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Query: UMLS:C0038454 (stroke)
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Previous studies have shown that local selective in situ injury of pial arteriolar endothelium eliminates the dilations produced by acetylcholine or bradykinin. One means of producing such injury employs a helium-neon laser in the presence of intravascular Evans blue. Since the endothelium-dependent dilations produced by acetylcholine or bradykinin may be initiated by interaction with endothelial surface receptors, it is possible that the light simply inactivates or destroys these receptors. We used calcium ionophore A-23187, another dilating agent known from in vitro studies of large arteries to be endothelium-dependent, which moves calcium into endothelial cells rather than interacting with surface receptors. Our data in 10 mice show that before injury, 10(-5)M A-23187 dilated arterioles to 109 +/- 2% of control diameter. After selective endothelial injury by helium-neon laser, dilation was essentially abolished (101 +/- 1% of baseline diameter; p less than 0.01, Wilcoxon test). Undamaged sites along the arteriole still dilated to A-23187. Our data indicate that the laser must do more than inactivate surface receptors and are the first in vivo microvascular (vessels of less than 100 micron diameter) data showing endothelium dependence of the response to A-23187.
Stroke 1988 Nov
PMID:Endothelium dependence of dilation of pial arterioles in mouse brain by calcium ionophore. 314 11

1. The effects of sodium nitroprusside, acetylcholine and bradykinin on cardiac output and its distribution were studied in the anaesthetized, vagotomised rat preparation by use of 113Sn-labelled microspheres. 2. All three vasodilators lowered peripheral arterial blood pressure, but only bradykinin significantly reduced total peripheral resistance without reducing cardiac output. Bradykinin caused tachycardia, but this was offset by a reduction in stroke volume. These effects of bradykinin were not altered by indomethacin (4 mg kg-1). Acetylcholine and sodium nitroprusside both caused significant (P less than 0.05) reductions in stroke volume and cardiac output. 3. Bradykinin reduced vascular resistance in the liver, stomach, small intestine, large intestine, pancreas/mesentery, epididimides, skeletal muscle and fat. These responses were not affected by indomethacin, whereas, the reduction in vascular resistance in the brain induced by bradykinin was abolished by indomethacin. 4. Acetylcholine caused a reduction in renal vascular resistance, where bradykinin had no effect. However, acetylcholine did not cause any haemodynamic changes in the bradykinin-sensitive intestinal vasculature. 5. Acetylcholine caused vasoconstriction in the coronary and epididymal vasculature. Bradykinin in the presence of indomethacin induced vasoconstriction in the skin. 6. In conclusion, the data show that, with the possible exception of the brain and the skin, the vasodilator actions of bradykinin can adequately be transduced (presumably by endothelium-derived relaxing factor, EDRF) in the absence of prostacyclin synthesis. Additionally, these results indicate that the vasculature of the stomach, pancreas/mesentery, epididimides and skeletal muscle are equally sensitive to both acetylcholine and bradykinin, whereas the kidneys showed selectivity towards acetylcholine and the intestines towards bradykinin. These results may indicate differential receptor populations.
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PMID:The effects of endothelium-dependent vasodilators on cardiac output and their distribution in the anaesthetized rat: a comparison with sodium nitroprusside. 326 37

The changes in pial arterioles of 7 cats were examined by electron microscopy after injury that eliminates endothelium-dependent relaxation to acetylcholine or bradykinin. The injury was produced by exposing the vessels to mercury light in situ in the presence of intravascular sodium fluorescein dye. Previous studies showed that, at the time of initial injury and loss of endothelium-dependent responses, the endothelial cells displayed minimal ultrastructural evidence of injury. Because these changes might indicate the beginning of a sequence of irreversible alterations representing or leading to cell death, the present study was carried out 31/2-4 hours later, when ultrastructural evidence of progressive cell degeneration should readily be recognized. No such changes were observed. Instead, most vessels showed only the minimal alterations observed initially (endothelial vacuolation, blebs, and lucencies). Four of 19 vessels were completely normal. The findings fail to support the hypothesis that irreversible cell damage or death caused by the light + dye injury has caused the associated loss of endothelium-dependent relaxation. Rather, the findings support the concept that much lesser degrees of trauma are sufficient to impair the dilating responses of cerebral microvessels. This greatly expands the potential spectrum of pathologic states that might result in loss of endothelium-dependent relaxation.
Stroke
PMID:Ultrastructural studies of pial vascular endothelium following damage resulting in loss of endothelium-dependent relaxation. 362 54

