ISSN:1018-1172    

DOI:10.1159/000158968

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

This study in isolated rabbit superior artery (RMA) investigated the interactions between glyburide, a known blocker of vascular ATP-sensitive K+ channels (Katp), and several chemically diverse potassium channel openers (PCOs): minoxidil sulfate (MNXS; 5 µM), pinacidil (1 µM), cromakalim (0.5 µM)and RP-49356 (1 µM;a PCO from Rhône Poulenc). Relaxation time courses for these PCOs were obtained in norepinephrine (NE; 5 µM)-precontracted RMA, and the concentrations of PCOs found to be equipotent to each other in terms of the degree of maximum relaxation (about 80%) and the time course of relaxation (within 15 min) were chosen for further study. This was taken as a functional indicator of a similar degree as well as similar kinetics of K+ channel opening by these PCOs. Pretreatment with glyburide (10-500 nM)produced a dose-dependent inhibition of the PCO relaxation time course. The glyburide IC50S against pinacidil, MNXS and RP-49356 were statistically similar and ranged from 72-79 nM. The glyburide IC50 against cromakalim was a modest 2-fold higher, at 148 nM. In contrast, pretreatment with charybdotoxin (200 nM) produced no significant inhibition of the maximum relaxation produced by these PCOs. Furthermore, glipizide, a sulfonylurea that is 10- to 25-fold less potent than glyburide for insulin secretion, was found to be 20- to 30-fold less potent than glyburide as a vascular KATP antagonist. These data suggest a mechanistic model in which these structurally diverse PCOs share a common critical step in the sequence of events leading to the KATP opening, and that glyburide interferes with this common critical step to produce a similar type of blockade against all four PCOs. Interaction studies with glyburide and pinacidil demonstrated 15 min to be the optimal pretreatment time for glyburide to produce maximal inhibition. Glyburide also reversed existing pinacidil relaxation regardless of the degree of pre-existing relaxation. These data suggest that glyburide is able to produce its blockade regardless of the state of K+ channel activation. Studies on the effect of pH (6.4 vs.7.3) showed that at acidic pH, pinacidil became less effective and the effectiveness of glyburide was significantly enhanced, whereas the actions of D600 remained unchanged. These data suggest the effects of both openers and blockers of the KATP are strongly pH depe

ISSN:1018-1172    

DOI:10.1159/000158969

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Products of inositol lipid hydrolysis and levels of c-myc, c-fos and H-ras mRNAs were measured in rat left ventricle and vascular tissues 72 h and 9 days after the induction of aortic coarctation in order to examine inositol phosphate and proto-oncogene signals during the development of pressure-related cardiac and vascular structural changes. There was a significant increase in left ventricular and proximal aortic mass at both time points but no change in mesenteric resistance artery morphology in rats with coarctation. At 72 h there was a significant increase in c-myc, c-fos and H-ras mRNAs in the left ventricle of rats with coarctation, and this was accompanied by increased levels of inositol (1,4,5)-trisphosphate. Similar results were obtained in the proximal but not the distal aorta. In resistance arteries inositol phosphate production and proto-oncogene mRNA expression were unchanged. The results indicate that at 72 h aortic coarctation induced structural thickening in the left ventricle and proximal aorta and was associated with increased inositol phosphate production and stimulation of specific proto-oncogene mRNAs. By 9 days following surgery much of the structural change in these tissues was completed, and these raised cellular signals were no longer observed. The results suggest that both increased inositol lipid hydrolysis and a rise in the expression of these proto-oncogenes are important processes in the development of vascular hypertrophy seen in this model of hypertension.

