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Biomedical subjects

D G Harrison

Publications and source records attributed to D G Harrison.

At least 109 records · Page 6Linked to original sources
PubMed1993

The nitrovasodilators. New ideas about old drugs.

The nitrovasodilators are a diverse group of pharmacological agents that produce vascular relaxation by releasing nitric oxide. The mechanisms by which these compounds release nitric oxide vary, depending on their chemical structure. Compounds with lower oxidation states of nitrogen such as nitroprusside, nitrosamines, and nitrosothiols release nitric oxide nonenzymatically. In the case of nitroprusside, this involves a one-electron reduction that may occur upon exposure to a variety of reducing agents and tissues such as vascular smooth muscle membranes. In the case of the organic nitrates, which have higher oxidation states of nitrogen, the release of nitric oxide in vascular tissue occurs predominantly by a poorly understood enzymatic process. This interesting property of nitroglycerin is important because it "targets" its effect to vascular tissues that are capable of this enzymatic process. In the case of the coronary circulation, nitroglycerin predominantly dilates the larger coronary arteries while having a minimal effect on coronary resistance vessels < 100 microns in diameter. This prevents the development of coronary steal, which is often encountered with agents that produce intense vasodilation of the coronary resistance vessels. In this review, the mechanisms by which the nitrovasodilators (particularly nitroglycerin) release nitric oxide will be considered, and recent studies of nitroglycerin bioconversion in various-sized coronary vessels will be discussed in detail.

Animals↗
PubMed1993

Hypercholesterolemia increases endothelial superoxide anion production.

Indirect evidence suggests accelerated degradation of endothelium-derived nitric oxide (ENDO) by superoxide anion (O2-) in hypercholesterolemic vessels (HV). To directly measure O2- production by normal vessels (NV) and HV, we used an assay for O2- based on the chemiluminescence (CL) of lucigenin (L). HV (1 mo cholesterol-fed rabbits) produced threefold more O2- than NV (1.47 +/- 0.20 nM/mg tissue/min, n = 7 vs. 0.52 +/- 0.05 nmol/mg tissue/min, n = 8, P < 0.001). Endothelial removal increased O2- production in NV (0.73 +/- 0.08, n = 6, P < 0.05), while decreasing it in HV (0.76 +/- 0.15, n = 5, P < 0.05). There was no difference between denuded HV and denuded NV. Oxypurinol, a noncompetitive inhibitor of xanthine oxidase, normalized O2- production in HV, but had no effect in NV. In separate isometric tension studies treatment with oxypurinol improved acetylcholine induced relaxations in HV, while having no effect on responses in normal vessels. Oxypurinol did not alter relaxations to nitroprusside. Thus, the endothelium is a source of O2- in hypercholesterolemia probably via xanthine oxidase activation. Increased endothelial O2- production in HV may inactivate endothelium-derived nitric oxide and provide a source for other oxygen radicals, contributing to the early atherosclerotic process.

Acridines↗
PubMed1992

Normal and pathophysiologic considerations of endothelial regulation of vascular tone and their relevance to nitrate therapy.

During the past decade, it has become clear that the vascular endothelium critically influences vascular permeability, controls vessel growth, modulates hemostasis, and regulates vasomotion. This latter role of the endothelium is mediated by the liberation of a number of potent vasoactive compounds, including endothelium-derived relaxing factors, one of which is either nitric oxide or a compound that releases nitric oxide, vasoactive prostaglandins, hyperpolarizing factors, and a number of constricting factors. This role of the endothelium is dramatically altered by several diseases, including atherosclerosis, hypertension, and diabetes. Abnormalities of endothelial regulation of vascular tone may contribute to a number of clinical syndromes, including variant angina, unstable angina, syndrome X, and perhaps many others. In this review, several aspects of the endothelium-derived relaxing factor will be considered, including recent concepts regarding its synthesis, its chemical identity, and alterations in atherosclerosis. Finally, its action in the coronary microcirculation as contrasted to that of nitroglycerin will be considered.

Animals↗
PubMed1992

Effect of inclusion of saliva salts in the diet on milk yield and composition in dairy cows.

Twenty multiparous Jersey cows, paired according to previous lactation yield and expected date of calving, were given two diets in a cross-over experiment in early lactation. The diets had forage: concentrate ratios maintained at 3:7, the forage being wilted grass silage and the concentrate either a proprietary dairy cake or the same cake containing saliva salts (SS) at 40 g/kg dry matter. The SS diet proved acceptable to the animals and had no effect on gestation length or calf survival. Absolute milk yields were not affected, but the SS diet caused a significant increase in the proportions of milk fat, total solids (both P less than 0.001) and protein (P less than 0.05) and in the yield of fat-corrected milk (P less than 0.001). Analysis of rumen liquor samples showed that giving the SS diet resulted in a significant increase in the molar proportion of acetate and a decrease in the proportions of propionate and to a lesser extent butyrate. Milk fat content showed significant correlations with ruminal acetate (r = 0.67), propionate (r = -0.59) and the acetate: propionate ratio (r = 0.64).