We have previously shown that topical brain application of kallikrein, an enzyme which converts kininogen to bradykinin, induces rabbit pial arteriole dilation. The purpose of the present investigation was to utilize a newly developed competitive kinin receptor antagonist to test the hypothesis that kallikrein-induced dilation was due to the conversion of brain kininogen to vasoactive kinins. As in our previous study, we measured rabbit pial arteriole diameter with a microscope using the closed cranial window technique. The kinin antagonist (6 microM) reduced the dose-dependent dilation produced by bradykinin and blocked the dilation induced by kallikrein. In addition, the kinin antagonist was specific since it did not alter the cerebral arteriole dilation produced by adenosine, acetylcholine, or vasoactive intestinal polypeptide. These experiments provide further evidence for a possible role of the endogenous brain kallikrein-kinin system in the modulation of the cerebral circulation and provide the necessary pharmacologic foundation for future use of this antagonist in testing the role of kinins in the normal or altered cerebral circulation.
Stroke
PMID:Inhibition of bradykinin- and kallikrein-induced cerebral arteriolar dilation by a specific bradykinin antagonist. 364 92

The endothelium of mouse pial arterioles was injured in situ with a light/dye technique. The response of the arterioles to acetylcholine or to bradykinin was compared before and after the injury. All vessels failed to dilate after injury. In fact the predominant response now became constriction. The injured vessels were still capable of dilating to papaverine. Uninjured vessels continued to dilate to acetylcholine or bradykinin. The data show that relaxation of pial arterioles to acetylcholine or bradykinin is dependent on a normal endothelium. This is in keeping with demonstrations by others that an endothelial dependent relaxing factor or factors is(are) the mediator of the dilation to either acetylcholine or bradykinin. The present demonstration of such endothelial dependence is important because in contrast with the bulk of the literature it deals with in vivo, rather than in vitro data, and with microcirculation rather than large vessels. It is also important because it concerns brain circulation. The data suggests that endothelial injury, known to occur in a wide variety of pathologic states, could enhance vasospastic potential by eliminating dilating influences and/or converting them to constricting forces.
Stroke
PMID:Endothelial dependent relaxation demonstrated in vivo in cerebral arterioles. 371 49

Intraocular pressure (IOP) and arterial blood pressure (BP) were recorded manometrically in normotensive Wistar Kyoto rats (NR) and stroke-prone spontaneously hypertensive rats (SHR). IOP was significantly lower in SHR (7.8 +/- 0.2 mm Hg) compared to NR (15.9 +/- 0.4 mm Hg). In NR, administration of vasoactive substances (kallikrein, bradykinin, angiotensin I and II) or bloodletting resulted in significant IOP reactions, which ran nearly parallel to the acute BP changes. In SHR, however, IOP showed little reaction after comparable changes in BP. The cause of the low IOP in SHR is unknown. It is assumed that in SHR rarefaction of arterioles and capillaries and a decrease in the compliance of eye vessels, in combination with an increase in the distensibility of the bulbus at this low IOP level, contribute to the lack of IOP response after administration of vasoactive drugs.
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PMID:Intraocular pressure and systemic blood pressure after administration of vasoactive substances in hypertensive and normal rats. 384 58

1. Long-lasting haemorrhagic hypotension (4.5 hr at 35 mmHg) leading to irreversible haemorrhagic shock, has been studied in normal dogs, in dogs treated with a bradykinin potentiating nonapeptide (BPP(9a)), which blocks the conversion of angiotensin I to angiotensin II, and in dogs with experimental chronic diabetes insipidus (DI dogs). BPP(9a) was given by I.V. injection before the start of bleeding (BPP pre-treated group), 45 min after blood pressure had reached 35 mmHg (BPP early treated group) or 2 hr after blood pressure had reached 35 mmHg (BPP late-treated group). After retransfusion of blood all dogs were allowed to recover and observed for a further period of 3 days.2. Untreated control dogs developed haemorrhagic shock with tachycardia, low cardiac output, low total peripheral conductance and low stroke volume. All died within 24 hr of retransfusion, with pathological lesions typical of irreversible haemorrhagic shock.3. BPP pre-treated dogs developed haemorrhagic shock with bradycardia (during early shock), high cardiac output, high peripheral vascular conductance and high stroke volume when compared with the untreated controls. All pre-treated animals survived the 3 day observation period. They were then killed and on post-mortem showed no signs of irreversible haemorrhagic shock.4. BPP early-treated animals behaved like controls before BPP, but like pre-treated animals after the drug. Only one out of eight died within the 3 day observation period.5. BPP late-treated dogs behaved like controls before BPP. They responded to the drug with a rise in cardiac output, peripheral vascular conductance and stroke volume, and with a fall in heart rate. These responses were, however, short-lived. Four out of these eight animals died within the 3 day observation period, with lesions of irreversible haemorrhagic shock.6. DI dogs developed haemorrhagic shock with tachycardia (like controls), but with high cardiac output and peripheral vascular conductance (like BPP pre-treated dogs). The stroke volume of DI dogs was intermediate between those of controls and pre-treated groups. All six dogs survived the 3 day observation period.7. BPP(9a) had no measurable effect on the course of endotoxic shock.8. It is suggested that the normally severe vasoconstriction of the mesenteric vascular bed, which is thought to be responsible for irreversible haemorrhagic shock, is absent or attenuated in the absence of vasopressin or angiotensin. The consequences of this on the development of irreversibility are discussed.
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PMID:On the role of vasopressin and angiotensin in the development of irreversible haemorrhagic shock. 437 70