ISSN:1018-1172    

DOI:10.1159/000158970

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Acute converting enzyme inhibition relaxes arterial smooth muscle and increases arterial complicance in several models of animal and human hypertension. However, it is unknown whether the doses needed for the relaxation of large arteries are similar to those inducing arteriolar relaxation and blood pressure (BP) decrease. To answer this question, we used a previously described model of the in situ carotid artery to determine the pressure-volume relationship over a range of transmural pressures from 25 to 200 mm Hg in normotensive rats (WKY) and spontaneously hypertensive rats (SHR). The pressure-volume relation was determined after an acute single oral administration of either a placebo or the converting enzyme inhibitor quinapril given at two different doses (0.3 or 3 mg/kg). At the end of each experiment, the total relaxation of arterial smooth muscle was achieved after a local administration of potassium cyanide (KCN). In the WKY placebo group, from 25 to 100-125 mm Hg transmural pressure, carotid compliance increased and reached a maximum value at 100-125 mm Hg (i.e. close to the operating range of systemic mean BP of the animals), and decreased thereafter. In the SHR placebo group, carotid compliance was significantly lower than in the WKY placebo group for transmural pressure up to 125 mm Hg, and thereafter was equal or even higher; the maximum value of compliance was reached at 125-150 mm Hg transmural pressure, i.e. substantially less than the operating range of the systemic mean BP of the SHR placebo (180 mm Hg). For transmural pressure steps up to 100 mm Hg in WKY and 125 mm Hg in SHR, both doses of quinapril produced an identical relaxation of arterial smooth muscle which approximated 80-90% of the maximum relaxation produced by KCN. For higher transmural pressure levels, neither quinapril nor KCN were able to change compliance values. Although the two doses caused the same degree of arterial smooth muscle relaxation in SHR, operating carotid compliance was substantially increased only with the higher dose, i.e. the dose which significantly shifted the operating systemic BP towards normotensive levels. The study provides evidence that, although low, nonhypertensive doses of quinapril are able to induce maximal relaxation of the carotid artery, operating compliance is substantially increased only if blood pressure is significantly decreased.

ISSN:1018-1172    

DOI:10.1159/000158971

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

The effects of the close arterial infusion of histamine upon the microcirculation of facial and nasal tissues were examined in dogs. Blood flow through arteriovenous anastomoses (AVA flow), capillaries (CAP flow) and collaterals (COL flow) were determined by electromagnetic flowmetry and the tracer-microsphere technique following an infusion of histamine at doses ranging from 0.5 to 50 nmol/min. Low doses of histamine (0.5-5.0 nmol/min) resulted in an increase in blood flow through the ipsilateral internal maxillary artery (IMA), which could be mainly attributed to a significant elevation of the CAP flow. A concomitant marked increase in AVA flow was observed only after the administration of higher doses (20-50 nmol/min). Significant changes in systemic blood pressure, heart rate and cardiac output occurred only after the infusion of histamine at doses of 20 and 50 nmol/min. Significant increases in the CAP flow of tissues with relatively low perfusion were observed after the infusion of histamine at lower doses. The CAP flow of structures which play an essential role in conditioning the inspired air and exhibit high perfusion rates under control conditions exhibited significant increases only after the administration of higher doses. The present experiments provide direct evidence for a dose-dependent vasodilatory effect of histamine on different microcirculatory compartments of cutaneous and mucosal vascular beds supplied by the IMA in the dog. The results indicate that at low blood histamine levels, an increase in CAP flow predominates, and at higher doses, both elevated CAP flow and elevated AVA flow contribute to the vasodilatory response to histamine. The investigation suggests that histamine is not involved directly in a selective dilation of the AVA of the facial and nasal vasculature which is characteristic for cold-induced vasodilation.

ISSN:1018-1172    

DOI:10.1159/000158972

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

The concentration dependence of ATP-induced contractions in isolated resistance arteries was estimated using photolysis of caged ATP. Rat mesenteric vessels were isolated and mounted for force registration in a small chamber allowing illumination from a xenon-flash lamp. Photolysis of 100 µM caged ATP, which released about 20 µM ATP within a few milliseconds in the vessel, induced a transient contraction with an amplitude approximately 40-50% of the response induced by 10 µM noradrenahne. The responses could neither be induced by the light flash as such nor by caged ATP alone nor by photolysis of caged phosphate. The amplitude of the contractions was dependent on the concentration of caged ATP, and the effective concentration for ATP was estimated to be in the range of 1-10 µM. In contrast, when ATP was introduced by diffusion, about a 100-fold higher concentration was required. Thus photolytic release of ATP minimizes metabolism before its action on receptors and reveals action of ATP in a concentration range consistent with a role of ATP as a transmitter in nervous regulation of the tone of resistance vess

