Biomedical subjects

P R Saxena

Publications and source records attributed to P R Saxena.

At least 19 recordsLinked to original sources

PubMed2001

A61603-induced vasoconstriction in porcine carotid vasculature: involvement of a non-adrenergic mechanism.

It has recently been shown that the pharmacological profile of alpha(1)-adrenoceptors mediating constriction of porcine carotid arteriovenous anastomoses resembles that of alpha(1A)- and alpha(1B)-adrenoceptor subtypes. In an attempt to verify the involvement of alpha(1A)-adrenoceptors, we used the potent alpha(1A)-adrenoceptor agonist N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl]methane sulphonamide (A61603) and found that intracarotid (i.c.) administration of A61603 (0.3-10 microg kg(-1)) dose-dependently decreased porcine carotid blood flow and vascular conductance. This decrease was exclusively due to a constriction of carotid arteriovenous anastomoses; the capillary blood flow and conductance remained unchanged. Surprisingly, the responses to A61603 were little modified by prior i.v. treatment with 5-methylurapidil (1000 microg kg(-1)), prazosin (100 microg kg(-1)) or a combination of prazosin and rauwolscine (100 and 300 microg kg(-1), respectively). The 5-HT(1B/1D) receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'(5-methyl-1,2,4-oxadiazol-3-yl)[1,1,-biphenyl]-4-carboxamide hydrochloride monohydrate (GR127935; 500 microg kg(-1)) and ketanserin (500 microg kg(-1)) also failed to modify carotid vascular responses to A61603, but, interestingly, methiothepin (3000 microg kg(-1)) proved to be an effective antagonist. Taken together, the present results show that A61603 is a relatively poor agonist at the alpha(1A)-adrenoceptor in anaesthetised pigs and that the carotid vasoconstriction produced by A61603 is mediated by a novel non-adrenergic mechanism.

Adrenergic alpha-1 Receptor Agonists↗

PubMed2001

Unravelling the pharmacological profile of the canine external carotid vasodilator '5-HT1-like' receptors: coexistence of sympatho-inhibitory 5-HT1B and postjunctional 5-HT7 receptors.

It has been suggested that the external carotid vasodilatation produced by serotonin (5-hydroxytryptamine; 5-HT) in anaesthetised dogs with intact vagosympathetic trunks is mediated by sympatho-inhibitory '5-HT1D' receptors and musculotropic '5-HT1-like' receptors. The present study has re-analysed this suggestion with regard to the classification schemes recently proposed by the NC-IUPHAR subcommittee on 5-HT receptors. In pentobarbital-anaesthetised dogs with intact vagosympathetic trunks, 1-min intracarotid (i.c.) infusions of 5-carboxamidotryptamine (5-CT; 0.01-0.3 microg/min), 5-HT (0.3-30 microg/ min), 5-methoxytryptamine (5-MeO-T; 1-100 microg/min) or sumatriptan (1-100 microg/min) dose-dependently increased the external carotid blood flow without affecting blood pressure or heart rate. The selective 5-HT1D receptor agonist, PNU-142633 (1-1000 microg/min), was essentially inactive. After mesulergine (300 microg/kg, i.v.), an antagonist at cardiovascular 5-HT7 receptors, the above responses to 5-HT, 5-CT and 5-MeO-T were blocked, whilst those to sumatriptan remained unaffected. In contrast, after the 5-HT1B/1D receptor antagonist, GR127935 (10 microg/kg, i.v.), the responses to 5-HT, 5-CT and 5-MeO-T were not affected, but those to sumatriptan were abolished. Furthermore, after the selective 5-HT1B receptor antagonist, SB224289 (300 microg/kg, i.v.), the responses to 5-HT, 5-CT and 5-MeO-T were significantly enhanced, whereas those to sumatriptan were abolished. Interestingly, the responses to all these agonists remained unmodified after the selective 5-HT1D receptor antagonist, BRL15572 (300 microg/kg, i.v.). The above results suggest that the '5-HT1-like' receptors, which mediate canine external carotid vasodilatation, display the pharmacological profile of sympatho-inhibitory 5-HT1B receptors and musculotropic 5-HT7 receptors, and confirm the existence of vasoconstrictor 5-HT1B receptors.

