Effects of prazosin on autonomic control of circulation in essential hypertension.

Prazosin, an antihypertensive agent that reduces blood pressure (BP) mainly through a blockade of alpha-adrenergic receptors, may, in theory, affect sympathetic control of circulation to an extent that impairs circulatory hemeostasis. This possibility was studied in subjects with essential hypertension by examining the cardiovascular effects of several stimuli that induce a powerful and diversified activation of the sympathetic noradrenergic activity (dynamic and isometric exercise, cold exposure) and of stimuli that exert a powerful inhibitory influence upon the sympathetic nervous system (carotid baroreceptor reflex). Before and after 15 days of continuous administration of prazosin (2-5 mg), 3 times a day, measurements were made of BP (intraarterial catheter), heart rate, cardiac output (thermodilution), and peripheral resistance. Prazosin reduced mean arterial pressure (10%) and peripheral resistance (9%) at rest, and it did not affect heart rate and cardiac output. Neurally mediated changes in arterial pressure, cardiac output, and peripheral resistance during dynamic or isometric exercise and cold exposure were unaffected by the drug; also unaffected were the cardiovascular responses to increase and decrease in carotid baroreceptor activity obtained by varying carotid transmural pressure through a variable neck pressure chamber device. Thus, the hypotensive and vasodilating effect of prazosin in essential hypertension is not accompanied by an impaired response to neural excitation influences upon the cardiovascular system. Also, the inhibitory influences originating from the carotid baroreflex are unchanged. These data indicate that circulatory homeostasis is largely preserved during administration of prazosin at clinically effective doses.

Altered blood pressure variability in patients with congestive heart failure.

OBJECTIVE: Congestive heart failure (CHF) is characterized by sympathetic overactivity but reduced variability of heart interval and sympathetic nerve activity; little information exists, however, about the alterations in blood pressure variability in this syndrome, especially during excitatory manoeuvres such as tilting or exercise. DESIGN AND METHODS: Nine patients with CHF (age 62+/-1 years, NYHA class II-III, ejection fraction 33+/-1%, peak VO2 14.1+/-3.2 ml/min per kg body weight [mean +/- SEM]) and eight healthy control subjects (age 58+/-1 years) with normal left ventricular function were studied. Blood pressure (Finapres), R-R interval (ECG) and respiration (nasal thermistor) were recorded during 15-min periods of supine rest, 70 degree head-up tilting, submaximal bicycling exercise and post-exercise recovery. Total variance and the power of the spectral components of blood pressure (HF, respiratory-related; LF, 0.03-0.14 Hz; and VLF, 0.02-0.003 Hz) were measured. RESULTS: Compared with control subjects, CHF patients have, first, a normal overall blood pressure variability during supine rest but a failure to increase this variability in response to head-up tilt and exercise; second, a suppressed LF spectral component of blood pressure at rest and in response to head-up tilt and exercise; and third, reappearance of LF blood pressure power during postexercise recovery. CONCLUSIONS: In CHF patients, overall blood pressure variability and its LF spectral component are altered at rest and during sympathoexcitatory manoeuvres. Somewhat paradoxically, however, the depressed LF blood pressure power is partially restored during a 15-min recovery period, indicating that at least part of the CHF-related alterations of blood pressure variability have the potential to revert back towards normal under appropriate physiological circumstances.

Control of renin release: a review of experimental evidence and clinical implications.

Present knowledge of the mechanisms regulating release of renin is reviewed with particular emphasis on neural factors. Evidence is given for a direct effect of renal innervation on beta adrenergic receptors in juxtaglomerular cells, and for the involvement of reflex release of renin in conditions such as tilting and acute salt depletion. Participation of neural and nonneural mechanisms of control is also shown to occur in other conditions, such as aortic constriction and hemorrhage. The view is held that neural sympathetic factors might explain some of the renin disturbances found in essential hypertension. First, in patients with high renin hypertension part of the hypertension is renin-dependent, and these pressor levels of renin seem to be neurally induced since they can commonly be suppressed by beta adrenoreceptor blocking agents. Second, the hypothesis is presented that patients with low renin hypertension, at least those who have no volume disturbance, have a blunted sympathetic control of renin release. Therefore a sufficiently precise test of sympathetic activity, and possibly of body fluid volumes, should be associated with renin profiles for a better understanding of the pathophysiology of arterial hypertension and as a better guide to therapeutic management. Indeed, most of the available antihypertensive drugs act on sympathetic activity, body fluid volume or renin, and this multifaceted profile would provide more rational guidelines for treatment.

