Large Resistance Vessels Research Articles

Cerebral Hemodynamics at Altitude Using Diffuse Correlation Spectroscopy and Transcranial Doppler

Studies of cerebral hemodynamics at altitude have been hampered by the lack of a portable, real-time, noninvasive monitor of intracranial blood flow. Most studies to date have relied on cerebral blood flow velocities (CBF-V) measured by transcranial Doppler, as a surrogate for cerebral blood flow. The use of this measurement to accurately reflect cerebral blood flow is predicated on the recently disproven notion that middle cerebral artery (MCA) diameter remains constant with changes in altitude. We used a novel technology, diffuse-correlation spectroscopy (DCS), which is not dependent on MCA diameter changes and has been previously validated against Xenon CT, to assess the cerebrovascular response to hyperventilation during acclimatization and compared this to traditional transcranial Doppler (TCD). Eleven subjects from the Xtreme Alps medical research expedition were studied at sea level and 2 and 7 days after ascent to 4559 m before and after hyperventilation to reduce end-tidal CO2 by 50%. Transcranial Doppler was used to measure peak systolic velocity (PSV) in the MCA. Diffuse-correlation spectroscopy was used to measure changes in relative CBF (rCBF). Diffuse-correlation spectroscopy revealed a decrease in rCBF of 19.6% ± 18.9% following hyperventilation at sea level, 28.9% ± 13.6% following hyperventilation after 2 days at altitude and 33.0% ± 29.0% following 7 days at altitude. PSV as measured by TCD demonstrated a decrease of 32% ± 12.7%, 28.9% ± 32.3% and –29.4% ± 7.6% respectively. Diffuse-correlation spectroscopy provides a safe, portable, and noninvasive measure of cerebral blood flow at altitude, reflecting cerebral perfusion at the parenchymal level. By contrast TCD provides a measure of velocity of flow through large resistance vessels, with no direct information about end-organ perfusion. While DCS correlates poorly with TCD, further studies are necessary to elucidate which test is a more accurate reflection of cerebral blood flow.

A new approach to assessing the structural total peripheral resistance amplifier in renal (Page) hypertension in conscious rabbits

Structural changes in the large resistance vessels in hypertension amplify resistance responses in vitro, but their role in vivo has been controversial. To resolve this matter, we re-examined earlier data in Page hypertension. Total peripheral resistance (TPR) and total peripheral conductance (TPC) responsiveness were compared in hypertensive and normotensive rabbits, 5 weeks after bilateral renal cellophane wrapping or sham operation. The rabbits were studied with effectors intact; during ganglionic blockade; during neurohumoral blockade (NHB). For each condition extended scaled dose (ScD)-TPC and TPR curves were derived from individual dose-response curves to two constrictors and two dilators. The ScD-response curves had two major nonlinearities: at high constrictor doses, due to functional (reversible) rarefaction (reduction in microcirculatory density); at high dilator doses, due to impaired autoregulation. The amplifier is best assessed during NHB over the intervening ScD range, by determining the TPR and TPC ratios from hypertensive and normotensive rabbits. Over this range the hypertensive: normotensive (H: N) ratio averaged 1.88 +/- 0.03 TPR units and was the same for constrictor and dilator responses, suggesting a structural basis; the resting H: N TPR ratio was also closely similar. At higher ScDs functional rarefaction developed initially at a greater rate in normotensive than in hypertensive rabbits. We conjecture that this was because some permanent rarefaction had already developed in hypertensive rabbits since the onset of hypertension. The systemic structural TPR amplifier is haemodynamically important in vivo and contributes to hypertension.

The phenotypic patterns of essential hypertension are the key to identifying “high blood pressure” genes.