5-Methoxytryptamine↗

PubMed2001

The GR127935-sensitive 5-HT(1) receptors mediating canine internal carotid vasoconstriction: resemblance to the 5-HT(1B), but not to the 5-HT(1D) or 5-ht(1F), receptor subtype.

This study has further investigated the pharmacological profile of the GR127935-sensitive 5-HT(1) receptors mediating vasoconstriction in the internal carotid bed of anaesthetized vagosympathectomized dogs. One-minute intracarotid infusions of the agonists 5-hydroxytryptamine (5-HT; 0.1 - 10 microg min(-1); endogenous ligand) and sumatriptan (0.3 - 10 microg min(-1); 5-HT(1B/1D)), but not PNU-142633 (1 - 1000 microg min(-1); 5-HT(1D)) or LY344864 (1 - 1000 microg min(-1); 5-ht(1F)), produced dose-dependent decreases in internal carotid blood flow without changing blood pressure or heart rate. The responses to 5-HT were apparently resistant to blockade by i.v. administration of the antagonists SB224289 (300 microg kg(-1); 5-HT(1B)), BRL15572 (300 microg kg(-1); 5-HT(1D)) or ritanserin (100 microg kg(-1); 5-HT(2)). In contrast, the responses to sumatriptan were antagonized by SB224289, but not by BRL15572. In the animals receiving SB224289, but not those receiving BRL15572, the subsequent administration of ritanserin abolished the 5-HT-induced vasoconstriction and unmasked a vasodilator component. Similarly, in ritanserin-treated animals, the subsequent administration of SB224289, but not BRL15572, completely blocked the 5-HT-induced vasoconstriction, revealing vasodilatation. In animals receiving initially BRL15572, the subsequent administration of SB224289 did not affect (except at 10 microg min(-1)) the vasoconstrictor responses to 5-HT. Notably, in animals pretreated with 1000 microg kg(-1) of mesulergine, a 5-HT(2/7) receptor antagonist, 5-HT produced a dose-dependent vasoconstriction, which was practically abolished by SB224289. After BRL15572, no further blockade was produced and the subsequent administration of ritanserin was similarly inactive. These results suggest that the GR127935-sensitive 5-HT(1) receptors mediating canine internal carotid vasoconstriction resemble the 5-HT(1B) but not the 5-HT(1D) or 5-ht(1F), receptor subtype.

Animals↗

PubMed2001

Evidence for 5-HT(1B/1D) and 5-HT(2A) receptors mediating constriction of the canine internal carotid circulation.

The present study has investigated the preliminary pharmacological profile of the receptors mediating vasoconstriction to 5-hydroxytryptamine (5-HT) in the internal carotid bed of vagosympathectomised dogs. One minute intracarotid infusions of the agonists 5-HT (0.1 - 10 microg min(-1)), sumatriptan (0.3 - 10 microg min(-1); 5-HT(1B/1D)), 5-methoxytryptamine (1 - 100 microg min(-1); 5-HT(1), 5-HT(2), 5-HT(4), 5-ht(6) and 5-HT(7)) or DOI (0.31 - 10 microg min(-1); 5-HT(2)), but not 5-carboxamidotryptamine (0.01 - 0.3 microg min(-1); 5-HT(1), 5-ht(5A) and 5-HT(7)), 1-(m-chlorophenyl)-biguanide (mCPBG; 1 - 1000 microg min(-1); 5-HT(3)) or cisapride (1 - 1000 microg min(-1); 5-HT(4)), resulted in dose-dependent decreases in internal carotid blood flow, without changing blood pressure or heart rate. The vasoconstrictor responses to 5-HT, which remained unaffected after saline, were resistant to blockade by i.v. administration of the antagonists ritanserin (100 microg kg(-1); 5-HT(2A/2B/2C)) in combination with tropisetron (3000 microg kg(-1); 5-HT(3/4)) or the cyclo-oxygenase inhibitor, indomethacin (5000 microg kg(-1)), but were abolished by the 5-HT(1B/1D) receptor antagonist, GR127935 (30 microg kg(-1)). Interestingly, after administration of GR127935, the subsequent administration of ritanserin unmasked a dose-dependent vasodilator component. GR127935 or saline did not practically modify the vasoconstrictor effects of 5-MeO-T. In animals receiving GR127935, the subsequent administration of ritanserin abolished the vasoconstrictor responses to 5-MeO-T unmasking a dose-dependent vasodilator component. The vasoconstriction induced by sumatriptan was antagonized by GR127935, but not by ritanserin. Furthermore, ritanserin (100 microg kg(-1)) or ketanserin (100 microg kg(-1); 5-HT(2A)), but not GR127935, abolished DOI-induced vasoconstrictor responses. The above results suggest that 5-HT-induced internal carotid vasoconstriction is predominantly mediated by 5-HT(1B/1D) and 5-HT(2A) receptors.

