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Biomedical subjects

M J Mulvany

Publications and source records attributed to M J Mulvany.

At least 37 records · Page 2Linked to original sources
PubMed1999

Mechanisms involved in the vasorelaxant effect of (-)-stepholidine in rat mesenteric small arteries.

The purpose of the present investigation was to clarify whether the hypotensive action of the protoberberine alkaloid, and dopamine receptor antagonist, (-)-stepholidine, can be ascribed to an effect on peripheral small arteries. For this purpose isolated mesenteric small arteries were suspended in microvascular myographs for isometric tension recording. Relaxations mediated by dopamine D1 receptors were antagonized by (-)-stepholidine. (-)-Stepholidine inhibited in a concentration-dependent manner the contractile responses evoked by noradrenaline (10(-6) M), but not the contractile responses evoked by depolarizing solution (KCl, 60 mM) or 9,11-dideoxy-11alpha,9alpha-epoxymethano prostaglandin F2alpha (U46619, 10(-7) M). Mechanical endothelial cell removal, blockade of K+ channels, muscarinic receptors or adrenoceptors did not influence the inhibitory effect of (-)-stepholidine on the contractile response evoked with noradrenaline in the segments. (-)-Stepholidine caused rightward shifts of the concentration-response curves for noradrenaline and phenylephrine. The pA2 values for (-)-stepholidine were 6.05 and 5.94 against noradrenaline and phenylephrine, respectively. Electrical field stimulation induced prazosin-sensitive frequency-dependent contractions in mesenteric small arteries. These contractions were significantly inhibited by 10(-6) and 10(-5) M (-)-stepholidine. In membranes from the rat cerebral cortex labelled with [3H]prazosin, (-)-stepholidine (10(-7)-10(-4) M) completely inhibited the specific binding of the ligand with a pKi of 5.6. The present investigation suggests the inhibitory effect of (-)-stepholidine on the alpha1-adrenoceptor-mediated contractions induced by exogenously added and nerve-released noradrenaline in peripheral small arteries might contribute to a hypotensive effect of the drug.

Animals↗
PubMed1999

Reduced vasodilator capacity in syndrome X related to structure and function of resistance arteries.

The combination of angina pectoris, angiographically normal epicardial coronary arteries, and a positive exercise test is referred to as syndrome X. Previous studies have demonstrated an impaired coronary flow reserve and a peripheral vascular dysfunction, suggesting that vascular abnormalities in syndrome X may not be confined to the heart. The aim of this study was to investigate whether any vascular disorder of syndrome X is due to intrinsic structural or functional disturbances in resistance arteries. We compared 16 patients with syndrome X (56.6+/-1.2 years, 3 men) with 15 matched control subjects. Myocardial blood flow was measured with 13N-ammonia positron emission tomography. Forearm blood flow was measured in the brachial artery with high-resolution ultrasound. Gluteal subcutaneous resistance arteries were dissected and mounted on a myograph for measurement of active tension development, lumen diameter, and media thickness. Baseline myocardial blood flow was similar in patients and controls, but dipyridamole-induced hyperemia was decreased in patients (1.67+/-0.13 vs 2.31+/-0.12 ml/ min/g, p <0.01). Patients and controls had similar baseline forearm blood flow, but hyperemic flow after transient occlusion of the brachial artery was impaired in patients (198+/-20 vs 273+/-32 ml/min, p <0.05). Isolated resistance arteries showed no differences in constriction to noradrenaline, or relaxation to acetylcholine, dipyridamole, or nitroglycerin. Furthermore, the ratio between media thickness and lumen diameter were similar in syndrome X patients and controls. Our data show that when compared with a well-matched control group, syndrome X patients have a decreased coronary and peripheral vasodilator capacity. However, this is not reflected by functional abnormalities or structural changes as evaluated in subcutaneous resistance arteries. We conclude that syndrome X is not a generalized intrinsic abnormality of the resistance circulation.

