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 primary mechanism of regulation of smooth muscle contraction involves the phosphorylation of myosin catalyzed by Ca2+/calmodulin-dependent myosin light chain kinase. However, additional mechanisms, both Ca(2+)-dependent and Ca(2+)-independent, can modulate the contractile state of smooth muscle. Protein kinase C was first implicated in the regulation of smooth muscle contraction with the observation that phorbol esters induce slowly developing, sustained contractions. Protein kinase C occurs in at least four Ca(2+)-dependent (alpha, beta I, beta II, and gamma) and four Ca(2+)-independent (delta, epsilon, zeta, and eta) isoenzymes. Only the alpha, beta, epsilon, and zeta isoenzymes have been identified in smooth muscle. Both classes of isoenzymes have been implicated in the regulation of smooth muscle contraction. However, the physiologically important protein substrates of protein kinase C have not yet been identified. Specific isoenzymes may be activated by different contractile agonists, and individual isoenzymes exhibit some degree of substrate specificity. Prolonged activation of protein kinase C can result in its proteolysis to the constitutively active catalytic fragment protein kinase M, which would dissociate from the sarcolemma and phosphorylate proteins such as myosin that are inaccessible to membrane-bound protein kinase C. Protein kinase M induces relaxation of demembranated smooth muscle fibers contracted at submaximal Ca2+ concentrations. We suggest that protein kinase C plays two distinct roles in regulating smooth muscle contractility. Stimuli triggering phosphoinositide turnover or phosphatidylcholine hydrolysis induce translocation of protein kinase C (probably specific isoenzymes) to the sarcolemma, phosphorylation of protein, and a slow contraction. Prolonged association of the kinase with the membrane may lead to proteolysis and release into the cytosol of protein kinase M, resulting in myosin phosphorylation and relaxation.
Hypertension 1992 Nov
PMID:Protein kinase C of smooth muscle. 142 8

We examined effects of a putative myosin light chain kinase inhibitor in the cerebral circulation in vivo. In anesthetized rats, diameter of basilar arteries was measured through a cranial window (control, 232 +/- 10 microns, mean +/- SEM). Vessel diameter was measured during topical application of agonists and antagonists. ML-7, which has been reported to compete with adenosine triphosphate for binding to the catalytic site on myosin light chain kinase, attenuated vasoconstriction in response to prostaglandin F2 alpha (10(-6) M; -22 +/- 1% before versus -14 +/- 1% and -3 +/- 2% during ML-7, 10(-7) and 10(-6) M, respectively; p less than 0.05). ML-7 (10(-6) M) did not affect baseline diameter. Responses to serotonin (10(-8) M) and phorbol 12,13-dibutyrate (10(-8) M) were not attenuated by ML-7. Thus, constriction of the basilar artery induced by prostaglandin F2 alpha in vivo is attenuated by an inhibitor of myosin light chain kinase.
Hypertension 1992 Jun
PMID:Signal transduction pathways in constriction of the basilar artery in vivo. 159 75

Intracellular calcium concentration ([Ca2+]i)-dependent activation of myosin light chain kinase and its phosphorylation of the 20-kd light chain of myosin is generally considered the primary mechanism responsible for regulation of contractile force in arterial smooth muscle. However, recent data suggest that the relation between [Ca2+]i and myosin light chain phosphorylation is variable and depends on the form of stimulation. The dependence of myosin phosphorylation on [Ca2+]i has been termed the "[Ca2+]i sensitivity of phosphorylation." The [Ca2+]i sensitivity of phosphorylation is "high" when relatively small increases in [Ca2+]i induce a large increase in myosin phosphorylation. Conversely, the [Ca2+]i sensitivity of phosphorylation is "low" when relatively large increases in [Ca2+]i are required to induce a small increase in myosin phosphorylation. There are two proposed mechanisms for changes in the [Ca2+]i sensitivity of phosphorylation: Ca(2+)-dependent decreases in the [Ca2+]i sensitivity of phosphorylation induced by phosphorylation of myosin light chain kinase by Ca(2+)-calmodulin protein kinase II and agonist-dependent increases in the [Ca2+]i sensitivity of phosphorylation by inhibition of a myosin light chain phosphatase. I will review the proposed mechanisms responsible for the regulation of [Ca2+]i and the [Ca2+]i sensitivity of phosphorylation in arterial smooth muscle.
Hypertension 1992 Aug
PMID:Regulation of contraction and relaxation in arterial smooth muscle. 163 54

