[Hypertension and depression].
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Depression↗
Biomedical subjects
A Salvetti
Publications and source records attributed to A Salvetti.
Effect of insulin on acetylcholine-induced vasodilation in normotensive subjects and patients with essential hypertension.
BACKGROUND: The present study was designed to directly test the vasodilation action of insulin and its relation to endothelium-dependent mechanisms. METHODS AND RESULTS: In 18 normotensive subjects and 27 patients with untreated mild to moderate essential hypertension, we studied the effect of intrabrachial insulin on the changes in forearm blood flow (strain-gauge plethysmography) induced by intrabrachial acetylcholine (at doses of 0.15, 0.45, 1.5, 4.5, and 15 micrograms.min-1.dL-1), an endothelium-dependent vasodilator, or sodium nitroprusside (at doses of 1, 2, and 4 micrograms.min-1.dL-1), and endothelium-independent vasodilator. Local hyperinsulinemia (deep venous plasma insulin, 48 +/- 6 and 51 +/- 5 microU/mL in control subjects and hypertensive patients, respectively) did not affect basal forearm blood flow and stimulated forearm glucose extraction (control subjects, 3 +/- 1% to 11 +/- 2%, P < .001; hypertensive patients, 3 +/- 1% to 6 +/- 1%, P < .001; P < .01 for the between-group difference). In both normotensive and hypertensive subjects, insulin significantly potentiated acetylcholine-induced vasodilation, whereas it did not alter the vasodilatory response to sodium nitroprusside. NG-monomethyl-L-arginine, an inhibitor of endothelial nitric oxide synthesis, blunted insulin-induced facilitation of acetylcholine vasodilation in normotensive but not in hypertensive subjects. In contrast, in hypertensive patients but not in normotensive control subjects, the potentiation of the vascular response to acetylcholine induced by local hyperinsulinemia was abolished by intrabrachial ouabain, an inhibitor of Na(+)-K+ pump. CONCLUSIONS: In healthy humans and essential hypertensive patients alike, local physiological hyperinsulinemia per se does not increase forearm blood flow but potentiates the vasodilation induced by acetylcholine regardless of metabolic insulin resistance. This effect is endothelium-dependent because it is not seen with nitroprusside and is related to the L-arginine-nitric oxide pathway in normotensive subjects and to smooth muscle cell hyperpolarization in essential hypertensive patients.
Acetylcholine↗
Aging and endothelial function in normotensive subjects and patients with essential hypertension.
BACKGROUND: Experimental data from normotensive and hypertensive animals indicate that aging is associated with impaired endothelium-dependent relaxations to acetylcholine, and this possibility appears to be confirmed in the human coronary artery. In the present study, we evaluated the effect of age on endothelial responsiveness in the forearm vessels of either normotensive control subjects or essential hypertensive patients. METHODS AND RESULTS: Within the normotensive or hypertensive group (n = 53 and n = 57, respectively), subjects were selected with similar blood pressure, plasma cholesterol, and glucose values, and hypercholesterolemic subjects, diabetics, and smokers were excluded. We evaluated forearm blood flow (by strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 micrograms/100 mL per minute), an endothelium-dependent vasodilator, and sodium nitroprusside (1, 2, and 4 micrograms/100 mL per minute), an endothelium-independent vasodilator. Acetylcholine caused a dose-dependent vasodilation that was significantly (P < .01) lower in essential hypertensive patients than in normotensive control subjects. However, a significant negative correlation was observed between acetylcholine-induced vasodilation and patient age in both normotensive (r = -.86, P < .001) and hypertensive (r = -.85, P < .001) patients. In contrast, vasodilation to sodium nitroprusside was similar in normotensive control subjects and essential hypertensive patients with a poorer inverse correlation with patient age (normotensive control subjects, r = -.37; hypertensive patients, r = -.36) compared with acetylcholine. CONCLUSIONS: The present data indicate that there is a blunted response to acetylcholine with advancing age in both normotensive control subjects and essential hypertensive patients, suggesting that aging is associated with reduced endothelium-dependent vasodilation in humans.
Acetylcholine↗
Functional retroviral vector for gene therapy of xeroderma pigmentosum group D patients.
Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder characterized by an increased frequency of skin cancer following minimal sunlight exposure. Cells isolated from XP patients are also hypersensitive to UV rays and UV-like chemicals. This sensitivity is directly related to a defect in the early steps of nucleotide excision repair (NER) of damaged DNA. No efficient treatment is available for this disease and skin cancer prevention can only be achieved by strict avoidance of sunlight exposure. Thus, we are developing a model for gene therapy in XP, particularly for patients belonging to group D. We report here the construction of a retroviral vector (LXPDSN) containing the XPD (ERCC2) cDNA, which fully complements the DNA repair deficiency of primary skin fibroblasts. Efficient integration, mRNA synthesis, and protein expression of the XPD gene were obtained in all LXPDSN-transduced XP-D fibroblasts tested. Full correction of the DNA repair defect was observed with all DNA repair assays used, such as an increased survival after UV-radiation of the transduced cells, a normal level of DNA repair synthesis (UDS), and the reactivation of a UV-irradiated reporter vector. This retroviral vector will be used to modify keratinocytes genetically to produce repair proficient reconstituted skin for engraftment to XP patients.
Cell Survival↗
In vivo delivery of human alpha-L-iduronidase in mice implanted with neo-organs.
Mucopolysaccharidose type I is a lysosomal storage disease caused by a deficiency in the enzyme alpha-L-iduronidase (IDUA). The existence of a secretory pathway for lysosomal enzymes and the capture of secreted molecules by distant cells through binding to mannose-6-phosphate receptors have provided a rationale for enzyme replacement therapy in lysosomal storage diseases. We have used genetically modified fibroblasts implanted into neo-organs as an in vivo delivery system for IDUA. The human IDUA cDNA was isolated and inserted into a retroviral vector where it was expressed from the phosphoglycerate kinase 1 gene promoter. MPS I fibroblasts transduced with this vector showed high levels of IDUA activity and secreted phosphorylated molecules that could be internalized by naive deficient cells. Neo-organs containing 2 x 10(7) IDUA-secreting cells were implanted into nude mice. Human and murine IDUA activities were measured in the liver and spleen of animals sacrificed 35-77 days after implantation. Human IDUA activity corresponded to 0.6-2.3% of the murine enzyme activity in the liver and to 0.1-0.3% in the spleen. These data indicated that human IDUA was secreted from neo-organs and internalized in distant tissues.
Animals↗
Gene therapy of lysosomal storage disorders.
Lysosomal storage disorders (LSD) result from deficiencies in enzymes normally implicated in the catabolism of macromolecules inside the lysosome. Many of these enzymes can reach the lysosome after being secreted in the extracellular medium and recaptured by specific cell surface receptors. This has suggested a rationale for therapeutic approaches in LSD, in which the missing enzyme is provided by an external source. Current therapies based on this concept, including the administration of purified enzyme and bone marrow transplantation, have been shown to result in clinical improvements in both animal models and patients. Although considerable difficulties must be surmounted, LSD present a favourable situation for gene therapy. The gene corresponding to the affected enzyme has been identified in most diseases and cDNAs are available. Low and unregulated levels of enzyme activity should be sufficient for correction. Importantly, a variety of gene transfer strategies can be carefully evaluated in animal models.
Animals↗
Lack of correlation between microalbuminuria and endothelial function in essential hypertensive patients.
OBJECTIVE: To evaluate whether microalbuminuria, defined as urinary albumin excretion between 30 and 300 mg/24 h, is associated with endothelial dysfunction in essential hypertensive patients. DESIGN: We correlated urinary albumin excretion with vasodilatation in response to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) agonists in the forearm vascular bed in essential hypertensive patients with (n = 13) and without (n = 23) microalbuminuria and matched normotensive controls (n = 21). METHOD: We studied forearm vascular responses (strain-gauge plethysmography) to intrabrachial infusion of acetylcholine (0.15, 0.45, 1.5, 4.5 and 15 ng/100 ml forearm tissue/min) and of sodium nitroprusside (1, 2, 4ng/100 ml forearm tissue per min). Minimal forearm vascular resistances (the ratio between mean arterial pressure and maximal forearm vasodilation induced by 13 min of ischaemia + 1 min of exercise) were also evaluated. RESULTS: Responses to acetylcholine, but not to sodium nitroprusside, were significantly blunted and minimal forearm vascular resistances were increased in hypertensive patients compared with controls. However, no correlation was found between urinary albumin excretion and vasodilatation in response to acetylcholine or to sodium nitroprusside or between urinary albumin excretion and minimal forearm vascular resistances. CONCLUSIONS: In hypertensive patients, increased urinary albumin excretion is associated neither with functional nor with structural dysfunction in the forearm vasculature.
Acetylcholine↗
Angiotensin II and sympathetic activity in sodium-restricted essential hypertension.
