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Biomedical subjects

S Taddei

Publications and source records attributed to S Taddei.

At least 127 records · Page 7Linked to original sources
PubMed1989

Indenolol, a beta-blocker with partial agonism at vascular beta-adrenoceptors.

Intrinsic sympathomimetic activity may attenuate some effects caused by treatment with beta-adrenoceptor blockers. Indenolol is a nonselective beta-adrenoceptor antagonist whose sympathomimetic properties have been shown in vitro but not in human beings. We infused indenolol cumulatively (5, 15, and 50 micrograms/100 ml tissue per minute for 15 minutes each, preceded by an infusion of saline solution) into the brachial arteries of nine hypertensive patients. Forearm blood flow (venous plethysmography), mean arterial pressure, and heart rate were monitored. During infusion at 5 micrograms/100 ml tissue per minute, forearm blood flow did not change, but it did increase dose-dependently at the greater infusion rates. This action was determined to be mediated by beta-adrenoceptor stimulation because propranolol (10 micrograms/100 ml tissue per minute for 15 minutes), given before treatment and then concomitantly with indenolol, abolished it (n = 5). Indenolol vasodilated forearm arterioles and this effect was antagonized by beta-blockade, thus demonstrating vascular intrinsic sympathomimetic activity. This property may contribute to its therapeutic action in human beings.

Adrenergic beta-Antagonists↗
PubMed1989

Calcium entry blockade and alpha-adrenergic vascular reactivity in human beings: differences between nicardipine and verapamil.

The interference by two unrelated calcium entry blockers, nicardipine and verapamil, with the forearm vascular response to graded exogenous norepinephrine was evaluated in two groups (n = 6 each) of patients with uncomplicated hypertension. Drugs were infused into the brachial artery at systemically ineffective rates and forearm blood flow was measured by venous plethysmography. Nicardipine (1 microgram/dl forearm tissue/min) relaxed forearm arterioles and antagonized the vasoconstrictor effect of norepinephrine, whereas verapamil (1 microgram/dl forearm tissue/min) was ineffective, although vasodilating to a comparable extent. Therefore, functional alpha-antagonism may contribute to the vasodilating and, possibly, the antihypertensive effect of nicardipine but, apparently, not verapamil. The data further stress the heterogeneity of calcium channel entry blockers even in human beings.

Adult↗
PubMed1989

Sympathetic vasoconstriction as a mechanism of action of ouabain in forearm arterioles of hypertensive patients.

1. The interaction of ouabain, a Na+/K+ adenosine 5'-triphosphatase inhibitor, with sympathetic mechanisms of vasoconstriction, as well as its possible site(s) of action, were investigated in forearm arterioles of patients with uncomplicated hypertension. 2. Intra-arterial infusion of ouabain per se decreased forearm blood flow without changes in systemic arterial pressure or contralateral flow. However, the vasoconstrictor effect of the glycoside was abolished after local pretreatment with either phentolamine, a competitive alpha-adrenoceptor antagonist, or bretylium tosylate, a neurotransmitter blocker. 3. To exclude a non-specific effect due to the vasodilatation, a similar protocol was performed using histamine, which acts independently of sympathetic mechanisms. The vascular effect of ouabain was maintained in spite of histamine-induced increases in forearm blood flow even greater than those obtained from either blocker. 4. To discriminate between pre- and post-synaptic site(s) of action of ouabain, exogenous noradrenaline was infused intra-arterially after inactivation of local neurotransmitter release by bretylium, thus causing direct postsynaptic vascular alpha-adrenoceptor stimulation. Under these conditions, noradrenaline decreased forearm blood flow irrespective of the presence or absence of ouabain. 5. Thus, local sympatholysis by drugs acting on different levels of the sympathetic neuroeffector junction abolished the effect of ouabain, whereas histamine did not influence it. The data provide positive evidence for an effect of ouabain on sympathetically mediated vasoconstriction. This action is apparently not exerted at a postsynaptic site but possibly by enhancing neurotransmitter release. 6. If a circulating endogenous ouabain-like Na+/K+ adenosine 5'-triphosphatase inhibitor is relevant to the development of hypertension in man, it might act through a similar mechanism.

Arterioles↗
PubMed1989

Persistence of sympathetic-mediated forearm vasoconstriction after alpha-blockade in hypertensive patients.

