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K U Malik

Publications and source records attributed to K U Malik.

17 recordsLinked to original sources
PubMed1992

Prostaglandin E2 synthesis elicited by adrenergic stimuli in guinea pig trachea is mediated primarily via activation of beta 2 adrenergic receptors.

Prostaglandin (PG) E2 synthesis elicited by adrenergic agonists in the guinea pig trachea has been shown to be mediated via activation of beta-adrenergic receptors. The purpose of this study was to examine arachidonic acid (AA) metabolism and to characterize the subtype of beta receptor involved in PG synthesis. [14C]AA was incubated with guinea pig tracheal rings, and the radiolabelled products were extracted from the medium. Thin layer chromatographic analysis and radioimmunoassay of the extract showed that [14C]AA was incorporated into guinea pig tracheal rings and metabolized mainly into radiolabeled and immunoreactive PGE2 (iPGE2) and smaller amounts into PGF2 alpha. Trace amounts of PGD2, TxB2 and 6-keto-PGF1 alpha but not LTB4 or LTC4 were detected by enzyme immunoassay. Incubation of guinea pig tracheal rings for 10 min with isoproterenol or salbutamol resulted in a significant increase in PGE2 synthesis (optimum concentration 0.1 microM for both compounds). In contrast, dobutamine, BRL 37344, BRL 28410, norepinephrine, phenylephrine, and xylazine (up to 1 microM) did not significantly increase PGE2 production. Isoproterenol-induced iPGE2 production was inhibited by the selective beta 2 receptor antagonist butoxamine (0.1-1.0 microM) and somewhat reduced by the beta 1 receptor antagonist practolol (1 microM). The increase in PGE2 synthesis was diminished with increasing concentrations of isoproterenol (0.5-5.0 microM) or salbutamol (0.5-1.0 microM); but it was reversed by pretreatment of tracheal rings with the protein synthesis inhibitors cycloheximide (0.9 microM) and actinomycin D (2 microM) but not by phenylisopropyl adenosine (0.1-1.0 microM), an inhibitor of adenylyl cyclase. These data suggest that isoproterenol-induced iPGE2 synthesis is primarily via activation of a beta 2 adrenergic receptor. Failure to enhance iPGE2 synthesis by a high concentration of isoproterenol is likely to be due to an induction of new inhibitory protein synthesis.

Albuterol↗
PubMed1992

Dual regulation by cAMP of beta-hexosaminidase-induced mitogenesis in bovine tracheal myocytes.

beta-Hexosaminidases, potent mitogens in bovine tracheal myocytes (BTM), stimulate a rapid and transient increase in intracellular cyclic adenosine monophosphate (cAMP) accumulation. The objective of this study was to elucidate the contribution of cAMP in hexosaminidase-induced airway muscle proliferation. Rate of DNA synthesis was measured by 3H-thymidine incorporation in quiescent cells prepared by a low-serum treatment (0.4%) for 48 h after reaching confluency in microtiter wells. cAMP accumulation was measured in acetylated cell extracts in the presence of isobutyl methylxanthine (100 microM) by radioimmunoassay using 125I-cAMP as tracer. Exposure of quiescent cells to purified human placental hexosaminidase B (5 micrograms/ml, 50 nM) caused a significant transient increase in cAMP accumulation (49 to 107 fmol/micrograms protein, or a 20- to 70-fold increase from basal level). Maximum increase occurred at 15 min followed by a rapid decline in cAMP accumulation within 30 min after exposure to hexosaminidase. Similar results were obtained in cells treated with neoglycoprotein mannose bovine serum albumin (100 to 500 nM). The increase in cAMP accumulation was inhibited by mannan (mannose receptor blocker, 0.1 mg/ml), as well as phenylisopropyladenosine (PIA; A1 receptor agonist that inhibits adenylyl cyclase, 0.1 to 1.0 microM). The increase in 3H-thymidine incorporation induced by hexosaminidase B was also inhibited by mannan and PIA. Exposure to 8-(4-chlorophenylthio)-cAMP (cpt-cAMP; a cell-permeable analog of cAMP, 100 microM) or forskolin (a direct activator of catalytic subunit of adenylyl cyclase, 24 microM) up to 6 h enhanced 3H-thymidine incorporation. In contrast, a prolonged exposure (18 to 30 h) to these agents inhibited 3H-thymidine incorporation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Comparison of signal transduction mechanisms of alpha-2C and alpha-1A adrenergic receptor-stimulated prostaglandin synthesis.

