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Biomedical subjects

T Hussain

Publications and source records attributed to T Hussain.

At least 55 records · Page 3Linked to original sources
PubMed1998

Renal dopamine receptor function in hypertension.

Dopamine plays an important role in the regulation of renal sodium excretion. The synthesis of dopamine and the presence of dopamine receptor subtypes (D1A, D1B, as D1-like and D2, and D3 as D2-like) have been shown within the kidney. The activation of D1-like receptors located on the proximal tubules causes inhibition of tubular sodium reabsorption by inhibiting Na,H-exchanger and Na,K-ATPase activity. The D1-like receptors are linked to the multiple cellular signaling systems (namely, adenylyl cyclase, phospholipase C, and phospholipase A2) in the different regions of the nephron. Defective renal dopamine production and/or dopamine receptor function have been reported in human primary hypertension as well as in genetic models of animal hypertension. There may be a primary defect in D1-like receptors and an altered signaling system in the proximal tubules that lead to reduced dopamine-mediated effects on renal sodium excretion in hypertension. Recently, it has been shown in animal models that the disruption of either D1A or D3 receptors at the gene level causes hypertension in mice. Dopamine and dopamine receptor agonists also provide therapeutic potential in treatment of various cardiovascular pathological conditions, including hypertension. However, because of the poor bioavailability of the currently available compounds, the use of D1-like agonists is limited to the management of patients with severe hypertension when a rapid reduction of blood pressure is clinically indicated and in acute management of patients with heart failure. In conclusion, there is convincing evidence that dopamine and dopamine receptors play an important role in regulation of renal function, suggesting that a defective dopamine receptor/signaling system may contribute to the development and maintenance of hypertension. Further studies need to be directed toward establishing a direct correlation between defective dopamine receptor gene in the kidney and development of hypertension. Subsequently, it may be possible to use a therapeutic approach to correct the defect in dopamine receptor gene causing the hypertension.

Animals↗
PubMed1998

Bromocriptine regulates angiotensin II response on sodium pump in proximal tubules.

-Dopamine and angiotensin II (Ang II) receptors have been reported to exhibit an interaction in renal proximal tubules. The present study was designed to investigate the regulation by a D2-like dopamine receptor of Ang II-mediated stimulation of Na,K-ATPase activity in the renal proximal tubules. Ang II (10(-13) to 10(-9) mol/L) stimulated Na,K-ATPase activity in the proximal tubules that was completely abolished when the tubules were pretreated with the D2-like receptor agonist bromocriptine (1 micromol/L) for 30 minutes. The effect of bromocriptine on Ang II response was prevented by domperidone (1 micromol/L), a D2-like dopamine receptor antagonist. Similarly, the inhibition of forskolin (1 micromol/L)-induced cAMP accumulation caused by Ang II (10 pmol/L) was also abolished in bromocriptine-pretreated tubules. Basal and forskolin-stimulated cAMP was not significantly different in bromocriptine-treated tubules compared with the control. [3H]-Ang II binding sites (angiotensin type 1 [AT1] receptors) were reduced by approximately 65% in bromocriptine-treated proximal tubules, a result that was further substantiated by Western blot analysis revealing a 50% decrease in AT1 receptors in bromocriptine-treated tubules compared with the control. Western blot analysis of G proteins revealed a 2-fold increase in Gsalpha and a 20% decrease in Gialpha1 and Gialpha2 in the bromocriptine-treated proximal tubules. Bromocriptine (1 micromol/L) alone stimulated Na,K-ATPase activity during the first 30 minutes of incubation, and thereafter the stimulation fell to the basal level. Similarly, bromocriptine-mediated inhibition of cAMP lasted only up to 20 minutes. The data suggest that preactivation of D2-like dopamine receptors abolishes Ang II-mediated stimulation of Na,K-ATPase activity and inhibition of cAMP accumulation. This phenomenon may be a consequence of a decrease in AT1 receptors and alterations in G protein levels in the proximal tubules. We propose that such a regulation of Ang II response by bromocriptine is the result of heterologous desensitization of the D2-like receptor system.

Angiotensin II↗
PubMed1998

Angiotensin II AT1 receptor/signaling mechanisms in the biphasic effect of the peptide on proximal tubular Na+,K+-ATPase.

