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PubMed2005

Dominant role for calpain in thromboxane-induced neuromicrovascular endothelial cytotoxicity.

Thromboxane A(2) (TXA(2)) is an important lipid mediator generated during oxidative stress and implicated in ischemic neural injury. This autacoid was recently shown to partake in this injury process by directly inducing endothelial cytotoxicity. We explored the mechanisms for this TXA(2)-evoked neural microvascular endothelial cell death. Stable TXA(2) mimetics 5-heptenoic acid, 7-[6-(3-hydroxy-1-octenyl)-2-oxabicyclo[2.2.1]hept-5-yl]-[1R-[1alpha,4alpha,5beta(Z),6alpha,(1E,3S)]]-9,11-dedioxy-9alpha,11alpha-methanolpoxy (U-46619) [as well as [1S-[1alpha,2alpha(Z),3beta(1E,3S(*)),4alpha]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.1.1]-hept-2-yl]-5-heptenoic acid; I-BOP] induced a retinal microvascular degeneration in rat pups in vivo and in porcine retinal explants ex vivo and death of porcine brain endothelial cells (in culture). TXA(2) dependence of these effects was corroborated by antagonism using the selective TXA(2) receptor blocker (-)-6,8-difluoro-9-p-methyl-sulfonyl-benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid (L670596). In all cases, neurovascular endothelial cell death was prevented by pan-calpain and specific m-calpain inhibitors but not by caspase-3 or pan-caspase inhibitors. Correspondingly, TXA(2) (mimetics) augmented generation of known active m-calpain (but not mu-calpain) form and increased the activity of m-calpain (cleavage of fluorogenic substrate N-succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin; and of alpha-spectrin into specific fragments) but not of pan-caspase or specific caspase-3 (respectively, using sulforhodamine-Val-Arg-Asp-fluoromethyl ketone and detecting its active 17- and 12-kDa fragments). Interestingly, these effects were phospholipase C (PLC)-dependent [associated with increase in inositol triphosphate and inhibited by PLC blocker 1-[6-[[17beta-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122)] and required calcium but were not associated with increased intracellular calcium. U-46619-induced calpain activation resulted in translocation of Bax to the mitochondria, loss of polarization of the latter (using potentiometric probe 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide; JC-1) and in turn release of cytochrome c into the cytosol and depletion of cellular ATP; these effects were all blocked by calpain inhibitors. Overall, this work identifies (specifically) m-calpain as a dominant protease in TXA(2)-induced neurovascular endothelial cell death.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2004

Aging biology and geriatric clinical pharmacology.

Population aging evokes doomsday economic and sociological prognostication, despite a minority of older people suffering significant dependency and the potential for advances in therapeutics of age-related disease and primary aging. Biological aging processes are linked mechanistically to altered drug handling, altered physiological reserve, and pharmacodynamic responses. Parenteral loading doses need only be adjusted for body weight as volumes of distribution are little changed, whereas oral loading doses in some cases may require reduction to account for age-related increases in bioavailability. Age-related reduction of hepatic blood flow and hepatocyte mass and primary aging changes in hepatic sinusoidal endothelium with effects on drug transfer and oxygen delivery reduce hepatic drug clearance. Primary renal aging is evident, although renal clearance reduction in older people is predominantly disease-related and is poorly estimated by standard methods. The geriatric dosing axiom, "start low and go slow" is based on pharmacokinetic considerations and concern for adverse drug reactions, not from clinical trial data. In the absence of generalizable dosage guidelines, individualization via effect titration is required. Altered pharmacodynamics are well documented in the cardiovascular system, with changes in the autonomic system, autacoid receptors, drug receptors, and endothelial function to modify baseline cardiovascular tone and responses to stimuli such as postural change and feeding. Adverse drug reactions and polypharmacy represent major linkages to avoidable morbidity and mortality. This, combined with a deficient therapeutic evidence base, suggests that extrapolation of risk-benefit ratios from younger adults to geriatric populations is not necessarily valid. Even so, therapeutic advances generally may convert healthy longevity from an asset of fortunate individuals into a general social benefit.

Aged↗
PubMed1991

Rickettsial effects on leukotriene and prostaglandin secretion by mouse polymorphonuclear leukocytes.