Prostaglandin (PG) synthesis elicited by adrenergic transmitter in the vascular smooth muscle cells (VSMC) of rabbit aorta is primarily mediated through activation of alpha-2C and alpha-1A adrenergic receptors (ARs). We have now investigated and compared the signal transduction mechanisms involved in alpha-2C and alpha-1A AR-stimulated prostacyclin (PGI2) production, measured as 6-keto-PGF1 alpha, in vascular smooth muscle cells. Norepinephrine, methoxamine (an alpha-1 AR agonist) and UK-14304 (an alpha-2 AR agonist) enhanced 6-keto-PGF1 alpha production. UK-14304 and norepinephrine (in the presence of propranolol), but not methoxamine, reduced basal adenosine 2':3'-cyclic monophosphate (cyclic AMP) as well as forskolin- and isoproterenol-stimulated cyclic AMP accumulation. Forskolin and isoproterenol did not alter basal 6-keto-PGF1 alpha production and alpha AR agonist-induced 6-keto-PGF1 alpha production. Alpha-2C and alpha-1A AR-stimulated 6-keto-PGF1 alpha production was independent of cyclic AMP levels in vascular smooth muscle cells. Both alpha-2C and alpha-1A AR-stimulated 6-keto-PGF1 alpha production required extracellular Ca++. Pertussis toxin prevented inhibition of cyclic AMP accumulation and reduced 6-keto-PGF1 alpha production in response to AR agonists. Guanosine 5'-O-(3-thiotriphosphate) potentiated 6-keto-PGF1 alpha production induced by norepinephrine and UK-14304 but not by methoxamine, whereas at a higher Mg++ concentration (4 mM), guanosine 5'-O-(3-thiotriphosphate) potentiated 6-keto-PGF1 alpha production by all three agonists. In contrast, the effect of UK-14304 on cyclic AMP was prevented in the presence of 4 mM Mg++. These data suggest that the pertussis toxin-sensitive G protein(s) mediated the stimulation of PG synthesis by alpha-1A and alpha-2C AR activation and the decrease in cyclic AMP accumulation by alpha-2C AR activation.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Prostaglandin synthesis elicited by adrenergic stimuli is mediated via alpha-2C and alpha-1A adrenergic receptors in cultured smooth muscle cells of rabbit aorta.

This study was performed to characterize the subtype of adrenergic receptor(s) (AR) involved in prostacyclin synthesis [measured as 6-keto-prostaglandin (PG)F1 alpha] elicited by AR agonists in cultured vascular smooth muscle cells of rabbit aorta. Both alpha-1 and alpha-2 AR agonists enhanced 6-keto-PGF1 alpha synthesis in a dose-dependent manner with the following order of potency: norepinephrine greater than BHT 933 greater than UK 14304 greater than xylazine greater than phenylephrine greater than or equal to methoxamine greater than cirazoline. Isoproterenol and oxymetazoline did not alter 6-keto-PGF1 alpha synthesis. Methoxamine-induced 6-keto-PGF1 alpha synthesis was not reduced by the alpha-2 AR antagonist rauwolscine. The affinities of AR antagonists (PA2 value) in inhibiting methoxamine-induced 6-keto-PGF1 alpha synthesis were of the following order: prazosin greater than WB 4101 greater than corynanthine greater than yohimbine. Administration of WB 4101 and the irreversible alpha-1B AR antagonist chloroethylclonidine reduced norepinephrine (in the presence of rauwolscine, 10(-8) M)- or methoxamine-induced 6-keto-PGF1 alpha synthesis; WB 4101 was more potent than chloroethylclonidine. UK 14304-induced 6-keto-PGF1 alpha synthesis was not reduced by chloroethylclonidine or BRL 44408, a selective alpha-2A AR antagonist, but it was inhibited by other alpha AR antagonists. The affinities of AR antagonists (PA2 values) in inhibiting UK 14304-induced 6-keto-PGF1 alpha synthesis were of the following order: rauwolscine greater than yohimbine greater than BAM 1303 greater than BRL 41992 greater than WB 4101 greater than ARC 239 greater than or equal to prazosin greater than SKF 104078 greater than or equal to corynanthine. The order of affinity of alpha-2 AR antagonists in inhibiting UK 14304-induced 6-keto-PGF1 alpha synthesis in vascular smooth muscle cells was similar to that derived from radioligand binding studies in opossum kidney cell line receptors classified as alpha-2C receptors. These data suggest that 6-keto-PGF1 alpha synthesis elicited by adrenergic stimuli in cultured vascular smooth muscle cells of rabbit aorta is mediated primarily via alpha-2C and to a lesser extent alpha-1A receptors.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Characterization of prejunctional alpha-2 adrenergic receptors involved in modulation of adrenergic transmitter release in the isolated perfused rat kidney.

