Regional differences in the vascular response of the canine esophagus to vasodilators

The basal blood flow of the proximal and distal body of the esophagus, and that of the lower esophageal sphincter, and the vascular response of these sites to intravenous infusion of nifedipine (1.0 microgram/kg.min) and isoproterenol (0.1 microgram/kg.min) were studied. The basal blood flow of the mucosa plus submucosa, muscularis propria, and the whole wall was significantly higher in the lower esophageal sphincter than in the proximal or the distal body. Intravenous nifedipine caused a similar decrease in vascular tone of the mucosa and the muscularis propria in all sites of the esophagus. Isoproterenol infusion significantly decreased the vascular tone of the mucosa with columnar epithelium (i.e., mucosa overlying the lower esophageal sphincter), but not of the mucosa with squamous epithelium (i.e., mucosa overlying the body). In the muscularis propria the vasodilatory effect of isoproterenol and nifedipine was significant at all sites, but this effect was greater in the striated muscle of the body than in the smooth muscle of the lower esophageal sphincter (p less than 0.05). Thus, not only do different vasodilators have different effects on the vasculature of the esophagus, but also a single agent may have differing effects on the various sites and layers of this organ.     

Role of vascular calcium-activated potassium channels in the regulation of human peripheral conduit artery diameter

The role of an endothelium-derived hyperpolarizing factor (EDHF), acting through the opening of vascular calcium-activated potassium (K(Ca)) channels, in the regulation of the basal diameter of human peripheral conduit arteries has never been investigated in vivo. We measured in 7 healthy subjects the effect of the local infusion of an inhibitor of K(Ca) channels, tetraethylammonium chloride (TEA, 9 micromol/min, 8 min), on radial artery diameter (echotracking) and flow (Doppler). Endothelium-independent dilatation was assessed before and after TEA using sodium nitroprusside (SNP: 5, 10 and 15 nmol/min, 3 min each). TEA induced a decrease in radial artery diameter (2.65 +/- 0.09 to 2.52 +/- 0.09 mm: p < 0.05) and flow (9.4 +/- 1.2 to 7.4 +/- 1.1 ml/min; p < 0.01) without modification in the radial artery dilatation in response to SNP (NS). The decrease in radial artery diameter was still significant even when the decrease in flow was taken as covariate into analysis (p < 0.05). These results demonstrate the role of vascular K(Ca) channels in the regulation of basal peripheral conduit artery diameter and arteriolar tone in human strongly suggesting the involvement of an EDHF a these two levels.     

Arterial vascular compliance response to vasodilators by Fourier and pulse contour analysis

Vasodilator drugs are widely used in the management of cardiovascular disease. They decrease systemic vascular resistance, but they also may influence vascular arterial compliance. This study evaluated the effects of three vasodilators--nitroprusside, nitroglycerin, and hydralazine--on vascular compliance using impedance parameters determined by pulse contour and Fourier analyses. The open chest study was performed on anesthetized dogs. Mean arterial pressure decreased by a minimum of 20% after vasodilator intervention. The decrease in systemic vascular resistance was significant (p less than 0.01) only after hydralazine treatment. Proximal compliance increased after administration of all drugs, but the increase was not statistically significant. Distal compliance determined by pulse contour analysis increased by 60 to 120% after all three drug treatments (p less than 0.05 for nitroprusside, p less than 0.02 for nitroglycerin and hydralazine). Characteristic impedance from Fourier analysis responded variably, and changes were not statistically significant. The sensitivity of changes in distal compliance as a marker for the vascular effect of these drugs suggests that it might be used as a more reliable guide than blood pressure or vascular resistance in monitoring clinical response to such intervention. The more traditional measure of characteristic impedance provides a vascular measurement that is less sensitive than distal compliance to the effects of these vasodilator drugs.     