Arteries↗
PubMed1999

Large juxtamedullary glomeruli and afferent arterioles in healthy primates.

BACKGROUND: Differences in the functional demands of superficial and juxtaglomerular nephrons could result in differences in glomerular size between these two types of nephrons. This concept is based on animal models in which the juxtamedullary glomeruli and afferent arteriole diameters are indeed larger than those in the outer cortical zones. However, this difference was not confirmed in human necropsy studies. To obtain further information in living primates, we have made unbiased estimates of glomerular and afferent arteriole dimensions in three cortical zones (superficial, midcortical, and juxtamedullary) in young, adult, normotensive monkeys. METHODS: In each animal (N = 6), the right kidney was perfusion fixed and prepared for unbiased stereological estimation of glomerular number and size. The left kidney vasculature was fixed while relaxed and at a known intravascular pressure. Thereafter, afferent arteriolar dimensions were estimated using light and confocal microscopy. RESULTS: The mean glomerular volume was variable between animals (coefficient of variation, 23%) and was largest in the juxtamedullary zone. Afferent arteriolar lumen diameter varied little between animals (coefficient of variation, 3%), but was also the largest in the juxtamedullary zone. No sclerotic glomeruli were found in any of the animals. CONCLUSION: The findings show that in normal primates, as previously shown in other animals, juxtamedullary glomeruli and afferent arteriolar diameters are larger compared with those in the outer cortical zones.

Animals↗
PubMed1999

Effect of short- and long-term heart failure on small artery morphology and endothelial function in the rat.

Chronic heart failure (HF) is associated with hemodynamic changes and activation of several neurohormonal systems, which are able both to inhibit and to facilitate arterial growth or remodeling and also to influence endothelial function. As these vascular changes may depend on the duration of HF, we evaluated morphologic and endothelial functional alterations in a rat model of HF after a short and long duration of HF. Rats with coronary ligation and sham-operated controls were investigated either 8 or 26 weeks after the operation with measurements of hemodynamics and isolated mesenteric small artery morphology and endothelial function. The effect of HF and duration of HF were examined by using two-way analysis of variance (ANOVA). HF rats had altered hemodynamics with reductions in cardiac output, left ventricular systolic pressure, and mean blood pressure, whereas left ventricular diastolic pressure was increased. HF caused remodeling of anatomically well-defined mesenteric small arteries with a reduction in media thickness and media-to-lumen ratio, but without change in the media cross-sectional area. Neither HF nor time had any influence on sensitivity or maximal relaxation to acetylcholine in the presence of indomethacin, but HF reduced vasoconstriction due to nitric oxide synthase blockade with N(G)-nitro-L-arginine independent of time. Our results indicate that HF, induced by coronary ligation in the rat, has a remodeling effect on mesenteric small arteries. However, the remodeling is moderate compared with that observed in hypertension. Furthermore, our results suggest that HF reduces basal release of NO.

Acetylcholine↗
PubMed1999

The myogenic response: established facts and attractive hypotheses.

The myogenic response of small arteries and arterioles has been shown to contribute significantly to autoregulation in different vascular beds. It is characterized by a constriction of the vessel after an increase of transmural pressure and a dilation of the vessel after a decrease of transmural pressure. This review examines the evidence for the mechanisms of the myogenic response, with the aim of distinguishing between facts and hypotheses. It appears to be established that the myogenic response is stimulated by an alteration of vessel wall tension, that it does not require the presence of the endothelium and, for pressure increases, that it is accompanied by a membrane depolarization and an increase of the intracellular Ca2+ concentration, which depends largely on an influx of extracellular calcium via voltage-operated calcium channels. Under in vitro conditions, it may further be considered an established fact that the myogenic response can be modulated by transmitters, like noradrenaline, and factors released from the endothelium upon its activation. In contrast, many other aspects of the myogenic response remain hypothetical. Thus, the mechanism of the depolarization, its importance for the development of the myogenic response, the participation of other pathways for calcium influx, and the role of an intracellular calcium release in the myogenic response are still under debate. Furthermore, the participation of a variety of intracellular second messenger systems in the myogenic response, i.e. inositol trisphosphate, diacylglycerol, phospholipase A2, protein kinase C or 20-hydroxyeicosatetraenoic acid, is still unclear. Additionally, the roles of the pulsatility of the blood pressure and of remote signals from neighbouring vessel segments as well as of different metabolites are not clarified. This review suggests that while the primary mechanisms of the myogenic response are well understood, the details of the signalling pathways are still undefined. The clinical significance of the myogenic response remains to be determined.