Sympathetic vasoconstriction not mediated by alpha-adrenoceptors has been identified in vitro and in animals but not in humans. We evaluated the effect of alpha-adrenoceptor blockade on either endogenous vascular sympathetic activation (obtained through the application of a nonhypotensive lower-body negative pressure, -10 mm Hg for 5 minutes) or selective postsynaptic alpha-adrenoceptor stimulation by exogenous norepinephrine (0.005 micrograms/100 ml forearm tissue/min for 3 minutes) in the presence of beta-blockade by propranolol (10 micrograms/100 ml forearm tissue/min for 15 minutes). Drugs were infused into the brachial artery at systemically ineffective rates while continuously monitoring forearm blood flow (by venous plethysmography), intra-arterial mean arterial pressure, and heart rate in patients with essential hypertension. The irreversible antagonist phenoxybenzamine was used at a rate of 20 micrograms/100 ml forearm tissue/min for 1 hour, which antagonized the local responses to norepinephrine in a range of 0.005-0.05 micrograms/100 ml forearm tissue/min. During saline administration, either lower-body negative pressure or exogenous norepinephrine decreased forearm blood flow comparably. However, after phenoxybenzamine administration, forearm vasoconstriction to norepinephrine was abolished while a residual response to lower-body negative pressure remained in each patient. To exclude insufficient alpha-adrenoceptor blockade, the same experimental protocol was repeated by doubling phenoxybenzamine concentrations. No difference from the data obtained with the lower level of antagonist was found. Further studies were performed to confirm the sympathetic origin of the residual vasoconstriction. Bretylium tosylate, a neurotransmitter blocker, infused into the brachial artery (50 micrograms/100 ml forearm tissue/min for 90 minutes) abolished the effect of endogenous sympathetic activation but did not alter the effect of exogenous norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1989

Low dose atrial natriuretic factor in primary aldosteronism: renal, hemodynamic, and vascular effects.

Whether atrial natriuretic factor (ANF) plays a physiological role in primary aldosteronism has yet to be determined. In the present study, the renal, hemodynamic, humoral, and vascular effects of a synthetic (WY-47663) human analogue were studied in five water-loaded (15 ml H2O/kg) patients with adenomatous primary aldosteronism, a salt-sensitive, low renin, volume-expanded syndrome. ANF was infused for 3 hours at a low rate (0.005 micrograms/kg/min), which approximately doubled circulating immunoreactive ANF. Glomerular filtration rate and renal blood flow (inulin and para-aminohippurate clearance) remained stable, but sodium excretion increased significantly suggesting a dissociation between renal hemodynamics and natriuresis as well as a direct inhibitory effect on tubular sodium reabsorption by ANF. Intra-arterial diastolic blood pressure, heart rate, forearm blood flow (plethysmographic method), and arterial plasma norepinephrine did not change, but systolic blood pressure declined and hematocrit rose suggesting plasma volume contraction by ANF. Plasma aldosterone levels were unchanged indicating a loss of ANF-mediated aldosterone inhibition, possibly related to qualitative or quantitative alterations of ANF receptors in tumoral adrenal tissue. Infusion of the analogue into the brachial artery was at a rate of 0.005 micrograms/dl forearm tissue/min x 30 minutes, which also doubled local immunoreactive venous ANF concentrations and vasodilated forearm arterioles. These data suggest a physiological role for ANF in modulating body fluid volume even in human primary aldosteronism.

Adult↗
PubMed1988

Further evidence for the existence of alpha 2-mediated adrenergic vasoconstriction in human vessels.

To confirm the presence of alpha 2-mediated vasoconstriction in human vasculature, the effect of selective alpha 1- and alpha 2-agonists (methoxamine and B-HT 933) and antagonists (indoramin and Yohimbine) was studied in fourteen patients with mild, uncomplicated, essential hypertension. Drugs were infused, into the brachial artery at systemically ineffective rates, and concomitant changes in forearm blood flow were measured by strain gauge venous plethysmography. During control conditions, cumulative infusions either of methoxamine or B-HT 933 caused dose-related vasoconstriction, while both indoramin and yohimbine doubled forearm blood flow. Subsequently, the alpha 1-adrenoceptor mediated vasoconstriction produced by methoxamine was shown to be completely blocked by indoramin pretreatment, and to be left unchanged by yohimbine. The alpha 2-vascular stimulation by B-HT 933 was antagonized by previous yohimbine but not by indoramin pretreatment, thus fulfilling the pharmacological requirements for identification of distinct alpha-adrenoceptor mediated excitation-contraction pathways. The data provide further evidence of the existence of alpha 2-mediated vasoconstriction in human forearm vessels.