Collateral response to activation of potassium channels in vivo

Activation of ATP-sensitive K⁺ channels is involved in the coronary vascular response to decreases in perfusion pressure and ischemia. Since activation of ATP-sensitive K⁺ channels in collateral vessels may be important in determining flow to collateral-dependent myocardium, the ability of collaterals to respond to activation of the channel was tested. In the beating heart of dogs, we compared responses of non-collaterals less than 100 μm in diameter to collaterals of similar size using computer-controlled stroboscopic epi-illumination of the left ventricle coupled to a microscope-video system. Aprikalim, a selective activator of ATP-sensitive K⁺ channels (0.1–10 μM) produced similar dose-dependent dilation of non-collaterals and collaterals. Relaxation was decreased by inhibition of ATP-sensitive K⁺ channels with glibenclamide, but not by inhibition of nitric oxide synthase with nitro-L-arginine. Bradykinin (10–100 μM) produced similar dilation of non-collaterals and collaterals which was decreased by nitro-L-arginine but not glibenclamide. Thus, in microvascular collaterals, relaxation to both nitric oxide and activation of ATP-sensitive K⁺ channels is similar to non-collaterals. Received: 7 April 1997, Returned for revision: 5 May 1997, Revision received: 23 December 1997, Accepted: 13 January 1998     

Role of NO pathway, calcium and potassium channels in the peripheral pulmonary vascular tone in dogs.

Because hypoxic pulmonary vasoconstriction occurs mainly in the small pulmonary arteries, the authors investigated the effects of drugs acting on the nitric oxide (NO) pathway and the calcium and potassium channels in the peripheral pulmonary circulation, without interference with the overall pulmonary or systemic circulation. Mixed venous blood was infused in wedged areas to study the pressure/flow relationship and to compute peripheral pulmonary vascular resistance (PPVR). The authors studied the effects of Nomega-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, sodium nitroprusside (SNP, an NO donor), the calcium channel blockers verapamil, nifedipine and nicardipine, and the potassium channel opener levcromakalim, during normoxia and acute mild normocapnic hypoxia. In the peripheral pulmonary circulation, L-NAME caused an increase in PPVR during normoxia (+95%; p<0.001) and hypoxia (+60%; p<0.01). Following the increase by L-NAME, SNP decreased PPVR during normoxia (-24%; p<0.05) and hypoxia (-23%; p<0.05). Verapamil, nifedipine and nicardipine did not modify PPVR during normoxia but during hypoxia they decreased PPVR (-28%, nonsignificant; -27%, p<0.01 and -33%, p<0.05, respectively). Levcromakalim did not modify PPVR during normoxia or hypoxia. In conclusion, the nitric oxide pathway and voltage-dependent calcium channels, and not adenosine triphosphate sensitive potassium channels, play an important role in the control of peripheral pulmonary circulation in dogs.     

Ca(2+)-activated potassium channels and ATP-sensitive potassium channels as modulators of vascular tone

Membrane hyperpolarization through activation of potassium channels in arterial smooth muscle appears to be an effective mechanism to dilate arteries. Conversely, membrane depolarization through inhibition of potassium channels can lead to vasoconstriction. Here, I briefly review the roles of Ca(2+)-activated K(+) (K(Ca)) channels and ATP-sensitive K(+) (K(ATP)) channels in the control of arterial smooth muscle function. K(Ca) channels regulate arterial tone in response to changes in intravascular pressure and possibly to a variety of vasoconstrictors. K(ATP) channels respond to changes in the cellular metabolic state and are targets of a variety of synthetic and endogenous vasodilators.     

Activation of potassium channels: relationship to the heat shock response.