Animals↗
PubMed1998

Mechanisms of Ca2+ sensitization of force production by noradrenaline in rat mesenteric small arteries.

1. Mechanisms of Ca2+ sensitization of force production by noradrenaline were investigated by measuring contractile responses, intracellular Ca2+ concentration ([Ca2+]i) and phosphorylation of the myosin light chain (MLC) in intact and alpha-toxin-permeabilized rat mesenteric small arteries. 2. The effects of noradrenaline were investigated at constant membrane potential by comparing fully depolarized intact arteries in the absence and presence of noradrenaline. Contractile responses to K-PSS (125 mM K+) and NA-K-PSS (K-PSS + 10 microM noradrenaline) were titrated to 30 and 75%, respectively, of control force, by adjusting extracellular Ca2+ ([Ca2+]o). At both force levels, [Ca2+]i was substantially lower with NA-K-PSS than with K-PSS. With K-PSS, the proportion of MLC phosphorylated (approximately 30%) was similar at 30 and 75% of control force; with NA-K-PSS, MLC phosphorylation was greater at the higher force level (40 vs. 34%). 3. In alpha-toxin-permeabilized arteries, the force response to 1 microM Ca2+ was increased by 10 microM noradrenaline, and MLC phosphorylation was increased from 35 to 45%. The protein kinase C (PKC) inhibitor calphostin C (100 nM) abolished the noradrenaline-induced increase in MLC phosphorylation and contractile response, without affecting the contraction in response to Ca2+. Treatment with ATP gamma S in the presence of the MLC kinase inhibitor ML-9 increased the sensitivity to Ca2+ and abolished the response to noradrenaline. 4. The present results show that that in rat mesenteric small arteries noradrenaline-induced Ca2+ sensitization is associated with an increased proportion of phosphorylated MLC. The results are consistent with a decreased MLC phosphatase activity mediated through PKC. Furthermore, while MLC phosphorylation is a requirement for force production, the results show that other factors are also involved in force regulation.

Animals↗
PubMed1998

Effects of angiotensin-converting enzyme inhibition on vascular remodeling of resistance vessels in hypertensive patients.

Essential hypertension is known to be associated with a decrease in the lumen diameter and an increase in the wall thickness to lumen diameter ratio of the resistance vessels. Recently, it has been clarified that this alteration does not necessarily involve vascular growth, but could be due to a rearrangement of the same amount of material, a phenomenon now termed "eutrophic remodeling." These changes are found both in human essential hypertension and in animal models of genetic hypertension. Antihypertensive treatment with angiotensin-converting enzyme (ACE) inhibitors causes a dose-dependent regression of the media to lumen ratio in rats. Clinical studies have now confirmed these findings, showing that when previously untreated essential hypertensive patients are treated with the ACE inhibitor perindopril (PE), the abnormal structure of resistance vessels regresses toward normal values; in contrast, treatment with a beta-blocker does not affect the abnormal vascular structure. The available evidence thus indicates that ACE inhibitors are able to normalize the abnormal resistance vessel structure in essential hypertension, and suggest that this effect may not only be dependent on their ability to reduce blood pressure. This review summarizes these findings, and discusses the extent to which this is desirable.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Effect of antihypertensive treatment on cardiac and subcutaneous artery structure: a comparison between calcium channel blocker and thiazide-based regimens.

