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Biomedical subjects

R Pedrinelli

Publications and source records attributed to R Pedrinelli.

At least 91 records · Page 5Linked 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

Forearm vasodilatory capacity in patients with syndrome X: a comparison with normal and hypertensive subjects.

Minimal forearm vascular resistances during maximal postischaemic vasodilation were measured in normotensive subjects with syndrome X, a condition characterized by angina and normal coronary arteries, in which a reduced coronary and systemic vasodilatory capacity has been reported. Age- and sex-matched normals and essential hypertensives constituted the control groups. The syndrome X patients had a significantly higher minimal forearm vascular resistance than the normals, indicating that arteriolar alterations may occur in the normotensive state and therefore cannot be considered solely as a consequence of hypertension.

Angina Pectoris↗
PubMed1989

Regional and systemic hemodynamic and humoral effects of transdermal nitroglycerin in mild hypertension.

Venous distensibility, forearm blood flow (FBF, plethysmographic technique), systemic blood pressure (BP), and derived forearm vascular resistances were measured in 11 borderline-mild hypertensive, otherwise healthy male subjects for a 24-h period during either placebo or transdermally delivered nitroglycerin (NTG 10 mg/24 h). The drug caused arteriolar and venular forearm vasodilation and hypotension which, although persisting throughout the 24-h observation period, reached an apparent maximum during the first hours but later tended to wane. Since NTG plasma levels were constant at that time, the data may suggest development of vascular hyporesponsiveness during continuous exposure to NTG. Venous hematocrit (Hct) decreased during transdermal NTG, indicating the plasma volume expanding action of the drug, apparently dissociated from vasodilation per se. Because no significant changes in either plasma norepinephrine (NE) or plasma renin activity occurred in these subjects, counterregulatory sympathetic or angiotensin II (AII)-mediated vasoconstriction was probably not involved in the hemodynamic action of transdermally delivered NTG.

Administration, Cutaneous↗
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

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

Insulin resistance in essential hypertension.

High blood pressure is prevalent in obesity and in diabetes, both conditions with insulin resistance. To test whether hypertension is associated with insulin resistance independently of obesity and glucose intolerance, we measured insulin sensitivity (using the euglycemic insulin-clamp technique), glucose turnover (using [3H]glucose isotope dilution), and whole-body glucose oxidation (using indirect calorimetry) in 13 young subjects (38 +/- 2 years [+/- SEM]) with untreated essential hypertension (165 +/- 6/112 +/- 3 mm Hg), normal body weight, and normal glucose tolerance. In the postabsorptive state, all measures of glucose metabolism were normal. During steady-state euglycemic hyperinsulinemia (about 60 microU per milliliter), hepatic glucose production and lipolysis were effectively suppressed, and glucose oxidation and potassium disposal were normally stimulated. However, total insulin-induced glucose uptake was markedly impaired (3.80 +/- 0.32 vs. 6.31 +/- 0.42 mg per minute per kilogram of body weight in 11 age- and weight-matched controls, P less than 0.001). Thus, reduced nonoxidative glucose disposal (glycogen synthesis and glycolysis) accounted for virtually all the defect in overall glucose uptake (1.19 +/- 0.24 vs. 3.34 +/- 0.44 mg per minute per kilogram, P less than 0.001). Total glucose uptake was inversely related to systolic or mean blood pressure (r = 0.76 for both, P less than 0.001). These results provide preliminary evidence that essential hypertension is an insulin-resistant state. We conclude that this insulin resistance involves glucose but not lipid or potassium metabolism, is located in peripheral tissues but not the liver, is limited to nonoxidative pathways of intracellular glucose disposal, and is directly correlated with the severity of hypertension.

Adult↗
PubMed1987

Plasma renin activity does not predict the antihypertensive efficacy of chlorthalidone.