We examined the possibility that whole cell currents are involved and possibly trigger the response of mammalian cells to heat shock. Heat-sensitive cells from a radiation-induced fibrosarcoma (RIF-1) and heat-resistant variants (TR-4, TR-5) were heated at 45 degrees C for 3-30 min. We observed induction of voltage-dependent currents after heating in the heat-resistant cells. These currents decayed to nonmeasurable levels over a period of 6 h. In RIF-1 cells, however, voltage-dependent currents were detectable during heating only; these currents then decayed rapidly. Tetraethylammonium (TEA) cations blocked the currents; changing the concentration of extracellular K+ modified the current-voltage (I-V) relationship. These currents, therefore, resulted from the activation of voltage-dependent K+ channels. Addition of TEA during heating sensitized TR-4 cells to heat but had no effect on the heat response of the RIF-1 cells. Continuous exposure of the RIF-1 cells to 2% (vol/vol) dimethyl sulfoxide (DMSO) for 7 days induced the expression of additional functional, voltage-dependent K+ channels; these gave rise to currents that were measurable after heating. In parallel, these cells became heat resistant. Addition of TEA to DMSO-treated cells blocked channels and returned the heat response almost to the pre-DMSO levels. Our data show a correlation between heat resistance and expression of K+ channels. Because resistance to heat very likely relates to the heat shock response, our data suggest that activation of channels may be a very early event in initiation of the heat shock response.     

Role of endogenous brain kinins in the cardiovascular response to intracerebroventricular melittin

Intracerebroventricular infusion of the peptide melittin increases immunoreactive kinins in the cerebrospinal fluid of anesthetized dogs, probably secondary to activation of brain or cerebrospinal fluid kininogenases. Intracerebroventricular melittin also increases blood pressure and heart rate, possibly mediated by brain kinins, since intracerebroventricular bradykinin also increases blood pressure and heart rate. We tested whether the effects of centrally administered melittin on blood pressure and heart rate could be blocked by simultaneous infusion of a kinin receptor antagonist, [DArg0]Hyp3-Thi5,8[DPhe7]bradykinin, in normotensive awake rats. In the controls, intracerebroventricular infusion of kinin receptor antagonist given for 1 hour at a rate of 10 micrograms/hr blocked bradykinin-induced increases in blood pressure and heart rate by 80%. Basal blood pressure and heart rate were not affected by the kinin receptor antagonist alone. After a 30-minute infusion of melittin (8 micrograms/30 min), cerebrospinal fluid kininogenase activity (n = 17) rose from 0.13 +/- 0.05 to 0.43 +/- 0.1 ng/ml/min (p less than 0.02). Although cerebrospinal fluid kinins increased from below sensitivity (0.02 ng/ml, n = 12) to 0.19 +/- 0.1 ng/ml (n = 17), this change was due to drastic increases in three rats, whereas in 12 of them kinins were below sensitivity. Incubation of bradykinin (10 ng) with 0.1 ml rat cerebrospinal fluid for 5 minutes destroyed 70% of kinins, suggesting that rapid destruction may have made detection of increased CSF kinins difficult.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels

Pharmacological augmentation of neuronal KCNQ muscarinic (M) currents by drugs such as retigabine (RTG) represents a first-in-class therapeutic to treat certain hyperexcitatory diseases by dampening neuronal firing. Whereas all five potassium channel subtypes (KCNQ1–KCNQ5) are found in the nervous system, KCNQ2 and KCNQ3 are the primary players that mediate M currents. We investigated the plasticity of subtype selectivity by two M current effective drugs, retigabine and zinc pyrithione (ZnPy). Retigabine is more effective on KCNQ3 than KCNQ2, whereas ZnPy is more effective on KCNQ2 with no detectable effect on KCNQ3. In neurons, activation of muscarinic receptor signaling desensitizes effects by retigabine but not ZnPy. Importantly, reduction of phosphatidylinositol 4,5-bisphosphate (PIP₂) causes KCNQ3 to become sensitive to ZnPy but lose sensitivity to retigabine. The dynamic shift of pharmacological selectivity caused by PIP₂ may be induced orthogonally by voltage-sensitive phosphatase, or conversely, abolished by mutating a PIP₂ site within the S4–S5 linker of KCNQ3. Therefore, whereas drug-channel binding is a prerequisite, the drug selectivity on M current is dynamic and may be regulated by receptor signaling pathways via PIP₂.     

Role of ATP dependent potassium channels in myocardial ischaemia.