Adult↗
PubMed1988

Ouabain vasoconstricts human forearm arterioles through alpha-adrenergic stimulation.

Studies on the role of endogenous sodium pump inhibitors in hypertension have used ouabain, a Na,K-ATPase inhibitor, as a pharmacological probe to test the effect of direct vascular Na,K-ATPase inhibition in man. Previous work has suggested that there are no alpha-adrenoceptor mediated components in the vasoconstrictor effect of this drug, although several animal and in vitro studies have shown a complex interaction between ouabain and either sympathetic neurotransmission or alpha-adrenergic excitation-contraction coupling mechanisms. To re-examine this issue, we infused ouabain at 7 micrograms/dl per min for 20 min without (saline infusion) or with phentolamine (8.0 micrograms/dl per min for 15 min), an alpha-adrenoceptor blocking agent, in uncomplicated mild to moderate hypertensive patients. The drugs were infused into the brachial artery, and forearm blood flow (by strain-gauge plethysmography), systemic blood pressure and heart rate were measured concomitantly. After local phentolamine pretreatment, ouabain lost its vasoconstrictor effect (n = 5). This result is unlikely to have been related to vasodilation because histamine, a non-alpha-adrenergic vasodilator, infused in another group (n = 5) of patients at rates roughly equieffective to phentolamine (0.05 microgram/dl per min for 15 min) did not modify the vasoconstrictor action of ouabain. Thus alpha-adrenoceptor mediated components caused the forearm vascular effect of ouabain and must be taken into account when using ouabain to study endogenous sodium pump inhibitor(s) in human hypertension.

Adult↗
PubMed1988

Independent stimulation of glucose metabolism and Na+-K+ exchange by insulin in the human forearm.

Insulin promotes potassium uptake into skeletal muscle by stimulating the activity of the Na+-K+ pump. To test whether insulin-induced glucose and potassium uptake are linked processes in vivo, we used the perfused forearm technique in healthy volunteers. Local hyperinsulinemia (125 +/- 11 microU/ml for 100 min) induced a net uptake of glucose and potassium (4.79 +/- 0.61 and 0.76 +/- 0.22 mumol.min-1.100 ml-1 of forearm volume, respectively). When an intra-arterial ouabain infusion (0.72 microgram.min-1.100 ml-1, producing local levels of approximately 0.5 mM) was superimposed on the insulin infusion, potassium uptake was blocked (0.026 +/- 0.190 ml.min-1.100 ml-1, P less than 0.02), and glucose uptake was decreased (to 3.31 +/- 0.34 mumol.min-1.100 ml-1, P less than 0.03). The latter change was explained by a 30% fall in forearm blood flow (from 2.95 +/- 0.10 to 2.01 +/- 0.18 ml.min-1.100 ml-1, P less than 0.001). To separate out the effect of blood flow, in another series of studies forearm blood flow was clamped by co-infusing propranolol and phentolamine (7 and 8 micrograms.min-1.100 ml-1, respectively). Under these conditions of fixed flow (7.0 +/- 0.8 ml.min-1.100 ml-1), ouabain still abolished the stimulatory effect of insulin on potassium uptake but had only a small (and statistically insignificant) effect on forearm glucose extraction (from 20 +/- 2 to 16 +/- 2%, P = N>). We conclude that in human forearm muscle ouabain inhibits Na+-K+ exchange and depresses insulin-induced glucose uptake via an adrenergic-mediated limitation of blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Dietary sodium change in primary aldosteronism. Atrial natriuretic factor, hormonal, and vascular responses.

Atrial natriuretic factor (ANF) may be physiopathologically involved in several clinical conditions including human hypertension. However, few data are available regarding this putative hormone and its relationship to aldosterone, blood pressure, and vascular responsiveness to alpha-adrenergic receptor stimulation in primary aldosteronism, a volume-expanded, low-renin model of human hypertension. For this reason, the behavior of supine and upright plasma ANF as related to aldosterone, blood pressure, and forearm alpha-adrenergic sensitivity (plethysmographic technique) to intra-arterial norepinephrine infusion was studied in eight patients with primary aldosteronism (five with adenomas, three with hyperplasia) before and at the end of two sequential 1-week low (20 mmol/day) and high sodium (200 mmol/day) diet periods. Basal, predict ANF concentrations decreased and increased after low and high sodium intakes, respectively. Furthermore, highly significant postural ANF decrements after 1 hour of standing occurred with each diet, although they were lower after the low than after the high sodium diet. Plasma aldosterone, either supine or upright, was insensitive to dietary sodium manipulations, suggesting the absence of ANF-mediated control of aldosterone secretion in our patients. In spite of about twofold higher ANF concentrations during the high than during the low sodium diet, forearm vascular sensitivity to intra-arterial norepinephrine infusion did not change during the study. Furthermore, systemic arterial blood pressure rose to a highly significant extent after dietary sodium content was increased, thus casting doubt on a role for ANF as an endogenous long-term modulator of systemic blood pressure and peripheral alpha-adrenergic sensitivity in patients with primary aldosteronism.