The converting enzyme inhibitors (CEI) SA446 and Captopril (CAP) were given orally at a dose of 50 mg/kg per day to adult stroke-prone spontaneously hypertensive rats (SHRSP) over a period of four weeks. Both CEI lowered arterial blood pressure (BP) to a similar extent. CAP was more inhibitory on the plasma renin-angiotensin system (RAS) than SA446. Both CEI lowered urinary aldosterone excretion but had little (SA446) or no (CAP) natriuretic effect. CAP reduced the pressor responses to intravenous (i.v.) angiotensin I (ANG I) more (52%) than SA446 (18%) and potentiated the depressor responses to i.v. bradykinin more (fortyfold) than SA446 (tenfold). In contrast, SA446 treatment reduced the pressor responses to intracerebroventricular (i.c.v.) ANG I by 21% and led to a rise in the hypothalamic renin concentration. Oral CAP treatment for four weeks did not produce these signs of a brain converting enzyme inhibition. It is concluded that SA446 is equally as antihypertensive as CAP in SHRSP. SA446 appears to penetrate more readily into the brain and to exert its action partly through inhibition of the brain RAS which is known to be stimulated in SHRSP.
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PMID:SA446, a new orally active converting enzyme inhibitor: antihypertensive action and comparison with captopril in stroke-prone spontaneously hypersensitive rats. 628 Oct 36

Evidence has accumulated that systemic administration of converting enzyme inhibitors (CEI) such as captopril, MK 421 or SA 446 not only produces an inhibition of the plasma renin angiotensin system (RAS), but also of the RAS in various target organs which are relevant for blood pressure (BP) regulation. A potential target organ is the brain, where a local CE inhibition could contribute to the BP lowering action of CEI. CE in the brain can be inhibited by intracerebroventricular (i.c.v.) injection of CEI as evidenced by an inhibition of the pressor and drinking responses to i.c.v. angiotensin I (ANG I) or renin and by potentiation of the pressor responses to i.c.v. bradykinin. Site of the inhibition is not only the cerebrospinal fluid but also periventricular brain tissue such as the hypothalamus. I.c.v. injection of captopril at doses which inhibit brain CE but do not leak into the peripheral blood were shown to lower BP in conscious stroke-prone spontaneously hypertensive rats (SHRSP), but not in normotensive Wistar Kyoto (WKY) controls. Acute peripheral administration of CEI can produce an inhibition of brain CE. This was shown by an attenuation of the drinking responses to i.c.v. ANG I and renin and by direct measurements of CE activity in brain tissue. Chronic oral treatment with CEI produces changes of brain RAS parameters which suggest an inhibition of ANG II formation in the brain.
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PMID:Central effects of converting enzyme inhibitors. 631 70

In congestive heart failure, acute administration of the converting enzyme inhibitor captopril leads to a decrease in arterial pressure, systemic vascular resistance, left ventricular filling pressure, and the end-diastolic volumes of both ventricles, as well as to an increase in cardiac index, stroke volume index, right and left ventricular ejection fractions. The mechanism of action appears not only attributable to a decrease in angiotensin II but, possibly, may also be accounted for by central and peripheral sympathicolytic effects diminished degradation of bradykinin and an increase in synthesis of vasoactive prostaglandins. During continued treatment with captopril over three months a further decrease in left ventricular filling pressure and an increase in cardiac output can be observed. While the exercise tolerance is not meaningfully affected at the beginning of treatment, a significant increase may be seen during long-term use. After three months of therapy an increase in the acutely-lowered mean arterial pressure can be noted. As compared with placebo-treated control patients, a more favorable clinical course was seen in those receiving captopril. There does not appear to be a relationship, however, between the initial hemodynamic effects and the clinical response. On combined use of captopril and hydralazine, as compared to treatment with captopril only, there is a greater increase in cardiac output and stroke volume without marked additional fall in pulmonary capillary pressure and a further decrease in systemic arterial pressure, incurred without symptomatic hypotension in the majority of patients. The adverse effect is hypotension which precludes long-term treatment in about 10% of patients. Proteinuria, neutropenia and renal insufficiency occur only rarely, usually in patients who are maintained on daily dosages above 300 mg or who have preexisting renal disease. Skin rashes and taste alterations are more common but are frequently well-tolerated and, generally, do not warrant discontinuation of treatment.
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PMID:Converting-enzyme inhibitor therapy for chronic heart failure. 634 10


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