The plasma renin activity in 46.2 percent of patients was normal, whereas in 25.5 percent it was low, and in 28.3 percent it was high. In patients with high plasma renin activity the excretion of noradrenaline and adrenaline was relatively high while that of dopamine was low. Significantly lower triglyceride levels were found in patients with low plasma renin activity in comparison with those with high and normal plasma renin activity. There was also a statistically significant difference in the euglobulin lysis time which was shorter in patients with low and longest in patients with normal plasma renin activity. The results of the study show that patients with different plasma renin activity may also differ in some hormonal and metabolic values.     

Unexpected pressor responses to propranolol in essential hypertension. An interaction between renin, aldosterone and sympathetic activity.

The blood pressure response to propranolol treatment was analyzed retrospectively in 187 patients with benign essential hypertension. In most patients (102 patients, 54 per cent) systolic and/or diastolic blood pressure was decreased by more than 10 per cent (responders). No significant change in blood pressure occurred in 35 per cent (65 patients) of the patients (nonresponders). Surprisingly, in 20 patients (11 per cent) systolic (8 patients) and/or diastolic (14 patients) blood pressure was increased by more than 7 per cent (pressor-responders). All three subgroups received similar amounts of propranolol and irrespective of the effect on the blood pressure, propranolol produced a similar reduction in pulse rates, suggesting similar degree of beta blockade. The three subgroups did not differ in their clinical characteristics, except that the nonresponders were significantly older than the responders. Pretreatment renin values were highest in the responders, somewhat lower in the nonresponders and significantly lower in the pressor-responders. In a representative subset of 66 patients, control and treatment values for plasma renin activity and aldosterone excretion were compared. The responders had the most pronounced decreases in both renin and aldosterone. In striking contrast, no significant changes were observed in the two hormones in those patients whose blood pressure levels rose. Moreover, in the pressor-responders, the drug produced the greatest increases in body weight, reflecting sodium retention. The differences in blood pressure responses observed in different patients may be explained by various interplays between the drug-induced suppression of renin and aldosterone, and the operation of unapposed or reactive alpha sympathetic activity. The latter is presumably active in all patients tending to cause vasoconstriction and hence an increase in peripheral resistance. In the pressor-responders such unopposed alpha-tone combined with the demonstrated lack of renin and aldosterone suppression with attendant fluid retention could work to produce the paradoxical pressor responses. In contrast, in those whose blood pressure levels drop, the drug-induced suppression of renin leads to decreased peripheral resistance despite the unopposed alphatone. The accompanying decrease in aldosterone limits sodium retention and contributes to the fall in blood pressure levels.     

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.     

Arterial baroreflex sensitivity, plasma catecholamines, and pressor responsiveness in essential hypertension

Arterial baroreflex sensitivity, plasma norepinephrine (NE) and epinephrine (E), and pressor and depressor responses were assessed in 25 patients with essential hypertension and 29 normotensive control subjects. Sensitivity of the cardiac limb of the baroreflex was determined by blood pressure and interbeat interval responses associated with the Valsalva maneuver, externally applied neck suction and pressure, and injection of phenylephrine and nitroglycerin. By all these techniques, patients with essential hypertension had significantly decreased baroreflex sensitivity, even after adjustment for age mismatching between the hypertensive and normotensive groups. Hypertensive patients also had significantly higher mean levels of plasma NE and E in both brachial arterial and antecubital venous blood (246 vs 154 pg/ml arterial NE, 286 vs 184 pg/ml venous NE, 99 vs 55 pg/ml arterial E, and 65 vs 35 pg/ml venous E) and significantly larger pressor responses to injected phenylephrine (30.9 mm Hg/100 micrograms vs 16.7 mm Hg/100 micrograms). When baroreflex-cardiac sensitivity values measured by the various techniques were averaged, there was a significant inverse relationship between sensitivity and venous NE and between sensitivity and pressor responsiveness. The results indicate that decreased baroreflex-cardiac sensitivity, increased sympathetic outflow, and pressor hyperresponsiveness tend to occur together in some patients with essential hypertension. Decreased arterial distensibility and altered central neural integration can account for these findings.     

Low-dose angiotensin II enhances pressor responses without causing sustained hypertension

