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At least 1,099 records · Page 61Linked to original sources
PubMed1990

Intracerebroventricular injections of endothelin increase arterial pressure in conscious rats.

We investigated the possible effects of endothelin (ET) on the central regulation of arterial pressure by injecting ET intracerebroventricularly (ICV) into conscious rats. ICV injections of ET caused dose-dependent elevation of arterial pressure and increase of heart rate. The first reaction was abolished by bunazosin, an alpha 1-adrenergic blocker, injected intravenously. However, the increase in arterial pressure and heart rate caused the rats, injected with ET ICV, to roll to the left on their long axis for 20-30 min, followed by prolonged sedation. Furthermore, the pressor responses and tachycardia were significantly attenuated by the ICV pretreatment with nicardipine, a calcium channel blocker, and nicorandil, a nitrate derivative, respectively. These results suggest that ET may elevate the intracellular Ca2+ concentration ([Ca2+]i) of sympathetic nerve activity regulatory neurons of the brain, leading to an accelerated outflow of sympathetic nerve activity and cause the elevation of arterial pressure.

Adrenergic alpha-Antagonists↗
PubMed2003

ATP-sensitive K+ channel openers: old drugs with new clinical benefits for the heart.

Different types of ATP-sensitive K+ (K(ATP)) channels have been identified in cardiomyocytes, vascular smooth muscle cells, pancreatic beta-cells, neurons and mitochondria. Years before the discovery of the K(ATP) channel in cardiomyocytes, pharmacological openers of this channel had been developed for the treatment of angina pectoris and hypertension. The K(ATP) channel plays an important role not only in coronary blood flow regulation but also in protection of cardiovascular cells from ischemia/reperfusion injury. In animal models of myocardial ischemia/reperfusion, activation of the mitochondrial K(ATP) channels by their pharmacological openers has been shown to attenuate endothelial dysfunction and to reduce myocardial necrosis. Conversely, blockade of the K(ATP) channel aggravates microvascular necrosis and the no-reflow phenomenon after ischemia/reperfusion, resulting in augmentation of post-infarct ventricular dysfunction. Recent clinical studies have shown that a combination of coronary reperfusion therapy and infusion of nicorandil, a hybrid of K(ATP) channel opener and nitrate, improved left ventricular function in patients with acute myocardial infarction. Furthermore, chronic treatment with nicorandil has been shown to significantly improve prognosis of patients with high-risk stable angina pectoris. Both of these clinical benefits cannot be attributed to the nitrate property of nicorandil. However, a recent basic investigation has suggested that the protective function of K(ATP) channel openers is compromised by concurrent hypercholesterolemia and administration of sulfonylureas for diabetes mellitus. These interferences in the beneficial action of K(ATP) channel openers by concurrent illness and pharmacological agents need to be further investigated to allow a more effective use of K(ATP) channel openers in patients with coronary artery diseases.

Adenosine Triphosphate↗
PubMed1999

A role for N-arachidonylethanolamine (anandamide) as the mediator of sensory nerve-dependent Ca2+-induced relaxation.

We tested the hypothesis that an endogenous cannabinoid (CB) receptor agonist, such as N-arachidonylethanolamine (anandamide), is the transmitter that mediates perivascular sensory nerve-dependent Ca2+-induced relaxation. Rat mesenteric branch arteries were studied using wire myography; relaxation was determined after inducing contraction with norepinephrine. Cumulative addition of Ca2+ caused dose-dependent relaxation (ED50 = 2.2 +/- 0.09 mM). The relaxation was inhibited by 10 mM TEA and 100 nM iberiotoxin, a blocker of large conductance Ca2+-activated K+ channels, but not by 5 microM glibenclamide, 1 mM 4-aminopyridine, or 30 nM apamin. Ca2+-induced relaxation was also blocked by the selective CB receptor antagonist SR141716A and was enhanced by pretreatment with 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (pefabloc; 30 microM), an inhibitor of anandamide metabolism. Anandamide also caused dose-dependent relaxation (ED50 =.72 +/- 0.3 microM). The relaxation was not inhibited by endothelial denudation, 10 microM indomethacin, or 1 microM miconazole, but was blocked by 3 microM SR141716A, 10 mM TEA, precontraction with 100 mM K+, and 100 nM iberiotoxin, and was enhanced by treatment with 30 microM pefabloc. Mesenteric branch arteries were 200-fold more sensitive to the relaxing action of anandamide than arachidonic acid (ED50 = 160 +/- 7 microM). These data show that: 1) Ca2+ and anandamide cause hyperpolarization-mediated relaxation of mesenteric branch arteries, which is dependent on an iberiotoxin-sensitive Ca2+-activated K+ channel, 2) relaxation induced by both Ca2+ and anandamide is inhibited by CB receptor blockade, and 3) relaxation induced by anandamide is not dependent on its breakdown to arachidonic acid and subsequent metabolism. These findings support the hypothesis that anandamide, or a similar cannabinoid receptor agonist, mediates nerve-dependent Ca2+-induced relaxation in the rat.

