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Biomedical subjects

P Pickkers

Publications and source records attributed to P Pickkers.

7 recordsLinked to original sources
PubMed1997

Direct vascular effects of furosemide in humans.

BACKGROUND: In humans, hemodynamic changes observed within minutes after systemic administration of furosemide are often referred to as direct vasoactivity. However, these immediate changes do not per se imply a direct vascular effect. We examined the genuine direct vascular effects of furosemide on the human forearm vascular bed and dorsal hand vein. METHODS AND RESULTS: Forearm blood flow in response to infusion of increasing dosages of furosemide into the brachial artery was recorded by venous occlusion plethysmography. Local plasma concentrations of furosemide reached a maximum of 234+/-40 microg/mL during the highest infused dose but did not significantly affect the ratio of flow in the infused/noninfused arms. Venous distensibility of a dorsal hand vein was measured with a linear variable differential transformer. During precontraction with norepinephrine, five increasing dosages of furosemide (1 to 100 microg/min) were administered locally. Additional experiments using local administration of indomethacin or N(G)-monomethyl-L-arginine (L-NMMA) were carried out to determine whether effects were dependent on local prostaglandin or nitric oxide synthesis, respectively. Also, the effects of systemic administration of furosemide were examined. Local administration of furosemide led to a dose-dependent venorelaxation of 18+/-6% at the first to 72+/-16% at the last dose. Indomethacin almost completely abolished furosemide-induced venorelaxation, whereas L-NMMA had no effect. Systemic administration of furosemide resulted in a time-dependent increase of hand vein distensibility, reaching 45+/-11% after 8 minutes. CONCLUSIONS: Furosemide does not exert any direct arterial vasoactivity in the human forearm, even at supratherapeutic concentrations. In contrast, at concentrations estimated to be in the therapeutic range, we observed a dose-dependent direct venodilator effect on the dorsal hand vein that appears to be mediated by local vascular prostaglandin synthesis.

Adult↗
PubMed1996

Vascular effects of loop diuretics.

Although it is generally believed that the beneficial effect of loop diuretics is the result of a rapid increase in diuresis, substantial evidence, from a large number of in vitro and in vivo experiments, has accumulated showing that administration of furosemide causes direct vascular effects, which probably contribute to its acute clinical effects. Several mechanisms are involved in the vascular response to loop diuretics. The role of the renin-angiotensin-adolsterone axis, prostaglandins and the direct vascular effects of loop diuretics on both the arterial and venous parts of the vasculature are discussed.

Animals↗
PubMed1995

Relaxation and decrease in [Ca2+]i by hydrochlorothiazide in guinea-pig isolated mesenteric arteries.

1. We examined the effect of the thiazide diuretic, hydrochlorothiazide, on on intracellular calcium concentration ([Ca2+]i) and tone in guinea-pig mesentery arteries. Vessels were mounted on a microvascular myograph and loaded with the Ca(2+)-sensitive fluorescent dye, Fura-2. 2. Hydrochlorothiazide caused relaxation of noradrenaline-precontracted arteries associated with a fall in [Ca2+]i. Preincubation of arteries with hydrochlorothiazide inhibited both contraction and rise in [Ca2+]i in response to noradrenaline. Hydrochlorothiazide did not affect tone and [Ca2+]i when this was elevated by a combination of depolarizing potassium solution and noradrenaline. 3. Hydrochlorothiazide-induced vasorelaxation and decrease of [Ca2+]i was abolished by charybdotoxin, a blocker of large conductance Ca(2+)-activated K channels. 4. The rise in [Ca2+]i elicited by caffeine in Ca(2+)-free physiological salt solution, and presumably reflecting Ca2+ release from intracellular stores, was not altered by preincubation with hydrochlorothiazide. 5. Under depolarizing conditions hydrochlorothiazide did not alter the relationship between the extracellular concentration of Ca2+ and [Ca2+]i; however, hydrochlorothiazide caused a small reduction in the contraction produced for a given rise in [Ca2+]i suggesting hydrochlorothiazide may cause a slight desensitization of the contractile machinery. 6. These findings suggest that hydrochlorothiazide opens Ca(2+)-activated K channels leading to hyperpolarization and consequent closing of voltage-operated calcium channels. The result of this is an impaired influx of extracellular Ca2+, a decrease in [Ca2+]i and vasorelaxation.

Animals↗
PubMed1995

Hydrochlorothiazide exerts no direct vasoactivity in the human forearm.

BACKGROUND: Recently, hydrochlorothiazide has been shown to relax vascular smooth muscle in vitro in clinically relevant concentrations by the opening of calcium-activated potassium channels, leading to hyperpolarization and consequent closing of voltage-operated calcium channels. Long-term administration of hydrochlorothiazide reduces peripheral vascular resistance in vivo in man. These results indicate that hydrochlorothiazide has hemodynamic activity, and we therefore examined the direct vascular action of this drug in vivo. SUBJECTS AND METHODS: Forearm vasodilator responses to the infusion of a placebo and five increasing doses of hydrochlorothiazide into the brachial artery were recorded by venous occlusion strain-gauge plethysmography (perfused forearm technique) in eight normotensive male volunteers. Venous samples were taken from an ipsilateral antecubital vein at the end of each infusion period to measure the hydrochlorothiazide concentration. RESULTS AND DISCUSSION: Plasma concentrations of hydrochlorothiazide averaged 3.5 +/- 0.3 mu g/ml at the highest infusion rate. This concentration leads to a 60 +/- 10% relaxation in vitro and is more than 10 times the therapeutic plasma concentration. Despite these supratherapeutic levels, we were unable to demonstrate a change in forearm blood flow and vascular resistance. Also, no significant changes were observed in blood pressure and heart rate. CONCLUSION: In contrast to in vitro results, hydrochlorothiazide does not exert any direct vasoactivity in the forearm vascular bed of healthy normotensive male volunteers at (supra)therapeutic plasma concentrations.

Antihypertensive Agents↗