The effects of two antihypertensive regimens (isradipine and hydrochlorothiazide-amiloride) on the ratio between media thickness and lumen diameter of subcutaneous arteries and on left ventricular mass in essential hypertension were compared. Fifty patients, aged 46.3+/-8 (mean+/-SD) years, with newly diagnosed or poorly controlled essential hypertension were randomized to treatment with either isradipine or hydrochlorothiazide-amiloride. Atenolol and hydralazine were added in both groups as secondary and tertiary drugs, respectively, when needed for normalization of diastolic blood pressure. A subcutaneous gluteal biopsy was taken surgically before medication and again after 9 months of successful antihypertensive treatment. Two small resistance arteries were isolated from each biopsy and mounted in a Mulvany-Halpem isometric small vessel myograph. The media thickness-to-lumen diameter ratio (percentage) of the vessels was measured under standardized conditions and meaned. Left ventricular mass (LVM) index was determined by echocardiography according to the Penn convention. Ten patients were treated with isradipine as monotherapy, whereas only one patient was well controlled on diuretics as monotherapy. Mean blood pressure was reduced equally with the two regimens, from 131+/-9 mm Hg to 101+/-10 mm Hg with the isradipine and from 128+/-9 mm Hg to 99+/-7 mm Hg with the thiazide/atenolol regimen. LVM decreased significantly in both groups by 130+/-75 g with the isradipine-based regimen and by 70+/-53 g with the hydrochlorothiazide/atenolol-based regimen. The reduction of LVM was significantly greater on the isradipine-based regimen than on the thiazide-based regimen (P < .01). There was a significant reduction of media thickness-to-lumen diameter ratio during treatment with the isradipine-based regimen from 10.9% to 8.8% (P < .01). The reduction in the thiazide regimen was from 9.7% to 8.5%, which was not significant (P = .07). The study demonstrated significant reduction of hypertensive changes in peripheral resistance artery structure during antihypertensive treatment with an isradipine-based regimen. The thiazide/betablocker-based regimen did not have a significant effect on the vessels. Significant reduction of LVM was achieved with both isradipine-based and thiazide/atenolol-based regimens. The reduction of LVM obtained with the isradipine-based regimen was significantly greater than that of the thiazide/atenolol-based regimen.

Adult↗
PubMed1998

Mechanisms of relaxations of bovine isolated bronchioles by the nitric oxide donor, GEA 3175.