Typhus rickettsiae were incubated with mouse exudative polymorphonuclear leukocytes (PMN), and supernatants were examined for leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) secretion by radioimmunoassay. PMN incubated with native rickettsiae secreted significantly more LTB4 and PGE2 than did those incubated with buffer alone. Autacoid secretion was dependent on both the time of PMN incubation with rickettsiae and the number of rickettsiae present in the incubation suspension. Rickettsial stimulation of LTB4 secretion was associated with rickettsial hemolytic activity; treatments which inactivated the rickettsial hemolysin abolished the ability of rickettsiae to stimulate PMN LTB4 secretion. Trifluoperazine, which did not alter the rate of phagocytosis of rickettsiae by PMN, stimulated rickettsial effects on secretion of both LTB4 and PGE2 but inhibited the PMN LTB4 response to A23187. This suggested that the PMN response to rickettsiae and to the calcium ionophore involved differing mechanisms of activation. Finally, rabbit antirickettsial antiserum, which inhibited rickettsial hemolysis and was opsonic, did not block the effects of rickettsiae on PMN LTB4 secretion.

Acetophenones↗
PubMed2002

Role of cysteinyl leukotrienes in adenosine 5'-monophosphate induced bronchoconstriction in asthma.

BACKGROUND: Adenosine induced bronchoconstriction in patients with asthma is thought to be mediated by the synthesis and release of autacoids from airway mast cells. In vitro, adenosine induced constriction of asthmatic bronchi is blocked by a combination of specific histamine and cysteinyl leukotriene receptor antagonists, but the relative contribution of these mediators in vivo is unclear. We hypothesised that adenosine induced bronchoconstriction in asthmatic patients may be blocked by pretreatment with the orally active selective cysteinyl leukotriene-1 (CysLT(1)) receptor antagonist, montelukast. METHODS: In a randomised, double blind, crossover study, oral montelukast (10 mg) or placebo was administered once daily on two consecutive days to 18 patients with mild to moderate persistent atopic asthma. Incremental doses of adenosine 5'-monophosphate (AMP) from 0.39 to 400 mg/ml were inhaled by dosimeter and the dose producing a 20% fall in FEV(1) (PC(20)AMP) after AMP inhalation was recorded. Leukotriene E(4) (LTE(4)) urinary concentrations were measured by enzyme immunoassay 4 hours after AMP challenge. RESULTS: Montelukast pretreatment provided highly significant protection against adenosine induced bronchoconstriction, with geometric mean PC(20)AMP values of 52.6 mg/ml (95% CI 35.2 to 78.7) after placebo and 123.9 mg/ml (95% CI 83.0 to 185.0) after montelukast (p=0.006). The geometric mean of the montelukast/placebo PC(20)AMP ratio was 2.4 (95% CI 1.3 to 4.2). Montelukast had no significant effect on 4 hour urinary excretion of LTE(4) compared with placebo. CONCLUSIONS: Selective CysLT(1) receptor antagonism with montelukast provides highly significant protection against AMP induced bronchoconstriction in patients with atopic asthma, implying that cysteinyl leukotrienes are generated from airway mast cells through preferential activation of their A(2B) receptors.

Acetates↗
PubMed2005

Actin cytoskeletal dynamics in smooth muscle contraction.

Smooth muscles develop isometric force over a very wide range of cell lengths. The molecular mechanisms of this phenomenon are undefined, but are described as reflecting "mechanical plasticity" of smooth muscle cells. Plasticity is defined here as a persistent change in cell structure or function in response to a change in the environment. Important environmental stimuli that trigger muscle plasticity include chemical (e.g., neurotransmitters, autacoids, and cytokines) and external mechanical signals (e.g., applied stress and strain). Both kinds of signals are probably transduced by ionic and protein kinase signaling cascades to alter gene expression patterns and changes in the cytoskeleton and contractile system. Defining the signaling mechanisms and effector proteins mediating phenotypic and mechanical plasticity of smooth muscles is a major goal in muscle cell biology. Some of the signaling cascades likely to be important include calcium-dependent protein kinases, small GTPases (Rho, Rac, cdc42), Rho kinase, protein kinase C (PKC), Src family tyrosine kinases, mitogen-activated protein (MAP) kinases, and p21 activated protein kinases (PAK). There are many potential targets for these signaling cascades including nuclear processes, metabolic pathways, and structural components of the cytoskeleton. There is growing appreciation of the dynamic nature of the actin cytoskeleton in smooth muscles and the necessity for actin remodeling to occur during contraction. The actin cytoskeleton serves many functions that are probably critical for muscle plasticity including generation and transmission of force vectors, determination of cell shape, and assembly of signal transduction machinery. Evidence is presented showing that actin filaments are dynamic and that actin-associated proteins comprising the contractile element and actin attachment sites are necessary for smooth muscle contraction.