The subclassification of alpha-2 adrenergic receptors into A and B subtypes is based on radioligand binding and functional studies. Radioligand binding studies also have suggested the existence of C and D subtypes, which have only been described as binding sites. This study was designed to determine the subtype of prejunctional alpha-2 adrenergic receptor involved in inhibition of norepinephrine release from sympathetic nerves in the rat kidney. Electrically induced (0.25 Hz, 50 V, 0.5 msec, 10 pulses) fractional tritium overflow was measured in kidneys isolated from male Sprague-Dawley rats and prelabeled with [3H]norepinephrine. The alpha-2 receptor antagonists rauwolscine and yohimbine did not enhance fractional tritium overflow, suggesting the lack of autoinhibition at this frequency of stimulation. The alpha-2 receptor agonist, UK-14,304, inhibited electrically stimulated fractional tritium overflow with an ED50 of 4.85 +/- 0.35 nM. pA2 values for various alpha receptor antagonists against UK-14,304-induced inhibition of fractional tritium overflow were: rauwolscine, 8.8; yohimbine, 8.1; prazosin, 7.4; BAM 1303, 7.5; SKF 104078, 6.4; phentolamine, 8.7; WB 4101, 8.1; corynanthine, 6.1; and ARC-239, 7.2. The correlation coefficients and slopes of the regression lines between pA2 values of alpha receptor antagonists at the prejunctional alpha-2 adrenergic receptor and the reported pKi values obtained from radioligand binding studies were: 0.48 and 0.82; 0.61 and 0.58; 0.53 and 0.85; and 0.89 and 1.05 for the alpha-2A, B, C and D adrenergic receptors, respectively. These data suggest that the prejunctional alpha-2 adrenergic receptor modulating [3H]norepinephrine release in the rat kidney most closely resembles the alpha-2D adrenergic receptor characterized by radioligand binding studies.

Adrenergic alpha-Antagonists↗
PubMed1979

Metabolism of prostacyclin in the rabbit kidney.

In the isolated rabbit kidney perfused with Tyrode's solution, we examined the metabolism of radiolabeled prostacyclin. [9-3H]Prostacyclin was infused into the kidney and the radiolabeled products from the renal venous effluent were separated by thin layer chromatography and identified by gas chromatography-mass spectrometry. The major products were 7,9-dihydroxy-4,13-diketo-dinor-prostanoic acid and dinor-6-keto-prostaglandin F1alpha. They represented 25% and 10% of the total radioactivity, respectively. Metabolism of prostacyclin by the kidney may be an important determinant of the effects of prostacyclin on renal function.

Animals↗
PubMed1979

Attenuation by bradykinin of adrenergically-induced vasoconstriction in the isolated perfused kidney of the rabbit: relationship to prostaglandin synthesis.

1 In the isolated kidney of the rabbit perfused with oxygenated Tyrode solution, we studied the effect of bradykinin on the vasoconstriction evoked by sympathetic nerve stimulation (3Hz, 1 ms) and by injections of noradrenaline (50 to 75 ng) in the presence and in the absence of indomethacin (1 microgram/ml), an inhibitor of prostaglandin biosynthesis. Prostaglandin E(PGE)-like material in the renal effluent was measured by bioassay after extraction with organic solvents and separation by thin layer chromatography. 2 Bradykinin in concentrations of 10 to 100 ng/ml reduced the vasoconstrictor response to sympathetic nerve stimulation and to injected noradrenaline. Also, the peptide (1 to 10 ng/ml) increased the basal release of PGE-like material and the release induced by sympathetic nerve stimulation. 3 Indomethacin, 1 microgram/ml, diminished the inhibitory effect of bradykinin on the vasoconstrictor response to nerve stimulation, minimized the reduction of the noradrenaline-induced vasoconstriction caused by bradykinin (100 ng/ml), and abolished the release of PGE-like material. 4 This study indicates that bradykinin reduces the renal vascular reactivity to adrenergic stimuli and suggests that part of the action of the kinin at the vascular adrenergic neuroeffector junction in the rabbit kidney depends upon the biosynthesis of renal prostaglandins.

Animals↗
PubMed1978

Prostaglandins--modulation of adrenergic nervous system.