Acute hypotensive and renin-stimulating actions of captopril before and during treatment with a beta-blocking drug.

There is no general agreement on the relation between the hypotensive effect of captopril and the pretreatment plasma renin levels of hypertensive patients. To determine whether the hypotensive effect of captopril was directly related to plasma renin, the angiotensin-converting enzyme inhibitor was administered acutely to 10 essential hypertensive patients with normal or suppressed plasma renin activity before and after inhibition of renin secretion with propranolol. Captopril was equally effective in reducing blood pressure both when administered alone (25 mg: -29/-17; 50 mg: -37/-23 mm Hg) and after chronic treatment with propranolol (25 mg: -33/-20; 50 mg: -30/-20 mm Hg). The increase in renin induced by captopril was not decreased by propranolol therapy. The persistence of the hypotensive effect of captopril after renin suppression by propranolol suggests that this drug has some blood pressure decreasing properties independent of plasma renin.

Renal effects of felodipine in hypertension.

The results of 2 recent studies on the renal effects of felodipine in hypertensive patients are described. Antihypertensive doses of felodipine (10mg bid) displayed a clear natriuretic and diuretic effect associated with a constant glomerular filtration rate and an increase in renal plasma flow. With higher doses of felodipine (up to 50mg tid), the natriuretic effect was reversed to an antinatriuretic effect, accompanied by a reduction in glomerular filtration rate. The natriuretic effect of felodipine 10mg bid was evident during the first 2 days of administration, but a negative sodium balance was still present at the end of the seventh day. The mechanisms of the renal effects of calcium antagonists are discussed as well as the relevance of the natriuretic effect for the antihypertensive action of these compounds.

Antihypertensive and water and sodium balance effects of felodipine, a new vasodilating calcium antagonist, in hypertensive patients.

Felodipine, a new dihydropyridine derivative with a selective action on vascular smooth muscle, was investigated in 2 short term studies in hypertensive patients. In the first study, oral administration of felodipine 12.5 mg three times daily in a preliminary tablet formulation for 3 days significantly reduced supine and upright blood pressure with only a slight increase in heart rate and no clinically relevant signs of sodium and water retention. By increasing each dose to 25 and 50 mg three times daily, there was a further, but quite moderate, decrease in blood pressure; however, this was accompanied by an increase in heart rate and a tendency towards a reduction of creatinine clearance and urinary sodium output. In the second study, a new oral formulation containing 10 mg felodipine, administered twice daily for 7 days, was effective in lowering blood pressure without a clinically relevant tachycardia. Following the first dose of felodipine, urinary sodium excretion was slightly increased while potassium excretion showed only minor changes. The new calcium antagonist, felodipine, lowers blood pressure without the clinically relevant adverse reactions commonly related to other direct vasodilator antihypertensive drugs.

Advantages and limitations of diuretic therapy in essential hypertension.

The diuretics previously considered the "cornerstone" of the antihypertensive treatment have recently undergone a reevaluation and have been considered as a potential cause of the lack of "cardioprotection" found in different epidemiological studies. The reduction in plasma potassium and the changes in lipoproteins should represent the mechanisms of the negative interference of diuretics at cardiac levels. In spite of this common opinion, there is no clinically consistent evidence that the lowering of serum potassium and the changes in lipoproteins are responsible for the lack of cardioprotection during antihypertensive therapy. It is possible that other causes, for instance the reflex activation of sympathetic nervous system and/or renin secretion, may play an important role in determining the cardiac effects of antihypertensive therapy. However, it is also true that diuretics have been used in the past at doses that were too high, and the changes in serum potassium and lipoproteins can be minimized by administering lower doses of diuretics without decreasing their antihypertensive efficacy.

Systemic haemodynamic and humoral changes during urapidil treatment in hypertensive patients.

Urapidil, a new antihypertensive agent exerting a peripheral alpha 1-postsynaptic blocking action and an additional action at the central level, has some characteristics which may correct the underlying pathophysiological abnormalities found in the great majority of hypertensive patients. When administered acutely and chronically, urapidil significantly lowers blood pressure in hypertensive patients by reducing total peripheral resistance, while cardiac output is unchanged or only slightly elevated. The blood pressure reduction can cause a decrease in cardiac mass in patients with left ventricular hypertrophy. Urapidil has been successfully administered also in patients with congestive heart failure and in hypertensive crises during or following surgical procedures; in all these conditions urapidil lowers total peripheral resistance, but blood pressure is lowered only in patients with hypertensive crises and no clinically relevant reduction in blood pressure is found in patients with congestive heart failure. The acute administration of urapidil has shown a trend towards a rise in plasma renin activity, in plasma aldosterone and in plasma catecholamines; on the whole, however, the activation of these systems has been mild.