Ammonia↗
PubMed1992

Release of multiple endothelium-derived relaxing factors from porcine coronary arteries.

Using a chemiluminescence method in the present study, we measured nitric oxide and one-electron oxidation products of nitric oxide (NOX) released from porcine coronary artery segments in response to bradykinin, ADP, and the calcium ionophore A23187. Total NOX was compared with the bioactivity of endothelium-derived relaxing factors (EDRF) by a biodetector ring preparation before and after inhibition of L-arginine-dependent nitric oxide synthesis and in the presence of indomethacin. Under basal conditions, arterial segments released NOX and relaxed biodetector rings. Bradykinin, ADP, and A23187 elicited vasorelaxation greater than that observed basally; A23187, but not bradykinin or ADP, caused additional release of NOX greater than that measured basally. Hemoglobin completely reversed vasorelaxation elicited by all three agonists. We compared the amount of nitric oxide released under basal conditions and after stimulation with bradykinin, ADP, and A23187 with the amount of authentic nitric oxide necessary to elicit a bioequivalent response. Authentic nitric oxide did not account for the observed bioactivity as compared with the amount of nitric oxide actually measured in arterial segment effluent. To investigate whether a second non-nitric oxide-containing compound was responsible for the increased bioactivity and the discrepancy between the bioactivity and quantity of nitric oxide measured, we exposed arterial segments to omega-nitro-L-arginine methyl ester to inhibit L-arginine-dependent synthesis of nitroso compounds. The drug completely abolished the nitric oxide signal derived from both basally released and A23187-stimulated relaxing factor and completely reversed vasorelaxation. In contrast, omega-nitro-L-arginine methyl ester only partially reversed bradykinin-stimulated vasorelaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1992

Vasomotor properties of porcine endocardial and epicardial microvessels.

We sought to compare the sensitivity of endocardial and epicardial microvessels to several important neurohumoral substances. Porcine endocardial microvessels (86-200 microns diam) from the anterior papillary muscle and epicardial microvessels of similar size from the left anterior descending distribution were studied in a pressurized state using an in vitro microvessel-imaging apparatus. Endothelium-dependent relaxations to bradykinin, ADP, A23187, and to the endothelium-independent vasodilator nitroprusside were identical between endocardial and epicardial microvessels. In contrast, the sensitivity of endocardial microvessels to adenosine was substantially greater than that of epicardial microvessels (ED50s of -6.59 +/- 0.05 vs. -5.66 +/- 0.11, P less than 0.001, endocardial vs. epicardial, respectively), although adenosine caused 100% relaxation of both groups of vessels at the highest concentrations. Adenosine vasorelaxation was not affected by inhibition of cyclooxygenase by indomethacin (1 microM) or depletion of guanosine 3',5'-cyclic monophosphate by LY 83583 (1 microM). Forskolin dilated both endocardial and epicardial vessels completely but was more potent in endocardial vessels. These data show that endocardial and epicardial microvessels exhibit similar sensitivity to most vasodilator agents. Endocardial microvessels, however, are more sensitive to both adenosine and forskolin. The enhanced responsiveness to adenosine may be related to adenosine 3',5'-cyclic monophosphate-mediated mechanisms and may have important implications regarding regulation of myocardial perfusion in deeper subendocardial layers.

Adenosine↗
PubMed1992

Mechanisms of interaction between the sulfhydryl precursor L-methionine and glyceryl trinitrate.

BACKGROUND: L-Methionine potentiates systemic hemodynamic effects of intravenous glyceryl trinitrate (GTN) in tolerant and nontolerant patients to a similar extent as N-acetylcysteine (NAC). This potentiation of GTN action by L-methionine has been attributed to enhanced intracellular formation of nitrosothiols, known to be potent stimulators of soluble guanylyl cyclase. This study was performed to analyze directly the effects of L-methionine on GTN-induced dilation of large epicardial arteries and the venous capacitance system of the dog in the tolerant and nontolerant states. Cultured rat aortic vascular smooth muscle cells and purified guanylyl cyclase were used to study potential intracellular and extracellular mechanisms responsible for this interaction. METHODS AND RESULTS: In awake nontolerant dogs, L-methionine (100 mg/kg) potentiated the tachycardic response to GTN (5.0 and 15 micrograms/kg/min) and enhanced the hypotensive action of GTN (1.5 and 5.0 micrograms/kg/min) in anesthetized, nonreflexic dogs. In nontolerant and tolerant dogs, however, L-methionine did not alter the dose-response of large epicardial artery dilation to intravenous GTN challenges and did not modify nitrate tolerance of the low pressure system of the dog. The infusion of L-methionine (100 mg/kg) significantly increased plasma methionine levels (from 52 +/- 12 to 1,141 +/- 239 microM), cystine levels (from 12 +/- 4 to 26 +/- 7 microM), but not homocystine levels. In vitro, the L-methionine conversion product L-cysteine (0.1-1.0 mM) but not homocysteine significantly enhanced the augmentation of purified guanylyl cyclase activity by GTN (100 microM). Incubation of cultured rat aortic smooth muscle cells with L-methionine (10 microM or 1 mM) did not result in a significant increase of free intracellular sulfhydryl group content. CONCLUSIONS: The L-methionine conversion product L-cysteine mediates tolerance independent the potentiation of GTN action. This may result from an L-cysteine-induced formation of a vasoactive metabolite of GTN (nitric oxide) or nitrosothiol. This effect occurs primarily in the resistance vessel circulation, not in large epicardial arteries and veins. The lack of effect of L-methionine on sulfhydryl group content in large conductance vessels indicates that hepatic L-methionine metabolism constitutes the significant source of L-cysteine. These findings strongly suggest that administration of sulfhydryl-group precursor L-methionine does not represent a therapeutic alternative to a nitrate-free interval to restore nitrate sensitivity in tolerant large epicardial arteries and veins.