Angiotensin II (Ang II) potentiates sympathetic neurotransmission by presynaptic facilitation of norepinephrine release. We investigated whether endogenous Ang II modulates peripheral sympathetic activity in sodium-depleted essential hypertensive patients. We evaluated the effect of intrabrachial infusion of saralasin, an Ang II antagonist (5 micrograms/100 mL forearm tissue per minute), and benazeprilat, an angiotensin-converting enzyme inhibitor (2 micrograms/100 mL forearm tissue per minute), on forearm vasoconstriction (measured by strain-gauge venous plethysmography) induced by the application of lower body negative pressure (-10 mm Hg for 5 minutes). Both saralasin and benazeprilat (n = 6 for each group) blunted the vasoconstrictor action of lower body negative pressure, suggesting that circulating Ang II modulates peripheral sympathetic activity. In addition, since beta-adrenoceptor stimulation can activate the production of vascular Ang II, the effect of saralasin and benazeprilat on lower body negative pressure application was evaluated in the presence of isoproterenol (0.09 microgram/100 mL forearm tissue per minute) and propranolol (10 micrograms/100 mL forearm tissue per minute). In two other groups of hypertensive patients, isoproterenol infusion increased the release of Ang II in the forearm vasculature (arteriovenous values measured by radioimmunoassay). Furthermore, isoproterenol potentiated lower body negative pressure-induced vasoconstriction. This facilitating effect was abolished by either saralasin or benazeprilat (n = 6 for each group). In contrast, in two further groups of patients (n = 6 for each group), in the presence of the beta-blocker propranolol saralasin and benazeprilat did not alter the vasoconstrictor action of the endogenous sympathetic stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Endothelial function and arterial hypertension].
In normotensive humans, the endothelium modulates vascular tone mainly by the production of nitric oxide. In human essential hypertension the basal release of nitric oxide is reduced and forearm vasodilation to the endothelium-dependent agonists acetylcholine or bradykinin is blunted. Defective basal release of nitric oxide seems to be secondary to blood pressure increase while impaired agonist-evoked endothelium-dependent vasodilation is probably a primary phenomenon. This latter endothelial dysfunction seems to be caused by the simultaneous presence of an alteration in the L-arginine-nitric oxide pathway and the production of constrictor prostanoids. Defective nitric oxide production is already detectable in normotensive offspring of hypertensive patients and young essential hypertensives. In contrast, vasoconstrictor prostanoid production seems to be associated with aging. In essential hypertensive patients, although only scanty data are available, chronic effective pharmacological treatment seems to restore impaired basal production of nitric oxide but does not improve vascular response to endothelial agonists.
Aging↗
[The trough/peak ratio].
The trough-to-peak ratio expresses the quantitative relation between the antihypertensive effect of a drug or association of drugs measured at the end of a between-dose interval, and the maximum antihypertensive effect recorded during this interval. When this ratio is evaluated in responders, and a properly designed protocol that also takes blood pressure measurement into consideration is adopted, it becomes a reliable index of the duration-efficacy of antihypertensive therapy. For this reason, it constitutes a safety parameter required by the Food and Drug Administration to prevent the risk of drugs with shortlived action from being administered at excessive doses in the attempt to prolong the duration of drug action. In addition, a favorable trough-to-peak ratio (> 0.50 and preferably close to 1.0) is an index of homogeneous blood pressure control over a given between-dose interval. Pharmacological treatment that achieves this antihypertensive effect might be more efficient in preventing and/or causing regression of target organ damage and can improve patient compliance with antihypertensive therapy.
Antihypertensive Agents↗
[History of the pharmacologic therapy of arterial hypertension: from diuretics to angiotensin II receptor antagonists].
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Angiotensin II↗
Effects of long-term simvastatin treatment on testicular and adrenal steroidogenesis in hypercholesterolemic patients.
Simvastatin is an inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, the key enzyme in the synthesis of cholesterol, recently introduced in the therapy of hypercholesterolemic patients. Cholesterol is the precursor of the biosynthesis of steroid hormones; thus, a reduction of the availability of cholesterol in the adrenal and testicular cells may reduce the synthesis of corticosteroids and androgens. To establish whether chronic therapy with simvastatin interferes with the integrity of the hypothalamic-pituitary-adrenal axis and with the adrenal and testicular reserve, we administered simvastatin orally in a single-day 10 mg dose for 6 months in 8 mildly hypercholesterolemic male patients. At weeks 0, 6 and 24 of treatment we evaluated the lipids, the activity of the hypothalamic-pituitary-adrenal axis by means of the Corticotropin-Releasing Hormone (CRH) test, the adrenal reserve by means of the Corticotropin rapid test and, finally, the testicular reserve by means of the Human Chorionic Gonadotropin (HCG) test. Total cholesterol and LDL-cholesterol were significantly reduced by Simvastatin, while the HDL-cholesterol and triglycerides did not change significantly. The hormonal responses to CRH, ACTH and HCG tests at weeks 6 and 24 of treatment were comparable to those obtained in basal conditions. We conclude that Simvastatin, while effective in reducing total and LDL-cholesterol in hypercholesterolemic male patients, did not interfere with hypothalamic-pituitary-adrenal axis activity or with basal and stimulated adrenal and testicular steroidogenesis.