The genes that cause or increase susceptibility to essential hypertension (EH) and related animal models remain unknown. Their identification is unlikely to be realized with current genetic approaches, because of ambiguities in the genotype-phenotype relationships in these polygenic disorders. In turn, the phenotype is not just an aggregate of traits, but needs to be related to specific components of the circulatory control system at different stages of EH. Hence, clues about important genes must come through the phenotype, reversing the order of current approaches. A recent systems analysis has highlighted major differences in circulatory control in the two main syndromes of EH: (1) stress-and-salt-related EH (SSR-EH)--a constrictor hypertension with low blood volume; (2) hypertensive obesity--SSR-EH plus obesity. Each is initiated through sensitization of central synapses linking the cerebral cortex to the hypothalamic defense area. Several mechanisms are probably involved, including cerebellar effects on baroreflexes. The result is a sustained increase in sympathetic neural activity at stimulus levels that have no effect in normal subjects. Subsequent progression of EH is largely through interactions with non-neural mechanisms, including changes in concentration of vascular autacoids (e.g., nitric oxide) and the amplifying effect of structural changes in large resistance vessels. The rising vasoconstriction increases heterogeneity of blood flow, causing rarefaction (decreased microvascular density) and deterioration of vital organs. SSR-EH also increases food intake in response to stress, but only 40% of these individuals develop hypertensive obesity. Their brain ignores the adiposity signals that normally reduce eating. Hyperinsulinemia masks the sympathetic vasoconstriction through its dilator action, raises blood volume, whilst renal nephropathy and other diabetic complications are common. In each syndrome the neural and non-neural determinants of hypertension provide targets for identifying high BP genes. Reading the genome from the phenotype will require new approaches, such as those used in developmental genetics. In addition, transgenic technology may help verify hypotheses and examine whether an observed effect is through single or multiple mechanisms. To obtain answers will require substantial collaborative efforts between physiologists and geneticists.

Herz und Gefäße

Aging is one of the most important cardiovascular risk factors. Age-related morphologic changes in large resistance vessels include an intima-media-thickening and increased deposition of matrix substance, ultimately leading to a reduced compliance and an increased stiffness of the vessels. Aging of the heart is mainly characterized by an increase of the left ventricular mass in relation to the chamber volume and a decrease of diastolic function. There is some controversy in regard to the question if these changes in the vessel wall are the consequence of aging or if a decrease in physical activity is a major contributor of this process. With age the cardiovascular profile is changing. Whereas smoking is less prominent, arterial hypertension and diabetes mellitus are more often encountered. Primary and secondary prevention through cardiovascular risk factor management is also very important in the aging population due to the increased risk of acute vascular complications with age. Preventive measures have to include life style factor interventions as well as optimized drug therapy. There is no scientific evidence that vascular aging can be prevented by administration of supplements such as antioxidant vitamins. Aspirin is effective for cardiovascular prevention up to a higher age. Betablockers and ACE-inhibitors are generally underused in older patients after myocardial infarctions. Statins are effective in reducing cardiovascular complications up to an age of 80 years. Myocardial infarction in elderly patients is often characterized by atypical symptoms and may be even silent. Interventional therapy in elderly patients is as successful as in younger patients but has an increased complication rate. Ambulatory cardiac rehabilitation in elderly patients leads to significant improvements of physical capacity, well-being and quality of life and may help to prevent social isolation.

Blood flow in psoriatic plaques before and after selective treatment of the superficial capillaries

Blood flow is substantially raised in psoriatic plaques. In addition, mechanisms of vasoconstriction and vasodilatation (locally and neurally mediated), although intact, are altered in magnitude. The elevated blood flow is considered to be a result of abnormalities (increase in vessel number, width and length) in the superficial capillary loops rather than changes in the deeper feeding vessels (arterioles). To determine if selective thermolysis of psoriatic capillaries with a pulsed dye laser (PDL) leads to normalization of blood flow and also if the vasoconstrictor and vasodilator responses are returned to normal magnitude. Laser Doppler red cell flux was recorded from plaques on the forearm or elbow (untreated plaque site) and from clinically uninvolved skin at an equivalent site on the opposite limb. Plaques were treated on three occasions, at 2-weekly intervals, with a PDL. Laser Doppler red cell flux measurements were then repeated, 2 weeks after the final laser treatment was performed (treated plaque site). There was significant clinical improvement in plaques after treatment (P = 0.02), but complete clearance of lesions did not occur. Blood flow in plaques under basal conditions remained significantly elevated above blood flow in clinically uninvolved skin, despite laser treatment (P < 0.001). The physiological tests of resistance vessel function showed that the laser did not impair the ability of psoriatic resistance vessels to constrict and dilate. However, there was only partial resolution of the percentage responses to the provocation tests towards the values recorded in clinically uninvolved skin. The results indicate that it is unlikely that the reduced resistance of the expanded superficial capillary bed is solely responsible for the massively elevated blood flow in plaque skin. It is more likely that the vascular abnormalities in psoriasis also extend to involve the deeper, larger resistance vessels (arterioles).

