68 research outputs found
The interference by nicardipine and diltiazem on alpha-adrenergic receptor-mediated vasoconstriction in isolated human subcutaneous arterioles
No full textThe effects of nicardipine and diltiazem on alpha-adrenergic receptor-mediated vasoconstriction in isolated human subcutaneous arterioles was studied. Arterioles were mounted in a myograph and stimulated at 50% of maximal contraction with norepinephrine. The vasoconstrictor responses to an unrelated agonist, endothelin, was used for comparison. The percentage of decrement in tension produced by nicardipine or diltiazem was the parameter evaluated. Both calcium channel blockers caused an equipotent and dose-dependent relaxation of the vasoconstrictor responses to norepinephrine and endothelin I. The equipotent alpha-adrenolytic effect exerted by nicardipine and diltiazem in subcutaneous arterioles contrasts with the preferential antagonism by local nicardipine in the forearm. This suggests that the interaction between alpha-adrenergic receptor activation and structurally unrelated calcium channel blockers is affected by the regional and functional characteristics of the vessels under stud
Reactive hyperemia during short-term blood flow and pressure changes in the hypertensive forearm.
No full textThe aim of the present study was to further validate our method for the determination of minimal forearm vascular resistance after ischemia (13 min arterial occlusion and 1 min hand exercise) in patients with hypertension. This parameter, calculated as the ratio of mean blood pressure (intra-arterial recordings on the experimental side) to forearm blood flow (strain-gauge venous plethysmography), was measured basally and after either increasing (through unrelated vasodilators such as sodium nitroprusside or the calcium antagonist nicardipine in six mild-to-moderate uncomplicated hypertensives) or decreasing (norepinephrine, n = 4) flow without changes in systemic pressure. In spite of the divergent starting flow values, minimal postischemic forearm vascular resistance was unchanged, indicating a lack of relationship with functional arteriolar tone and the achievement of maximal dilatation. In two additional groups of patients, systemic arterial pressure was decreased by approximately equipotent oral doses of either nifedipine, a calcium antagonist (n = 6), or captopril, an angiotension converting enzyme inhibitor (n = 5). Under these conditions, minimal forearm vascular resistance was unchanged from pretreatment values, suggesting that local autoregulatory mechanisms were overridden during the reactive hyperemia, and that the vessel lumen was dependent on the distending pressure. Overall, the data show that our experimental conditions are suitable for measuring minimal forearm vascular resistance as a functional correlate of the morphological status of systemic arterioles in arterial hypertension
Calcium entry blockade and agonist-mediated forearm vasoconstriction in hypertensive patients. Difference between nicardipine and verapamil.
No full textThe interference by nicardipine and verapamil with the response to vasoactive stimuli, such as lower body negative pressure and angiotensin II, has been evaluated in the forearm of hypertensive patients. Forearm blood flow was monitored during the intraarterial infusion of either drug at rates equieffective on basal flow. Nicardipine blunted the peak forearm vasoconstrictor action of lower body negative pressure and a comparable result was obtained when angiotensin II was administered intraarterially. In spite of a comparable increase in forearm flow, nicardipine was more potent than verapamil in inhibiting vasoconstriction following both stimuli. Thus, nicardipine suppressed regional vascular reactivity, probably by blockade of the influx of extracellular calcium, in response to receptor activation, since both alpha-adrenergic and angiotensin II receptor-mediated vasoconstrictor responses were attenuated. However, the results of the comparison with an unrelated calcium entry blocker, such as verapamil, may suggest that nicardipine, and possibly other dihydropiridine derivatives, preferentially antagonize agonist-mediated vasoconstriction in the human forearm
Role of mechanical stress in the resistance drift of Ge2Sb2Te5 films and phase change memories
No full textMaximal postischemic forearm vasodilation in human hypertension: a reassessment of the method
No full textCalcium entry blockade and agonist-mediated vasoconstriction in hypertensive patients.
No full textThe effects of two chemically unrelated calcium channel blockers--nicardipine and verapamil--on vascular responses to exogenous norepinephrine were evaluated in uncomplicated hypertensive patients. Each drug was infused into the brachial artery at rates that did not affect systemic blood pressure or heart rate, and forearm blood flow was measured using strain gauge venous plethysmography. Nicardipine 1 microgram/100 ml forearm tissue/min dilated the forearm arterioles and antagonized the vasoconstrictor effect of norepinephrine, whereas verapamil 1 microgram/100 ml tissue/min was ineffective, even though both drugs relaxed basal tone to the same extent. The difference between nicardipine and verapamil was also evident when reflex forearm vasoconstriction was elicited by the application of a lower body negative pressure and the drugs were infused intra-arterially at 1 and 3 micrograms/100 ml tissue/min, respectively. To evaluate whether a comparable behavior might also hold for nonsympathomimetic agents, increasing doses of angiotensin II were administered to the forearm vascular bed after pretreatment with either nicardipine or verapamil. Both drugs increased forearm blood flow, but only nicardipine antagonized the effect of angiotensin II in the forearm, showing that the impairment of vasoconstrictor mechanisms was not dependent on a specific receptor. Important differences seem to exist between nicardipine and verapamil with regard to agonist-mediated vasoconstriction in hypertensive patients, which is consistent with the heterogeneity of calcium channel blockers as a pharmacological class. Preferential antagonism of a series of vasoconstrictor stimuli may characterize the vasodilatory and, possibly, the antihypertensive effect of nicardipin