Recently, a class of potassium (K) channels has been discovered which are regulated by the intracellular level of ATP. These channels have been termed ATP dependent K channels (KATP) and have been found to exist in the heart, skeletal muscle, pancreatic beta cells, brain, and smooth muscle. In this article, we discuss the function of the KATP channel in the ischaemic myocardium and present evidence to suggest that activation of these channels may, on the one hand, result in a marked cardioprotective effect from reversible or irreversible electrical, functional or biochemical damage or, on the other hand, have the potential to produce electrical instability and a proarrhythmic effect. The therapeutic potential of potassium channel modulators is also discussed.     

Role of potassium channels in stretch-promoted atrial natriuretic factor secretion

The cardiac polypeptide hormone atrial natriuretic factor (ANF) plays important roles in the regulation of blood volume and pressure. Few specific details are known about basal or stretch-promoted ANF secretion. Here, we investigated the involvement of K⁺ channels in ANF secretion based on investigations of their nature as revealed by oligonucleotide microarray analysis and on protein-protein interactions evidenced by a yeast two-hybrid approach using a heterotrimeric Gαo-1 G protein subunit, which is particularly abundant in the atrium. Based on these data, we investigated the effect of drugs known to pharmacologically affect the function of specific K⁺ channels on ANF secretion from the isolated rat atrium. These included adenosine triphosphate-sensitive K⁺ channels, TWIK-related K⁺ channel 1 (TREK-1), and the Ca⁺²-activated intermediate conductance K⁺ channel (SK4). The sulfonylurea ligands tolbutamide and repaglinide, but not glibenclamide, increased stretch-promoted ANF secretion. The channel openers diazoxide, pinacidil, and cromakalim all decreased this type of stimulated ANF secretion. TRAM 34, a specific SK4 inhibitor, and oleylamine, a nonspecific TREK-1 inhibitor, significantly decreased or increased respectively, both basal and stretch-stimulated ANF secretion. Inhibition of Gi/o by pretreatment with Pertussis toxin often significantly affected the effect of these treatments. We concluded that the atria express K⁺ channels that are related to Gi/o protein signaling and that significantly affect the endocrine function of the heart. These findings are significant for the development of therapeutic drugs with properties related to the manipulation of ANF plasma levels.     

Role of ATP-sensitive potassium channels in coronary microvascular autoregulatory responses

The purpose of the present study was to test the hypothesis that ATP-sensitive potassium channels mediate autoregulatory vasodilatation of coronary arterioles in vivo. Experiments were performed in 23 open-chest anesthetized dogs. Coronary arterial microvascular diameters were directly measured with fluorescence microangiography using an intravital microscope and stroboscopic epi-illumination synchronized to the cardiac cycle. A mild coronary stenosis (perfusion pressure = 60 mm Hg), a critical coronary stenosis (perfusion pressure = 40 mm Hg), and complete coronary artery occlusion were produced with an occluder around the left anterior descending coronary artery in the presence or absence of glibenclamide (10(-5) M, topically), which inhibits ATP-sensitive potassium channels, or of vehicle. During topical application of vehicle (0.01% dimethyl sulfoxide), there was dilatation of small (less than 100 microns diameter) arterioles during reductions in perfusion pressure (percent change in diameter: 6.7 +/- 1.5%, 11.7 +/- 3.5%, and 10.4 +/- 5.1% during mild stenosis, critical stenosis, and complete occlusion, respectively). In the presence of glibenclamide, arteriolar dilatations during coronary stenoses and occlusions were abolished. Glibenclamide did not affect responses of arterioles greater than 100 microns. Glibenclamide did not alter microvascular responses to nitroprusside. These data suggest that ATP-sensitive potassium channels play an important role in determining the coronary microvascular response to reductions in perfusion pressure.     

电压依赖性钾离子通道在肺动脉高压发病过程中的作用

肺动脉高压是一种肺血流受限引起肺血管阻力和压力持续性增高,最终导致右心衰竭甚至死亡的综合征.病理生理学改变主要为肺血管收缩、重塑及原位血栓形成.研究表明,钾离子通道尤其电压依赖性钾离子通道功能与表达水平的降低是引起肺血管平滑肌细胞增殖和凋亡异常、肺血管重塑的关键因素.本文着重论述近年来有关电压依赖性钾离子通道与肺动脉高...     