Actins↗
PubMed1989

Immunopharmacology: a new frontier.

Immunopharmacology is a hybrid science which has been founded upon the principles, theory, and technical developments of both immunology and pharmacology, but which has a unique identity incorporating both basic and applied areas of research. Basic immunopharmacological research is concerned with the underlying mechanisms by which endogenous and synthetic chemicals interact with the cells of the immune system. Important areas of research include the actions of chemicals such as lymphokines, cytokines, complement, kinins, autacoids, drugs, and even neuropeptides on immune function. Applied immunopharmacology is concerned with the development and testing of new immunomodulatory drugs which will be of benefit to clinical medicine but also as basic research tools. In the past, the two fields of immunology and pharmacology have contributed to each other in many significant ways. Immunology has contributed to pharmacological research by the development of antibodies which are frequently used today as specific probes for the quantitative and qualitative analysis of many different classes of chemicals of interest. Pharmacology has contributed to the field of immunology by providing basic pharmacological information on subjects such as the mediators of hypersensitivity reactions and inflammation. In the future, the truly hybrid field of immunopharmacology promises to have an expanding role in clinical medicine and basic research. This prediction is based on the observation that recombinant lymphokines and newly discovered immunomodulatory substances have begun to enter the clinic in ever increasing numbers. Future immunopharmacological research will include the study of the pharmacology of these lymphokines but also the rational development of new drugs that act as antagonists or agonists for the endogenous lymphokines that normally regulate the immune response.(ABSTRACT TRUNCATED AT 250 WORDS)

Allergy and Immunology↗
PubMed1995

Diverse interactions of calcitonin gene related peptide and nitric oxide in the gastric and cutaneous microcirculation.

Calcitonin gene related peptide (CGRP) is the major mediator of afferent nerve mediated vasodilatation in the gastric mucosa and skin of the rat. Since receptors for CGRP occur on both the vascular endothelium and smooth muscle, it is conceivable that the vascular actions of CGRP involve multiple mechanisms. The vasodilator effect of rat CGRP-alpha in the rat gastric mucosa is indeed inhibited by blockage of nitric oxide (NO) synthesis, as is the gastric mucosal hyperemia in response to gastric acid challenge, which is mediated by CGRP release from afferent nerve fibres. In contrast, the vasodilator response to rat CGRP-alpha in the rat hind paw and the CGRP-mediated vasodilatation evoked by antidromic stimulation of afferent nerve fibres do not depend on the formation of NO. These data indicate that NO plays regionally different roles in the local vasodilator action of CGRP. NO is a secondary vasorelaxant messenger of CGRP in the gastric, but not in the cutaneous, microcirculation. However, this L-arginine-derived autacoid may have a role in the irritant-induced CGRP release from afferent vasodilator fibres in the skin.

Animals↗
PubMed1979

The biosynthesis and metabolism of prostaglandins.

With improved techniques for isolation and identification of materials, thromboxane (TXA2) and prostacyclin (PGI2) derivatives are now recognized as more abundant in some tissues and more potent than PGE2 and PGF2alpha. The rapid appearance and disappearance of these autacoids can be regulated at many points along the enzymatic path. Two important features affecting the rate of overall prostaglandin formation are the availability of non-esterified substrate and the availability of hydroperoxide activator for the cyclooxygenase. The fate of the endoperoxide formed by this reaction then depends upon the different relative amounts of the synthases and dehydrogenases in each type of synthesizing cell. Important future developments will indicate ways in which the amounts of these enzyme activities are altered and the ways in which the prostaglandin receptors interact with cellular adenyl cyclase and adrenergic receptors.