How do blood vessels age? Mechanisms and clinical implications

Ageing is one of the most important cardiovascular risk factors. Vascular ageing is determined by genetic, mechanic and hemodynamic factors. The latter is strengthened by the fact that age-associated changes in capillaries and veins, vessels which are less prone to changes in pulsatility and blood pressure, are less pronounced or even absent. Age-related morphologic changes in large resistance vessels include an intima-media thickening, increased deposition of matrix substances, thus ultimately leading to a reduced compliance. Vascular ageing is mainly characterized by an impaired endothelium-dependent vasorelaxation. The expression of endothelial nitric oxide synthase (eNOS), producing vasodilatatory nitric oxide (NO), is markedly upregulated with increasing age. However, vasorelaxation is impaired, as the production of reactive oxygen species such as superoxide (O2-), concomitantly increases. NO and O2- react to form the powerful oxidant peroxynitrite (ONOO-). Peroxynitrite is known to initiate oxidative modification of proteins, including nitration of aromatic rings, thereby rendering functionally inactive certain regulatory proteins. Deposition of nitrated proteins is mainly found within endothelial mitochondria, suggesting that mitochondrial dysfunction plays a major role in the vascular ageing process. It yet remains to be shown whether oxidative stress, which is, according to the currently accepted "oxidative stress hypothesis", a key event of vascular ageing, can be pharmacologically prevented, e.g. by naturally occurring antioxidant vitamins. However, in a mammalian model of ageing, an unexpected accumulation of vitamin E was found to accumulate within the aortic wall. This may represent a self-regulatory adaptive mechanism to prevent age-associated oxidative stress. In contrast, ascorbic acid was found to decrease with increasing age. Eventually, it remains to be seen if vitamin C or other antioxidative substances may be useful therapies. Statins and ACE inhibitors are known to have effects on mechanisms interfering with the ageing process. Given the strong age-dependency of cardiovascular disease, the developments of therapies to delay vascular ageing might have enormous medical (and economic) consequences in the future.

Structural factors increase blood pressure through the interaction of resistance vessel geometry with neurohumoral and local factors: estimates in rabbits with renal cellophane-wrap hypertension with intact effectors and during neurohumoral blockade.

The structural changes in hypertension include narrowing of the lumen of the large resistance vessels and an increase in their wall thickness : lumen ratio. Their haemodynamic role has been controversial. To examine resting haemodynamics and the responses to graded drug-induced changes in tone in renal cellophane-wrap (wrap) and sham-operated (sham) rabbits, when their neurohumoral effectors were intact and during high-level blockade. Each rabbit was implanted with a flow probe for measuring cardiac output, had catheters inserted for drug infusions, and underwent mean arterial pressure (MAP) measurements. Resting values were determined and we infused graded doses of dilator and constrictor drugs: acetylcholine or adenosine; angiotensin II or methoxamine. The dilator and constrictor dose-response curves were combined into a single relationship for MAP, cardiac output, total peripheral conductance (TPC) and heart rate; total peripheral resistance (TPR) was estimated as 1/TPC. Throughout the range of vascular tone and with intact effector function, MAP was greater and TPC lower in wrap than in sham rabbits, and cardiac output was the same in both groups. The ratios of wrap : sham slopes of the log dose-response regression lines were 0.47 for TPC, 2.04 for TPR and 1.89 for MAP. Thus MAP and TPR responses were enhanced to the same degree in wrap rabbits. During neurohumoral block, baroreflex-mediated heart rate responses were abolished. In addition, resting vascular tone was lower than with intact effectors in both wrap and sham rabbits; however, the ratios of wrap : sham slopes for TPC and TPR were similar to those with intact effectors, whereas the ratio for the slope for MAP was slightly smaller, although still enhanced. In wrap hypertension, the enhanced MAP and TPR responses are in accord with an interaction between vascular geometry and the sum of altered neurohumoral + local activity, plus a rarefaction component.