1. The present study was designed to investigate the effects and mechanisms of relaxation induced by the nitric oxide (NO) donor, GEA 3175 (a 3-aryl-substituted oxatriazole derivative) on bovine bronchioles (effective lumen diameter 200-800 microm) suspended in microvascular myographs for isometric tension recording. 2. In segments of bovine bronchioles contracted to 5-hydroxytryptamine, GEA 3175 (10(-8)-10(-4) M) induced concentration-dependent reproducible relaxations. These relaxations were slow in onset compared to other NO-donors such as 3-morpholinosydonimine-hydrochloride (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP). 3. In 5-hydroxytryptamine-contracted preparations the order of relaxant potency (pD2) was: salbutamol (7.80) > GEA 3175 (6.18) > SIN-1 (4.90) > SNAP (3.55). In segments contracted to acetylcholine, the relaxant responses were reduced and GEA 3175 relaxed the bronchioles with pD2 = 4.41 +/- 0.12 and relaxations of 66 +/- 10% (n = 4), while SNAP and salbutamol caused relaxations of 19 +/- 6% (n = 4) and 27 +/- 6% (n = 8) at the highest concentration used, respectively. 4. Oxyhaemoglobin (10(-5) M), the scavenger of nitric oxide, caused rightward shifts of the concentration-relaxation curves to GEA 3175 and NO. 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 3 x 10(-6) M) and LY 83583 (10(-6) M), the inhibitors of soluble guanylate cyclase, also reduced the relaxations induced by GEA 3175 and nitric oxide. However, ODQ did not affect salbutamol-evoked relaxation in the bovine small bronchioles. 5. GEA 3175-induced relaxations were reduced in potassium-rich (60 mmol l(-1) K+) solution. Glibenclamide (10(-6) M) markedly inhibited the relaxations induced by the opener of ATP-sensitive K+ channels, levcromakalim (3 x 10(-8)-10(-5) M), but it did not modify the relaxations induced by GEA 3175 or salbutamol. Apamin (5 x 10(-7) M), a blocker of the small Ca2+-activated K+-channels did not affect the relaxations to GEA 3175. In contrast, blockers of large Ca2+-activated K+-channels, charybdotoxin (3 x 10(-8)-10(-7) M) and iberiotoxin (10(-8) M), did inhibit the relaxations to GEA 3175. The combination of apamin and charybdotoxin did not induce an additional inhibitory effect on the relaxations to GEA 3175 compared to charybdotoxin alone. 6. In preparations where a concentration-response curve to GEA 3175 or NO was first obtained in the presence of LY 83583, incubation with charybdotoxin (10(-7) M) did produce an additional inhibitory effect of the relaxations. However. in the presence of ODQ (3 x 10(-6) M), iberiotoxin (10(-8) M) did not produce additional reduction of the NO- or GEA 3175-induced relaxations. 7. The present results suggest that the slow-releasing NO-donor GEA 3175 is more potent than the traditional NO donors in inducing relaxations of bovine bronchioles. GEA 3175, as for exogenously added NO, elicits relaxations through a cyclic GMP-dependent mechanism followed by opening of large conductance Ca2+-activated K+-channels.

Albuterol↗
PubMed1998

Pharmacological characterization of coronary small arteries from pigs with chronic ischaemic myocardial remodelling.

1. The effect of chronic ischaemic myocardial remodelling on small coronary artery reactivity in vitro was studied in a newly developed pig model. 2. Pigs were subjected to selective intracoronary embolizations with microspheres in the left anterior descending artery and circumflex artery causing scattered myocardial fibrosis. After an observation period of 130 days, heart dimensions and ejection fraction were determined with magnetic resonance imaging. Small arteries were isolated from the left ventricle and mounted as ring preparations in a myograph. Control arteries were taken from matched non-embolized pigs. 3. Compared with control pigs, end-systolic and diastolic volumes increased and left ventricular mass nearly doubled in embolized pigs. This indicates substantial myocardial hypertrophy, as the fraction area of fibrosis was only 12%. 4. Coronary small arteries preconstricted with 30 mmol/l KCI showed a normal contractile response to acetylcholine and 5-hydroxytryptamine. Sensitivity of the relaxation to bradykinin was nearly 3-fold increased and also slightly enhanced to isoprenaline in arteries from embolized pigs compared with controls, whereas relaxation to 5-hydroxytryptamine in the presence of ketanserin was similar. After inhibition of nitric oxide synthase with NG-nitro-L-arginine the sensitivity to acetylcholine increased to a similar extent in arteries from embolized pigs and controls. NG-Nitro-L-arginine abolished the relaxing effects of bradykinin and of 5-hydroxytryptamine in the presence of ketanserin. 5. We conclude that both the contractile function of the smooth muscle cells and the endothelial production or action of nitric oxide is preserved or slightly enhanced in coronary small arteries from pigs with chronic myocardial remodelling.

Acetylcholine↗
PubMed1998

Effects of losartan and enalapril on small artery structure in hypertensive rats.