The present study was designed to determine the cellular signaling mechanisms responsible for mediating the effects of angiotensin II on proximal tubular Na+,K+-ATPase activity. Angiotensin II produced a biphasic effect on Na+,K+-ATPase activity: stimulation at 10(-13) - 10(-10) M followed by inhibition at 10(-7) - 10(-5) M of angiotensin II. The stimulatory and inhibitory effects of angiotensin II were antagonized by losartan (1nM) suggesting the involvement of AT1 receptor. Angiotensin II produced inhibition of forskolin-stimulated cAMP accumulation at 10(-13) - 10(-10) M followed by a stimulation in basal cAMP levels at 10(-7) - 10(-5) M. Pretreatment of proximal tubules with losartan (1nM) antagonized both the stimulatory and inhibitory effects of angiotensin II on cAMP accumulation. Pretreatment of the proximal tubules with pertussis toxin (PTx) abolished the stimulation of Na+,K+-ATPase activity but did not affect the inhibition of Na+,K+-ATPase activity produced by angiotensin II. Pretreatment of the tubules with cholera toxin did not alter the biphasic effect of angiotensin II on Na+,K+-ATPase activity. Mepacrine (10microM), a phospholipase A2 (PLA2) inhibitor, reduced only the inhibitory effect of angiotensin II on Na+,K+-ATPase activity. These results suggest that the activation of AT1 angiotensin II receptors stimulates Na+,K+-ATPase activity via a PTx-sensitive G protein-linked inhibition of adenylyl cyclase pathway, whereas the inhibition of Na+,K+-ATPase activity following AT1 receptor activation involves multiple signaling pathways which may include stimulation of adenylyl cyclase and PLA2.

Adenylate Cyclase Toxin↗
PubMed1998

Frostbite: epidemiology at high altitude in the Karakoram mountains.

During a 10-year period (December 1984 to December 1994), 1500 cases of frostbite were treated at a tertiary care medical facility. They were all males with their ages ranging from 17 to 43 years. All the patients sustained the frostbite injury in the northeastern part of Pakistan known as the Karakoram range of mountains. They included a large number of porters and guides employed by various mountaineering expeditions (approximately 250-300 expeditions per year) in that region, as well as local inhabitants. This retrospective study included the heights at which frostbite occurred (range 11,000-22,000 feet above sea level). Of the patients, 15% (n = 225) got frostbitten within 1 h of exposure, whereas the majority (71%) had an exposure of 1-3 h. The effect of seasonal variations (relative hypothermia) on the extent and depth (degree) of frostbite and the distribution of lesions as per body surface subunits (areas) was noted and found to be statistically significant with P < 0.05 for both. The occurrence of frostbite at various heights showed a very steep upward curve beyond a height of 17,000 feet above sea level. This has been termed the 'cut-off' point for frostbite by the authors, the increase depicting the true picture of 'high altitude frostbite'. Tobacco smoking and peripheral vascular disease were found to be important contributing factors. The feet were involved most frequently (64%) followed by the hands (32%), the head and neck region (3%) and the perineum (1%). Independent effects of the height (relative hypoxia) on the depth of frostbite lesion (degree) and on the involvement of multiple body areas (surface subunits) showed significant correlation with P values well below 0.05 for each. Of cases, 92% (n = 1386) had second- or third-degree frostbite necessitating definitive surgical intervention. Total frostbite-related mortality spanned over 10 years was 11%.

Adolescent↗
PubMed1998

Deletion analysis & calpain status for carrier detection in a family with Duchenne muscular dystrophy.

Eight females with a family history of Duchenne muscular dystrophy (DMD) were analysed for their carrier status by m-calpain test, which monitors the m-calpain (milli-calpain), a proteolytic enzyme in the platelets, using an ELISA technique. Four of the eight females were identified as carriers by virtue of their elevated enzyme levels as compared to control. DNA samples of these members were analysed to ascertain the carrier status, by PCR followed by dosage analysis by densitometry. DNA analysis confirmed the findings by calpain test, which underlines the reliability of this phenotypic test for carrier detection in DMD. Calpain test has been informative in a large group of patients and carriers tested so far. Since the calpain test is cost and labour effective, it is suited for routine and widespread screening purposes.

Blood Platelets↗
PubMed1997

Bromocriptine stimulates Na+, K(+)-ATPase in renal proximal tubules via the cAMP pathway.