Animals↗
PubMed2000

Pharmacological characterization of the discriminative stimulus effects of the potassium channel blocker 4-aminopyridine in rats.

The discriminative stimulus (DS) effects of 4-aminopyridine (4-AP) were evaluated in 36 male Sprague-Dawley rats that were trained to discriminate 4-AP from saline in a standard two-lever food reinforced drug discrimination procedure. 4-AP along with its structural analogs 3-aminopyridine (3-AP), 2-aminopyridine (2-AP), and 2,3-diaminopyridine (2,3-DIAP) produced dose-dependent increases in the percentage of responses on the 4-AP-associated lever with full substitution at one or more doses. 2,6-Diaminopyridine (2, 6-DIAP) and 3,4-diaminopyridine (3,4-DIAP) produced dose-dependent increases in the percentage of responses on the 4-AP-associated lever but only partially substituted for 4-AP. Neither 4-dimethylaminopyridine (4-DMAP) nor pyridine substituted for 4-AP. Substitution studies were also conducted with indirect dopamine, norepinephrine, serotonin, and acetylcholine agonists, and gamma-aminobutyric acid A (GABA(A)) agonists and antagonists. The norepinephrine reuptake inhibitor tomoxetine, but not nisoxetine or imipramine, produced dose-dependent increases in the percentage of responses on the 4-AP-associated lever and partially substituted for 4-AP. In addition, antagonism studies were conducted using indirect dopamine, norepinephrine, serotonin, acetylcholine antagonists, and GABA(A) agonists as pretreatments to the training dose of 4-AP. The benzodiazepine agonists chlordiazepoxide and diazepam dose dependently attenuated the DS effects of 4-AP. The present results demonstrate that the K-channel blocker 4-AP can be trained as a DS in rats and the DS effects of 4-AP are likely mediated through blockade of voltage-dependent K-channels. The results also demonstrate a novel interaction between benzodiazepines and K-channels.

4-Aminopyridine↗
PubMed2000

[The vasomotor effects of new fluorine-containing synthetic activators of ATP-dependent potassium channels].

The influence of new fluorine-containing activators of K+ channels on the vascular tone was investigated in vitro experiments on the guinea pig aorta. We exerted the identification of mechanisms of the action of these substances using the well-known ATP-sensitive K+ channel inhibitor--glibenclamid--and showed their dose-effect correlation. It was shown that new fluorine-containing activators of K+ channels--PF-5 and PF-10--are powerful vasodilator substances and PF-5 in concentration more than 0.1 mM exerts a distort of vascular reaction on the vasoconstriction.

Adenosine Triphosphate↗
PubMed2001

Functional implication of spare ATP-sensitive K(+) channels in bladder smooth muscle cells.

