Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The normal control of coronary blood flow is through alterations in the resistance of the intramyocardial arterioles (R2). Myocardial cellular hypoxia causes increased breakdown of ATP (or decreases synthesis) resulting in increased concentrations of the purine metabolite, adenosine. This potent endogenous, vascular smooth muscle relaxant vasodilates the R2 arterioles increasing coronary blood flow and myocardial O2 delivery. This mechanism autoregulates coronary blood flow according to myocardial O2 needs. Myocardial hypertrophy (from chronic hypertension) or coronary atherosclerosis interfere with this process and result in myocardial ischemia which may cause symptoms (angina), signs (ECG changes, regional muscle dysfunction) or tissue death (myocardial infarction). In addition, coronary atheroma disrupt endothelial function in the large R1 coronary arteries predisposing to vasoconstriction, platelet aggregation and thrombosis. Therapeutic measures for controlling ischemia may include decreasing oxygen demand (especially heart rate) and maintaining supply (R1 vasodilators and anti-thrombotic drugs such as non-steroidal anti-inflammatories). Intravenous, most inhalational and regional anesthesia appear to interfere minimally in the control of both the normal and ischemic coronary circulation. Thus optimizing myocardial oxygen balance (maintaining supply and decreasing demand) during anesthesia protects the ischemic myocardium. High doses of isoflurane, sevoflurane or desflurane are potent R2 coronary vasodilators which may cause redistribution of collateral blood flow away from ischemic regions (coronary steal). However, if tachycardia and hypotension are avoided, such an effect has not been shown experimentally or clinically. Preliminary evidence suggests that halothane may preferentially dilate R1 arteries and/or interfere with platelet aggregation. If these effects are confirmed, then halothane may prove to be the anesthetic of choice in the non-failing ischemic heart.
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PMID:Physiology, pathophysiology and pharmacology of the coronary circulation with particular emphasis on anesthetics. 164 43

We evaluated the contractile reactivity to various stimuli, and the content and release of noradrenaline (NA) from a non-vascular tissue, the vas deferens, isolated from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The concentration-contraction curves for NA in tissue from animals of two ages (10-25 weeks and 30-45 weeks) were shifted to the left in SHR as compared with in age-matched WKY, with significant differences at 1.0 and/or 10 microM of NA. Similarly, the amplitude of contraction produced by electrical stimulation at 4, 8 and 16 Hz in the tissue was much larger in SHR than in WKY. However, ATP (10-100 microM) evoked contractions of the tissue to a similar extent in both SHR and WKY. The electrically evoked contractions of vas deferens from both strains were inhibited by isoprenaline in an approximate dose-dependent and equipotent manner. The tissue NA content, determined by HPLC-ECD, was nearly same in both SHR and WKY. In addition, the same amount of NA was released from the vas deferens of both strains by electrical stimulation in the presence of 4-aminopyridine. The present findings indicate that the contractile response of vas deferens to stimulation of alpha 1-adrenoceptors, but not of beta-adrenoceptors or P2X-purinoceptors, is more pronounced in SHR than in WKY and that a response indicative of hypertension may also occur in non-vascular tissue as it does in vascular tissue.
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PMID:Hyperreactivity of alpha 1-adrenoceptors, but not of P2X-purinoceptors, in vas deferens of spontaneously hypertensive rats. 165 81

The (Na+,K+)-ATPase activity from the kidney cortex of the Milan hypertensive rat strain (MHS) and the corresponding normotensive control (MNS) was measured both in active solubilized enzyme preparations and in isolated basolateral membrane vesicles. Kinetic analysis of the purified enzyme showed that the Vmax value was significantly higher in MHS rats. The difference between MHS and MNS was not linked to a different number of sodium pumps, but was related to the molecular activity of the enzyme. Using basolateral membrane vesicles, an increased ATP-dependent ouabain-sensitive sodium transport was also demonstrated in MHS rats. These results support the hypothesis that a higher tubular sodium reabsorption may be involved in the pathogenesis of hypertension in this rat strain.
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PMID:Increased Na pump activity in the kidney cortex of the Milan hypertensive rat strain. 165 32

Some animal or plant toxins and man-made drugs exert agonist activity on Na+, Ca2+ and K+ channels. The increase in current through these channels is essentially due to an increase of 'open probability' and not of single channel conductance. The enhanced open probability is caused by a prolongation of the open time. In the case of voltage-operated channels this change in open time can be accompanied by increased reopenings and thus slowing of inactivation, or a shift in the activation process to more negative potentials. In the case of the ligand-operated K+ channel, a decrease in the affinity for the normal physiological ligand, ATP, is the mechanism underlying the enhancement of open probability. Agonists show potential clinical applications for Na+ and Ca2+ channels more specifically as positive inotropic agents in cardiac tissue. For K+ channels, the potential therapeutic field is even broader and spans from relaxation of smooth muscle (hypertension, asthma, bladder, uterus), reduction in excitability (arrhythmias, certain skeletal muscle myopathies) to inhibition of neurotransmitter release (depression, epilepsy).
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PMID:Ion channel agonists: expectations for therapy. 172 54