Calcium antagonists and responsiveness of the adrenal glands to aldosterone-releasing stimuli in hypertensive patients.

This study was designed to determine whether a reduced responsiveness of adrenal zona glomerulosa to physiological stimuli could be responsible for the lack of a proportional rise in plasma renin activity and plasma aldosterone during administration of calcium antagonists. We selected 11 hypertensive patients and measured the rise in plasma aldosterone in response to infusions of angiotensin II or potassium chloride before and after a 7-day treatment with fully antihypertensive doses of nifedipine (20 mg twice a day), while the patients were kept on a constant daily intake of sodium (100 mmol) and potassium (40 mmol). The treatment with nifedipine induced a significant reduction in both systolic and diastolic blood pressures; the infusions of angiotensin II (0.150, 0.375 and 0.750 microgram/min, each rate for 30 min) and of potassium chloride (50 mmol in 500 ml of 5% glucose in 50 min) caused similar rises in plasma aldosterone before and during the administration of the calcium antagonist. Therefore, our results indicate that responsiveness of the adrenal zona glomerulosa to physiological stimuli is maintained despite blockade of calcium channels capable of significantly lowering arterial blood pressure.

Nadolol prevents the exercise-induced rise in lymphocyte beta-receptor number in borderline hypertension.

Thirteen borderline hypertensives were investigated at rest and during dynamic exercise, before and after therapy with nadolol (40-80 mg/day for 7-28 days), in order to evaluate regulation of the number of lymphocyte beta-receptors. Systolic blood pressure and the heart rate were measured before and after 15 min of bicycle exercise, both with and without nadolol therapy; blood samples were withdrawn for adrenaline, noradrenaline and lymphocyte beta-receptor determinations. Nadolol induced a significant decrease in systolic blood pressure and the heart rate at rest, while plasma catecholamines and lymphocyte beta-receptors did not change significantly. Of the physiological responses to dynamic exercise (increases in systolic blood pressure, heart rate, plasma noradrenaline levels and adrenaline and lymphocyte beta-receptors), only the rise in beta-receptors was entirely prevented, and the increase in the heart rate was significantly attenuated by nadolol. It is suggested that the lack of a rise in the number of beta-receptors during exercise may contribute to the blunted exercise-induced tachycardia in patients taking nadolol.

Does beta 1-selective agonistic activity interfere with the antihypertensive efficacy of beta 1-selective blocking agents?

In order to investigate whether addition of beta 1-selective agonism can interfere with the antihypertensive efficacy of beta 1-selective adrenoceptor blockers, two separate studies were carried out to evaluate the effects on blood pressure and heart rate of three beta 1-selective blockers with or without varying degree of beta 1-selective agonism. In hypertensive patients at rest, the greatest blood pressure reduction and bradycardia were found with atenolol, a beta 1-selective blocker without any agonistic activity; a consistently smaller effect on blood pressure and heart rate was observed with Visacor (ICI 141 292), a beta 1-selective blocker with moderate beta 1-selective agonism, whereas no clinically relevant decrease in blood pressure occurred with Corwin (ICI 118 587), the beta 1-selective blocker with high beta 1-selective agonism. In contrast, during exercise-induced sympathetic activation, all three compounds reduced systolic blood pressure and heart rate to a similar degree.

Renal and antihypertensive effects of felodipine in hypertensive patients.

The effects of small doses of felodipine (10 mg twice daily) on blood pressure, renal function and sodium and water balance were studied in 11 patients with arterial hypertension. Felodipine significantly reduced systolic and diastolic blood pressure: most of the antihypertensive effect was already evident on day 1 of administration (-18/-11 mmHg) and only slightly increased during the subsequent week. Heart rate rose moderately only during day 1 of felodipine administration (+7 beats/min). Sodium excretion was increased during days 1 and 2, and no signs of water and electrolyte retention was observed in the week during which the balance study could be performed (Na, -135 +/- 65 mmol/7 days). At relatively low doses felodipine appears to be an effective antihypertensive agent, initially exerting some diuretic and natriuretic action and subsequently being devoid of a water- and sodium-retaining action.