Adult↗
PubMed1987

A renin-secreting tumor.

A 23-year-old white male was referred for hypertension resistant to triple antihypertensive treatment, with hypokalemia, hyperaldosteronism and elevated levels of circulating plasma renin activity (PRA). Renal angiography and echoscans put in evidence an avascular solid mass at the midlower level of the right kidney. Renal vein catheterization with sampling of blood from the lower branches of the right renal vein showed lateralization of renin secretion from that side. After surgical exeresis, the mass (1.0 cm) was diagnosed as a renal hemangiopericytoma on the basis of light and electron microscopy. Tumor exeresis was followed by a prompt normalization of blood pressure and plasma potassium, with a decrease in PRA and aldosterone. Two months after surgery the patient was still normotensive. Circulating levels of inactive (trypsin-activable) renin were around 60% of the total pool of plasma renin, i.e. much lower than those reported in other cases of renin-secreting tumors. After surgery, inactive and active renin fell in parallel, implying that both were secreted by the tumor. Tumoral PRA responded to postural stimulation, but was unresponsive to acute converting enzyme inhibition, suggesting that sympathetic stimuli were still operative, but the negative feedback inhibition by angiotensin II on renin secretion was lost. Acute converting enzyme inhibition by captopril dropped blood pressure; however, during long-term treatment, the drug (3 X 50 mg/day) was ineffective in terms of either blood pressure normalization or relief of secondary hyperaldosteronism. Acute calcium entry blockade by nifedipine (10 mg p.o.) caused an evident blood pressure drop.

Adult↗
PubMed1987

Verapamil and alpha-mediated vasoconstriction in human forearm: a comparison between norepinephrine and selective alpha 1- and alpha 2-adrenergic agonists.

To evaluate the hypothesis of alpha-antagonism as a contributing factor to the vascular action of calcium entry blockade (CEB) in man, we have compared the action of verapamil, a CEB, on nonselective (norepinephrine, NE) and selective alpha 1-(methoxamine, MET) and alpha 2-(B-HT 933, BHT) adrenergic agonists in human forearm vasculature. All drugs were infused into the brachial artery at systemically ineffective rates. Blood pressure and heart rate were continuously monitored; forearm blood flow was measured through strain gauge plethysmography. Sixteen mild, untreated hypertensive patients were studied. Cumulative forearm blood flow dose-response curves to three cumulative infusion rates (3 min each) of NE (0.015, 0.05, 0.15 micrograms/100 ml tissue/min), MET (0.06, 0.6, 6 micrograms/100 ml tissue), and BHT (3, 10, 30 micrograms/100 ml tissue/min) were obtained during saline and after verapamil (0.9 micrograms/100 ml tissue/min X 15 min) infusion. Verapamil did not modify to any significant extent NE-mediated vasoconstriction, but clearly blunted the vascular action of either MET or BHT. Because NE is the physiological neurotransmitter, the data cast doubts about the relevance of alpha-antagonism as a mechanism of action of calcium entry blockade through verapamil. Besides, the data caution against generalizing by using data obtained through several compounds, including CEBs, of alpha-adrenergic stimuli.

Adrenergic alpha-Agonists↗
PubMed1986

Vascular responses to ouabain and norepinephrine in low and normal renin hypertension.