Inhibition of the renin-angiotensin system, with particular reference to dual blockade treatment.

JRAAS 2001;2:146-52 Background The presence of diabetes profoundly increases the risk of developing cardiovascular disease, largely because of the adverse combination with hypertension. Hypertensive,diabetic patients carry a two-fold increase of developing cardiovascular complications compared with non-diabetics. Modulation of the renin-angiotensin system (RAS) has become essential in treating hypertension and delaying the onset of diabetic nephropathy. Since the 1980s, numerous studies have shown that the use of angiotensin-converting enzyme inhibitors (ACE-I) has beneficial effects when treating hypertension and renal disease in diabetes, as well as non-diabetic renal disease. Tight blood pressure (BP) control has become essential for this group of patients and the benefits are undisputed. The UKPDS study showed a 24% risk reduction among Type 2 diabetics in whom BP was reduced to below 150/85 mmHg over a study period of eight years. The HOT study showed significant risk reduction in cardiovascular events in diabetics in whom diastolic BP was reduced to approximately 80 mmHg (mean BP 144/81 mmHg). A remarkable proportion of this particular patient group was treated with an ACE-I. ACE inhibition alone is not always able to provide a satisfactory treatment strategy for the individual patient. Either insufficient BP control or continued microalbuminuria may prevail in spite of high doses of ACE-I; this has created interest in alternative ways of inhibiting the RAS. There are several reasons for optimising RAS blockade. During long-term ACE--I treatment, the phenomenon of ‘ACE-escape’ develops. It seems that plasma levels of angiotensin II (Ang II) and aldosterone may return to pre-treatment levels, which may induce incessant progression of nephropathy and chronic heart failure. In chronic heart failure patients, the angiotensin AT1-receptor blocker (ARB), valsartan, was added to the maximum recommended dose of ACE-I (40 mg of long-acting ACE-I) and significantly reduced the BP response to infused Ang II, even though the high-dose ACE-I had been given for over three months. This could be due to the fact that ACE-I do not completely block the conversion of angiotensin I (Ang I) to Ang II. Alternative pathways of converting Ang I to Ang II are of great influence, especially in the failing heart, kidneys and large resistance vessels. The chymase, cathepsin and serine protease–inhibitable conversion of Ang I to Ang II appear to be activated in disorders in which high levels of oxidative stress are present, such as vascular pro-inflammatory processes, atherogenesis and diabetes. In these circumstances, up to 60–70% of circulating Ang II may be produced by alternative pathways. Finally, tissue ACE activity, which is found in lung, blood vessels, myocardium and in the kidneys, has been proposed to mediate more long-term tissue effects, such as glomerular hypertrophy and left ventricular remodelling. This is of utmost importance, since tissue ACE activity is not always sufficiently blocked by regular doses of ACE-I, and also because the ‘ACE-escape’ mechanism returns plasma levels of Ang II to normal, so that tissue-ACE activity becomes uncontrolled at the level of the AT1 and AT2 receptors. 21

Large arterioles in the control of blood flow: role of endothelium-dependent dilation.