We evaluated the effects on cardiovascular structure of the angiotensin-converting enzyme (ACE) inhibitor enalapril and of the angiotensin II receptor blocker losartan, administered either at hypotensive or nonhypotensive dosage in spontaneously hypertensive rats (SHR). SHR were treated from ages 4 to 12 weeks with low-dose (1 mg x kg(-1) x d(-1)) enalapril, low-dose (0.5 mg x kg(-1) x d(-1)) losartan, high-dose (25 mg x kg(-1) x d(-1)) enalapril, or high-dose (15 mg x kg(-1) x d(-1)) losartan. Untreated WKY and SHR were also studied. Rats were killed at 13 weeks of age, and the heart was weighed. Mesenteric small arteries were dissected and mounted on a micromyograph for determination of media thickness and lumen diameter. In fixed arteries, cell volume, number of cells per segment length, and number of cell layers were measured using the unbiased "disector" method. Systolic blood pressure was significantly reduced by the high doses of both drugs, but the hypotensive effect was greater with enalapril than with losartan (P<0.05). In the high-dose enalapril and losartan groups, there were similar reductions in relative left ventricular mass, media/lumen ratio, and number of cell layers of resistance arteries; however, there were no differences in the cell volume or number of cells per segment length of resistance arteries. Low-dose enalapril did not affect systolic blood pressure or any of the structural parameters. The results show that the hypotensive effects of both losartan and enalapril were associated with outward remodeling of resistance arteries at the cellular level. The effect of losartan on resistance artery structure was equal to that of enalapril, despite the smaller hypotensive effect.

Animals↗
PubMed1997

The antipsychotic drug sertindole is a specific inhibitor of alpha1A-adrenoceptors in rat mesenteric small arteries.

We have investigated the adrenergic antagonist effect of the antipsychotic sertindole in rat resistance vessels and in membranes of HEK293 cells transfected with alpha1-adrenoceptors. Segments of rat mesenteric small arteries or rat aorta were mounted on a myograph for isometric tension recording. In mesenteric small arteries, specific alpha1A-adrenoceptor antagonists (5-methyl urapidil and WB-4101 (2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane)) inhibited phenylephrine responses with high affinity (pA2 9.1 and 9.5, respectively). Chlorethylclonidine (alpha1B- and alpha1D-adrenoceptor antagonist) and BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4,5] decane-7,9-dione dihydrochloride, alpha1D-adrenoceptor antagonist) had little effect. This indicated that the adrenoceptor subtype in the mesenteric small arteries was of the alpha1A subtype. Sertindole inhibited the phenylephrine response of mesenteric small arteries (pA2 9.0), but had little effect on the phenylephrine response of aorta (which lacks alpha1A-adrenoceptors). The specific action of sertindole on alpha1A-adrenoceptors was supported by experiments with membranes of HEK293 (human embryonic kidney) cells transfected with the alpha1A-, alpha1B- and alpha1D-adrenoceptors. Here, with concurrent incubation, sertindole showed selective competitive inhibition of BE2254 (2-beta(4-hydroxyphenyl)-ethylaminomethyl)-tetralone) binding to alpha1A-adrenoceptors (Ki 8.9), compared to alpha1B-adrenoceptors (Ki 7.1) and alpha1D-adrenoceptors (Ki 6.8). Despite the apparent competitive action sertindole, it was not possible to wash out its antagonist effect within 6 h in the functional phenylephrine concentration-response experiments. Furthermore, in the membranes of HEK293 cells transfected with the alpha1A-adrenoceptors, binding of [125I]BE2254 was reduced by 45% following preincubation with sertindole (1 nM). We conclude that the alpha-adrenoceptors of rat mesenteric small arteries are of the alpha1A-type, and that sertindole is a specific pseudo-irreversible competitive antagonist of this adrenoceptor subtype.

Adrenergic alpha-Antagonists↗
PubMed1997

Interactions between neuropeptide Y and the adenylate cyclase pathway in rat mesenteric small arteries: role of membrane potential.