A circulating Na+, K+-ATPase inhibitor may cause arterial hypertension in patients with suppressed plasma renin activity, either directly or by sensitizing peripheral vessels to alpha-adrenergic stimulation. This hypothesis was tested by evaluating forearm arteriolar (plethysmographic technique) response to exogenous alpha-adrenergic stimulation by a 2-minute intra-arterial infusion of norepinephrine (0.1 microgram/dl tissue per minute) and to Na+, K+-ATPase inhibition by sequential 20-minute intra-arterial infusions of ouabain (0.36 and 0.72 microgram/dl tissue per minute). Two groups of hypertensive subjects with suppressed plasma renin activity, either essential or secondary to aldosterone excess, were compared with age-matched and sex-matched hypertensive subjects with normal plasma renin activity (n = 7 per group). No significant differences in forearm vascular response to norepinephrine were found among the three groups. Ouabain caused a highly significant, dose-related increment in forearm vascular resistance that was not accompanied by changes in the contralateral limb or systemic blood pressure. No significant interindividual differences in vascular responsiveness to ouabain were found. The individual increments in forearm vascular resistance during ouabain administration were unrelated to basal values or to plasma aldosterone, norepinephrine, or potassium concentrations. These data are not consistent with the hypothesis that suppressed basal Na+, K+-ATPase activity is primarily a characteristic of hypertensive patients with unresponsive plasma renin activity. Overall, these results cast doubts on the possibility of linking the development of human low renin hypertension to an endogenous Na+, K+-ATPase inhibitor.

Adult↗
PubMed1986

Verapamil antagonizes forearm vasoconstriction mediated by selective alpha 1- and alpha 2-agonists in hypertensive patients.

Calcium channel blocking agents preferentially antagonize alpha 2-mediated pressor responses in various animal species. Whether the same happens in man is not clear. For this reason we studied the interference exerted by verapamil, a calcium entry blocker, on forearm vasoconstriction mediated by selective alpha 1- (methoxamine) and alpha 2- (B-HT 933) adrenergic agonists in untreated mild-to-moderately hypertensive patients (n = 22). Each patient underwent a single study. Forearm blood flow was recorded by strain gauge venous plethysmography; all drugs were infused into the brachial artery at systemically ineffective rates. Cumulative dose-response curves to intra-arterial methoxamine or B-HT 933 were obtained during saline or two different rates of verapamil infusion (0.9 and 3.1 micrograms/100 ml forearm tissue per min) which increased forearm blood flow dose-dependently without changing systemic blood pressure or heart rate. Either methoxamine or B-HT 933 decreased forearm blood flow during saline infusion, but their effect was blunted in a dose-dependent manner during verapamil. No evidence of preferential alpha 2-antagonism was present. At variance with animal data, calcium entry blockade by verapamil antagonizes either alpha 1- or alpha 2-mediated vasoconstriction in human forearm vessels.

Adrenergic alpha-Agonists↗
PubMed1986

Potassium-rich and sodium-poor salt reduces blood pressure in hospitalized patients.

To investigate whether a K-rich/Na-poor salt is able to reduce blood pressure, 10 mildly hypertensive inpatients (six males) aged 28-53 years, with supine diastolic blood pressure (DBP) greater than 95 mmHg after 5 days of hospitalization, on a standard diet containing about 20 mmol Na plus 4 g common salt (CS) were randomly given, in double-blind conditions, 2 g twice daily of either CS (five patients) or K-rich/Na-poor salt (five patients) to add to food for a further 8 days. Mean blood pressure was significantly (P less than 0.01) reduced to a similar extent in both groups in the first 4 days, and declined significantly (P less than 0.01) only in the K/Na group in the following 8 days, reaching values significantly (P less than 0.01) lower than those of the CS group. The heart rate did not change significantly while body weight decreased to a similar extent in both groups. Urinary sodium excretion was similarly and significantly (P less than 0.01) reduced in both groups in the first 4 days (CS 100.8 +/- 7.9 and K/Na 100.2 +/- 11.0 mmol/24 h, and remained unchanged in the CS group (109.9 +/- 4.3 mmol/24 h) but declined significantly (P less than 0.05) by about 50% in the K/Na group (62.9 +/- 3.6 mmol/24 h) in the following 8 days. Plasma renin activity (PRA) and plasma noradrenaline did not differ significantly between the two groups, nor among the days of treatment, but the mean blood pressure response to mental stress was reduced significantly (P less than 0.4) in the Na/K group compared with the CS group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Influence of food on acute and chronic effects of captopril in essential hypertensive patients.