The present study was undertaken to examine the effect of dopamine D2 receptor activation on Na+,K(+)-ATPase activity in rat renal proximal tubule suspension. Bromocriptine, a dopamine D2 receptor agonist, produced a concentration (10(-9)-10(-5) M) dependent stimulation of Na+,K(+)-ATPase activity which was antagonized by pretreating the tubules with domperidone (1 microM), a dopamine D2 receptor antagonist. Forskolin (1 microM), a direct activator of adenylyl cyclase, inhibited Na+ K(+)-ATPase activity and reversed the stimulation of Na+,K(+)-ATPase activity induced by bromocriptine. Pertussis toxin (200 ng/ml) treatment also abolished the bromocriptine-induced stimulation of Na+,K(+)-ATPase activity. Bromocriptine attenuated forskolin-stimulated cAMP accumulation which was blocked by pertussis toxin treatment of the tubules. The data suggest that dopamine D2 receptor activation by bromocriptine leads to stimulation of Na+,K(+)-ATPase activity which may be mediated through a pertussis-sensitive G protein and inhibition of adenylyl cyclase in rat renal proximal tubules.

Animals↗
PubMed1997

Renal dopamine DA1 receptor coupling with G(S) and G(q/11) proteins in spontaneously hypertensive rats.

The dopamine DA1 receptor transduces its signal via adenylyl cyclase and phospholipase C in the renal proximal tubule, which has been suggested to be defective at the level of receptor-G protein coupling in spontaneously hypertensive rats (SHR). We prepared basolateral membranes from Wistar-Kyoto (WKY) rats and SHR to determine the coupling of DA1 receptor with G proteins, especially G(q/11). Fenoldopam, a DA1-receptor agonist, produced a time- and concentration-dependent stimulation in 35S-labeled guanosine 5'-O-(3-thiotriphosphate) ([35S]GTPgammaS) binding in WKY rats. Fenoldopam-induced (10 microM) stimulation was significantly inhibited by a DA1-receptor antagonist, Sch-23390. Specific antibodies against COOH terminals of G(S)alpha and G(q/11)alpha produced 50-60% and 40-50% inhibition, respectively, in fenoldopam stimulation of [35S]GTPgammaS binding. Western analysis of basolateral membranes with these antibodies revealed the presence of G(S)alpha (45 kDa) and G(q/11)alpha (42 kDa). Fenoldopam stimulation of [35S]GTPgammaS binding was significantly attenuated in SHR compared with WKY rats. Parathyroid hormone stimulation of [35S]GTPgammaS binding was similar in SHR and WKY rats, whereas stimulation by phenylephrine was significantly reduced in SHR. Densitometric quantification of 42-kDa band showed a reduced amount in SHR, whereas the density of 45-kDa band was not significantly different compared with WKY rats. We provide the direct evidence showing the coupling of DA1 receptor with G(q/11)alpha and G(S)alpha and propose that, in addition to a defect in the receptor-G protein coupling, a reduced amount of G(q/11)alpha observed in the hypertensive animals may also contribute to the diminished dopamine-induced inhibition of Na+-K+-adenosinetriphosphatase in SHR.

Analysis of Variance↗
PubMed1997

Alterations in dopamine DA1 receptor and G proteins in renal proximal tubules of old rats.

The present study examines the effect of dopamine DA1-receptor agonists on the renal proximal tubular Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) activity and quantitates DA1 receptors and the coupled G proteins in Fischer 344 model of adult (6 mo old) and old (23 mo old) rats. Dopamine and the preferential DA1-receptor agonist, SKF-38393, produced a concentration-dependent inhibition of Na(+)-K(+)-ATPase activity in proximal tubules from adult rats, whereas the enzyme activity was unaffected by these agonists in the old rats. The binding of DA1-receptor antagonist [3H]Sch-23390 in the proximal tubular basolateral membranes showed a marked decrease (approximately 47%) in the receptor numbers in old compared with adult rats, whereas dissociation constant (Kd) values in old compared with adult rats were not significantly different. Dopamine and SKF-38393 stimulated 35S-labeled guanosine 5'-O-(3-thiotriphosphate) binding in adult rats, but there was no significant effect on the binding in the old rats. Quantification of G2 alpha and Gq/11 alpha using Western analysis revealed a significant increase in quantities of both the G proteins in old rats. The data suggest that a reduction in DA1 receptor number and subsequently reduced G protein activation may be the causative factors for the impairment in DA1 receptor-mediated inhibition of Na(+)-K(+)-ATPase activity in the proximal tubules of old rats.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1996

Altered arachidonic acid metabolism contributes to the failure of dopamine to inhibit Na+,K(+)-ATPase in kidney of spontaneously hypertensive rats.