15-Oxoprostaglandin 13-Reductase↗
PubMed1988

Identification and transmembrane signaling of leukotriene D4 receptors in human mesangial cells.

Although peptidoleukotriene (LTC4, LTD4) receptors have been characterized by radioligand binding studies, pathways of transmembrane signaling by activated leukotriene receptors remain obscure. We employed [3H]LTD4 binding studies and fluorescent measurements of intracellular Ca2+ concentration ([Ca2+]) and pH to identify LTD4 receptors and mechanisms of transmembrane signaling in cultured human mesangial cells. Mesangial cells expressed a single class of saturable, specific binding sites for [3H]LTD4. Kinetic, competition, and saturation analyses gave an average KD of approximately 12.0 nM with a Bmax of 987 fmol/mg protein. LTC4 competed with high affinity for [3H]LTD4 binding sites, as did LTB4 but with much lower affinity. [3H]LTD4 binding was blocked by a specific LTD4 receptor antagonist, SKF 102922. LTD4 and LTC4 also evoked a rapid (2-3 s), transient increase in intracellular [Ca2+], followed by a second, sustained increase. The transient phase was independent of extracellular Ca2+, whereas the sustained phase was dependent on extracellular Ca2+. Intracellular [Ca2+] was unaffected by LTB4. The LTD4-stimulated Ca2+ transients were dose dependent (1 nM-1 microM) and, similar to [3H]LTD4 binding, Ca2+ transients were inhibited by LTD4 receptor antagonists. We also report evidence that LTD4 affects intracellular pH and activates Na+-H+ exchange. Specifically, LTD4 induced an initial acidification within 1-2 min, followed by net alkalinization at 5 min. Alkalinization was due to activation of an amiloride-inhibitable Na+-H+ exchanger. LTD4 receptors were apparently not coupled to adenylate cyclase or phospholipase A2 as we detected no changes of adenosine 3',5'-cyclic monophosphate (cAMP) or prostanoids. Thus we conclude that [3H]LTD4 binding sites on human mesangial cells are coupled to a Ca2+-signaling system and Na+-H+ exchange. Moreover LTD4, a potent inflammatory mediator, failed to stimulate cAMP or prostaglandin E2/prostaglandin I2, two counterregulatory autacoids that preserve normal mesangial function.

Binding, Competitive↗
PubMed1995

C-type natriuretic peptide neuromodulates via "clearance" receptors.

A recently discovered endogenous autacoid, C-type natriuretic peptide, was tested in a pheochromocytoma (PC12) cell line for effects on 1) catecholamine release induced by a depolarizing stimulus, 2) guanylyl and adenylyl cyclase activities, and 3) specific 125I-labeled atrial natriuretic peptide (ANP) binding. C-type natriuretic peptide suppressed evoked neurotransmitter release in the absence of guanylyl cyclase activation or adenylyl cyclase inhibition; however, both a "clearance" (ANP-C) receptor binding agent, des-[Gln18Ser19Gly20Leu21Gly22]-ANF-(4-23)-NH2 (cANF), and pertussis toxin prevented this neuromodulatory effect. The C-type natriuretic peptide preferentially bound to receptors that also bound cANF. The results suggest that C-type natriuretic peptide suppressed evoked neurotransmitter efflux by binding to ANP-C receptors coupled to a pertussis toxin-sensitive process; furthermore, the neuromodulatory effect of C-type natriuretic peptide occurred independently of guanylyl cyclase activation or adenylyl cyclase inhibition. The novel aspects of these findings are 1) neuromodulatory effects of C-type natriuretic peptide, 2) guanylyl cyclase-independent actions of C-type natriuretic peptide, and 3) ANP-C receptors mediating C-type natriuretic peptide actions.

Animals↗
PubMed1996

Adenosine inhibits cytokine release and expression of adhesion molecules by activated human endothelial cells.