ATP-sensitive K(+) (K(ATP)) channels play important roles in the regulation of excitability in urinary bladder smooth muscle cells. Patch-clamp studies revealed that the current density was about 9-fold higher in the pig bladder smooth muscle cells, compared with guinea pig, although the rank order of potencies for suppression of electrical field-stimulated contraction of bladder strips by K(ATP) channel openers (KCOs) showed a nearly 1:1 correlation between pig and guinea pig. To investigate the existence of spare K(ATP) channels, P1075-evoked current and membrane potential responses were studied in bladder smooth muscle cells. During a 10-min exposure to P1075 (10 microM), K(ATP) currents ran down by approximately 30.5%, whereas membrane hyperpolarization remained constant. P1075 evoked membrane hyperpolarization with an EC(50) value of 0.20 +/- 0.02 microM, comparable to that required for smooth muscle relaxation (EC(50) = 0.11 +/- 0.01 microM). However, these potencies are 6-fold higher than those required for current activation (EC(50) = 0.73 +/- 0.4 microM). These findings demonstrate that the reduction in membrane excitability by KCOs is associated with membrane hyperpolarization, and that a low amount of K(ATP) channel opening is sufficient to suppress bladder smooth muscle contraction.

Acetylcholine↗
PubMed1992

Electromechanical effects of the putative potassium channel activator celikalim (WAY-120,491) on feline atrial and ventricular muscle.

Celikalim (WAY-120,491) is a putative potassium channel activator that has been shown to lower blood pressure in animal models and humans. In the present study, we have examined the effects of celikalim on contractility and ionic currents in feline cardiac muscle. Celikalim was found to decrease contractility in electrically stimulated (2 Hz frequency) left atrial and right ventricular papillary muscle preparations with IC50 values of 0.95 +/- 0.12 microM (n = 6) and 0.29 +/- 0.07 microM (n = 5), respectively. Glyburide (1 microM) reversed the celikalim-induced negative inotropy (left atrial halves). Celikalim was also shown to activate a glyburide-sensitive current in voltage-clamped isolated ventricular myocytes that reversed close to the calculated value of the potassium equilibrium potential (n = 4 cells). In addition, celikalim was found to inhibit voltage-activated calcium current (L-type) in isolated ventricular myocytes (51 +/- 2% inhibition at 1 microM; n = 4 cells). We conclude that celikalim is a potassium channel activator and hypothesize that both the negative inotropy and the glyburide-sensitive current evoked by this drug are mediated by ATP-regulated potassium channels. Inhibition of voltage-activated calcium channels by celikalim may also contribute to the negative inotropy induced by this drug.

Animals↗
PubMed2005

[Effect of adenosine triphosphate-sensitve potassium channel activator flokalin on the isolated heart functions].

In the experiments, using isolated, perfused according to Langendorff heart of guinea pig, was investigated the effect of flokalin, a new fluor-containing opener of ATP sensitive channels (K(ATP)), upon the functioning of the heart. It was shown, that flokalin in a dose dependent manner dilates coronary vessels, decreases final diastolic pressure in the left ventricle and the rate of extrasystoles. Flokalin does not significantly affect the developing pressure in the left ventricle, max and min dP/dt, the frequency of cardiac contractions. 5-hydroxydecanoic acid (5-HD), an inhibitor of KATP in the mitochondrial membranes, increases the developing pressure in the left ventricle, max and min dP/dt, perfusion pressure in the coronary vessels. Simultaneously the final diastolic pressure in the left ventricle is decreased. Inhibition of K(ATP) channels in the mitochondrial membrane does not affect the vasodilatory effects of flokalin in the coronary vessels. This data, under the condition of specific action of 5-HD, permits us to suppose the participation of sarcolemmal KATP channels in the mentioned processes. It was shown that inhibition of mitochondrial K(ATP) channels results in decrease of the final diastolic pressure in the left ventricle and can enhance the effect of flokalin upon the final diastolic pressure, thus urging the idea of the leading role of sarcolemmal K(ATP) channels in the mentioned above processes.

Adenosine Triphosphate↗
PubMed1991

Quantitative autoradiography of the binding sites for [125I] iodoglyburide, a novel high-affinity ligand for ATP-sensitive potassium channels in rat brain.