Animals↗

PubMed2001

The role of several alpha(1)- and alpha(2)-adrenoceptor subtypes mediating vasoconstriction in the canine external carotid circulation.

1. It has recently been shown that both alpha(1)- and alpha(2)-adrenoceptors mediate vasoconstriction in the canine external carotid circulation. The present study set out to identify the specific subtypes (alpha(1A), alpha(1B) and alpha(1D) as well as alpha(2A), alpha(2B) and alpha(2C)) mediating the above response. 2. Consecutive 1 min intracarotid infusions of phenylephrine (alpha(1)-adrenoceptor agonist) and BHT933 (alpha(2)-adrenoceptor agonist) produced dose-dependent decreases in external carotid blood flow, without affecting mean arterial blood pressure or heart rate. 3. The responses to phenylephrine were selectively antagonized by the antagonists, 5-methylurapidil (alpha(1A)) or BMY7378 (alpha(1D)), but not by L-765,314 (alpha(1B)), BRL44408 (alpha(2A)), imiloxan (alpha(2B)) or MK912 (alpha(2C)). In contrast, only BRL44408 or MK912 affected the responses to BHT933. 4. The above results support our contention that mainly the alpha(1A), alpha(1D), alpha(2A) and alpha(2C)-adrenoceptor subtypes mediate vasoconstriction in the canine external carotid circulation.

Adrenergic alpha-Agonists↗

PubMed2001

Angiotensin converting enzyme is the main contributor to angiotensin I-II conversion in the interstitium of the isolated perfused rat heart.

OBJECTIVES: Recent studies in homogenized hearts suggest that chymase rather than angiotensin converting enzyme (ACE) is responsible for cardiac angiotensin I to angiotensin II conversion. We investigated in intact rat hearts whether (i) enzymes other than ACE contribute to angiotensin I to angiotensin II conversion and (ii) the localization (endothelial/extra-endothelial) of converting enzymes. DESIGN AND METHODS: We used a modified version of the rat Langendorff heart, allowing separate collection of coronary effluent and interstitial fluid. Hearts were perfused with angiotensin I (arterial concentration 5-10 pmol/ml) under control conditions, in the presence of captopril (1 micromol/l) or after endothelium removal with 0.2% triton X-100. Endothelium removal was verified as the absence of a coronary vasodilator response to 10 nmol bradykinin. Angiotensin I and angiotensin II were measured in coronary effluent and interstitial fluid with sensitive radioimmunoassays. RESULTS: In control hearts, 45% of arterial angiotensin I was metabolized during coronary passage, partly through conversion to angiotensin II. At steady-state, the angiotensin I concentration in interstitial fluid was three to four-fold lower than in coronary effluent, while the angiotensin II concentrations in both fluids were similar. Captopril and endothelium removal did not affect coronary angiotensin I extraction, but increased the interstitial fluid levels of angiotensin I two- and three-fold, respectively, thereby demonstrating that metabolism (by ACE) as well as the physical presence of the endothelium normally prevent arterial angiotensin I from reaching similar levels in coronary effluent and interstitial fluid. Captopril, but not endothelium removal, greatly reduced the angiotensin II levels in coronary effluent and interstitial fluid. With the ACE inhibitor, the angiotensin II/I ratios in coronary effluent and interstitial fluid were 83 and 93% lower, while after endothelium removal, the ratios were 33 and 71% lower. CONCLUSIONS: In the intact rat heart, ACE is the main contributor to angiotensin I to angiotensin II conversion, both in the coronary vascular bed and the interstitium. Cardiac ACE is not limited to the coronary vascular endothelium.