1. Simultaneous measurements of membrane potential and tension were performed to investigate the intracellular mechanisms of neuropeptide Y (NPY) in rat mesenteric small arteries. 2. NPY (0.1 microM) depolarized arterial smooth muscle cells from -55 to -47 mV and increased wall tension by 0.22 N m-1, representing 11% of the contraction elicited by a high-potassium solution. Isoprenaline (1 microM) and acetylcholine (1 microM) evoked hyperpolarizations of 11 and 17 mV, respectively. NPY inhibited the isoprenaline-induced effects on membrane potential without affecting those of acetylcholine. 3. Forskolin evoked sustained concentration-dependent hyperpolarizations of small mesenteric arteries. NPY (0.1 microM) inhibited the responses to 1 microM forskolin, but did not alter the stable hyperpolarization elicited by the specific activator of protein kinase A (PKA) SP-5,6-DCl-cBIMPS (0.1 mM). Forskolin increased the cyclic AMP (cAMP) content of the arteries 21-fold, and NPY inhibited the forskolin-evoked increase in cAMP levels by 91%. 4. The hyperpolarization produced by 1 microM forskolin was not affected by either charybdotoxin (0.1 microM) or 4-aminopyridine (0.5 mM), but glibenclamide (5 microM) inhibited the hyperpolarization by 70%. Glibenclamide also inhibited the hyperpolarization evoked by SP-5,6-DCl-cBIMPS by 59%. 5. Neither depolarization nor contraction caused by NPY were significantly affected by either glibenclamide (5 microM) or nifedipine (1 microM), but they were reduced by gadolinium (10 microM). However, the blocking effect of NPY on forskolin-elicited hyperpolarization was not affected by gadolinium. 6. Charybdotoxin (0.1 microM) and 4-aminopyridine (0.5 mM) strongly enhanced the depolarization and contraction caused by NPY (0.1 microM), and nifedipine (1 microM) prevented the enhanced responses to NPY in the presence of charybdotoxin. 7. These findings suggest that NPY acts through at least two different intracellular mechanisms in mesenteric small arteries: a depolarization of arterial smooth muscle which is probably due to activation of non-selective cation channels, and a marked inhibition of adenylate cyclase activity, which in turn inhibits the hyperpolarization produced by cAMP accumulation in these arteries.

4-Aminopyridine↗
PubMed1997

Intestinal blood flow is controlled by both feed arteries and microcirculatory resistance vessels in freely moving rats.

1. In freely moving rats, intestinal blood flow, aortic blood pressure and blood pressure at the base of mesenteric arcades were measured simultaneously so as to determine the role of feed arteries and of the microcirculation in the control of intestinal vascular resistance. Segmental resistances of feed arteries (Rfeed) and of microcirculatory vessels (Rmicro) were calculated. 2. At rest, Rfeed and Rmicro were 32 and 68%, respectively, of the total intestinal vascular resistance. 3. Injection of noradrenaline (2 micrograms i.v,) increased Rfeed by 151% and Rmicro by 243%. Angiotensin II (400 ng i.v.) did not increase Rfeed significantly, but increased Rmicro by 239%. Conversely, serotonin (15 micrograms i.v.) increased Rfeed by 414% but did not affect Rmicro significantly. 4. Spontaneous physical activity increased Rfeed by 29% and Rmicro by 39%, while sudden environmental stress increased Rfeed by 116% and Rmicro by 129%. Infused noradrenaline (1 microgram min-1 i.v.) or adrenaline (0.8 microgram min-1 i.v.) reduced intestinal flow by 21 and 16% respectively, while noradrenaline, but not adrenaline, increased intestinal resistances. 5. alpha 1-Blockade with prazosin (0.1 mg i.v.) reduced Rfeed and Rmicro by 43 and 16%, respectively. Thereafter, environmental stress decreased Rfeed by 24% while Rmicro was unaffected. Intravenous noradrenaline and adrenaline responses were attenuated. 6. We conclude that in freely moving rats, mesenteric feed arteries, as well as microcirculatory vessels, are true resistance vessels, and that both participate in the control of intestinal blood flow.

Animals↗
PubMed1997

KCa-channel blockade prevents sustained pressure-induced depolarization in rat mesenteric small arteries.

