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.     

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.     

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.     

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.     

Adenosine strongly potentiates pressor responses to nicotine in rats.

Intravenous infusion of subhypotensive doses of adenosine strongly potentiates the pressor response of anesthetized rats to nicotine. A dose of nicotine (40 micrograms/kg, i.v.), which, given alone, elicits a peak increase in diastolic pressure of approximately equal to 15 mm Hg, increases pressure by approximately equal to 70 mm Hg when arterial plasma adenosine levels have been increased to 2 microM from a basal concentration of approximately equal to 1 microM. The pressor response to cigarette smoke applied to the lungs is also strongly potentiated during infusion of adenosine. Slightly higher adenosine concentrations (approximately equal to 4 microM) attenuate pressor responses to electrical stimulation of preganglionic sympathetic nerves, or to injections of the alpha-adrenergic agonist phenylephrine, but continue to potentiate pressor responses to nicotine. Low doses (0.25-5 micrograms/kg) of the synthetic adenosine receptor agonists 5'-N-cyclopropylcarboxamidoadenosine, 2-chloroadenosine, and N6-L-phenylisopropyladenosine also potentiate pressor responses to nicotine. Caffeine and theophylline (10 mg/kg) block the potentiating effect of adenosine, and also decrease basal responses to nicotine, suggesting that endogenous adenosine might normally potentiate some nicotine responses. The synergism between nicotine and adenosine appears to take place within sympathetic ganglia.     

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.     

Continuous positive airway pressure normalizes cardiac autonomic and hemodynamic responses to a laboratory stressor in apneic patients

OBJECTIVES: We examined the effect of continuous positive airway pressure (CPAP) treatment for sleep apnea on cardiac contractility, heart rate variability, and hemodynamics at rest and in response to a laboratory stressor. SUBJECTS AND INSTRUMENTATION: Forty-one apneic patients were studied on three occasions: before treatment, after 1 full night of CPAP treatment, and after 1 week of CPAP treatment. The subjects were randomly assigned to receive effective treatment or placebo. Contractility and hemodynamics were determined with impedance cardiography, and parasympathetic activity was assessed by analysis of heart rate variability. Measures were determined at rest and in response to a stressor. DESIGN AND RESULTS: For the cardiac sympathetic (contractility) measures (preejection period, cardiac acceleration index [CAI], and low-frequency/high-frequency ratio) significant interactions were found in the combination treatment (CPAP vs placebo) by study day (day 1, day 3, day 11) by test period (baseline, preparation, talking) [p < 0.01]. For these measures, there were no differences between the treatment groups or responses to the stressor on day 1. Levels in placebo-treated subjects did not change or respond on the subsequent study days. In the CPAP-treated subjects, there was a decrease in these indexes at baseline, which became significantly lower by day 11 (ie, CAI levels were 24 Omega/s(2), 22 Omega/s(2), and 14 Omega/s(2) on day 1, day 3, and day 11, respectively). These measures also became responsive to the stressor by showing increased sympathetic activity (CAI levels on day 11 were 14 Omega/s(2) at baseline, 32 Omega/s(2) during speech preparation, and 36 Omega/s(2) while speaking). The parasympathetic indexes, such as high-frequency power or band of heart rate variability as determined by spectral analysis, showed a significant day-by-treatment interaction (p < 0.005), whereas the CPAP- treated group had significantly more parasympathetic activity after 1 week of treatment. For the hemodynamic measures (stroke volume [SV], cardiac output, and systemic vascular resistance [SVR]), there were significant treatment-by-study day-by-test-period interactions (p < 0.01). SV and cardiac output increased across days, and SVR decreased in the CPAP-treated patients. CONCLUSIONS: These results indicate that CPAP normalizes contractility, increases cardiac vagal tone, and changes hemodynamic regulation from being resistance dominated to being cardiac dominated. Thus, after 1 week of treatment with CPAP, many of the indicators of poor cardiac functioning in apnea patients are improved.     

Infusion of epinephrine augments pressor responses to mental stress.

Circulating epinephrine may facilitate neural release of norepinephrine both during and after periods of sympathoadrenal activation by stimulation of prejunctional beta-adrenergic receptors. The present study was undertaken to examine possible effects and aftereffects of epinephrine on the hemodynamic reactivity to mental stress. To this end, two strictly standardized mental stress tests were performed in 14 normotensive men during and 1 hour after double-blind infusion of epinephrine (50 ng x kg-1 x min-1) or placebo given in random order. During epinephrine infusion, the systolic pressor response to psychosocial stress was augmented (+17 versus +10 mm Hg during epinephrine and placebo, respectively; p = 0.02). This was associated with an attenuated post-stress recovery, with the result that the stress exposure induced a prolonged elevation of systolic blood pressure. Heart rate was elevated and diastolic blood pressure lowered during epinephrine infusion without any change in the reactivity to stress. One hour after the end of the epinephrine infusion resting heart rate was still maintained on a higher level independently of level of arousal, but heart rate and blood pressure responses to stress were unaffected. The findings are consistent with the hypothesis that high circulating epinephrine levels amplify pressor responses to mental stress but do not support the suggestion that short-term infusion of epinephrine causes prolonged augmentation of blood pressure responses to psychosocial stress.     