Angiotensin I↗

PubMed2001

High-affinity prorenin binding to cardiac man-6-P/IGF-II receptors precedes proteolytic activation to renin.

Mannose-6-phosphate (man-6-P)/insulin-like growth factor-II (man-6-P/IgF-II) receptors are involved in the activation of recombinant human prorenin by cardiomyocytes. To investigate the kinetics of this process, the nature of activation, the existence of other prorenin receptors, and binding of native prorenin, neonatal rat cardiomyocytes were incubated with recombinant, renal, or amniotic fluid prorenin with or without man-6-P. Intact and activated prorenin were measured in cell lysates with prosegment- and renin-specific antibodies, respectively. The dissociation constant (K(d)) and maximum number of binding sites (B(max)) for prorenin binding to man-6-P/IGF-II receptors were 0.6 +/- 0.1 nM and 3,840 +/- 510 receptors/myocyte, respectively. The capacity for prorenin internalization was greater than 10 times B(max). Levels of internalized intact prorenin decreased rapidly (half-life = 5 +/- 3 min) indicating proteolytic prosegment removal. Prorenin subdivision into man-6-P-free and man-6-P-containing fractions revealed that only the latter was bound. Cells also bound and activated renal but not amniotic fluid prorenin. We concluded that cardiomyocytes display high-affinity binding of renal but not extrarenal prorenin exclusively via man-6-P/IGF-II receptors. Binding precedes internalization and proteolytic activation to renin thereby supporting the concept of cardiac angiotensin formation by renal prorenin.

Amniotic Fluid↗

PubMed2001

Cardiomyocytes bind and activate native human prorenin : role of soluble mannose 6-phosphate receptors.

Cardiomyocytes bind, internalize, and activate recombinant human prorenin through mannose 6-phosphate/insulin-like growth factor II (M6P/IGFII) receptors. To investigate whether this also applies to native human prorenin, neonatal rat myocytes were incubated for 4 hours at 37 degrees C with various prorenin-containing human body fluids. Uptake and activation by M6P/IGFII receptors were observed for plasma prorenin from subjects with renal artery stenosis and/or hypertension and for follicular fluid prorenin. The total amount of cellular renin and prorenin (expressed as percentage of the levels of renin and prorenin in the medium) after 4 hours of incubation was 4 to 10 times lower than after incubation with recombinant human prorenin. Although plasma contains alkaline phosphatases capable of inactivating the M6P label as well as soluble M6P/IGFII receptors that block prorenin binding in a competitive manner and proteins (eg, insulin, IGFII) that increase the number of cell-surface M6P/IGFII receptors, these factors were not responsible for the modest uptake of native human prorenin. Uptake did not occur during incubation of myocytes with plasma prorenin from anephric subjects or with amniotic fluid prorenin, and this was not due to the presence of excessively high levels of M6P/IGFII receptors and/or phosphatase activity in these fluids. In conclusion, myocytes are capable of binding, internalizing, and activating native human prorenin of renal and ovarian origin through M6P/IGFII receptors. Differences in prorenin glycosylation and/or phosphorylation as well as the concentration of soluble M6P/IGFII receptors and growth factors affecting cell-surface M6P/IGFII receptor density determine the amount of prorenin entering the heart and thus cardiac angiotensin II production.

Amniotic Fluid↗

PubMed2000

Craniovascular selectivity of eletriptan and sumatriptan in human isolated blood vessels.