In small blood vessels, elevation of transmural pressure induces myogenic constrictions and smooth muscle depolarization. The role of calcium-activated K+ channels (KCa channels) in these responses was examined in cannulated rat mesenteric small arteries. Inner and outer diameter were continuously monitored with a video technique. Smooth muscle membrane potential was recorded simultaneously using microelectrodes. To test for myogenic responsiveness, the transmural pressure was changed stepwise in the range between 10 and 120 mmHg. Pressure elevation induced moderate myogenic responses and significant depolarization, from -54.5 +/- 0.4 (SE) mV (n = 56) at 10 mmHg to -47.3 +/- 1.8 mV (n = 12) at 120 mmHg. Norepinephrine (NE, 0.67 and 10 microM) induced constriction and vasomotion, augmented myogenic responsiveness, and shifted the pressure-membrane potential relation to more depolarized values. Blockade of the Kca channels with charybdotoxin (ChTX) suppressed the responsiveness to pressure. In the absence of ChTX, with 0.67 microM NE, pressure elevation from 10 to 120 mmHg induced depolarization from -46.9 +/- 1.0 (n = 16) to -35.8 +/- 0.7 (n = 12) mV, whereas because of the myogenic response, the diameter increased only by 7%. In the presence of ChTX, with 0.3 microM NE, pressure changed the membrane potential from -41.0 +/- 1.1 (n = 12) to -37.8 +/- 0.7 mV (n = 4), which was not significant, and the diameter increased by 28%. These results demonstrate that blockade of KCa channels reduces responsiveness to pressure elevation. This suggests that pressure may induce depolarization and concomitant myogenic responsiveness by closure of KCa channels.

Animals↗
PubMed1997

Vasorelaxation in isolated bone arteries. Vasoactive intestinal peptide, substance P, calcitonin gene-related peptide, and bradykinin studied in pigs.

We assessed the effects of vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), substance P (SP), and bradykinin in arteries (diameter approximately 230 microns) isolated from cancellous bone from pigs. Arterial segments (2 mm long) were mounted on a myograph for measurement of isometric force development. After submaximal precontraction with norepinephrine, VIP (10(-10)-10(-7) M), CGRP (10(-11)-10(-7) M), SP (10(-6) M), and bradykinin (10(-11)-10(-6) M) were added. 44 arterial segments (23 pigs) were investigated. VIP-, CGRP-, and bradykinin induced a concentration-dependent vasorelaxation, while SP mediated a transient relaxation. After mechanical removal of the endothelium, the effects of SP and bradykinin were completely abolished, while the relaxation to CGRP was still pronounced. This indicates that the effects of SP and bradykinin are mediated by the endothelium, while CGRP mainly mediates relaxation by a direct effect on vascular smooth muscle cells. The relaxations to CGRP and bradykinin were still significant after inhibition of nitric oxide synthase with 10(-4) M N omega-nitro-L-arginine (L-NNA) and inhibition of prostaglandin synthesis with 10(-5) M indomethacin, indicating the existence of an alternative vasorelaxing pathway. Our findings support the theory of a vasoregulatory role of neuropeptides in bone.

Animals↗
PubMed1996

Corticotropin-releasing hormone (CRH) receptors in the mesenteric small arteries of rats resemble the (2)-subtype.

The potencies of the corticotropin-releasing hormone (CRH) agonistic peptides oCRH, h/rCRH, frog sauvagine, and carp urotensin I and of the antagonistic peptide alpha-helical CRH9-41 were compared in 3 different in vitro assays: (a) receptor binding to rat brain membranes; (b) release of ACTH/beta-endorphin from rat pituitary cells; and (c) relaxation of rat mesenteric small arteries. From their potency profiles, especially from the high potency of sauvagine relative to CRH in the relaxation assay, it is concluded that the receptors mediating the hypotensive action of systemic CRH in vascular smooth muscle are different from those in the pituitary and brain, and may be identical or very similar to the recently cloned new CRH receptor type 2.

Adrenocorticotropic Hormone↗