Interaction of sulphonylurea derivatives with vascular ATP-sensitive potassium channels in humans

Summary Cardiovascular adenosine-5-triphosphate-sensitive potassium (K_ATP) channels have been reported to play an important role in endogenous cardioprotective mechanisms. Sulphonylurea derivatives can inhibit these cardioprotective mechanisms in animal models. We investigated whether therapeutic concentrations of sulphonylurea derivatives can block vascular K_ATP channels in humans. The forearm vasodilator responses to administration of the specific K_ATP channel opener diazoxide into the brachial artery of healthy male volunteers were recorded by venous occlusion plethysmography. This procedure was repeated with concomitant intraarterial infusion of: 1) the sulphonylurea derivative glibenclamide (0.33 or 3.3 g · min^–1 · dl^–1, both n=12), 2) the new sulphonylurea derivative glimepiride (2.5 g · min^–1 · dl^–1, n=12) or 3) placebo (n=12). The effects of glibenclamide on the vasodilator responses to sodium nitroprusside were also studied (n=12). Glibenclamide significantly inhibited the diazoxide-induced increase in forearm blood flow ratio (ANOVA with repeated measures: p<0.01). During the highest diazoxide dose this ratio (mean ± SEM) was lowered from 892±165 to 449±105%, and from 1044±248 to 663±114% by low- and high-dose glibenclamide, respectively. In contrast, neither glimepiride nor placebo attenuate diazoxide-induced vasodilation. Furthermore, glibenclamide did not affect nitroprusside-induced vasodilation. We conclude that therapeutic concentrations of the classical sulphonylurea derivative glibenclamide result in significant blockade of vascular K_ATP channels in humans. The newly developed glimepiride seems to be devoid of these properties.Abbreviations K_ATP channel Adenosine-5-triphosphate-sensitive potassium channel - SU sulphonylurea - FBF forearm blood flow - SNP sodium nitroprusside - FVR forearm vascular resistance - MAP mean arterial pressure - NIDDM non-insulin-dependent diabetes mellitus     

Role of potassium channels in bronchodilator responses in human airways.

The plasma membrane of airway smooth muscle contains a high density of K+ channels of various types that mainly regulate membrane potential. To examine whether these K+ channels are involved in bronchodilating mechanisms in human airways, relaxation concentration-response studies to isoproterenol, theophylline, and a K(+)-channel opener, lemakalim (BRL 38227), were obtained in the presence or absence of charybdotoxin (ChTX) (10 or 100 nM), an inhibitor of large conductance Ca(2+)-activated K+ channels (KCa) in smooth muscle. The effects of other potassium channel blockers, apamin (0.1 microM, a small-conductance KCa blocker) and BRL 31660 (10 microM, an ATP-sensitive K(+)-channel blocker) on isoproterenol-induced bronchodilation were also examined. All relaxation studies were performed on spontaneous tone and in the presence of 1 microM indomethacin. ChTX produced a dose-dependent significant rightward shift in the isoproterenol relaxation response curves without changing maximum relaxation; geometric mean values of EC50 were 4.6 nM without and 19 nM with 10 nM ChTX (n = 7, p less than 0.005), and 3.4 nM without and 41 nM with 100 nM ChTX (n = 4, p less than 0.05), respectively. The theophylline relaxation responses were inhibited to a lesser extent by ChTX (10 nM) (ED50 of 32 microM without and 71 microM with ChTX, n = 7, p less than 0.05), whereas lemakalim-induced relaxation response was not affected. Other K(+)-channel blockers, apamin and BRL31660, failed to affect isoproterenol-induced bronchodilation. These results suggest that ChTX-sensitive K+ channels are involved in bronchodilation induced by beta-agonists and theophylline in human airways.