BACKGROUND: Eletriptan is a 5-HT(1B/1D) receptor agonist with proven efficacy in the acute treatment of migraine. OBJECTIVE: To assess the craniovascular selectivity of eletriptan and sumatriptan in blood vessels predictive of therapeutic efficacy (human middle meningeal artery) and adverse coronary side effects (human coronary artery and human saphenous vein). METHOD: The authors obtained coronary artery from organ donors (n = 9), middle meningeal artery from patients (n = 11) undergoing craniotomy, and saphenous vein from patients (n = 9) undergoing coronary bypass surgery. Concentration-response curves to eletriptan and sumatriptan were constructed to obtain measurements of efficacy (maximum contraction, E(max)) and potency (concentration eliciting 50% of E(max), EC(50)). The contraction that is likely to be induced at the maximal free plasma concentration (C(max)) was determined by calculating C(max)/EC(50) ratios and by interpolation of the concentration-response curves. RESULTS: Eletriptan and sumatriptan induced concentration-dependent contractions of meningeal artery, coronary artery, and saphenous vein. Eletriptan was less potent than sumatriptan in coronary artery, whereas both compounds had similar potency in meningeal artery and saphenous vein. However, the potency of eletriptan and sumatriptan was higher in meningeal artery than in coronary artery (86-fold for eletriptan and 30-fold for sumatriptan) or saphenous vein (66- and 25-fold). The efficacy of eletriptan and sumatriptan was similar within tissues. The predicted contraction by eletriptan (40 mg and 80 mg) and sumatriptan (100 mg) at free C(max) observed in clinical trials was similar in meningeal artery, whereas in coronary artery and saphenous vein it was lower for 40 mg eletriptan than for sumatriptan. CONCLUSIONS: At therapeutic concentrations both eletriptan and sumatriptan contract middle meningeal artery more than coronary artery. This suggests that in patients with healthy coronary arteries, they have a limited propensity to cause adverse coronary side effects. However, both drugs remain contraindicated in patients with coronary artery disease.

Aged↗

PubMed2000

Pharmacological analysis of contractile effects of eletriptan and sumatriptan on human isolated blood vessels.

Eletriptan, a second-generation triptan with high affinity for 5-HT(1B/1D) receptors, is highly effective in migraine, with or without aura. We compared the effects of eletriptan and sumatriptan on the human isolated middle meningeal and coronary arteries and saphenous vein, used as models for therapeutic efficacy and potential side effects, and have investigated the role of 5-HT(1B/1D) receptors in contractions induced by these triptans. Concentration-response curves to eletriptan and sumatriptan were constructed in the absence or presence of a selective 5-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-py rid yl) benzamide (GR125743). All three blood vessels constricted in response to eletriptan and sumatriptan, but the middle meningeal artery relaxed following the highest concentration (100 microM) of eletriptan. In the middle meningeal artery, GR125743 antagonised the contractions induced by both eletriptan (pEC(50): 7.34+/-0.13) and sumatriptan (pEC(50): 6.91+/-0.17) to a similar degree (pA(2): 8. 81+/-0.17 and 8.64+/-0.21, respectively). In the human coronary artery and saphenous vein, sumatriptan-induced contractions (pEC(50): 6.24+/-0.14 and 6.19+/-0.12, respectively) were also potently antagonised by GR125743 (pA(2): 8.18+/-0.27 and 8.34+/-0.12, respectively). The eletriptan-induced contractions of the human saphenous vein (pEC(50): 6.09+/-0.13) were antagonised less effectively by GR125743 (pK(B): 7.73+/-0.18), and those of the human coronary artery (pEC(50): 5.54+/-0.22) remained unaffected by GR125743 up to a concentration of 100 nM. These results suggest that (i) based on the differences in pEC(50) values, the cranioselectivity of eletriptan (63-fold) is higher than that of sumatriptan (5-fold) in coronary artery, (ii) the contractile effects of sumatriptan and eletriptan (lower concentrations) in the three blood vessels are mediated via the 5-HT(1B) receptor, and (iii) additional mechanisms seem to be involved in coronary artery and saphenous vein contractions and middle meningeal artery relaxation following high concentrations of eletriptan.

Adult↗

PubMed2000

Positive inotropy mediated via CGRP receptors in isolated human myocardial trabeculae.

Isometric contractile force were studied on isolated human myocardial trabeculae that were paced at 1.0 Hz in tissue baths. Alpha calcitonin gene-related peptide (alpha-CGRP) had a potent positive inotropic effect in most trabeculae from both the right atrium and left ventricle, and this effect was partially antagonized by the CGRP(1) receptor antagonist alpha-CGRP-(8-37) (10(-6) M). Amylin and the CGRP(2) receptor agonist [Cys(acetylmethoxy)(2, 7)]CGRP had a positive inotropic effect in some trabeculae, whereas adrenomedullin had no inotropic effect. Using reverse transcriptase-polymerase chain reaction (PCR) mRNAs encoding the human calcitonin receptor-like receptor and the receptor associated modifying proteins (RAMPs) RAMP1, RAMP2, and RAMP3 were detected in human myocardial trabeculae from both the right atrium and left ventricle. In conclusion, functional CGRP(1) and CGRP(2) receptors may mediate a positive inotropic effect at both the atrial and ventricular level of the human heart. mRNAs for calcitonin receptor-like receptor and specific RAMPs further support the presence of CGRP receptors.