We have developed a high specific activity ligand for localization of ATP-sensitive potassium channels in the brain. When brain sections were incubated with [125I]iodoglyburide (N-[2-[[[(cyclohexylamino)carbonyl]amino]sulfonyl]ethyl]-5-125I-2- methoxybenzamide), the ligand bound to a single site with a KD of 495 pM and a maximum binding site density of 176 fmol/mg of tissue. Glyburide was the most potent inhibitor of specific [125I]iodoglyburide binding to rat forebrain sections whereas iodoglyburide and glipizide were slightly less potent. The binding was also sensitive to ATP which completely inhibited binding at concentrations of 10 mM. Autoradiographic localization of [125I]iodoglyburide binding indicated a broad distribution of the ATP-sensitive potassium channel in the brain. The highest levels of binding were seen in the globus pallidus and ventral pallidum followed by the septohippocampal nucleus, anterior pituitary, the CA2 and CA3 region of the hippocampus, ventral pallidum, the molecular layer of the cerebellum and substantia nigra zona reticulata. The hilus and dorsal subiculum of the hippocampus, molecular layer of the dentate gyrus, cerebral cortex, lateral olfactory tract nucleus, olfactory tubercle and the zona incerta contained relatively high levels of binding. A lower level of binding (approximately 3- to 4-fold) was found throughout the remainder of the brain. These results indicate that the ATP-sensitive potassium channel has a broad presence in the rat brain and that a few select brain regions are enriched in this subtype of neuronal potassium channels.

Affinity Labels↗
PubMed1990

K(+)-channel openers: new antihypertensive drugs?

K(+)-channel openers are a new class of drugs. They interact in a not yet identified fashion with a not yet identified population of K+ channels resulting in an increase in K+ conductance of the surface membrane. K(+)-channel openers have a high affinity for K+ channels of smooth muscle and distinctly less for cardiac or neuronal K+ channels. The cellular effects of K(+)-channel openers in smooth muscle include hyperpolarization, decrease in membrane resistance, inhibition of propagation of excitation, suppression of spontaneous electrical and mechanical activity and inhibition of agonist-induced contraction. The pharmacodynamic profile of K(+)-channel openers is reminiscent of typical vasodilators with decreases in total peripheral resistance and blood pressure and reflex increases in heart rate and cardiac output. While there is no doubt that K(+)-channel openers are effective antihypertensive agents, it is too early, at present, to define their future role in cardiovascular therapy. A satisfactory treatment of hypertension by these drugs may require the addition of diuretics and/or beta-blockers. Other potential clinical indications of K(+)-channel openers include coronary heart disease and asthma.

Antihypertensive Agents↗
PubMed1985

Vasodilators in hypertension--a review with special emphasis on the combined use of vasodilators and beta-adrenoceptor blockers.

This paper presents a review of studies dealing with combined beta-adrenoceptor blockade and vasodilatation in the treatment of hypertension. This therapy can be achieved either through the combined use of conventional beta-adrenoceptor blocking compounds given together with vasodilator drugs or with agents which show multiple action of this kind. From a hemodynamic point of view this therapeutic approach is quite logical since most forms of established hypertension are characterized by increased vascular resistance. It can therefore be concluded that combined beta-adrenoceptor blockade and vasodilation offers a rational and useful treatment of hypertension.

Adrenergic alpha-Antagonists↗
PubMed1994

Protective effects of ATP-sensitive potassium-channel openers in experimental myocardial ischemia.

Adenosine triphosphate (ATP)-sensitive potassium channels (KATP) exist in cardiac tissue and a potential role in the pathogenesis of myocardial ischemia was hypothesized early after their discovery. Studies in in vitro models of myocardial ischemia and reperfusion have indicated that KATP openers, as a class, exert protective effects. This has been assessed by determination of recovery of contractile function, inhibition of contracture, or inhibition of necrosis. This protective effect appears to be exerted directly on the myocardium and is not dependent on peripheral or coronary dilator activities. These protective effects are uniformly abolished by blockers of KATP. The protective effects of KATP openers are accompanied by a conservation of myocardial energy during ischemia, and this occurs despite a relative lack of cardiodepressant effects. In vivo studies have shown more variable results with some investigators showing efficacy and others not showing efficacy. The lack of efficacy for some investigators may be related to the potent vasodilator activity of the KATP openers used. Efficacy for KATP openers has been shown in canine models of infarction and stunned myocardium. KATP blockers also appear to abolish the protective effects of KATP openers in these models. Future work on KATP openers is focused on the determination of the molecular mechanism of action for the cardioprotective effects of these agents, development of tissue selectivity, and the importance of action potential shortening in mediating cardioprotection.

Action Potentials↗