Ischemia induces excessive ATP catabolism with subsequent local release of its metabolite adenosine, an autacoid with anti-inflammatory properties. Because activation of the vascular endothelium is critical to the inflammatory host response during ischemia and reperfusion, the effects of adenosine on two major determinants of endothelial cell activation (i.e., the release of proinflammatory cytokines and the expression of adhesion molecules) were studied. Adenosine dose dependently inhibited the release of interleukin (IL)-6 and IL-8 by stimulated human umbilical vein endothelial cells (HUVEC). Expression of E-selectin and vascular cell adhesion molecule 1 (VCAM-1), but not intercellular adhesion molecule 1 (ICAM-1), by activated HUVEC was also reduced by adenosine. Inhibition of endogenous adenosine deaminase activity by erythro-9-(2-hydroxy-3-nonyl)adenine or 2'-deoxycoformycin strongly enhanced the inhibitory effects of exogenous adenosine on cytokine release and expression of E-selectin and VCAM-1. However, a clear role for specific adenosine receptors in the described inhibitory events could not be established. Together, these data imply that the vascular endothelium constitutes an important target for the anti-inflammatory actions of adenosine.

Adenosine↗
PubMed2000

Coordinate expression of secretory phospholipase A(2) and cyclooxygenase-2 in activated human keratinocytes.

PGE(2) levels are altered in human epidermis after in vivo wounding; however, mechanisms modulating PGE(2) production in activated keratinocytes are unclear. In previous studies, we showed that PGE(2) is a growth-promoting autacoid in human primary keratinocyte cultures, and its production is modulated by plating density, suggesting that regulated PGE(2) synthesis is an important component of wound healing. Here, we examine the role of phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) enzymes in modulation of PGE(2) production. We report that the increased PGE(2) production that occurs in keratinocytes grown in nonconfluent conditions is also observed after in vitro wounding, indicating that similar mechanisms are involved. This increase was associated with coordinate upregulation of both COX-2 and secretory PLA(2) (sPLA(2)) proteins. Increased sPLA(2) activity was also observed. By RT-PCR, we identified the presence of type IIA and type V sPLA(2), along with the M-type sPLA(2) receptor. Thus the coordinate expression of sPLA(2) and COX-2 may be responsible for the increased prostaglandin synthesis in activated keratinocytes during wound repair.

Cells, Cultured↗
PubMed1989

Immunological regulation of colonic ion transport.

Challenge of distal colonic epithelium from Trichinella spiralis-infected guinea pigs with parasite-derived antigen elevated short-circuit current (Isc) for approximately 60 min. The maximum elevation (delta Isc) was approximately 250 microA/cm2 at 5 min after the addition of trichinella antigen. The antigen-induced alterations in Isc were of greater magnitude and duration than those evoked in jejunum. Colonic electrical resistance was transiently reduced after exposure to antigen. There was no significant effect of antigen on electrical parameters of colon from nonimmunized (uninfected) guinea pigs. The antihistamine pyrilamine (10(-5) M) and the prostaglandin synthesis inhibitor indomethacin (10(-6) M) reduced the colonic Isc response to antigen by 40% when used in combination but had insignificant effects when used singly. In contrast, the jejunal Isc response to antigen was totally eliminated by the combined use of those inhibitors. Antigenic stimulation of sensitized colon released histamine and prostaglandin E2 (PGE2). However, the histamine released was only about one-tenth that stimulated by antigen in the jejunum, and PGE2 released was only one-tenth of that stimulated by bradykinin in the colon. PGE2 was not released after antigenic stimulation of jejunum. The antigen-induced colonic delta Isc was reduced approximately 50% by either furosemide or tetrodotoxin. Although histamine- and indomethacin-sensitive factors contribute greatly to the mediation of the antigen-induced delta Isc in jejunum, these autacoids contribute to a lesser extent to the antigen-induced delta Isc in guinea pig colon.

Animals↗
PubMed1997

Adenosine kinase inhibitor GP515 attenuates hepatic leukocyte adhesion after hemorrhagic hypotension.