Adrenomedullin↗

PubMed2000

Chronic administration of moxonidine suppresses sympathetic activation in a rat heart failure model.

Excessive sympathetic activity contributes to cardiovascular abnormalities, which negatively affect the prognosis of heart failure. The present study evaluated the effects of moxonidine, an imidazoline I(1) receptor agonist, on sympathetic activation and myocardial remodelling in a rat heart failure model. Rats were subjected to coronary artery ligation, and treated with moxonidine, 3 or 6 mg/kg/day, from 1 to 21 days after myocardial infarction. After 21 days, heart rate and blood pressure were measured in conscious, chronically instrumented rats. Plasma catecholamine levels were determined by high-performance liquid chromatography. Effects on post-myocardial infarction remodelling were evaluated from the ventricular weight body weight ratio and interstitial collagen deposition, measured morphometrically in the interventricular septum remote from the infarcted area. Moxonidine dose-dependently decreased myocardial infarction induced tachycardia but did not affect myocardial infarction reduced blood pressure. Plasma noradrenaline levels, which were elevated after myocardial infarction, decreased below sham-values with 6 mg/kg/day moxonidine. Ventricular weight-body weight ratio as well as interstitial collagen were significantly elevated in myocardial infarcted rats, and restored to sham values with 6 mg/kg/day moxonidine. These data suggest that moxonidine suppresses myocardial infarction induced sympathetic activation in a dose-dependent way as indicated by reduced heart rate and plasma noradrenaline levels. Furthermore, post-myocardial infarction remodelling may be attenuated at a higher dose-range of moxonidine as shown by normalisation of ventricular weight body weight ratio and interstitial collagen.

Animals↗

PubMed2000

Further pharmacological analysis of the orphan 5-HT receptors mediating feline vasodepressor responses: close resemblance to the 5-HT7, receptor.

It has been suggested that the late hypotensive response to serotonin (5-hydroxytryptamine; 5-HT) in vagosympathectomised cats, being potently mimicked by 5-carboxamidotryptamine (5-CT), not modified by ketanserin and blocked by methiothepin or methysergide, is mediated by '5-HT1-like' receptors. Nevertheless, current guidelines for 5-HT receptor classification refer to this receptor as an orphan receptor. Thus, the present study set out to reanalyse the above suggestion in terms of the classification schemes proposed in 1994 and 1998 by the NC-IUPHAR subcommittee on the classification of 5-HT receptors. Intravenous (i.v.) bolus injections of 5-CT (0.003-0.3 microg/kg), 5-HT (1-100 microg/kg) and 5-methoxytryptamine (5-MeO-T; 1-100 microg/kg) produced dose-dependent vasodepressor responses with a rank order of agonist potency of 5-CT >> 5-HT = 5-MeO-T with sumatriptan (10-300 microg/kg) virtually inactive. The vasodepressor responses to 5-HT, 5-CT and 5-MeO-T were not attenuated following i.v. administration of the antagonists GR127935 (5-HT(IB/ID); 30 microg/kg), tropisetron (5-HT3/4; 3000 microg/kg), (+/-)-pindolol (beta-adrenergic and 5-HT1A; 4000 microg/kg) or equivalent volumes of physiological saline. In contrast, the above vasodepressor responses were markedly and specifically antagonised by i.v. methiothepin (100 microg/kg), lisuride (30 microg/kg and 100 microg/kg), mesulergine (300 microg/kg and 1000 microg/kg) or LY215840 (300 microg/kg and 1000 microg/kg). The above lines of evidence, therefore, indicate that the orphan receptors mediating the vasodepressor responses to 5-HT in vagosympathectomised cats are pharmacologically similar to other 5-HT7 receptors mediating vascular and non-vascular responses (e.g. relaxation of the canine external carotid artery and guinea-pig ileum as well as feline tachycardia).

5-Methoxytryptamine↗

PubMed2000

Mediation of 5-HT-induced internal carotid vasodilatation in GR127935- and ritanserin-pretreated dogs by 5-HT7 receptors.