Frequency of laboratory testing and associated abnormalities in patients with hypertension

Clinical practice guidelines recommend several routine laboratory tests in patients diagnosed with hypertension. However, the rates of clinically relevant laboratory abnormalities are unknown. Therefore, we conducted a retrospective cohort study using administrative and laboratory data of patients diagnosed with hypertension between April 2010 and March 2015 in Alberta, Canada. Laboratory investigations for renal function, serum electrolytes (sodium and potassium), low‐density lipoprotein (LDL) cholesterol, and diabetes (fasting blood glucose and hemoglobin A1c), measured within 1 year of diagnosis, were examined, and the frequency of abnormalities determined. A total of 225 296 cases of incident hypertension were identified. Of these, 74.3% received at least one of the four guideline‐recommended laboratory tests, but only 42.3% received all four tests. Patients who received any testing, compared to subjects who did not, were on average older (median age 55.9 vs 51.2 years, P < .001) and had more comorbidity (14.5% vs 2.8% with a Charlson comorbidity index ≥ 3, P < .001). Laboratory abnormalities with the potential to affect clinical decision‐making were more common among multi‐comorbid patients. Patients with renal dysfunction (6.7% vs 11.6%, 26.3%, P < .001), electrolyte abnormalities (9.8% vs 12.6%, 20.5%, P < .001), and diabetes (13.4% vs 25.1% vs 38.8%, P < .001) were found in patients with Charlson scores of 0 vs 1‐2 vs ≥3, respectively. Our study found most patients diagnosed with hypertension received some laboratory testing, but rates of laboratory testing and frequency of abnormalities varied by clinical context. Testing and abnormalities detected were both more common among older patients and patients with comorbidities.     

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.     

Comparative plasma catecholamine and hemodynamic responses to handgrip, cold pressor and supine bicycle exercise testing in normal subjects

Serial hemodynamic and plasma catecholamine responses were compared among 10 healthy men (27 +/- 3 years) (+/- 1 standard deviation) during symptom-limited handgrip (33% maximal voluntary contraction for 4.4 +/- 1.8 minutes), cold pressor testing (6 minutes) and symptom-limited supine bicycle exercise (22 +/- 5 minutes). Plasma catecholamine concentrations were measured by radioenzymatic assays: ejection fraction and changes in cardiac volumes were assessed by equilibrium radionuclide angiography. During maximal supine exercise, plasma norepinephrine and epinephrine concentrations increased three to six times more than during either symptom-limited handgrip or cold pressor testing. Additionally, increases in heart rate, systolic blood pressure, rate-pressure product, stroke volume, ejection fraction and cardiac output were significantly greater during bicycle exercise than during the other two tests. A decrease in ejection fraction of 0.05 units or more was common in young normal subjects during the first 2 minutes of cold pressor testing (6 of 10 subjects) or at symptom-limited handgrip (3 of 10), but never occurred during maximal supine bicycle exercise. The magnitude of hemodynamic changes with maximal supine bicycle exercise was greater, more consistent and associated with much higher sympathetic nervous system activation, making this a potentially more useful diagnostic stress than either handgrip exercise or cold pressor testing.     

Clinical significance of arrhythmia in patients with hypertension

Cardiac arrhythmias were studied in patients with essential hypertension in relation to their myocardial function. It was found that the arrhythmias occurring in the early period of the disease (borderline hypertension, Stage I hypertension) were primarily functional and affected the course of the disease and hemodynamics to a small degree. The life-threatening arrhythmias recorded in early hypertension were more commonly caused by mitral prolapse. The duration and severity of hypertension, development of left ventricular myocardial hypertrophy, myocardial fiber distension in relative heart failure play a decisive role in the development of cardiac arrhythmias in patients with Stage II hypertensive disease. It is essential to make comprehensive clinical and instrumental studies to clarify the genesis of the arrhythmic syndrome and to correctly choose the management policy in these patients.     

Further studies on the existence of a sensitizing factor to pressor agents in hypertension.

Further studies are reported on the existence of a sensitizing factor in plasma of hypertensive subjects, which increases the vascular sensitivity to pressor agents when injected iv into nephrectomized rats. Plasma samples from normotensive subjects, patients with malignant hypertension, normotensive dogs, and dogs with experimental renovascular hypertension were fractionated on Bio-Gel P-10 columns after cold acetone precipitation, and on DEAE-cellulose columns eluted with sodium chloride and pH gradients. The effect of the various fractions on the vascular sensitivity to angiotensin was tested utilizing nephrectomized rats. The sensitizing activity was found only in fractions obtained from plasma of hypertensive patients and dogs and it was concentrated primarily in three fractions. Th results suggest that the sensitizing factor is negatively charged at neutral pH and it could be a polypeptide or a small protein.