Subpressor doses of angiotensin II (SP-Ang II) cause a slow increase in blood pressure in rats as assessed by tail cuff plethysmography (TCP), reflecting either sustained hypertension or an exaggerated pressor response to diverse stimuli. We examined whether subpressor doses of Ang II enhance blood pressure responses to simple stress (handling of trained rats for TCP). We implanted telemetry in Sprague-Dawley rats. After 10 days of recovery and TCP training, we implanted osmotic minipumps with either SP-Ang II (50 ng/kg per minute) or vehicle, and then measured systolic blood pressure continuously in unrestrained rats for 13 days. We also recorded telemetry readings while obtaining TCP measurements every 2 days. SP-Ang II increased blood pressure from 134+/-19 to 159+/-22 mm Hg by TCP, which matched the simultaneous telemetry readings of 131+/-20 to 154+/-25 mm Hg. In contrast, SP-Ang II did not change the blood pressure in the unrestrained rats (measured with continuous telemetry: 124+/-2 versus 127+/-1 mm Hg). The blood pressure in the control rats did not change in the unrestrained state (125+/-3 versus 128+/-5 mm Hg on days 0 and 12, respectively), and only slightly increased during TCP (11+/-5 and 6+/-4 mm Hg by TCP and simultaneous telemetry, respectively; P=NS). In summary, SP-Ang II, although unable to provoke sustained hypertension, nonetheless magnifies the pressor response to otherwise trivial stimuli. We speculate that even modestly elevated Ang II levels may contribute to hypertensive complications because such levels promote the punctuation of an apparent normotensive state by episodic hypertension occasioned by seemingly innocuous stimuli.     

Clinical significance of pressor responses to laboratory stressor testing in hypertension.

We investigated the relation between pressor responses to laboratory stressors and 24-hour blood pressure (BP) variability or left ventricular mass. Mental arithmetic tests, isometric hand grip exercise, and bicycle ergometer exercise were carried out in middle-aged normotensive subjects (n=10) and in age-matched WHO stage I (n=23) and stage II (n=11) patients with essential hypertension. Mental arithmetic was associated with a greater rate of increase in plasma epinephrine than in norepinephrine, and handgrip exercise was associated with a greater rate of increase in plasma norepinephrine than in epinephrine in all three groups. Bicycle ergometer exercise caused a remarkable increase in plasma norepinephrine and a mild increase in plasma epinephrine in all three groups. In mental arithmetic tests, pressor responses of hypertensive patients were significantly greater than those of normotensives. The pressor response during mental tests was significantly correlated with the value of 24-hour BP variability in all subjects (r=0.56, p< 0.01). The pressor response to handgrip increased with the stage of hypertension. A good correlation existed between the pressor response to handgrip and the left ventricular mass index in the subjects (r=0.73, p < 0.001). There was no difference in the pressor response to ergometer exercise between any of the groups. The findings suggest that the pressor response to mental stress reflects BP variability and that the response to handgrip is correlated with target-organ disease associated with hypertension, especially the degree of cardiac hypertrophy.     

Sympathetic and respiratory responses to hypoxia in essential hypertension

An increased sympathetic nervous response to hypoxia and reduced beta-adrenergic receptor function have been reported in hypertension. This study examines the relationship between hypoxia and beta-adrenergic receptor function in sixteen normotensive and eight hypertensive subjects. We measured the average arterial oxygen saturation and the end tidal carbon dioxide partial pressure in hypertensive and normotensive groups under normoxia and mild isocapnic hypoxia (15% O2, 85% N2). The ratio of isoproterenol-stimulated cAMP to basal cAMP on lymphocytes was measured in the two groups under normoxia. We also measured plasma norepinephrine levels and calculated the "Chronotropic 25 Dose" of isoproterenol in the two groups under normoxia and hypoxia. Hypertensives had higher plasma norepinephrine levels for either breathing condition (F=7.16, p=0.015). Under hypoxia, hypertensives showed a significant decrease in the average arterial oxygen saturation (F=4.92, p=0.038) and higher "Chronotropic 25 Dose" implying decreased beta-adrenergic receptor sensitivity (F=6.30, p=0.011). These results suggest that hypertensives have a diminished ventilatory response and impaired beta-adrenergic response under hypoxia.     

Hemodynamic and hormonal effects of atrial natriuretic factor in patients with essential hypertension

Hemodynamic and hormonal effects of two graded infusions of alpha-human-(1-28)-atrial natriuretic factor (0.5 microgram/kg prime followed by 0.05 microgram/kg per min for 20 minutes and by 0.1 microgram/kg per min for 20 minutes) were evaluated in 13 patients with mild to moderate essential hypertension. The lower dose of atrial natriuretic factor did not change significantly any of the considered variables, although it tended to reduce aortic mean blood pressure (from 132.6 +/- 5.3 to 125.5 +/- 4.6 mm Hg), cardiac index (from 3.67 +/- 0.2 to 3.54 +/- 0.18 liters/min per m2) and forearm vascular resistance (from 178.6 +/- 15 to 148.3 +/- 10 mm Hg/ml per s). The higher dose of atrial natriuretic factor significantly reduced mean aortic pressure (118.6 +/- 5 mm Hg), cardiac index (3.29 +/- 0.16 liters/min per m2) and stroke volume index (from 45.9 +/- 2.6 to 38.9 +/- 3 ml/m2) and slightly decreased pulmonary wedge pressure, whereas both total peripheral resistance and forearm vascular resistance were not modified. With this latter dose a reduction in aortic pressure was observed in all patients at the steady state, and this was associated with a fall in stroke volume index in 10 of the 13 patients and with a reduction in total peripheral resistance in only 6 patients. Heart rate and right atrial and pulmonary pressures did not change during infusion of atrial natriuretic factor. Plasma renin activity was only slightly reduced by atrial natriuretic factor, whereas plasma norepinephrine rose significantly (from 233 +/- 34 to 330 +/- 58 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

