1,721,323 research outputs found
Dipyridamole Potentiates the Endothelium-Dependent and -Independent Vasomotion in Isolated Human Small Arteries.
No full textBACKGROUND: To investigate the effects of dipyridamole, a drug with phosphodiesterase-, adenosine reuptake-inhibiting, and prostacyclin-stimulating activity on the biological actions of nitric oxide, 30 norepinephrine-precontracted subcutaneous arterioles were prepared from specimens removed during surgery.
METHODS AND RESULTS: Specimens were mounted on a myograph and relaxes through either acetylcholine, a muscarinic agonist that stimulates endothelial nitric oxide production, or sodium nitroprusside, an endothelium-independent vasodilator. Studies were performed under control conditions and after dipyridamole which potentiated in a concentration-dependent manner the vasorelaxation induced both by acetylcholine and sodium nitroprusside, indicating an endothelium-independent mechanism of action. The contribution of nitric oxide to the relaxation produced by acetylcholine was confirmed by N-monomethyl-L-arginine, a nitric oxide synthase inhibitor. In contrast, indomethacin, a cyclo-oxygenase inhibitor, was ineffective, indicating that prostacyclin stimulation could not explain the effect of dipyridamole. CGS 21680 C, an A(2)-selective adenosine receptor agonist insensitive to tissue deaminase, did not influence the relaxations induced by acetylcholine, suggesting that interference with adenosine metabolism was not implicated in the potentiating action of dipyridamole.
CONCLUSIONS: Dipyridamole potentiated the vasorelaxing effect of acetylcholine and sodium nitroprusside in human subcutaneous arterioles; neither prostacyclin stimulation nor A(2) adenosine receptor stimulation could explain this effect. The data are consistent with an increase in intracellular cyclic 3' 5'-guanosine monophosphate levels secondary to the phosphodiesterase-inhibiting properties of the dru
Heterogeneous interference of nicardipine, verapamil, and diltiazem with forearm arteriolar responsiveness to adrenergic stimulation in hypertensive patients.
No full textThe interference of intraarterial nicardipine, verapamil, and diltiazem with the forearm vascular response to graded exogenous norepinephrine was evaluated in hypertensive patients. Nicardipine antagonized the vasoconstrictor effect of norepinephrine in a dose-dependent manner, whereas verapamil was ineffective, suggesting that functional alpha-adrenergic antagonism may participate in the vasodilatory and possibly the antihypertensive effect. Nicardipine also blunted the vasoconstriction to lower-body negative pressure and the action of angiotensin II administered intraarterially. Despite a comparable increase in basal forearm flow, verapamil was less potent than nicardipine in inhibiting vasoconstriction after both stimuli. Therefore nicardipine suppressed preferentially regional vascular reactivity, probably by blockade of the influx of extracellular calcium in response to receptor activation, because both alpha-adrenergic and angiotensin II receptor-mediated vasoconstrictor responses were attenuated. At variance with both nicardipine and verapamil was potentiation of the responses to norepinephrine after the administration of diltiazem. Because intraarterial propranolol abolished that potentiating action and the local vasodilatation to isoproterenol was clearly reduced, diltiazem probably interfered also with beta-adrenergic receptor-mediated vasorelaxing mechanisms in human forearm arterioles. The data further stress the heterogeneity of calcium channel blockers in humans
Interference of calcium entry blockade in vivo with pressor responses to alpha-adrenergic stimulation: effects of two unrelated blockers on responses to both exogenous and endogenously released norepinephrine
No full textTo the extent that calcium availability is the final common mediator of vasoconstrictor responses, calcium entry blockade might interfere with physiologic responses to adrenergic stimulation. To test this hypothesis, we studied the effects of calcium entry blockade on pressor responses to norepinephrine in pithed, normal Sprague-Dawley rats in two different ways: (1) by evaluating the effects on pressor responsiveness to exogenous norepinephrine during differential blockade of alpha 1-(prazosin, 0.3 mg/kg) and of alpha 2-receptors (yohimbine, 0.3 mg/kg) and (2) by comparing the effects of calcium entry blockade with those of prazosin and those of rauwolscine (a specific alpha 2-antagonist) on pressor responses to infusions of both endogenously released norepinephrine (electrical stimulation of the pithing rod) and exogenous norepinephrine. In the presence of alpha 1-blockade, both nitrendipine (0.01 mg/kg) and verapamil (0.6 mg/kg) shifted the norepinephrine pressor dose-response curve to the right but were ineffective in alpha 2-blocked animals. Furthermore, nitrendipine (range 0.01 to 0.3 mg/kg) proved to be more effective (p less than .001) against exogenous norepinephrine than against electrical stimulation of the spinal cord, a behavior opposite that of selective alpha 1-blockade (prazosin) and directionally comparable to that of selective alpha 2-antagonism (rauwolscine). These data indicate that calcium entry blockade in vivo preferentially antagonizes the alpha 2-pressor component of exogenous norepinephrine. In addition, both calcium entry blockers were consistently more active (p less than .01) than rauwolscine (0.01 to 1 mg/kg) in antagonizing the pressor response to neural stimulation, suggesting that mechanisms different from "classical" alpha 2-antagonism may also contribute to the overall effect of calcium entry blockade on the adrenergic control of peripheral vascular tone
Calcium entry blockade by nitrendipine and alpha adrenergic responsiveness in vivo: comparison with noncalcium entry blocker vasodilators in absence and presence of phenoxybenzamine pretreatment
No full textTo investigate the in vivo interaction between calcium entry blockade by nitrendipine (a dihydropyridine calcium entry blocker) and alpha adrenergic-mediated end-organ responsiveness, four series of experiments were carried out in normal Sprague-Dawley rats. In ganglion-blocked rats (hexamethonium, 10 mg/kg i.p. plus atropine, 1.0 mg/kg i.p.), nitrendipine (0.3 mg/kg) antagonized the pressor responses to angiotensin II and vasopressin as well as to norepinephrine, thus indicating the lack of specificity of its antagonism to alpha adrenergic vasoconstriction. The results of the next two series of experiments showed first that, in pithed rats, nitrendipine (0.01 to 0.3 mg/kg) in presence of prazosin shifted the norepinephrine pressor dose-response curves to the right whereas it was ineffective in yohimbine-pretreated animals. These data, suggesting a preferential alpha-2 antagonism by nitrendipine, were confirmed further by its little effect on pressor responses to methoxamine as contrasted with its marked progressive depression of the maximum response to B-HT 920 (about 80% at the highest rate of infusion). However, qualitatively similar results were obtained by the noncalcium entry blocker vasodilators, both sodium nitroprusside and hydralazine, both of which led to minor shifts to the right of the methoxamine pressor dose-response curves, whereas dose-dependently depressing the maximum pressor response to B-HT 920 (about 70 and 40%, respectively). Thus, calcium entry blockade appeared to antagonize preferentially alpha-2-mediated vasoconstriction, but this effect was common to other vasodilators devoid of calcium entry blocking properties.(ABSTRACT TRUNCATED AT 250 WORDS
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
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