ISSN:1018-1172    

DOI:10.1159/000158973

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Experiments were designed to determine the viability of endothelial cells and their responses to products released by aggregating platelets following single flush perfusion of the coronary arteries with cardioplegic solutions used for cardiac transplantation. Porcine coronary arteries were perfused with crystalloid (Plegisof®) or blood cardioplegic solutions; nonperfused hearts placed in 0.9% saline were used as controls. Immediately following perfusion and after 5-hour storage of the hearts in the same cardioplegic solution, rings were cut from the right coronary arteries and suspended in organ chambers for the measurement of isometric force. In some rings the endothelium was removed deliberately. The left circumflex coronary arteries were flushed with collagenase and the harvested endothelial cells were plated for cell culture. Left anterior descending coronary arteries were perfusion fixed with glutaraldehyde for scanning electron microscopy. In the organ chamber experiments, aggregating platelets and adenosine diphosphate caused relaxations in rings with endothelium. These relaxations were reduced immediately following crystalloid cardioplegia and were restored following 5-hour storage. Serotonin caused contractions in all rings. Rings without endothelium were more sensitive than rings with endothelium to the amine; this difference was augmented following 5-hour storage of the heart. Significantly fewer foci of endothelial cells grew in culture following 5-hour storage of the hearts in crystalloid cardioplegic solution compared to control (p < 0.05). There were no anatomical differences identified among groups by scanning electron microscopy. These results suggest that crystalloid cardioplegia alters the responses of coronary arteries to substances released by aggregating platelets and reduces the ability of endothelial cells to replicate. Such changes may contribute to altered vascular resistance following reperfusion of transplanted hearts and potentially to later structural changes in the coronary arteries

ISSN:1018-1172    

DOI:10.1159/000158974

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

The contribution of cytochrome P-450 metabolites of arachidonic acid in elevating vascular tone in the kidneys of adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats was examined using a juxtamedullary nephron microvascular preparation perfused in vitro with a physiological salt solution containing 5% albumin. At 80 mm Hg, the basal internal diameters of arcuate and interlobular arteries and proximal and distal afferent arterioles of the SHR averaged 341 ± 15.81 ± 5.24 ± 0.5 and 19 ± 0.3 µm, respectively. These diameters were 5-29% smaller (p < 0.05) than those measured in corresponding vessels in WKY rats. Addition of the P-450 inhibitors, ketoconazole (100 µM) or 17-octadecynoic acid (17-ODYA, 20 µM), to the perfusate and bath increased the diameters of the preglomerular vasculature of the SHR by 6-29%, but by only 3-13% in WKY rats and reduced significantly the differences in pressure-diameter relations between the two groups. The rate of formation of 20-hydroxyeicosatetraenoic acid (20-HETE) by renal cortical microsomes was similar in SHR and WKY rats. However, the production of epoxyeicosatrienoic acids (EETs) by cortical microsomes was 87% lower and dihydroxyeicosatrienoic acids (DHETs) 70% higher in the SHR than WKY rats. Ketoconazole (100 µM) reduced the formation of 20-HETE by 80%, and EETs and DHETs production by more than 98% in SHR and WKY rats. 17-ODYA (20 µM) reduced the formation of 20-HETE, EETs and DHETs by more than 98% in both groups. These results suggest that cytochrome P-450 metabolites of arachidonic acid contribute to the elevated renal vascular tone in adult SHR. This may be due to an enhanced vascular responsiveness to vasoconstrictor P-450 metabolites in SHR or an elevated local production of vasoconstrictor eicosanoids in the renal vasculature of SHR rather than in renal cortica

ISSN:1018-1172    

DOI:10.1159/000158975

出版商:S. Karger AG    

年代:1993

数据来源: Karger