Prostaglandins (PGs) affect vascular tone by a direct action on the vascular smooth muscle and by influencing vascular reactivity to adrenergic simuli and several vasoactive substances. Thus, in the isolated Tyrode's perfused rabbit renal, mesenteric and splenic vasculature PGE2 inhibited adrenergically induced vasoconstriction. Since the vasoconstrictor responses to renal nerve stimulation were enhanced by the blockade of PG synthesis and were reduced by stimulation of PG synthesis with arachidonic acid, this suggests that PGE2 functions as an inhibitory modulator of the adrenergic nervous system. However, our demonstration that PGE2 enhanced adrenergically induced vasoconstriction in the renal and mesenteric vasculature of the rat, but had opposite effects in the rat splenic vasculature indicates that the modulatory-effect of PGE-compounds on the adrenergic neuromuscular junction is species dependent and varies in different vascular beds within the same species. Prostaglandins, the release of which is evoked by several vasoactive substances including angiotensins, kinins, and adenine nucleotides, may also contribute to the regulation of vascular tone by either opposing or amplifying the vascular actions of vasoactive substances.

Adenosine Diphosphate↗
PubMed1977

Prostaglandins in adrenergic transmission of isolated perfused rat pancreas.

In the isolated, perfused rat pancreas, prostaglandins (PGs) E1 and E2 1-5 ng/ml, reduced the vasoconstrictor responses to periarterial nerve stimulation and variably affected those to injected norepinephrine. Prostaglandin F2alpha had no consistent effect on the vasoconstrictor responses to both adrenergic stimuli. Stimulation of adrenergic nerves or administration of norepinephrine released a PGE-like substance from the perfused pancreas which was abolished by inhibitors of PG synthesis, acetylsalicylic acid, indomethacin, meclofenamate, and eicosa-5,8,11,14-tetraynoic acid. The latter three agents did not potentiate, but rather reduced the vasoconstrictor responses to both adrenergic stimuli. Arachidonic acid that was converted by the pancreas into PGE2 and PGF2alpha inhibited the vasoconstrictor responses to adrenergic stimuli. The latter effect of arachidonic acid was not altered by the simultaneous infusion of PG synthetase inhibitors. Although these results, which could be attributed to a direct effect of inhibitors of PG synthesis and arachidonic acid on adrenergic neuroeffector junction, fail to establish the role of endogenous PGs in modulating adrenergic responses in rat pancreatic vessels, they emphasize the differences in the effect of PGE1 and PGE2 on adrenergic responses in various vascular beds of the rat.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1976

Facilitation of adrenergic transmission by locally generated angiotensin II in rat mesenteric arteries.

When studied on isolated rat mesenteric arteries perfused with Tyrode's solution, angiotensin I and angiotensin II (1 ng/ml), a synthetic tetradecapeptide renin substrate, and a purified hog renin substance (50-100 ng/ml) potentiated vasoconstrictor responses to sympathetic nerve stimulation and to injected norepinephrine without altering basal pressure. These agents produced a greater augmentation of the vasoconstrictor responses to nerve stimulation than to injected norepinephrine. The potentiation of vasoconstrictor responses to sympathetic nerve stimulation and injected norepinephrine which was elicited by renin substrate and angiotensin I was abolished by an inhibitor of angiotensin I-converting enzyme, SQ 20,881, and by an angiotensin II receptor antagonist, [Sar1-Ile8]angiotensin II. In contrast, the potentiating effect of angiotensin II was blocked only by the latter compound. We conclude that utilization of renin substrate within the vascular wall by renin or renin-like enzymes results in the formation of angiotensin I, which is converted to angiotensin II. Angiotensin in turn potentiates the vasoconstrictor responses to adrenergic stimuli presumably by augmenting release of the adrenergic transmitter and inhibiting its neuronal reuptake as well as by increasing vascular reactivity to norepinephrine.

Angiotensin II↗
PubMed1976

Modification by prostaglandins E1 and E2, indomethacin, and arachidonic acid of the vasoconstrictor responses of the isolated perfused rabbit and rat mesenteric arteries to adrenergic stimuli.