Adrenocorticotropic Hormone↗
Vascular renin-angiotensin system and sympathetic nervous system activity in human hypertension.
Experimental data indicate the existence of a vascular tissue renin-angiotensin system in several different vessels from various animal models. Active renin can be locally synthesized into the vessel wall or taken up from circulating plasma to produce vascular angiotensin II. Using the human forearm technique, we produced evidence indicating the release of active and inactive renin and of angiotensin II from the vessels of hypertensive patients. Moreover, the production of vascular angiotensin II seems to be strictly correlated to the circulating renin profile, suggesting the possibility that vascular renin might be at least partially taken up from plasma. To investigate a possible function of the vascular renin-angiotensin system, we studied its interaction with sympathetic neurotransmission in essential hypertensive patients. In line with animal studies, vascular angiotensin II increases the vasoconstriction induced by the stimulation of the sympathetic nervous system through the potentiation of noradrenaline release at a presynaptic level, and this effect seems to be mediated by beta-adrenoceptor activation. This facilitating effect on sympathetic neurotransmission exerted by vascular angiotensin II can be antagonized by both angiotensin II antagonists and angiotensin-converting enzyme inhibitors.
Blood Vessels↗
Clinical pharmacology of long-acting calcium antagonists: what relevance for therapeutic effects?
The pharmacologic goals of long-acting calcium (Ca) antagonists are to obtain effective drug concentrations with low interdose fluctuations and therefore a more efficacious hypotensive effect throughout the interval of administration, with a reduction in blood pressure variability. The therapeutic relevance of these pharmacologic properties could be more efficient prevention of target-organ damage (TOD) and improvement of treatment compliance. Because TOD seems to be more closely related to 24-h mean blood pressure and blood pressure variability, effective control of blood pressure throughout the entire dosage interval, with a concomitant reduction in blood pressure variability, may reduce TOD. However this hypothesis awaits validation in prospective studies. Long-acting Ca antagonists can improve medication compliance through the following mechanisms: a more favorable dosage schedule by avoidance of more than two doses daily during combination therapy and by allowing choice of timing of dosing; efficacy in reducing blood pressure, which can be assessed by the patients themselves; and reduction in incidence and severity of side effects. Lacidipine, a long-acting dihydropyridine Ca antagonist, when given at the dose of 4 mg once daily has a favorable trough:peak efficacy and reduces blood pressure variability. Moreover, compared with a shorter-acting dihydropyridine drug, lacidipine caused a lower incidence of adverse effects linked to vasodilation.
Calcium Channel Blockers↗
Effect of potassium on vasodilation to acetylcholine in essential hypertension.
Patients with essential hypertension show impaired endothelium-dependent vasodilation induced by acetylcholine. Because dietary potassium supplementation increases endothelium-dependent relaxations to acetylcholine in hypertensive rats, we designed the present study to investigate whether potassium increases endothelium-dependent vasodilation in essential hypertensive patients. Therefore, in patients with essential hypertension (n = 13) and in normotensive control subjects (n = 13) we evaluated the effect of intrabrachial potassium chloride (0.2 mmol/min) on forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 micrograms/100 mL forearm tissue per minute). In both groups of patients, potassium chloride infusion augmented local plasma potassium concentrations. Furthermore, in essential hypertensive patients but not in normotensive subjects it increased the vasodilating effect of the first three infusion rates of acetylcholine. In contrast, in seven adjunctive essential hypertensive patients, potassium chloride did not alter intrabrachial sodium nitroprusside-induced forearm vasodilation (1, 2, and 4 micrograms/100 mL forearm tissue per minute). Finally, to evaluate the role of nitric oxide on potassium-dependent facilitation of acetylcholine-induced vasodilation in essential hypertension, we studied the effect of intrabrachial NG-monomethyl L-arginine (100 micrograms/100 mL per minute) in another group of seven hypertensive patients. Vasodilation to acetylcholine was again increased by potassium chloride; NG-monomethyl L-arginine slightly blunted the vasorelaxing effect of acetylcholine but abolished the potentiating effect of potassium.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine↗
Hemodynamic and humoral effects of low-dose aspirin in treated and untreated essential hypertensive patients.