Endothelium-dependent relaxations are depressed in hypertension. In this study we investigated the possible involvement of endothelium-dependent smooth muscle hyperpolarization in this phenomenon. In isolated aortic segments from control rats, acetylcholine (10(-8)-10(-5) M) elicits relaxations after precontraction with norepinephrine (10(-7) M), and acetylcholine or carbachol (10(-5) M) induce smooth muscle hyperpolarization (10.6 +/- 0.9 mV). Both effects disappear after removal of the endothelium and are depressed by tetraethylammonium (3 x 10(-3) M), a rather nonspecific blocker of K+ channels, but not by glibenclamide (10(-5) M), a potent blocker of the ATP-regulated K+ channels, which has a marked effect on the relaxation induced by BRL 38227. The relaxation effect of acetylcholine is impaired in norepinephrine-contracted preparations from hypertensive rats but is not further depressed by tetraethylammonium. In aorta from hypertensive rats, hyperpolarization induced by carbachol was significantly reduced to a mean of only 21.8% of the values obtained in preparations from normotensive rats. From the relaxation-hyperpolarization relation obtained with BRL 38227 (opening K+ channels), it is derived that the endothelium-dependent hyperpolarization (approximately 10 mV) contributes for at least 20-30% of the maximal relaxation effect of acetylcholine on rat aorta. It is concluded that the diminished endothelium-dependent hyperpolarization may contribute to the depression of the endothelium-dependent relaxation in hypertension.
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PMID:Endothelium-dependent relaxation and hyperpolarization in aorta from control and renal hypertensive rats. 172 81

We have investigated hypertension-associated alterations in intracellular cations in the kidney by measuring intracellular pH, free Mg2+, free Ca2+, and Na+ concentrations in perfused normotensive and hypertensive rat (8-14 weeks old) kidneys using 31P, 19F, and double quantum-filtered (DQ) 23Na NMR. The effects of both anoxia and ischemia on the 23Na DQ signal confirmed its ability to detect changes in intracellular Na+. However, there was a sizable contribution of the extracellular Na+ to the 23Na DQ signal of the kidney. The intracellular free Ca2+ concentration, measured using 19F NMR and 5,5'difluoro-1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid, also increased dramatically during ischemia; the increase could be partly reversed by reperfusion. No significant differences were found between normotensive and hypertensive kidneys in the ATP level, intracellular pH, intracellular free Mg2+, and the 23Na DQ signal or in the extent of the extracellular contribution to the 23Na DQ signal. Oxygen consumption rates were also similar for the normotensive (5.02 +/- 0.46 mumol of O2/min/g) and hypertensive (5.47 +/- 0.42 mumol O2/min/g) rat kidneys. The absence of a significant difference in intracellular pH, Na+ concentration, and oxygen consumption between normotensive and hypertensive rat kidneys suggests that an alteration in the luminal Na+/H+ antiport activity in hypertension is unlikely. However, a highly significant increase (64%, p less than 0.01) in free Ca2+ concentration was found in perfused kidneys from hypertensive rats (557 +/- 48 nM, blood pressure = 199 +/- 5 mmHg, n = 6) compared with normotensive rats (339 +/- 21 nM, blood pressure = 134 +/- 6, n = 4) indicating altered renal calcium homeostasis in essential hypertension. An increase in intracellular free Ca2+ concentration without an accompanying change in the intracellular Na+ suggests, among many possibilities, that the Ca2+/Mg(2+)-ATPase may be inhibited in the hypertensive renal tissue.
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PMID:Multinuclear NMR studies of intracellular cations in perfused hypertensive rat kidney. 174 Apr 16

Potassium channel activators (PCAs) open the membrane potassium channels, thus increasing the cell potassium efflux. This results in hyperpolarization of the cell membrane, the main result of which is a reduction of the penetration of calcium into cells. The resulting decrease of intracellular Ca++ produces relaxation of the smooth muscle fibres, notably in blood vessels. In animals, PCAs reduce total peripheral resistance and lower blood pressure. These vasodilator and hypotensive effects are accompanied by reflex tachycardia and stimulation of the renin-angiotensin system and they are antagonized by glibenclamide, an antagonist of ATP-dependent potassium channels. Very recent experimental data have shown that in the ischaemic myocardium PCAs tend to improve the balance between oxygen supply and demand and to exert a cardioprotective effect. Up to now, the only use of PCAs has been in arterial hypertension, and the only drugs used are pinacidil, minoxidil and diazoxide. Unfortunately, the PCAs that are available at present are rather poorly tolerated, which limits their development in this particular field. However, their combination with beta-blockers and/or diuretics reduces the incidence of their side-effects and improves their effectiveness. A synergistic effect between PCAs and angiotensin-converting enzyme inhibitors is probable.
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PMID:[Potassium channel activators. Perspectives in the treatment of arterial hypertension]. 182 8