Development and Validation of Novel Z-360-Based Macromolecules for the Active Targeting of CCK2-R
No full textThe cholecystokinin type 2 receptor (CCK2-R) represents an ideal target for cancer therapy since it is overexpressed in several tumors and is associated with poor prognosis. Nastorazepide (Z-360), a selective CCK2-R antagonist, has been widely investigated as a CCK2-R ligand for targeted therapy; however, its high hydrophobicity may represent a limit to cell selectivity and optimal in vivo biodistribution. Here, we present three new fluorescent Z-360 derivatives (IP-002(G)-Rho, IP-002(L)-Rho, and IP-002(M)-Rho) in which nastorazepide was linked, through spacers bearing different saccharides (glucose (G), lactose (L), and maltotriose (M)), to sulforhodamine B. A fourth compound (IP-002(H)-Rho) with no pendant sugar was also synthesized as a control. Through two-dimensional (2D) and three-dimensional (3D) in vitro studies, we evaluated the compound association with and selectivity for CCK2-R-overexpressing cells (A431-CCK2-R+) vs CCK2-R-underexpressing cells (A431 WT). 2D in vitro studies highlighted a progressive increase of IP-002(x)-Rho association with A431-CCK2-R+ cells according to the linker hydrophilicity, that is, maltotriose > lactose > glucose > hydrogen, with IP-002(M)-Rho showing a 2.4- and a 1.36-fold higher uptake than IP-002(G)-Rho and IP-002(L)-Rho, respectively. Unexpectedly, IP-002(H)-Rho showed a similar cell association to that of IP-002(L)-Rho but with no difference between the two tested cell lines. On the contrary, association with A431-CCK2-R+ cells as compared to the A431 WT was found to be 1.08-, 1.14-, and 1.37-fold higher for IP-002(G)-Rho, IP-002(L)-Rho, and IP-002(M)-Rho, respectively, proving IP-002(M)-Rho to be the best-performing compound, as also confirmed by competition studies. Trafficking studies on A431-CCK2-R+ cells incubated with IP-002(M)-Rho suggested the coexistence of receptor-mediated endocytosis and simple diffusion. On the contrary, a high and selective uptake of IP-002(M)-Rho by A431-CCK2-R+ cells only was observed on 3D scaffolds embedded with cells, underlining the importance of 3D models in in vitro preliminary evaluation
Atrial natriuretic factor as a vasodilator agent in hypertensive patients.
No full textTo investigate the role of Atrial Natriuretic Factor (ANF) in modulating arteriolar tone in hypertension, a synthetic 25 AA human ANF-analogue (anaritide) was infused intraarterially in the forearm vascular bed of five patients with mild hypertension. A dose-dependent increase in blood flow (plethysmographic technique) was seen at rates covering a thousand-fold range (0.008, 0.08, 0.8, 8.0 micrograms/dl tissue/min x 15 minutes each). At the lowest infusion rate, the forearm blood flow increment was associated with changes in local venous ANF concentrations comparable with those reported during biological stimuli in hypertensive man and consistent with an ANF physiologic role in forearm arterioles of hypertensive patients. However, at local venous concentrations greater than 1000 pg/ml, ANF did not relax forearm vessels by more than about one-fourth of the total forearm vasodilator capacity (as assessed through a maximally active ischemic stimulus). These data confirm the low potency of ANF as an endogenous vasodilator, although vasodilator potency is not a necessary requirement for physiologic systems involved in the regulation of muscular vascular tone. Systemic arterial pressure, heart rate, and contralateral flow did not change during the study in spite of the markedly increased peripheral ANF levels recirculating from the local forearm administration. This behavior indicates that arteriolar vasodilation is apparently not the main mechanism of action of ANF on systemic hemodynamics in hypertensive patients
An atrial natriuretic factor analogue at low doses attenuates forearm reflex vasoconstriction to cardiopulmonary receptor deactivation in patients with hypertension.
No full textContrasting data exist about a possible modulation of the autonomic function by atrial natriuretic factor (ANF) in human beings, particularly at low, biologically, significant concentrations. We have evaluated that possibility by increasing plasma ANF levels through the infusion of a synthetic analogue (WY-47,663, anaritide) in five male patients with mild to moderate uncomplicated hypertension. Nonhypotensive lower body negative pressure (-10 mm Hg x 5 min) was used to selectively deactivate cardiopulmonary receptors and to stimulate sympathetic efferent tone reflexogenically. ANF was given at either a low rate (0.005 micrograms/kg/min x 60 min, which was previously shown to increase plasma ANF in a range compatible with physiologic stimuli) or at a high rate (0.05 micrograms/kg/min x 60 min, each). Administration of ANF was preceded and followed by vehicle infusion (Haemacell x 30 min). Forearm blood flow (venous plethysmography), intraarterial blood pressure, and heart rate were monitored continuously, and venous immunoreactive ANF, plasma renin activity, aldosterone level, and venous hematocrit were measured at the end of both control and infusion periods. Arterial norepinephrine values, an indirect index of sympathetic discharge, were measured at rest and during lower body negative pressure conditions. Graded systemic ANF infusion increased immunoreactive ANF and venous hematocrit, decreased aldosterone level and plasma renin activity, whereas resting norepinephrine levels, blood pressure, and heart rate did not change. Lower body negative pressure decreased forearm blood flow during vehicle infusion, but it lost its vasoconstrictor effect during infusion of ANF. To identify the site of that inhibitory action, ANF was also infused into the brachial artery at rates that raised local but not systemic levels of immunoreactive ANF.(ABSTRACT TRUNCATED AT 250 WORDS
Forearm vasodilatory capacity in patients with syndrome X: a comparison with normal and hypertensive subjects.
No full textMinimal 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 hypertensio
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