Considerable evidence suggests that protein kinase C activation participates in the regulation of vascular smooth muscle tone. The objective of the current study was to examine the relations between inhibition of protein kinase C (PKC) and myosin light-chain kinase (MLCK) and vasorelaxation and blood pressure regulation in spontaneously hypertensive rats (SHR). Putative PKC inhibitors from two chemical classes, staurosporinelike (staurosporine and K252A) and isoquinolinesulfonamides (H7 and HA1004), were tested for their ability to 1) inhibit PKC and MLCK from SHR aorta, 2) relax isolated SHR aorta, and 3) lower blood pressure in conscious SHR. A rank order of potency for the inhibition of PKC and MLCK was established, with the staurosporinelike compounds (staurosporine PKC IC50 = 54 nM) clearly more potent than the isoquinolinesulfonamides (H7 PKC IC50 = 128 microM). The rank order of potency for inhibition of PKC was retained for inhibition of MLCK for all compounds. Staurosporine (EC50 = 75 nM) and H7 (EC50 = 2 microM) caused concentration-dependent relaxation of SHR aorta, but only staurosporine produced vasorelaxation at concentrations consistent with the inhibition of PKC or MLCK. Dose-dependent reductions in arterial pressure of SHR were demonstrated after intravenous injection of staurosporine and HA1004. A single intravenous injection of staurosporine (0.3 mg/kg) lowered blood pressure for more than 10 hours. Staurosporine also lowered blood pressure after oral administration. The depressor response to staurosporine was unaffected by sympathetic beta-adrenergic blockade. In conclusion, the vasorelaxant and antihypertensive actions of staurosporine in SHR are consistent with the inhibition of PKC but could also be equally related to inhibition of MLCK. Not all PKC inhibitors produce vasorelaxation and lower blood pressure. Moreover, the lack of correlation between in vitro vasodilation and PKC or MLCK inhibition for the isoquinolinesulfonamide protein kinase inhibitors H7 and HA1004 suggests that these agents do not cause vasorelaxation in SHR by inhibition of these enzymes.
Hypertension 1991 Jan
PMID:Protein kinase inhibitors and blood pressure control in spontaneously hypertensive rats. 198 86

For many years the simple view was held that contractile force in smooth muscle was proportional to cytosolic Ca2+ concentrations ([Ca2+]i). With the discovery that phosphorylation of myosin light chain by Ca2+/calmodulin-dependent myosin light chain kinase initiated contraction, regulation of the contractile elements developed more complex properties. Molecular and biochemical investigations have identified important domains of myosin light chain kinase: light chain binding sites, catalytic core, pseudosubstrate prototope, and calmodulin-binding domain. New protein phosphatase inhibitors such as okadaic acid and calyculin A should help in the identification of the physiologically important phosphatase and potential modes of regulation. The proposal of an attached, dephosphorylated myosin cross bridge (latch bridge) that can maintain force has evoked considerable controversy about the detailed functions of the myosin phosphorylation system. The latch bridge has been defined by a model based on physiological properties but has not been identified biochemically. Thin-filament proteins have been proposed as secondary sites of regulation of contractile elements, but additional studies are needed to establish physiological roles. Changes in the Ca2+ sensitivity of smooth muscle contractile elements with different modes of cellular stimulation may be related to inactivation of myosin light chain kinase or activation of protein phosphatase activities. Thus, contractile elements in smooth muscle cells are not dependent solely on [Ca2+]i but use additional regulatory mechanisms. The immediate challenge is to define their relative importance and to describe molecular-biochemical properties that provide insights into proposed physiological functions.
Hypertension 1991 Jun
PMID:Vascular smooth muscle contractile elements. Cellular regulation. 204 32

The Ca2+, calmodulin (CaM)-dependent phosphorylation of the 20 kDa myosin light chain (LC20) is accepted as an important component of the regulatory mechanism in smooth muscle contraction. Since we have originally developed selective inhibitors of each process of the intracellular Ca2+ messenger system, the effect of a newly synthesized compound ML-9, a myosin light chain kinase (MLCK) inhibitor on superprecipitation of actomyosin, isometric tension development and phosphorylation of LC20 in vascular smooth muscle was investigated. Superprecipitation of actomyosin from bovine aorta was inhibited by the addition of ML-9 in a dose-dependent manner. In chemically skinned smooth muscle cells of the rabbit mesenteric artery, ML-9 inhibited both Ca2+ and Ca2+, CaM-independent MLCK-induced contraction. In the intact vascular strips, increase in LC20 phosphorylation reached a maximal value within 10 sec from a resting value, and then declined to near the basal level during the maintained isometric force developed in response to 50 mmol/L KCl. Both the maximal rate and extent of KCl-induced contraction and the phosphorylation of LC20 were also inhibited by ML-9. It antagonized the contraction induced by various contractile agonists, such as NE, 5HT, His, and Ang II concomitant with the inhibition of LC20 phosphorylation. These results suggest that ML-9 inhibits the actin-myosin interaction through the modulation of LC20 phosphorylation via the inhibition of MLCK activity. ML-9 will aid in determining pathophysiological functions of MLCK of increased vascular contractility in hypertension.
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PMID:Molecular pharmacology of calcium, calmodulin-dependent myosin phosphorylation in vascular smooth muscle. 222 74