Although it is generally assumed that small arterioles form the major site of vascular resistance, microcirculatory studies revealed that 40-55% of the total network resistance can reside in large arterioles and small arteries. Thus, the mechanisms that control smooth muscle tone in these vessels have a major impact on the overall conductance of the vascular network. These control mechanisms are different from those in small arterioles: Aside from an apparently reduced sensitivity to metabolites, the large resistance vessels are normally too far away from the capillary areas which they feed to be reached by diffusing metabolites from dependent cells within a reasonable period of time. Rather, recent intravital microscopic studies suggest that large resistance vessels are under tight control of endothelial factors such as nitric oxide and endothelium-derived hyperpolarising factor (EDHF). Nitric oxide opposes myogenic constrictions of large arterioles that potentially would impair tissue perfusion and oxygenation. Moreover, nitric oxide and EDHF play an important role in the co-ordination of large and small resistance vessel behaviour that is pivotal for the adaptation of blood flow to altered tissue oxygen demands.

Heterogeneity of glyceryl trinitrate response in isolated bovine coronary arteries.

Factors determining heterogeneity of response to glyceryl trinitrate in coronary microvessels have been extensively documented in recent years, but determinants of heterogeneity between conduit and large resistance vessels are poorly understood. The current study has characterised heterogeneity to glyceryl trinitrate and other vasodilators in bovine isolated proximal (4.5 mm i.d.) and distal (0.5 mm i.d.) segments of left anterior descending artery. Compared with proximal segments, distal segments were less responsive to glyceryl trinitrate and sodium nitroprusside, equi-responsive to S-nitroso-N-acetylpenicillamine, and more responsive to isoprenaline. Heterogeneity to glyceryl trinitrate was unaffected by the presence of the thiols (cysteine or N-acetylcysteine, 100 microM). The results are interpreted as evidence that heterogeneity of vascular responsiveness to glyceryl trinitrate reflects impairment in the small artery of the cellular events which precede activation of the cyclic GMP pathway. An implication is that the impairment is not a consequence of limited thiol availability, and in this respect the cellular mechanism of heterogeneity differs from those proposed for the coronary microvasculature.

Intestinal absorption of sodium and nitric oxide-dependent vasodilation interact to dominate resting vascular resistance.

The villi of the small intestine maintain a hypertonic interstitium at all times, and the submucosal glands constantly secrete ions and accompanying water into the lumen. Generation of the 400- to 600-mOsm interstitial fluid in the villus and secretion by glands may require a large expenditure of energy and, consequently, have major effects on intestinal vascular regulation to supply oxygen and nutrients. Blood flow and oxygen consumption were measured in the ileum of anesthetized rats during natural resting conditions with physiological sodium chloride in the bathing fluid and during isosmotic replacement of sodium chloride with mannitol. Microvascular pressures and blood flow were used to determine the changes in resistance of the major arterioles and the terminal vasculature. When mannitol replaced sodium chloride in contact with the villi, intestinal blood flow decreased to 58.6 +/- 2.8% of control, and oxygen consumption was 54.2 +/- 3.4% of control. Resistance of the major arterioles increased 101.7 +/- 9.9%, and that of the terminal vasculature increased 40.4 +/- 6.2%. The increased resistance appeared to be caused by suppression of a nitric oxide mechanism. Local application of 10(-4) mol/L NG-nitro-L-arginine methyl ester caused about the same reduction in flow and increases in regional vascular resistance as during replacement of sodium but did not alter the oxygen consumption. These data indicate that about half of the intestinal metabolic rate during natural resting conditions is devoted to sodium secretion/absorption. Large resistance vessels are dilated to maintain a high blood flow through release of nitric oxide. We propose that dilation of the terminal vasculature in the metabolically active tissues increased flow velocity sufficiently in the major resistance vessels to cause a flow-mediated release of nitric oxide.

Effects of vasopressin and oxytocin on canine cerebral circulation in vivo.