In isolated perfused rabbit mesenteric arteries, prostaglandin (PG) E1 and E2, 1-5NG/ML, did not alter the basal perfusion pressure, but reduced the vasoconstrictor responses to sympathetic nerve stimulation; the responses to injected norepinephrine were reduced by PGE1 and variably affected by PGE2. In contrast, in rat mesenteric arteries PGE1 and PGE2, 1-5 ng/ml, potentiated the vasoconstrictor responses to nerve stimulation and to injected norepinephrine. In rabbit mesenteric arteries, the inhibitor of PG synthesis, indomethacin, augmented the responses to sympathetic nerve stimulation and to injected norepinephrine, whereas in rat mesenteric arteries indomethacin inhibited the responses to both adrenergic stimuli. Arachidonic acid, a PG precursor, reduced the vasoconstrictor responses to sympathetic nerve stimulation and to injected norepinephrine in rabbit, whereas in rat, potentiation of the responses to adrenergic stimuli occurred. Since these effects of arachidonic acid were abolished by the simultaneous infusion of indomethacin, they appear to be mediated through conversion of arachidonic acid to PG. We conclude that prostaglandins modulate adrenergic transmission in mesenteric arteries and this effect is species dependent.

Animals↗
PubMed1976

Prostaglandins as determinants of vascular reactivity.

Prostaglandins are primarily local or tissue hormones that have their effects at, or near to, the site of synthesis. Some blood vessels synthesize prostaglandins intramurally, where their local release influences vascular tone and reactivity. Endogenous prostaglandins (primarily prostaglandin E2 (PGE2) participate in the regulation of vascular reactivity by opposing the vasoconstrictor and antinatriuretic actions of circulating pressor hormones; and by braking the release of norepinephrine from vasoconstrictor nerves. The proposal that one or more prostaglandins affect vascular reactivity is supported by the following observations: enhanced vascular reactivity to pressor stimuli occurs in organs with low basal rates of prostaglandin synthesis and after inhibition of prostaglandin synthetase in organs with high biosynthetic capacity; and exogenous PGE2 reversibly inhibits the vasoconstrictor activity of pressor stimuli.

Angiotensin II↗
PubMed1976

Renal prostaglandins.

1. Renal prostaglandins act primarily as local hormones, having their effects at, or near to, sites of synthesis. PGE2 is a major determinant of renal vascular reactivity; it opposes the vasoconstrictor and natriuretic actions of pressor hormones and brakes the release of noradrenaline from adrenergic nerves. In the unanaesthetized rabbit prolonged inhibition of prostaglandin synthesis results in hypertension. In the rat, however, renal prostaglandins augment pressor stimuli. 2. Basal efflux of renal prostaglandins is positively correlated with blood flow to the inner cortex and medulla. Those stimuli which increase renal medullary blood flow do so primarily by activating prostaglandin synthetase. 3. Kinins increase prostaglandin synthesis which action modifies the renal effects of kinins. Thus, one or more renal prostaglandins contribute to the renal vasodilator action of bradykinin and mediate its effect on excretion of water as well as possibly attenuating the natriuretic action of the polypeptide. Kinins in addition to stimulating prostaglandin synthesis may determine the principal product of synthetase by regulating the enzyme PGE 9-ketoreductase, which converts PGE to PGF. The coupling of these systems within the kidney appears unique--prostaglandins mediate some of the actions of kinins and modulate others, whereas they depend on the intrarenal generation of kinins to set their level and type of activity.

Animals↗
PubMed1975

Modulation by prostaglandins of adrenergic transmission in the isolated perfused rabbit and rat kidney.

In the isolated perfused rabbit kidney prostaglandins (PGS) E1 (0.02-0-1 ng/ml), E2 (0.02-0.1 ng/ml), and A2 (1-5 ng/ml) inhibited the vasoconstrictor responses to sympathetic nerve stimulation by 21-44%, 31-39%, and 20-23%, respectively, without alerting those to injected norepinephrine. In contrast, in the rat kidney PGE1 (0.5 ng/ml), PGE2 (0.5 ng/ml), and PGA2 (5 ng/ml) enhanced the vasoconstrictor responses to sympathetic nerve stimulation by 41%, 27%, and 11%, respectively; the equiconstrictor responses to injected norepinephrine remained unaltered. Higher concentrations of these agents produced vasodilation in the rabbit kidney and vasoconstriction in the rat kidney. In both species PGF2alpha produced vasoconstriction and enhanced the response to both adrenergic stumuli. In the rabbit kidney inhibitors of PG synthesis augmented the responses to sympathetic nerve stimulation without altering those to injected norepinephrine, whereas in the rat kidney inhibition of the responses to both adrenergic stimuli occurred. Arachidonic acid inhibited the vasoconstrictor responses to sympathetic nerve stimulation in the rabbit kidney, but in the rat kidney it caused augmentation of these responses. Since these effects of arachidonic acid were reduced by indomethacin, they appear to be mediated through the acid's conversion to PGS. We conclude that PGS of the E series modulate adrenergic transmission in the kidney and that their modulatory actions are species dependent.

Animals↗