To determine if food reduces the hemodynamic and humoral effects of captopril in patients with essential hypertension, we performed two studies. In the acute study, 15 inpatients with uncomplicated essential hypertension randomly received a single oral dose of placebo or captopril (25 mg) while fasting or after eating, or captopril (50 mg) after eating. Blood pressure and heart rate were measured every 30 min up to 4 h (and up to 10 h in six out of the 15 patients), while plasma renin activity, plasma aldosterone, and serum angiotensin-converting enzyme were measured 2 h after dosing. Compared with placebo, captopril significantly reduced mean blood pressure (p less than 0.001), serum angiotensin-converting enzyme (p less than 0.005), and aldosterone (p less than 0.001), increased plasma renin activity (p less than 0.05), and did not change heart rate; there was no difference between the fasting and the fed state. In the six patients followed up to 10 h, captopril both before and after food significantly and similarly reduced mean blood pressure up to 8 h (p less than or equal to 0.05). In the chronic study, 10 patients with uncomplicated essential hypertension, while having prolonged (3-12 months) treatment with captopril (50 mg twice a day), were asked to take captopril for 1 month 1 h before eating and for another month during or immediately after eating. The sequence was randomized, and blood pressure, heart rate, plasma renin activity, serum angiotensin-converting enzyme, and plasma aldosterone were measured at the end of each period 12 h after last dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Naloxone does not modify the antihypertensive effect of captopril in essential hypertensive patients.

It has been reported that endogenous opioid antagonism through naloxone (NAL) blunts the hypotensive effect of captopril (CAP) in normal man. For this reason a study was carried out to determine whether NAL interacts with the antihypertensive effect of CAP in patients with mild-to-moderate essential hypertension (n = 6; age 22-43 years). Patients received, according to a randomized code, placebo (PL) during saline infusion, CAP (25 mg orally) during saline infusion, PL + NAL (0.4 mg as a bolus followed by a continuous infusion of 4.0 mg/h for 2 h) and CAP + NAL at the same doses. Three-day intervals elapsed between each phase of the study. Blood pressure (BP) and heart rate (HR) were recorded before (-20 to 0 min) and every 15 min for the next 2 h after drug administration. Blood samples for plasma renin activity (PRA), noradrenaline (NA) and aldosterone (ALD) were collected before (time 0) and 120 min after drug administration. Neither PL nor NAL changed any of the parameters examined, while CAP alone reduced mean BP to a highly significant extent. Naloxone did not change the hypotensive effect of CAP to any significant extent. Captropril, either alone or associated with NAL, tended to reduce plasma ALD and increase PRA (P less than 0.05) without changing HR or plasma NA. These data indicate that, at least under the experimental conditions used, endogenous opioid antagonism does not interfere with the haemodynamic and humoral effect of CAP in essential hypertensive man. This suggests that endogenous opioids do not mediate the pharmacological actions of CAP.

Adult↗
PubMed1985

Angiotensin-converting enzyme inhibitors in hypertension: a review.

Angiotensin-converting enzyme (ACE) inhibitors are a new class of drugs, whose main indications are the treatment of hypertension and of heart failure. Data obtained with captopril, the first orally active ACE inhibitor, affords an understanding of the rationale of their therapeutic use based on the knowledge of their mechanisms of action, efficacy, contraindications and precautions, dosage and frequency of administration, side-effects, interactions and advantages. ACE inhibitors appear to exert their haemodynamic effect mainly by inhibiting the renin-angiotensin-aldosterone system, but also by modulating sympathetic nervous system activity and by increasing prostaglandin synthesis. Therefore they act both on vasoconstrictor and volume factors, since they cause vasodilation (the main effect) and mild natriuresis without affecting the heart rate and contractility and, probably, favourably influencing renal, coronary and cerebral circulation. So far it appears that ACE inhibitors can be usefully employed in the treatment of heart failure, in which they reduce both pre- and after-load, and mainly of hypertension. In the past captopril has been used to treat only severe and or resistant hypertension and some secondary forms, like renal parenchymal and renovascular hypertension, but now it seems that captopril is useful also to treat mild to moderate essential hypertension. Their efficacy in reducing blood pressure is similar to that of thiazide diuretics and of beta-blockers, the two drugs now considered of first choice and they exert their hypotensive action without the development of pseudotolerance or tolerance. ACE inhibitors seem, at the moment, contraindicated in pregnancy and in hyperkalaemic syndromes and must be used with caution in patients with collagen disease (mainly associated with renal failure), with severe bilateral renal artery stenosis (and with severe artery stenosis of a solitary kidney) and with severe sodium depletion. It is now established that captopril has a flat dose response curve and that it must be given (twice daily) at a dose not exceeding 150 mg/day. The same pharmacological approach must be used with future ACE inhibitors in order to establish the right posology and the frequency of administration. In this respect enalapril seems to be a promising ACE inhibitor with a prolonged action (at least 24 hours). The exact posology of ACE inhibitors might be crucial, since it has been shown that the side-effects of captopril (skin rashes, fever, taste disturbances, proteinuria and neutropenia) are dose dependent.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