In vivo experiments on the vasoactive effects of vasopressin and oxytocin on cerebral circulation were carried out in anesthetized dogs, using an electromagnetic flowmeter to measure vertebral blood flow and angiography to measure the internal diameter of the basilar artery. Direct bolus infusion of 1 pmol to 1 nmol of vasopressin or 10 pmol to 10 nmol of oxytocin into a femoral-vertebral artery shunt produced a dose-dependent decrease in vertebral artery blood flow without significantly affecting mean arterial blood pressure. Vasopressin was more potent than endothelin and neuropeptide Y, which have also been demonstrated to induce long-lasting decreases in vertebral artery blood flow. However, direct bolus infusion of vasopressin (100 pmol and 1 nmol) or oxytocin (1 nmol and 10 nmol) into the vertebral artery dilated major vessels including the vertebral, anterior spinal, and basilar arteries, as well as the circle of Willis and its main branches, while endothelin (1 nmol) and neuropeptide Y (5 nmol) caused no change in the diameters of major cerebral arteries. The V1 antagonist d(CH2)5tyrosine(methyl) arginine vasopressin suppressed the effects of both vasopressin and oxytocin. Vasopressin was over 10 times as potent as oxytocin in both assays. The vasodilatory effect of vasopressin, which may be mediated by an endothelium-dependent mechanism, was functionally damaged in dogs after experimental subarachnoid hemorrhage. These data suggest regional differences in the sensitivity and responsiveness of vasculature to vasopressin and oxytocin, and specifically that both peptides act through V1 receptors to decrease the resistance of large vessels and increase the resistance of small vessels.

Cerebral microcirculatory changes during and following transient ventricular tachycardia in cats

Although reduced cerebral perfusion is believed to be the cause of syncope due to cardiac arrhythmias, investigations on the cerebral microcirculation during cardiac arrhythmias have been rare. We therefore studied the effects of transient ventricular tachycardia on the local cerebral blood volume and blood flow. Experimental ventricular tachycardia was induced in cats by electrically stimulating the ventricle of the heart at a rate of 300/min for 1 min. Using our photoelectric method, the local cerebral blood volume, mean transit time of blood, and cerebral blood flow in the parieto-temporal region were measured during and for 3 h after ventricular tachycardia. Transient ventricular tachycardia of as short as 1 min caused cerebral ischemia with a blood flow reduction of approximately 30%. This was considered to be due to reduced blood pressure plus transient autonomic dysfunction, or dysautoregulation, during the ventricular tachycardia. Mild and transient reactive hyperemia occurred immediately after termination of the dysrhythmia, but continuous reductions of cerebral blood flow were observed thereafter for 3 h. This delayed hypoperfusion is attributable to either vasoconstriction of the large resistance vessels or changes in the hemorheological properties of the blood caused by cerebral ischemia. Ventricular tachycardia of the type reported has significant and long-lasting effects on the cerebral microcirculation.

Differential activation of alpha 1- and alpha 2-adrenoceptors on microvascular smooth muscle during sympathetic nerve stimulation.

The relative contribution of postjunctional alpha 1- and alpha 2-adrenoceptors to constriction of microvessels was examined during sympathetic nerve stimulation and sympathetic escape (difference between peak and steady-state constriction). Large arterioles (120 +/- 4 microns control diameter) and venules (174 +/- 6 microns) and small arterioles (13 +/- 4 microns) were examined in rat cremaster skeletal muscle during stimulation of the cremaster efferent innervation (decentralized lumbar sympathetic chain, 0.5-16 Hz, 2-minute train). The muscle was suspended in a tissue bath, and diameter was measured with intravital microscopy. Frequency-response curves were obtained after vehicle (prazosin or rauwolscine) was added to the bath. In large arterioles, prazosin (10(-7) M) significantly attenuated constriction by 60-80%; a fivefold higher concentration had no additional effect. In contrast, rauwolscine (1 to 5 x 10(-7) M) had no effect. Venules evidenced minimal response to nerve stimulation. In small arterioles, rauwolscine (5 x 10(-7) M) significantly attenuated constriction by 50-60%, while prazosin (10(-7) M) had no effect. These data suggest that for large arterioles, which are known to possess both receptors, alpha 1-adrenoceptors are preferentially stimulated by nerve-released norepinephrine. In contrast, sympathetic constriction of small arterioles is mediated by alpha 2-adrenoceptors. Compared with large arterioles, small arterioles exhibited greater peak and steady-state constriction at all frequencies, with maximal responses achieved over the 0.5-4 Hz range. Large arterioles exhibit graded constriction over the entire frequency range. Sympathetic escape exhibited a small, negatively correlated frequency dependence for large arterioles, tended to be greater for small arterioles, and was more evident in large arterioles during alpha 2-adrenoceptor constriction at low-frequency stimulation. This distinct neural control of large resistance vessels by alpha 1-adrenoceptors and small terminal arterioles by alpha 2-adrenoceptors may allow neurogenic regulation of these vessel segments to be differentially susceptible to modulation by other extrinsic and intrinsic vasoactive controls that preferentially interact with alpha 1- and alpha 2-adrenergic contractile mechanisms.