Adhesion of leukocytes to the vascular endothelium hallmarks a key event in neutrophil-mediated organ injury after ischemia-reperfusion. The autacoid adenosine has been shown to inhibit activated neutrophil function and to interfere with leukocyte-endothelial adherence. Its therapeutic use in ischemia-reperfusion, however, has been limited by severe cardiovascular side effects. We therefore investigated the effects of the adenosine kinase inhibitor GP515 in vivo on hepatic leukocyte-endothelial interactions in a rat model of hemorrhagic hypotension and resuscitation, using intravital microscopy. Rats were pretreated with either GP515 (0.25 mg/kg) or saline in a randomized and blinded manner and subjected to pressure-controlled hemorrhagic hypotension at a mean arterial pressure of 40 mmHg for 60 min followed by 5 h of resuscitation. Five hours after resuscitation in saline-treated animals, firm leukocyte-sinusoidal adhesion was strongly enhanced in the periportal and midzonal sublobular regions, and sinusoidal diameters were also markedly reduced. Compared with saline treatment, GP515 significantly attenuated shock and resuscitation-induced leukocyte adhesion in both sublobular regions. Moreover, although GP515 did not significantly affect macrohemodynamical and hematological parameters, it enlarged narrowed sinusoidal diameters and tended to improve sinusoidal blood flow. We propose that the adenosine-regulating agent GP515 has a therapeutic potential to attenuate ischemia-reperfusion-induced inflammation by capitalizing on the beneficial anti-inflammatory effects of endogenous adenosine.

Adenosine Kinase↗
PubMed1999

Blood flow-dependent prostaglandin f(2alpha) regulates intestinal glucose uptake from the blood.

Intestinal glucose uptake (GUi) from blood increased when blood flow (BF) was increased. The increase in BF could elevate shear stress. Therefore, we hypothesize that shear stress-induced release of autacoids mediates the increase in GU(i). A surgically separated segment of small intestine was perfused in situ with the use of an arterial circuit in anesthetized cats. Arterial and portal blood samples were taken simultaneously for assessment of GU(i). Adenosine was used to elevate intestinal BF. The GU(i) increased by 45.0 +/- 18.3 from 25.3 +/- 3.8 micromol. min(-1). 100 g tissue(-1) when the BF increased about four times. It was not a direct effect of adenosine because GU(i) was not altered if the flow was held constant. This increase was blocked by a cyclooxygenase inhibitor, indomethacin, but not by nitric oxide synthase blocker N(G)-nitro-L-arginine methyl ester. Furthermore, prostaglandin F(2alpha) (PGF(2alpha)) but not PGE(2) or PGI(2) reversed the blockade of the increase in GU(i) after indomethacin during elevated blood flow, whereas they had no influence on basal uptake. The results suggest that shear stress-induced release of PGF(2alpha) mediated the increase in GU(i) when blood flow was elevated.

Animals↗
PubMed1986

A nimodipine-resistant Ca2+ pathway is involved in myogenic tone in a resistance artery.

After stretch, tone develops in ring segments of rabbit ear resistance arteries (75-150 micron unstretched lumen diam). This is myogenic tone, since it is not dependent on the presence of sympathetic nerves, endothelial cells, or the local release of any known vasoactive autacoids. It is sensitive to the extracellular Ca2+ concentration, and disappears in a low Ca2+ (25 microM) environment. Tone is restored immediately on the reintroduction of Ca2+ (0.1-1.6 mM). High K+-induced tone in these resistance arteries is also extracellular Ca2+-dependent. The Ca2+ ED50 of this tone is 2.45 X 10(-4) M, which is significantly lower than that for myogenic tone (Ca2+ ED50; 8.31 X 10(-4) M). Both tone moieties are influenced by inorganic Ca2+ antagonists (Mn2+ and Mg2+) and some organic Ca2+ antagonists (verapamil and diltiazem). Among all the Ca2+ antagonists studied, only Mn2+ completely inhibits myogenic tone. In contrast, myogenic tone is resistant to nimodipine (up to 10(-6) M), the most potent Ca2+ antagonist of K+-induced contraction (ID50; 1.0 X 10(-9) M). Other 1,4-dihydropyridine Ca2+ antagonists such as nifedipine and (-)-PN 200-110 selectively antagonize K+-induced contractions, whereas they do not affect the development and the maintenance of myogenic tone. The fact that the (+)-enantiomer of PN 200-110 does not have an inhibitory effect proves that the 1,4-DHP site is stereospecific. These results indicate that extracellular Ca2+ is essential for both stretch-dependent (myogenic) and K+-induced tone, and the Ca2+ entry pathways for the two tone moieties are differently influenced by dihydropyridines.