Aspirin at low doses is used as an inhibitor of platelet aggregation and is frequently administered to essential hypertensive patients with arterial thrombotic complications. However, it is unknown whether aspirin can modify blood pressure values either in treated or untreated hypertensive patients, as described for other non steroidal anti-inflammatory drugs. Thus 30 patients. 10 with mild uncomplicated and untreated essential hypertension, 10 with essential hypertension under chronic treatment with captopril, 50 mg bid, and 10 with essential hypertension under chronic treatment with atenolol, 100 mg oid, received aspirin, 100 mg oid, and the corresponding placebo for one month, according to a double blind randomized cross-over design. At the end of each treatment, blood pressure, heart rate, generated serum thromboxane B2 and urinary excretion of thromboxane B2 and 6 keto prostaglandin F1 alpha and plasma renin activity were measured. Both in treated and untreated essential hypertensive patients, aspirin administration did not affect blood pressure, heart rate and urinary 6 keto prostaglandin F1 alpha, while it significantly reduced serum and urinary excretion of thromboxane B2 and plasma renin activity. In conclusion, while the present data confirm that low doses of aspirin selectively inhibit thromboxane B2 synthesis, they indicate that aspirin at 100 mg oid can be administered to treated and untreated essential hypertensive patients without any harmful effect on blood pressure values.
Adult↗
[Clinical experience with angiotensin II antagonists in arterial hypertension].
Theoretical considerations and experimental data suggest that AT1-antagonists can offer the same advantages as ACE-inhibitors in the treatment of hypertensive patients without causing side effects such as angioedema and cough. The pharmacokinetic properties of these drugs suggest that AT1-antagonists can be given once-daily. Preliminary data obtained with losartan indicate that this drug, given once daily, significantly reduced blood pressure with a favourable trough to peak ratio. Moreover the hypotensive effect of this drug was similar to that exerted by other hypotensive drugs currently employed in the treatment of hypertensive patients. Losartan can be usefully combined with a thiazide diuretic inducing an additive antihypertensive effect. No negative effect on lipid and glucose profiles was recorded. Furthermore, losartan exerted an uricosuric action, thus reducing serum uric acid. Preliminary data suggest that the incidence of cough in patients treated with losartan was similar to that observed in patients receiving placebo or a thiazide diuretic. Although these data need to be confirmed by ongoing and future studies, it is tempting to hypothesize that this new class of antihypertensive drugs can offer a further useful tool in the treatment of hypertensive patients.
Angiotensin II↗
Effects of cilazapril and nitrendipine on blood pressure, mood, sleep, and cognitive function in elderly hypertensive patients: an Italian multicenter study.
To evaluate its antihypertensive efficacy and safety in elderly hypertensive patients, the angiotensin-converting enzyme inhibitor cilazapril was compared to the calcium antagonist nitrendipine in a randomized, double-blind, multicenter trial with 114 subjects (mean age, 68 years; diastolic blood pressure, 90-115 mm Hg; systolic blood pressure, 140-220 mm Hg). After a 1-month placebo washout period, patients received either cilazapril, 2.5-5 mg, or nitrendipine, 10-20 mg, once daily for 12 weeks. After 4 weeks, the dose was doubled in non-responders. The higher dosage level was administered to 42% of patients in the cilazapril-treated group and to 47% in the nitrendipine-treated group. Blood pressure was measured before (at 60 min and 30 min, and just prior to administration) and at 60, 90, and 120 min after drug administration. Both cilazapril and nitrendipine significantly (p < 0.01) reduced systolic and diastolic blood pressure. The decrease in systolic blood pressure measured at trough was significantly greater with cilazapril than with nitrendipine (-17 vs. -12 mm Hg, p < 0.05), but the effect of the two drugs on diastolic blood pressure was similar (-11 mm Hg). Tolerability was assessed by means of adverse events, laboratory assessments, psychometric tests, and questionnaires on mood states and sleep. Adverse events were reported by 9% of patients in the cilazapril group and by 21% of patients in the nitrendipine group (p < 0.05). Laboratory test results and profiles for mood, sleep, memory, and attention were not affected by either treatment. Thus, cilazapril and nitrendipine both appear to be effective and well tolerated antihypertensive agents in the elderly patient.
Affect↗