Role of intracellular calcium for noradrenaline-induced depolarization in rat mesenteric small arteries.

We have investigated the effect of intracellular calcium levels for membrane potential during noradrenaline application in isolated small arteries. Rat mesenteric small arteries were mounted for isometric tension measurement. Smooth muscle membrane potentials were measured by conventional intracellular electrodes, and intracellular calcium concentration was measured using Fura-2 fluorescence. Under control conditions, noradrenaline caused contraction and depolarization from -55.5 to -29.3 mV. In intact arteries, depleting intracellular calcium stores with thapsigargin caused smooth muscle hyperpolarization and inhibited contraction to noradrenaline. In de-endothelialized vessels, thapsigargin still depleted calcium stores, but did not affect either the depolarization or contraction caused by noradrenaline. In noradrenaline-activated vessels, inhibition of calcium influx by amlodipine caused tension and calcium levels to fall to near-baseline levels, but membrane potential returned by only 55%. Treatment with a combination of thapsigargin, D-600 and BAPTA-AM inhibited the tension and calcium responses to noradrenaline, but the membrane potential response was reduced by only 34%. Acute reduction of extracellular chloride concentration caused similar, small depolarization at rest and during noradrenaline exposure. It is concluded that an elevation of intracellular calcium concentration is not essential for noradrenaline depolarization, although part of the depolarization is associated with the raised intracellular calcium level.

Crossover comparison of the pharmacokinetics of amlodipine and felodipine ER in hypertensive patients.

The pharmacokinetics of amlodipine 5 mg and felodipine ER (extended release) 5 mg o.d. after single and 2 weeks of repeated oral doses, were compared in 28 essential hypertensive patients using a crossover design. As a secondary parameter the effects of the drugs on blood pressure were assessed. Significant differences were found between all principal pharmacokinetic variables, when comparing the 2 treatments after both single and repeated dosing. The coefficients of variation of maximal drug concentration and AUC after single dosing and at steady-state were significantly higher for felodipine ER than for amlodipine. After repeated dosing the peak-to-trough plasma concentration ratio were 1.58 and 4.43 (p < 0.001) for amlodipine and felodipine ER, respectively. Both drugs lowered systolic and diastolic blood pressure to the same extent after 2 weeks of repeated dosing. No significant differences between the blood pressure lowering vs time profile of the 2 drugs were encountered. In conclusion, the interpatient drug concentration variability and the peak-to-trough plasma concentration ratio were more favorable for amlodipine compared to felodipine ER. It remains to be established whether these characteristics are also reflected in a more smooth and consistent blood pressure control.

Time course of action of amlodipine and felodipine in the rat is most rapid in small arteries.

The time course of action of amlodipine was compared to that of felodipine in rat mesenteric resistance arteries and aorta. Both amlodipine and felodipine caused a concentration-dependent relaxation of K(+)-depolarized resistance arteries: with amlodipine 3 x 10(-8) M and felodipine 10(-9) M, complete relaxation was reached after 40 min and 10 min, respectively. Furthermore, in resistance arteries, the time course of action of both drugs was shortest in vessels with the smallest diameter. In aorta, both drugs caused a marked relaxation of K(+)-induced tone, without reaching a maximal effect within 2 h. Recovery of K(+)-induced tone after both drugs was complete in resistance arteries, but not aorta, within 2 h. In resistance arteries exposed to K+ depolarization or noradrenaline, both drugs displayed the characteristics of 1,4-dihydropyridine Ca2+ channel antagonists. The results show that amlodipine was slower to have an effect than felodipine, but that both drugs acted fastest in the smallest arteries.

[Asymptomatic benign mediastinal teratoma]. / Asymptomatisk benignt mediastinalt teratom.

A case of asymptomatic benign mediastinal teratoma is presented. The necessity for definite diagnosis of mediastinal tumours is stressed together with the need for conferences involving several specialties.

Effect of pinacidil on ion permeability in resting and contracted resistance vessels.