The pressor response to angiotensin II in patients with low renin essential hypertension

The etiology of low renin essential hypertension (LREH) has not been established with certainty, but mineralocorticoid excess has been implicated frequently in its pathogenesis. The finding of several investigators of a normal exchangeable sodium space and extracellular fluid volume, however, does not support this hypothesis. To evaluate the possible role of sodium and water retention in LREH, the pressor response to infused angiotensin II (A II) was determined and compared to that of normal subjects and that of subjects with normal renin essential hypertension (NREH). This approach was based on the known suprasensitivity of vascular receptors to A II in situations in which sodium and water compartments are expanded as they are, for example, in proven hypermineralocorticoid states such as primary aldosteronism. In this study, we found that subjects with LREH demonstrated no increased pressor response to graded doses of A II; this suggests that LREH is not primarily mediated by sodium and water retention.     

Changes in hormonal activities relative to the severity of essential hypertension.

Endocrine activity in patients with essential hypertension was studied by measuring the urinary excretion of catecholamines, prostaglandin E (PGE) and cyclic adenosine monophosphate (cAMP). Simultaneously, plasma renin activity, concentrations of serum sodium, potassium, blood urea nitrogen (BUN) and creatinine were determined. Systolic blood pressure and BUN increased progressively with age until the sixth decade. Urinary excretion of norepinephrine was correlated with the systolic blood pressure. In contrast, plasma renin activity and urinary excretion of PGE decreased progressively with the increase in systolic blood pressure. Although the cause of essential hypertension is not known, it is suggested that hypertension accelerates the aging process in the kidney and thus decreases renal PGE synthesis. This decrease of PGE in turn causes a reduction of plasma renin activity, possibly either by accelerating the retention of sodium and water or by failing to stimulate renin synthesis. A decrease of PGE may also potentiate the vasopressor action of norepinephrine.     

Abnormal renal sodium handling in essential hypertension. Relation to failure of renal and adrenal modulation of responses to angiotensin II

This study assessed renal sodium handling in a group of patients with essential hypertension in whom control of the renal blood supply and aldosterone release by angiotensin II is abnormal ("non-modulating") because of recent evidence that these patients have sodium-sensitive hypertension. Sixty-one patients were studied, 25 as balance was achieved with a daily sodium intake of 10 meq and 36 after a shift from a 10 meq to 200 meq sodium intake for five days. Renal and adrenal responsiveness to angiotensin II was assessed by measurement of para-aminohippurate clearance and plasma aldosterone prior to and during the infusion of 3 ng/kg per minute of angiotensin II, to identify the non-modulator group (n = 32). The half-time of the exponential function relating sodium excretion to time during the three to five days when external balance was being achieved with a 10 meq sodium intake was 23.9 +/- 0.3 hours in 60 normal subjects, 24.5 +/- 1.8 hours in the patients with essential hypertension in whom renal responsiveness to angiotensin II was normal, and prolonged (p less than 0.001) to 36.6 +/- 2.1 hours in the non-modulating patients. A prolonged half-time suggests that, with a shift to a high sodium intake, more time will be required to achieve external sodium balance and at the expense of more retained sodium. During the shift from a 10 to 200 meq sodium intake, the non-modulator group showed a delayed rate at which external sodium balance was achieved, greater cumulative positive sodium balance, more weight gain, and a greater frequency of blood pressure rise. The abnormality in the rate at which external sodium balance is achieved in non-modulation results in a difference in total body sodium that varies with sodium intake and that may well contribute to, or cause, sodium-sensitive hypertension.     

The role of Na,K-ATPase inhibitor on pressor responsiveness in patients with benign essential hypertension

To clarify the role of Na,K-ATPase inhibitor in the enhanced pressor response to infused noradrenaline (NA-R) in patients with benign essential hypertension (EHT), NA-R, plasma noradrenaline concentration (PNA), and blood ionized calcium (Ca2+) were investigated before and after intravenous injection of ouabain in 15 normotensive subjects (NT) and 13 EHT. NA-R was enhanced by ouabain in both NT and EHT. The augmentation of NA-R following ouabain injection (delta NA-R) and % delta NA-R were significantly lower in EHT than in NT. Following ouabain injection, no significant change in PNA and blood Ca2+ was observed in both NT and EHT. NA-R negatively correlated with PNA and blood Ca2+, which were estimated just prior to noradrenaline infusion, before ouabain injection as well as after. After ouabain, the regression line between NA-R and PNA or blood Ca2+ shifted toward higher NA-R level in NT, unlike in EHT. These results suggest that an exogenous Na,K-ATPase inhibitor brings about a blunted enhancement of NA-R in EHT consistent with the presence of an endogenous Na,K-ATPase inhibitor in EHT.