[Pain assessment in terminally-ill cancer patients on admission in hospice and its modification after the first three days of care. A monocentric experience]. / Il dolore nel paziente oncologico terminale: valutazione del sintomo all'ingresso in hospice e delle sue modifi cazioni nei primi tre giorni di assistenza. Esperienza monocentrica.

AIMS: Pain is among the most frequent and distressing symptoms in terminally-ill cancer and, to date, many patients still experience uncontrolled pain. In this paper we evaluated prevalence and intensity of pain on admission in our palliative care center and during the first three days of care. PATIENTS AND METHODS: From September 2009 to October 2009 we consecutively recruited 96 terminally-ill cancer patients : on admission more than 50% had severe pain and only 4% referred to be pain-free. 54% of patients was on treatment with strong opioids. RESULTS: After three days from admission in our palliative care unit only 7% of patients experienced severe pain, 25% reported absence of pain and 80% of patients was on treatment with strong opioids. CONCLUSIONS: The beginning of palliative care led to a meaningful and rapid reduction of pain in the vast majority of terminally-ill cancer patients evaluated in this study.

Considerations on physiopathological approaches to the treatment of hypertension.

1. Two main physiopathological approaches to the treatment of hypertension are discussed, the first based on renin profiling and the second on haemodynamic measurements. 2. Reduction in plasma renin activity does not appear to be a clinically important mechanism in the hypotensive effect of beta-adrenergic blockers and of alpha-methyldopa. In particular, alpha-methyldopa has been found equally effective as a hypotensive agent both in normal renin and in low renin hypertensive patients. 3. Diuretics are certainly possessed of a renin-stimulating action, but in most patients this action does not obscure the hypotensive effect of these drugs. 4. Responders and non-responders to the hypotensive activity of beta-adrenergic blockers do not differ among them in their control haemodynamics.

Dose-response curve and time course of the antihypertensive effect of SKF 92 657, a beta-receptor-blocking and vasodilating compound.

1. The antihypertensive effect of the new drug, SKF 92 657, a hydrazinopyridazine derivative, possessing both beta-adrenoreceptor-blocking and vasodilating properties, was investigated in essential hypertension. 2. Single oral doses of 1.0 or 2.0 mg/kg did not produce any consistent decrease in blood pressure; 4.0 mg/kg was the threshold dose for a mild but not significant blood pressure reduction, whereas 8.0 mg/kg caused a significant and marked blood pressure decrease without clinically relevant changes in heart rate. 3. Continued administration of the drug for 7 days induced a significant and uniform reduction in blood pressure without tachycardia. The increase in systolic blood pressure and in heart rate caused by dynamic exercise was left unaffected by the drug.

Time-course of the anti-hypertensive action of atenolol: comparison of response to first dose and to maintained oral administration.

To show whether repeated administration of atenolol for several days would influence its pharmacokinetic parameters and the extent and duration of the pharmacologic responses, the plasma level of atenolol and changes in heart rate, blood pressure and plasma renin activity were measured in 12 hypertensive patients at various times of day (9 a. m., 12 noon, 3 p. m. and 7 p. m.) after oral administration of the first dose of atenolol 100 mg, again during the 7th and 14th days of continued once-daily administration of the same dose, and finally during the three days following withdrawal of the drug. The peak plasma concentration of atenolol (about 600 ng/ml) was found 3 h after administration of the first dose, and measurable amounts (50-70 ng/ml) were found after 24 h. None of the pharmacokinetic characteristics were changed by administration of a single daily dose for two weeks. After withdrawal of the drug, detectable amounts of atenolol were found in plasma for at least 48 h. The first dose of atenolol caused prompt (3 h) and prolonged (up to 24 h) lowering of supine and standing systolic and diastolic blood pressures, slowing of supine and standing heart rate, reduction of the blood pressure and heart rate responses to dynamic exercise, and a decrease in plasma renin activity. The extent and time-course of all these responses were not influenced by repeated once-daily administration of the 100 mg dose for two weeks. Most of the effects continued during the withdrawal days, the lowering of blood pressure being somewhat more prolonged than the slowing of heart rate. It is concluded that a once-daily dose of atenolol 100 mg decreases blood pressure and heart rate throughout the following 24 h, without excessive daily fluctuation in its effects, and without signs of tolerance or accumulation.