Effect of pulmonary venous pressure elevation on vascular resistance and compliance

The effect of pulmonary venous pressure elevation on the longitudinal distribution of resistance and compliance in the canine pulmonary circulation was determined at control vascular tone and after vascular tone was increased with histamine. The arterial, venous, and double-occlusion techniques were used in isolated dog lungs blood perfused at constant flow. The large and small blood vessel resistances and compliances were studied under both vascular tone conditions when pulmonary venous pressure was elevated above isogravimetric venous pressure conditions in successive 5 cmH2O increments up to 30 cmH2O. The results of this study indicate that pulmonary venous pressure elevations to 20 cmH2O above isogravimetric venous pressure significantly decrease total vascular resistance by reducing both the small and large vein resistances, an effect which is more pronounced in the histamine-treated lungs. Also, under control vascular tone, both the middle compartment compliance and total compliance were greatly decreased over this pressure range. Histamine treatment significantly reduced both the large vessel and middle compartment compliances before and during low venous pressure elevation. When venous pressure was then raised to at least 25 cmH2O above control outflow pressure with histamine present, the middle compartment compliance was again significantly decreased.

Isolation of rabbit pulmonary microvascular endothelial cells and characterization of their angiotensin converting enzyme activity

An in vitro model using cultured rabbit pulmonary endothelial cells of microvascular origin was developed to define the luminal surface membrane characteristics of microvascular endothelium. Endothelial cells were isolated from peripheral lung segments and sorted after preferential uptake of a fluorescent derivative, diiodoindocarbo cyanine acetylated-LDL. Cells were further characterized by demonstrating angiotensin converting enzyme (ACE) on their surface by means of indirect immunofluorescence. ACE activity and its pharmacologie modification were then studied as functional assays of cell activity. Hydrolysis of Benz-phe-ala-pro (BPAP), a synthetic substrate for ACE was saturable over a concentration range of 1 to 100 μm. Thus, BPAP hydrolysis in cultured microvascular endothelial cells behaves overall in a manner similar to that seen in large resistance vessels except that a portion of the hydrolysis is not inhibited by captopril, an ACE-specific inhibitor, indicating the presence of another protease capable of BPAP hydrolysis. Accordingly, this system can be used to compare ACE and other protease kinetics in microvessel cells with those of large vessel endothelium or perfused lungs.

Hyperosmotic mannitol and collateral blood flow to ischemic myocardium

Elevation of extracellular osmolality reduces the extent of myocardial and endothelial cell swelling that accompanies acute ischemia, and the reduction of cell swelling is associated with an increase in collateral blood flow to the ischemic area. However, little is known about the effects of hyperosmolality on the vascular resistance of the collateral coronary vasculature. We compared the effects of hyperosmolar mannitol with those of nitroglycerin and dipyridamole on the vascular resistance of large collateral coronary vessels and of the small arterial vasculature in an isolated heart model of regional ischemia. Elevation of osmolality by mannitol increased collateral blood flow to the ischemic region through at least two mechanisms. First, increasing osmolality resulted in dilation of large arterial conductance vessels, similar to that produced by nitroglycerin. In addition, mannitol produced an effect on the coronary circulation at a microvascular level which, per se or in combination with its effect on larger collateral conductance vessels, increased collateral blood flow to ischemic regions.