The effect of acute ethanol perfusion on the intracellular free magnesium level, intracellular pH, and high energy phosphate levels of isolated adult rat hearts (n = 13) were studied using 31P nuclear magnetic resonance (NMR) spectroscopy. Perfusion with 1% ethanol solution resulted in a 43% decrease in the intracellular free magnesium level in Langendorff perfused rat hearts while intracellular pH was not significantly altered. In most hearts ethanol perfusion also resulted in increased intracellular inorganic phosphate and reduced phosphocreatine and ATP levels, corresponding to a significant reduction in phosphorylation potential. The implications of these results in the pathogenesis of alcohol-induced hypertension are discussed in light of our previous studies on spontaneously hypertensive and normotensive rats which demonstrated a correlation between cardiac free magnesium levels and blood pressure.
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PMID:Depletion of intracellular free magnesium in rat hearts during acute alcohol perfusion: a 31P nuclear magnetic resonance study. 184 46

We superimposed extreme hypercapnia (arterial Pco2 400-450 mmHg) immediately before and during incomplete cerebral ischemia to distinguish the role of intracellular pH (pHi) and bicarbonate [( HCO3-]i) in postischemic metabolic and electrophysiological recovery. Incomplete global ischemia was produced in seven anesthetized dogs by 30 min of intracranial hypertension followed by 4 h of reperfusion. ATP, phosphocreatine (PCr), and pHi were measured with 31P magnetic resonance spectroscopy, and [HCO3-]i was calculated from the Henderson-Hasselbalch equation using the measured pHi and sagittal sinus Pco2. Cerebral blood flow was reduced to 7 +/- 1 ml.min-1.100 g-1 (+/- SE) during ischemia with extreme hypercapnia, and pHi decreased to 5.72 +/- 0.09. During normocapnic reperfusion, pHi rapidly returned to near baseline values by 14 min. [HCO3-]i fell from 12.1 +/- 0.9 to 6.0 +/- 1.2 mM by the midpoint of ischemia and recovered by 30 min of reperfusion. ATP, PCr, and O2 consumption also recovered rapidly and completely. Somatosensory-evoked potentials (SEP) recovered to 43 +/- 10% of control amplitude. These results are in marked contrast to the poor metabolic and SEP recovery previously observed in hyperglycemic dogs in which pHi decreased to the same range as with hypercapnic ischemia, but in which [HCO3-]i was much lower (1.1 +/- 0.5 mM). Therefore, [HCO3-]i depletion during hyperglycemic ischemia may be a more important factor in recovery than end-ischemic pHi per se. We speculate that higher [HCO3-]i may improve glial cell buffering capacity or decrease iron availability for hydroxyl radical production.
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PMID:Bicarbonate conservation during incomplete cerebral ischemia with superimposed hypercapnia. 190 5

Adenosine is known to regulate myocardial and coronary circulatory functions. Adenosine not only dilates coronary vessels, but attenuates beta-adrenergic receptor-mediated increases in myocardial contractility and depresses both sinoatrial and atrioventricular node activities. The effects of adenosine are mediated by two distinct receptors (i.e., A1 and A2 receptors). A1 adenosine receptors, located in atrial and ventricular myocardium and sinoatrial/atrioventricular nodes, are responsible for inhibition of adenylyl cyclase activity. A2 adenosine receptors, located in coronary endothelial and smooth muscle cells, are responsible for stimulation of this enzyme activity. During increased myocardial oxygen demand due to rapid pacing and exercise, although both coronary blood flow and adenosine concentrations in the myocardium and coronary efflux increased, there is no clear consensus explaining its cause and effect relation at present. However, ischemia/reperfusion-induced coronary hyperemia is believed to be mostly attributed to released adenosine, and it has been proven that adenosine attenuates the severity of ischemia due to its coronary vasodilatory action. The beneficial effects of adenosine during ischemia/reperfusion processes do not seem simple. This is because myocardial ischemia and reperfusion injury is caused by 1) activated leukocytes and platelets, 2) ATP depletion and calcium overload of myocardium, and 3) catecholamine release from the presynaptic nerves as well as 4) the impaired coronary circulation. Intriguingly adenosine attenuates all of these deleterious actions and thereby attenuates ischemia/reperfusion injury. Indeed, adenosine attenuates the severity of contractile dysfunction (myocardial stunning) and limits the infarct size. Thus, administration of adenosine or potentiators of adenosine production in the ischemic myocardium may be beneficial for the attenuation of ischemic and reperfusion injuries, although further clinical investigations are necessary.
Hypertension 1991 Nov
PMID:Adenosine, the heart, and coronary circulation. 193 58


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