The vasoconstrictor effects of 5-hydroxytryptamine (5-HT) in the internal carotid bed of anaesthetised dogs with bilateral vagosympathectomy are mainly mediated by both 5-HT1B and 5-HT2 receptors. The blockade of this vasoconstrictor effect of 5-HT by the combined use of the antagonists, GR127935 (5-HT1B/1D) and ritanserin (5-HT2), unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present study set out to analyse the pharmacological profile of this vasodilator 5-HT receptor in the internal carotid bed of vagosympathectomized dogs systematically pretreated with intravenous (i.v.) injections of GR127935 (30 microg/kg) and ritanserin (100 microg/kg). One-minute (1-min) intracarotid (i.c.) infusions of 5-HT (0.1-10 microg/min), 5-carboxamidotryptamine (5-CT; 0.01-0.3 microg/min), 5-methoxytryptamine (5-MeO-T; 1-100 microg/min) and acetylcholine (ACh; 0.003-0.1 microg/min) resulted in dose-dependent increases in internal carotid blood flow (without changes in blood pressure or heart rate) with a rank order of agonist potency of ACh > 5-CT >> 5-HT > or =5-MeO-T. The internal carotid vasodilator responses to 5-HT, 5-CT and 5-MeO-T, which remained unaffected after saline (0.03 ml/kg and 0.1 ml/kg, i.v.), were specifically and dose-dependently blocked by i.v. administration of lisuride (10 microg/kg and 30 microg/kg), clozapine (1000 microg/kg), mesulergine (300 microg/kg and 1000 microg/kg) and LY215840 (300 microg/kg and 1000 microg/kg) with the following apparent rank order of potency: lisuride >> mesulergine = LY215840 > or = clozapine. The above results suggest that the 5-HT receptor mediating internal carotid vasodilatation in vagosympathectomized dogs pretreated with GR127935 and ritanserin is operationally similar to other 5-HT7 receptors mediating vascular and non-vascular responses.

Animals↗

PubMed2000

Altered cardiac collagen and associated changes in diastolic function of infarcted rat hearts.

OBJECTIVE: Anti-inflammatory drugs have been shown to modulate collagen deposition during myocardial infarction (MI) induced remodeling. Chronic effects of methylprednisolone (5 mg/kg/day) and low-dose aspirin (25 mg/kg/day) on cardiac collagen and left ventricular diastolic function were studied in rat hearts, 21 days after MI. METHODS: Left ventricular function was assessed at baseline and after beta-adrenergic stimulation with isoproterenol in isolated perfused hearts, using an intraventricular balloon. After diastolic arrest, left ventricular pressure-volume curves were obtained. Left ventricular dilation was defined as the corresponding left ventricular volume at 20 mmHg left ventricular diastolic pressure. In histological sections, perivascular and interstitial collagen content were quantified morphometrically as the Sirius Red positive area in the non-infarcted interventricular septum. RESULTS: Impaired baseline left ventricular function of MI-hearts was improved by methylprednisolone but not by low-dose aspirin. Isoprotenerol significantly enhanced systolic function in all hearts, whereas it augmented the decrease in left ventricular diastolic pressure only in methylprednisolone-treated MI-hearts. The rightward shift of the pressure-volume curve after MI was aggravated by methylprednisolone but not with low-dose aspirin treatment. Low-dose aspirin reduced perivascular but not interstitial collagen whereas methylprednisolone decreased both perivascular and interstitial collagen. CONCLUSIONS: Our findings indicate that MI-induced collagen deposition in the spared myocardium can be affected by chronic therapy with low-dose aspirin or methylprednisolone. The effects on interstitial collagen seemed reflected in an altered left ventricular diastolic function.

Adrenergic beta-Agonists↗

PubMed2000

Influence of ageing on vasomotor responses of human epicardial coronary arteries.