Pinacidil is thought to cause vasodilatation by opening K+ channels and consequent hyperpolarization. This proposed mechanism of action is based mainly on membrane potential measurements and 42K or 86Rb efflux experiments under resting conditions. We have measured the simultaneous effect of pinacidil on force and membrane potential in resting and norepinephrine-contracted rat mesenteric resistance vessels. Also the effect of pinacidil on 42K and 36Cl efflux and 22Na uptake in the absence and presence of norepinephrine was examined. From the membrane potential and ion flux measurements the ion permeabilities were calculated. In both resting and norepinephrine-contracted vessels, pinacidil caused a large hyperpolarization, the latter situation being associated with an almost complete relaxation. In both resting and norepinephrine-stimulated vessels, pinacidil caused a large increase in K+ permeability and a decrease in Cl-permeability, whereas no significant change of Na+ permeability was found. Our results suggest that pinacidil causes vasodilation due to hyperpolarization. The major cause for the hyperpolarization is an increase in K+ permeability.

Mechanism of the vasodilator action of pinacidil.

The mechanism of the vasodilator action of pinacidil has been studied in rat mesenteric small arteries. The results show, first, that the use of flux studies to make measurements of ion permeability requires knowledge of the membrane potential, especially as regards K+ permeability. Second, the results confirm that the vasodilator effect of pinacidil is due to an increase in K+ permeability. Lastly, the results suggest that the K+ channels involved are sensitive to glibenclamide.

Pinacidil opens K+-selective channels causing hyperpolarization and relaxation of noradrenaline contractions in rat mesenteric resistance vessels.

1. The effects of pinacidil on noradrenaline-induced tone, smooth muscle membrane potential and 42K- and 86Rb-efflux from isolated mesenteric resistance vessels (internal diameter 200 microns) of the rat have been studied. 2. Pinacidil (0.3-10 microM) produced concentration-dependent suppression of noradrenaline-induced tone. 3. Pinacidil (0.3-10 microM) caused concentration-dependent hyperpolarization of the smooth muscle. 4. In rat resistance vessels loaded with 42K, pinacidil (1-10 microM) significantly increased the 42K-efflux rate constant. 5. With the use of 86Rb as a marker for K+, 1 microM pinacidil did not affect the 86Rb-efflux rate constant, while 10 microM pinacidil transiently increased the 86Rb rate constant. 6. The results indicate that the relaxant action of pinacidil in these vessels is due to the opening of K+-channels and consequent hyperpolarization. The K+-channels opened are selective for 42K over 86Rb.

Vasodilatation with pinacidil. Mode of action in rat resistance vessels.

Pinacidil is a newly developed antihypertensive vasodilator, proposed to belong to the new group of smooth muscle relaxants, the K+ channel openers. The in vitro effects of pinacidil on induced tone, smooth muscle membrane potential and 86Rb and 42K efflux from rat resistance vessels (internal diameter about 200 microns) were studied. Tone induced with noradrenaline was concentration-dependently inhibited by pinacidil. Responses to electrical field stimulation were also inhibited. However, tone induced with high K+ depolarisation, noradrenaline in the presence of high K+, caffeine-induced contractions and noradrenaline contractions in the presence of felodipine were little affected by pinacidil. Pinacidil caused concentration-dependent hyperpolarisation of the resting smooth muscle. Pinacidil caused only a small and transient increase of the 86Rb efflux rate constant, while the same concentrations of pinacidil produced a significant increase in the 42K efflux rate constant. Our results seem to indicate that the relaxant effect of pinacidil is the result of an increase in K+ permeability, thus causing hyperpolarisation and relaxation. The opened K+ channels appear to be selective for K+ over Rb+.

Effect of pinacidil on norepinephrine- and potassium-induced contractions and membrane potential in rat and human resistance vessels and in rat aorta.

The effect of pinacidil on contractile responses to norepinephrine, potassium, and membrane potential was examined in rat and human resistance vessels. In some experiments rat aorta was also used. Pinacidil (0.1-30 microM) caused a concentration-dependent relaxation of norepinephrine-induced contractions in all vessels studied. In the same concentration range, pinacidil had only little effect on potassium (125 mM) activated rat mesenteric and femoral resistance vessels. In denervated rat mesenteric resistance vessels, a depolarization with potassium (125 mM) before superimposing a norepinephrine tone markedly diminished the effect of pinacidil. In resting rat mesenteric resistance vessels, pinacidil (1-10 microM) caused a hyperpolarization of 10-15 mV. In rat aorta, pinacidil (10 microM) caused a significant (p less than 0.001) increase in 86Rb+ efflux rate constant whereas 1 microM had no effect. The results of these experiments indicate that the vasodilating effect may be caused by a hyperpolarization of the vascular smooth muscle cell membrane.