Analysis of Variance↗
PubMed1993

Inhibition of platelet aggregation and the stimulation of prostacyclin synthesis by insulin in humans.

An intravenous bolus injection of insulin (35.5 microM) followed by an infusion of insulin (0.53 microM.kg-1.h-1) for 2.5 h (which maintained plasma levels between 0.71 nM to 1.4 nM) in normal fasting volunteers (n = 16), increased [3H]prostaglandin E1 (a probe for prostacyclin) binding to platelets by two- to threefold over the control. Scatchard analyses showed that the increased binding was due to the increase of both high and low affinity receptor numbers with little change in the receptor affinities. Similar results were obtained by using [3H]prostacyclin as the radioligand. The increased binding was associated with more than a twofold decrease of the minimum concentration of prostanoid needed to inhibit aggregation of platelets through the increased formation of adenosine 3',5'-cyclic monophosphate. Furthermore, the infusion increased the mean plasma prostacyclin level from 12.10 +/- 4.5 pM to 23.9 +/- 6.7 pM (n = 16; P < 0.001). These effects of insulin were at least partially direct, since the treatment of endothelial cells with insulin in tissue culture stimulated the production of the autacoid. Bolus injection of insulin (0.71 microM/kg) showed that the above effects of insulin could be demonstrated within 20 min after the injection, attained maximal ranges in approximately 60 min, and disappeared by 2-4 h.

Adult↗
PubMed2001

Role of EP(2) and EP(3) PGE(2) receptors in control of murine renal hemodynamics.

The kidney plays a central role in long-term regulation of arterial blood pressure and salt and water homeostasis. This is achieved in part by the local actions of paracrine and autacoid mediators such as the arachidonic acid-prostanoid system. The present study tested the role of specific PGE(2) E-prostanoid (EP) receptors in the regulation of renal hemodynamics and vascular reactivity to PGE(2). Specifically, we determined the extent to which the EP(2) and EP(3) receptor subtypes mediate the actions of PGE(2) on renal vascular tone. Renal blood flow (RBF) was measured by ultrasonic flowmetry, whereas vasoactive agents were injected directly into the renal artery of male mice. Studies were performed on two independent mouse lines lacking either EP(2) or EP(3) (-/-) receptors and the results were compared with wild-type controls (+/+). Our results do not support a unique role of the EP(2) receptor in regulating overall renal hemodynamics. Baseline renal hemodynamics in EP(2)-/- mice [RBF EP(2)-/-: 5.3 +/- 0.8 ml. min(-1). 100 g kidney wt(-1); renal vascular resistance (RVR) 19.7 +/- 3.6 mmHg. ml(-1). min. g kidney wt] did not differ statistically from control mice (RBF +/+: 4.0 +/- 0.5 ml. min(-1). 100 g kidney wt(-1); RVR +/+: 25.4 +/- 4.9 mmHg. ml(-1). min. 100 g kidney wt(-1)). This was also the case for the peak RBF increase after local PGE(2) (500 ng) injection into the renal artery (EP(2)-/-: 116 +/- 4 vs. +/+: 112 +/- 2% baseline RBF). In contrast, we found that the absence of EP(3) receptors in EP(3)-/- mice caused a significant increase (43%) in basal RBF (7.9 +/- 0.8 ml. min(-1). g kidney wt(-1), P < 0.05 vs. +/+) and a significant decrease (41%) in resting RVR (11.6 +/- 1.4 mmHg. ml(-1). min. g kidney wt(-1), P < 0.05 vs. +/+). Local administration of 500 ng of PGE(2) into the renal artery caused more pronounced renal vasodilation in EP(3)-/- mice (128 +/- 2% of basal RBF, P < 0.05 vs. +/+). We conclude that EP(3 )receptors mediate vasoconstriction in the kidney of male mice and its actions are tonically active in the basal state. Furthermore, EP(3) receptors are capable of buffering PGE(2)-mediated renal vasodilation.

Animals↗