Dopamine decreases tubular sodium reabsorption in part by inhibition of Na+,K(+)-ATPase activity in renal proximal tubules. The signaling mechanism involved in dopamine-mediated inhibition of Na+,K(+)-ATPase is known to be defective in spontaneously hypertensive animals. The present study was designed to evaluate the role of phospholipase A2 (PLA2) and its metabolic pathway in dopamine-induced inhibition of Na+,K(+)-ATPase in renal proximal tubules from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Renal proximal tubular suspensions were prepared and Na+,K(+)-ATPase activity was measured as ouabain-sensitive adenosine triphosphate hydrolysis. Dopamine inhibited Na+,K(+)-ATPase activity in a concentration (1 nM-10 microM)-dependent manner in WKY rats while it failed to inhibit the enzyme activity in SHR. Dopamine (10 microM)-induced inhibition of Na+,K(+)-ATPase activity in WKY rats was significantly blocked by mepacrine (10 microM), a PLA2 inhibitor, suggesting the involvement of PLA2 in dopamine-mediated inhibition of Na+,K(+)-ATPase. Arachidonic acid (a product released by PLA2 action) inhibited Na+,K(+)-ATPase in a concentration-dependent (1-100 microM) manner in WKY rats while the inhibition in SHR was significantly attenuated (IC50: 7.5 and 80 microM in WKY rats and SHR, respectively). Furthermore, lower concentrations of arachidonic acid stimulated (30% at 1 microM) Na+,K(+)-ATPase activity in SHR. This suggests a defect in the metabolism of arachidonic acid in SHR. Proadifen (10 microM), an inhibitor of cytochrome P-450 monoxygenase (an arachidonic acid metabolizing enzyme) significantly blocked the inhibition produced by arachidonic acid in WKY rats and abolished the difference in arachidonic acid inhibition of Na+,K(+)-ATPase between WKY rats and SHR. These data suggest that PLA2 is involved in dopamine-induced inhibition of Na+,K(+)-ATPase and altered arachidonic acid metabolism may contribute to reduced dopaminergic inhibition of Na+,K(+)-ATPase activity in spontaneously hypertensive rats.

Animals↗
PubMed1996

125I-APE binding to adenosine receptors in coronary artery: photoaffinity labeling with 125I-azidoAPE.

Coronary arteries are known to contain adenosine receptors that elicit vasodilation. Past attempts to characterize these receptors by radioligand binding have been unsuccessful. In the present study, a newly synthesized iodinated adenosine analogue, [125I]2-[2-(4-amino-3-iodophenhyl)ethylamino]adenosine (125I-APE), was found to bind to adenosine receptors in porcine coronary artery smooth muscle membranes. Specific 125I-APE binding is temperature sensitive with maximal binding detected at 4 degrees C. 125I-APE binds to a high affinity low density site with a KD of 0.59 +/- 0.11 nM and a Bmax 7 +/- 0.8 fmoles/mg protein. A high abundance lower affinity site is suggested by the fact that APE competes for 125I-APE binding with a concentration that inhibits 50% (IC50) of 0.96 microM. Competition with various other adenosine receptor agonists results in a potency order of (IC50, microM): 2-phenylaminoadenosine (CV 1808, 0.34) > APE (0.96) > CGS 22988 (5.2) > 2-chloroadenosine (30) > CGS 21680 and NECA (> 100). Agonist binding is not affected by GppNHp (10(-7)-10(-3) M). Among antagonists the potency order is (microM): CGS 15943 (1.1) > 8-(3-chlorostyryl)-caffeine (CSC, 5.3) > 8-sulfophenyltheophylline (SPT, 86) > theophylline (> 100). These binding characteristics are similar to the properties of a putative A4 binding site characteristic of A2a receptors assayed at a low temperature. Photoaffinity labeling of porcine coronary artery membrane proteins with the azide derivative of 125I-APE revealed a 45,000-Da binding site. Photolabeling is prevented by coincubation of membranes at 4 degrees C with various adenosine receptor antagonists (1 microM CSC, 1 microM CGS 15943 or 100 microM theophylline). In conclusion, adenosine receptors of coronary arteries have been detected for the first time by radioligand binding and photoaffinity labeling. This ligand appears to label porcine A4 binding sites that may correspond to A2a receptors assayed at 4 degrees C.

Adenosine↗
PubMed1995

Role of nitric oxide in adenosine receptor-mediated relaxation of porcine coronary artery.