It has been established that angiotensin II stimulation may limit the antihypertensive potential of diuretic therapy in some patients. It is less clear, however, whether renin-angiotensin II stimulation is the cause of the flat blood pressure dose-response relationship to diuretics. To investigate this, 75 out-patients with essential hypertension were treated with chlorthalidone 12.5, 25 or 50 mg o.d. for 3 weeks, in a double-blind, placebo controlled cross-over study. Chlorthalidone significantly reduced blood pressure in all the groups, a plateau being reached at 25 mg o.d. Similarly, plasma renin activity was increased by each dose level of chlorthalidone, but it showed a different trend, being increased to a comparable extent at 12.5 mg and 25 mg o.d., and still higher at 50 mg o.d. Thus, greater stimulation of renin was coincident with the levelling of the blood pressure response to chlorthalidone. However no significant correlation was found between interindividual plasma renin activity and change in blood pressure, either in the entire series, or in each treatment subset. The data suggest overall that renin stimulation may influence the characteristic dose-hypotensive response relationship to diuretic agents in antihypertensive therapy, but it is unlikely that measurement of individual plasma renin activity will provide an useful guide to the optimal dose of a diuretic agents.

Adult↗
PubMed1987

Hemodilution affects the pressor response to norepinephrine.

A hindlimb preparation of 19 male rats was used to determine the responses to norepinephrine (NE) at different levels of hemodilution at a constant flow, at increased flow and maintained pressure, and after reversal of hemodilution. An initial series demonstrated that the preparation remained stable with unchanged blood pressure, plasma electrolytes, and blood gases; and had reproducible responses to NE throughout the experiment. Two levels of isovolumic hemodilution were achieved by blood/hetastarch exchanges equivalent to 1.5% and 3.0% body weight, which reduced hematocrit to 30.8 +/- 2% and 18.7 +/- 1.5%, respectively. Hemodilution reduced the perfusion pressure from 73.6 mmHg to 58.6 and 55.7 mmHg following 1.5% and 3.0% hemodilution, respectively. A dose-response relationship to NE (0.1, 0.3, 1.0 micrograms/kg) was obtained. The responses to NE were markedly reduced following both 1.5% and 3.0% hemodilution. Retransfusion of packed red blood cells increased the hematocrit from 21.1 +/- 2.2% during hemodilution to 41.2 +/- 2.1% (P less than .01). Concomitantly, perfusion pressure increased from 46.2 +/- 3.6 to 68.3 +/- 6.5 mmHg (P less than .001), close to prehemodilution levels (65.3 +/- 5.3 mmHg). Restoration of hematocrit levels restored responses to NE. In a third series, hemodilution was continued, but the blood flow was increased from 4.0 to 8.3 +/- 0.9 mL/min, and perfusion pressure returned to baseline values. This also restored the pressor responsiveness to NE to near normal.

Animals↗
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

Indomethacin reduces the antihypertensive action of enalapril.

We evaluated the influence of indomethacin on the pharmacological actions of Enalapril in 9 uncomplicated essential hypertensives. While on chronic treatment with Enalapril, these patients randomly received indomethacin (50 mg bid) or a corresponding placebo for 1 week and the opposite treatment after a 2 week interval. Indomethacin, which decreased serum thromboxane B2 and urinary 6-keto prostaglandin-F1 alpha, reduced the plasma renin activity (PRA) increased by Enalapril. Indomethacin did not modify serum ACE, whose activity had been reduced by the ACE inhibitor. Mean blood pressure (MBP) values, which were significantly and to a similar extent reduced by Enalapril at the beginning of the cross-over, after placebo addition and at the end of the two week interval, were significantly increased by indomethacin, despite being still significantly lower than baseline values. These data show that systemic and renal prostaglandin (PG) synthesis inhibition induced by indomethacin can blunt the antihypertensive effect of chronic Enalapril treatment in patients with essential hypertension.

6-Ketoprostaglandin F1 alpha↗
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

Nitrendipine, a calcium-entry blocker. Renal and humoral effects in human arterial hypertension.

Thirteen patients with hypertension and normal renal function received nitrendipine, a calcium entry blocker. Nitrendipine did not modify renal blood flow (RBF) or glomerular filtration rate (GFR), decreased mean arterial pressure (MAP) and total peripheral resistance, and did not significantly change cardiac output. Individual RBF changes did not correlate with MAP or cardiac output modifications. Mean arterial pressure changes were inversely correlated with basal renin levels and directly associated with age. Plasma catecholamines and plasma renin activity increased, but plasma aldosterone and plasma volume did not change significantly. However, the greater decrements of MAP tended to be associated with the greater increases in plasma volume. Data show that long-term calcium entry blockade by nitrendipine does not modify RBF or GFR despite the decreased renal perfusion pressure. Further, nitrendipine may be more effective in older patients and the presence of low renin.

Adult↗