Tension development in arterial smooth muscle is regulated by variations of calcium concentration in the submicromolar range. The receptor for Ca2+ is calmodulin, which through stimulation of myosin light chain kinase can activate sequentially two apparently different contractile states. A third possible contractile state may be related to C-kinase activation. These contractile states are thought to have different Ca2+ sensitivities. Ca2+ is supplied from two major sources: the sarcoplasmic reticulum and the extracellular space. The release of sarcoplasmic reticulum Ca2+ is mediated by the intracellular messenger inositol-1,4,5-trisphosphate (IP3) and perhaps by Ca2+ itself. These two messengers have the potential for amplification; for example, IP3 may release some Ca2+ that may subsequently cause Ca2+-induced Ca2+ release. The entry of Ca2+ from the extracellular space into the cytoplasm is mediated by a Ca2+ leak and by excitable Ca2+ channels and is modulated by a Ca2+ buffer barrier consisting of the superficial sarcoplasmic reticulum. Two types of adenosine 5'-triphosphate-driven Ca2+ pumps in the sarcoplasmic reticulum and plasmalemma are responsible for returning the cytoplasmic Ca2+ concentration to resting level after contraction and for maintaining Ca2+ homeostasis during the life of the cells.
Hypertension 1986 Jun
PMID:Calcium activation of vascular smooth muscle. State of the art lecture. 242 35

Regulation of vascular resistance is generally explained in terms of neural, hormonal, metabolic, and myogenic factors altering intracellular calcium [Ca++] in vascular smooth muscle. Ca++ acts as a second messenger regulating the number of active crossbridges and force generation by binding to a myofilament regulatory protein. A search for the Ca++-binding regulatory protein in arterial smooth muscle has uncovered what appears to be a new type of regulation. In addition to its interaction with an undefined Ca++-binding site which determines force development, Ca++ stimulates phosphorylation of the crossbridges. Phosphorylated crossbridges cycle more rapidly than dephosphorylated crossbridges in the presence of Ca++. Some known characteristics of the myosin light chain kinase/phosphatase system and the effects of crossbridge phosphorylation on the mechanics of arterial smooth muscle are described. Chronic alterations in this system have potential effects on vascular resistance and merit investigation in studies of arterial smooth muscle from hypertensive animal models.
Hypertension
PMID:Myosin phosphorylation and crossbridge regulation in arterial smooth muscle. State-or-the-art review. 627 5

Smooth muscle contraction is the basis of the physiological reactivity of several systems (vascular, respiratory, gastrointestinal, urogenital ...). Hyperresponsiveness of smooth muscle may also contribute to a variety of problems such as arterial hypertension, asthma and spontaneous abortion. An increase in cytoplasmic calcium concentration ([Ca2+]i) is the key event in excitation-contraction coupling in smooth muscle and the relationship linking the [Ca2+]i value to the force of contraction represents the calcium sensitivity of the contractile apparatus (CaSCA). Recently, it has become evident that CaSCA can be modified upon the action of agonists or drugs as well as in some pathophysiological situations. Such modifications induce, at a fixed [Ca2+]i value, either an increase (referred to as sensitization) or a decrease (desensitization) of the contraction force. The molecular mechanisms underlying this modulation are not yet fully elucidated. Nevertheless, recent studies have identified sites of regulation of the actomyosin interaction in smooth muscle. Sensitization primarily results from the inhibition of myosin light chain phosphatase (MLCP) by intracellular messengers such as arachidonic acid or protein kinase C. In addition, phosphorylation of thin filament-associated proteins, caldesmon and calponin, increases CaSCA. Activation of small (monomeric) G-proteins such as rho or ras is also involved. Desensitization occurs as a consequence of phosphorylation of myosin light chain kinase (MLCK) by the calcium-calmodulin activated protein kinase II, or stimulation of MLCP by cyclic GMP-activated protein kinase. In the present review, examples of physiological modulation of CaCSA as well as pharmacological and pathophysiological implications are illustrated for some smooth muscles.
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PMID:Modulation of the calcium sensitivity of the smooth muscle contractile apparatus: molecular mechanisms, pharmacological and pathophysiological implications. 926 58

Abnormal smooth-muscle contractility may be a major cause of disease states such as hypertension, and a smooth-muscle relaxant that modulates this process would be useful therapeutically. Smooth-muscle contraction is regulated by the cytosolic Ca2+ concentration and by the Ca2+ sensitivity of myofilaments: the former activates myosin light-chain kinase and the latter is achieved partly by inhibition of myosin phosphatase. The small GTPase Rho and its target, Rho-associated kinase, participate in this latter mechanism in vitro, but their participation has not been demonstrated in intact muscles. Here we show that a pyridine derivative, Y-27632, selectively inhibits smooth-muscle contraction by inhibiting Ca2+ sensitization. We identified the Y-27632 target as a Rho-associated protein kinase, p160ROCK. Y-27632 consistently suppresses Rho-induced, p160ROCK-mediated formation of stress fibres in cultured cells and dramatically corrects hypertension in several hypertensive rat models. Our findings indicate that p160ROCK-mediated Ca2+ sensitization is involved in the pathophysiology of hypertension and suggest that compounds that inhibit this process might be useful therapeutically.
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PMID:Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. 935 12


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