Acetylcholine's effect on vascular resistance and compliance in the pulmonary circulation

Acetylcholine's effect on the distribution of vascular resistance and compliance in the canine pulmonary circulation was determined under control and elevated vascular tone by the arterial, venous, and double occlusion techniques in isolated blood-perfused dog lungs at both constant flow and constant pressure. Large and small blood vessel resistances and compliances were studied in lungs given concentrations of acetylcholine ranging from 2.0 ng/ml to 200 micrograms/ml. The results of this study indicate that acetylcholine dilates large arteries at low concentrations (less than or equal to 20 ng/ml) and constricts small and large veins at concentrations of at least 2 micrograms/ml. Characterization of acetylcholine's effects at constant pulmonary blood flow indicates that 1) large artery vasodilation may be endothelial-derived relaxing factor-mediated because the dilation is blocked with methylene blue; 2) a vasodilator of the arachidonic acid cascade (blocked by ibuprofen), probably prostacyclin, lessens acetylcholine's pressor effects; 3) when vascular tone was increased, acetylcholine's hemodynamic effects were attenuated; and 4) acetylcholine decreased middle compartment and large vessle compliance under control but not elevated vascular tone. Under constant pressure at control vascular tone acetylcholine increases resistance in all segments except the large artery, and at elevated vascular tone the pressor effects were enhanced, and large artery resistance was increased.

Histamine's effect on pulmonary vascular resistance and compliance at elevated tone

Histamine's effect on the longitudinal resistance and compliance distribution in the canine pulmonary circulation was determined under control and elevated vascular tone using the thromboxane analogue U46619. The arterial-, venous-, and double-occlusion techniques were used in isolated blood-perfused dog lungs at both constant flow and constant pressure. Large and small blood vessel resistances and compliances were studied in lungs given the following treatments: 1) histamine; 2) histamine in lungs pretreated with the H1-receptor antagonist diphenhydramine, and 3) histamine in lungs pretreated with the H2-receptor antagonist cimetidine. The results of this study indicate that histamine constricts small and large veins through H1-receptor mediation at both normal and elevated vascular tone. When vascular tone was elevated, H2-receptor vasodilatation was also apparent in all blood vessel segments. Histamine decreased total, middle compartment, and large vessel vascular compliances by an H1-receptor effect. When vascular tone was elevated, histamine's H1-receptor-mediated vasoconstrictor effect on compliance vessels was less due to the presence of an H2-receptor-mediated vasodilatory system.

Effects of arginine vasopressin on cerebral microvascular pressure.

The goal of this study was to examine effects of arginine vasopressin and angiotensin on cerebral microvascular pressure and segmental vascular resistance. We measured pressure (servo-null) in pial arteries that were approximately 200 micron in diameter and cerebral blood flow (microspheres) in anesthetized cats, and we calculated resistance of large and small cerebral vessels. Resistance of large arteries (greater than 200 micron diam) was approximately 45% of total cerebral vascular resistance under control conditions. Vasopressin (40 mU/kg iv) decreased resistance of large arteries by 22 +/- 7%, increased pial artery pressure by 10 +/- 2 mmHg when aortic pressure was maintained at control levels, and increased small vessel resistance by 27 +/- 11%. This increase in small vessel resistance apparently was an autoregulatory response to the increase in pial pressure. Cerebral blood flow was not changed (38 +/- 4 vs. 37 +/- 3 ml.min-1.100 g-1). Intravenous infusion of angiotensin (2 micrograms.kg-1.min-1) increased large artery resistance by 32 +/- 6%, decreased pial artery pressure 6 +/- 3 mmHg with aortic pressure maintained constant, and decreased cerebral blood flow by 12 +/- 1%. Thus circulating vasopressin, at concentrations similar to those observed during hemorrhage, selectively dilates large cerebral arteries and increases microvascular pressure without changes in cerebral blood flow. In contrast to vasopressin, angiotensin selectively increases resistance of large cerebral arteries and decreases cerebral microvascular pressure. Thus vasopressin and angiotensin, at doses that have minimal effects on cerebral blood flow, may play an important role in regulation of cerebral microvascular pressure.