In the present study, using porcine coronary artery rings in vitro, we examined the role of the nitric oxide (NO) pathway in endothelium-dependent vasorelaxant effects of the 5'-uronamide adenosine agonists, 5'-(N-ethylcarboxamido)adenosine (NECA) and 2-[p-(2-carboxyethyl)]phenylethyl-amino-5'-N-ethylcarboxamidoadenosine (CGS-21680) as opposed to the endothelium-independent actions of the C2- and N6-substituted analogues, 2-chloroadenosine (CAD) and N6-cyclopentyladenosine (CPA). The NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA, 30 microM), and the NO-destroying agent, 6-anilino-5,8-quinolinedione (LY-83583, 10 microM), attenuated the relaxations of endothelium-intact but not -denuded rings to NECA and CGS-21680. The effect of L-NMMA on NECA-induced relaxation was reversed by L-arginine (100 microM), a substrate for NO synthesis. In the endothelium-intact tissues, both NECA and CGS-21680 elicited enhanced production of nitrite, a stable metabolite of NO. This was also attenuated by L-NMMA or endothelium removal. Furthermore, NECA (10 microM) induced augmentation of guanosine 3',5'-cyclic monophosphate (cGMP) production in the intact arteries, which was also inhibited by L-NMMA, LY-83583, or endothelium removal. In contrast, vasorelaxant responses generated by CAD and CPA were not altered by either L-NMMA or LY-83583. Both agents (10 microM) were also unable to alter nitrite and/or guanosine 3',5'-cyclic monophosphate (cGMP) levels of the coronary artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoquinolines↗
PubMed1995

Binding of A1 adenosine receptor ligand [3H]8-cyclopentyl-1,3-dipropylxanthine in coronary smooth muscle.

Vascular smooth muscle has been reported to contain the A1 subtype of adenosine receptors, but the existence of such receptor(s) in coronary smooth muscle has not been established. In the present study, the 3H-labeled A1-selective antagonist [3H]8-cyclopentyl-1,3-dipropylxanthine ([3H]DPCPX) was used to demonstrate the specific binding in porcine coronary artery smooth muscle membranes. The binding was saturable with a Bmax of 6.43 +/- 1.02 fmol/mg protein. Scatchard analysis of the binding data provided a single binding site with a Kd of 0.21 +/- 0.025 nmol/L. In the competition experiments, adenosine receptor agonists and antagonists showed the following order of potency (nmol/L): S-N6-(2-endonorbornyl)adenosine (S-ENBA) 0.11 = R(-)-N6-phenylisopropyladenosine 0.32 > DPCPX 3.2 = xanthine amine congener 2.4 = N6-cyclopentyladenosine 2.67 > 5'-(N-ethylcarboxamido)-adenosine 7.35 >> 2-[p-(2-carboxyethyl)-phenethyl-amino]-5'-(N-ethylcarboxamido)- adenosine 1000 > theophylline 83,000. This order of potency fits the criteria for the A1 adenosine receptor. S-ENBA, a highly selective A1 receptor agonist, was used to investigate the effect on isoproterenol-mediated vasorelaxation and cAMP accumulation. S-ENBA (0.1 to 10 nmol/L) dose-dependently shifted the isoproterenol-mediated (10(-8) to 10(-5) mol/L) vasorelaxation to the right in vascular rings. S-ENBA (10 nmol/L) inhibited the basal cAMP levels by 36% and attenuated the isoproterenol (10(-5) mol/L)-stimulated cAMP by 25% in the coronary rings. These inhibitory effects of S-ENBA on isoproterenol-mediated cAMP-accumulation and vasorelaxation were abolished by pertussis toxin (100 ng/mL, overnight) treatment of the arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1995

Alterations of trace elements in kidney, spleen and lungs in treated and untreated experimental liver cirrhosis.

Repeated administration of carbon tetrachloride (CC1(4)) to the experimental animals not only produces liver cirrhosis but also pathological changes in different organs. The alteration of trace elements in the plasma and in the liver has been documented. Very limited studies were carried out regarding the alteration of trace elements in different organs in experimental animals subjected to CC1(4) toxicity and the influence of scavengers such as superoxide dismutase (SOD) and allopurinol as preventative measurements. Four groups of animals were studied: CC1(4) and allopurinol (group 1), CC1(4) and SOD (group 2), CC1(4) alone (group 3) and olive oil (group 4). Analysis of tissue concentrations of trace elements in different organ's tissues (e.g. lung, spleen and kidneys) were performed. Histopathological assessments were studied in all groups after 7 weeks of repeated administration of the solutions. Copper contents in the spleen and lungs were significantly high in group 2, while kidney copper contents were significantly high in all experimental groups. Selenium contents in the kidneys and lungs were significantly low in group 1, while it was significantly high in group 2 in all organs. Manganese contents in kidneys was significantly low in group 1 and significantly increased in group 2 in the case of spleen and lung. Lung zinc content was significantly increased in group 2. Spleen zinc decreased significantly only in group 3. Histopathological assessment indicated evidence of interstitial pneumonia in the group treated with allopurinol. The low levels of selenium predisposes to the development of interstitial pneumonia.

Allopurinol↗