Vasomotor responses to various agonists were studied on isolated circular segments of human epicardial coronary arteries from three different age groups; 23-38 years, 40-58 years and 63-86 years. Noradrenaline had no or only weak contractile effect on coronary arteries from younger patients but induced contraction of all artery segments from older patients. The Emax value was significantly (P<0.0001) higher in arteries from the oldest group compared to each of the two younger age groups, whereas the potency was similar in all three groups. Linear regression analysis of noradrenaline-induced contraction in individual patients revealed a significantly positive age-correlation (correlation coefficient 0.67, P<0.0001). Contraction induced by endothelin-1 and relaxation induced by substance P, calcitonin gene-related peptide and vasoactive intestinal peptide on arteries precontracted with U46619 showed no significant differences in maximum responses and potencies between the three age groups, and no significant linear age-correlation. These data demonstrate a large variability in contractile responses to noradrenaline with contractions seen mostly in coronary arteries from older patients. It thus seems that sympathetic activation could contribute to coronary ischaemia in some patients.

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

PubMed2000

Modulation of contractile force by endothelin receptors in porcine myocardial trabeculae.

The aim of the study was to determine possible inotropic effects mediated by endothelin-A and endothelin-B receptors in porcine myocardial trabeculae from right atria and left ventricles. Isolated trabeculae were paced at 1.5 Hz in tissue baths, and changes in isometric contractile force upon exposure to agonist were studied. Endothelin-1 and endothelin-3 had a strong and potent positive inotropic effect in all trabeculae. In all atrial and in some ventricular trabeculae this effect was preceded by a transient negative inotropic effect at 10(-7) M. The endothelin-B receptor agonist IRL 1620 had a positive inotropic effect in some of the ventricular trabeculae, and no negative inotropic effect. Another endothelin-B receptor agonist, sarafotoxin S6c, had no positive inotropic effect, but induced a transient negative inotropic effect in some atrial trabeculae at 10(-7) M. In atrial trabeculae the preincubation with the endothelin-A receptor antagonist FR139317 (10(-6) M) decreased significantly (P<0.01) the maximum positive inotropic responses and abolished negative inotropic responses to endothelin-1. In conclusion, both endothelin-A and endothelin-B receptors may have the potential to mediate both positive and negative inotropic responses, but a positive inotropic effect mediated mainly via endothelin-A receptors seems to predominate.

Analysis of Variance↗

PubMed2000

L-NAME-resistant bradykinin-induced relaxation in porcine coronary arteries is NO-dependent: effect of ACE inhibition.

1. NO synthase (NOS)inhibitors partially block bradykinin (BK)-mediated vasorelaxation. Here we investigated whether this is due to incomplete NOS inhibition and/or NO release from storage sites. We also studied the mechanism behind ACE inhibitor-mediated BK potentiation. 2. Porcine coronary arteries (PCAs) were mounted in organ baths, preconstricted, and exposed to BK or the ACE-resistant BK analogue Hyp(3)-Tyr(Me)(8)-BK (HT-BK) with or without the NOS inhibitor L-NAME (100 microM), the NO scavenger hydroxocobalamin (200 microM), the Ca(2+)-dependent K(+)-channel blockers charybdotoxin+apamin (both 100 nM), or the ACE inhibitor quinaprilat (10 microM). 3. BK and HT-BK dose-dependently relaxed preconstricted vessels (pEC(50) 8.0+/-0.1 and 8.5+/-0.2, respectively). pEC(50)'s were approximately 10 fold higher with quinaprilat, and approximately 10 fold lower with L-NAME or charybdotoxin+apamin. Complete blockade was obtained with hydroxocobalamin or L-NAME+ charybdotoxin+apamin. 4. Repeated exposure to 100 nM BK or HT-BK, to deplete NO storage sites, produced progressively smaller vasorelaxant responses. With L-NAME, the decrease in response occurred much more rapidly. L-Arginine (10 mM) reversed the effect of L-NAME. 5. Adding quinaprilat to the bath following repeated exposure (with or without L-NAME), at the time BK and HT-BK no longer induced relaxation, fully restored vasorelaxation, while quinaprilat alone had no effect. Quinaprilat also relaxed vessels that, due to pretreatment with hydroxocobalamin or L-NAME+charybdotoxin+apamin, previously had not responded to BK. 6. In conclusion, L-NAME-resistant BK-induced relaxation in PCAs depends on NO from storage sites, and is mediated via stimulation of guanylyl cyclase and/or Ca(2+)-dependent K(+)-channels. ACE inhibitors potentiate BK independent of their effect on BK metabolism.

Angiotensin-Converting Enzyme Inhibitors↗