Animals↗
PubMed1992

Effect of hypertension and hypertrophy on coronary microvascular pressure.

We tested the hypothesis that transmural differences in coronary microvascular pressures may be greater in the setting of hypertension and left ventricular hypertrophy. Epicardial and endocardial microvascular pressures were measured in isolated lidocaine-arrested hearts during adenosine vasodilation. In both normotensive (n = 19) and hypertensive (one clip, one kidney, n = 10) dogs, microvascular pressures in endocardial arterioles at 60, 70, 80, 90, and 100 mm Hg of left main coronary perfusion pressures were lower than in epicardial arterioles (p less than 0.05 at all perfusion pressures). The pressures in epicardial arterioles as a percentage of the left main coronary perfusion pressure were similar in normotensive versus hypertensive hearts at all perfusion pressures. In contrast, the pressures in endocardium at 90 and 100 mm Hg of perfusion pressure were significantly (p less than 0.05) lower in dogs with hypertension and hypertrophy than in the controls (41 +/- 4 versus 50 +/- 2 and 40 +/- 4 versus 50 +/- 3 mm Hg at 90 and 100 mm Hg of perfusion pressure, respectively). Thus, there is a greater transmural resistance to microvascular perfusion in hearts with myocardial hypertrophy secondary to hypertension. This is likely due to differences in the vascular anatomy, secondary to hypertension and hypertrophy, and may contribute to vulnerabilities in subendocardial ischemia encountered in this condition.

Animals↗
PubMed1992

Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase.

The constitutive endothelial cell nitric oxide synthase (NOS) importantly regulates vascular homeostasis. To gain understanding of this enzyme, a pEF BOS cDNA library of 5 x 10(5) clones was prepared from bovine aortic endothelial cells (BAEC) and screened with a 2.8-kb cDNA BamHI fragment of rat brain NOS. Clone pBOS13 was found to express NO synthase activity when transfected into COS-7 cells. Sequence analysis revealed sequences compatible with binding domains for calcium/calmodulin, flavin mononucleotide, flavin adenine nucleotide and NADPH. The deduced amino acid sequence revealed a protein with a relative mol mass of 133,286, which is 58% homologous to the rat cerebellar NOS and 51% homologous to the mouse macrophage NOS. The amino-terminal portion of the protein exhibits several characteristics peculiar to the endothelial cell NOS. These include a proline-rich region and several potential sites for proline-directed phosphorylation as well as a potential substrate site for acyl transferase. Northern hybridization to mRNA from cultured BAEC revealed an abundant 4.8-kb message, which was not increased by coincubation with tumor necrosis factor alpha, but was markedly increased by exposure to shear stress for 24 h. The unique features of the endothelial cell NO synthase, particularly in the amino terminal portion of the molecule, may provide for novel regulatory influences of enzyme activity and localization.

Amino Acid Oxidoreductases↗
PubMed1991

Nitric oxide generation from nitroprusside by vascular tissue. Evidence that reduction of the nitroprusside anion and cyanide loss are required.

Nitric oxide (NO) was produced from sodium nitroprusside in the presence of vascular tissue but was not released spontaneously from the nitroprusside anion. In the absence of tissue in the dark nitroprusside did not release NO. When solutions of nitroprusside alone were irradiated with visible light, nitric oxide was released at rates linearly proportional to nitroprusside concentration and light intensity. Nitric oxide was produced from solutions of nitroprusside in the dark after the addition of vascular tissue, including lengths of rabbit aorta, subcellular fractions of aorta, and human plasma. NO was also released from nitroprusside after reaction with various reducing agents including cysteine and other thiols, ascorbic acid, sodium dithionite, ferrous chloride, hemoglobin, myoglobin, and partially purified cytochrome P450 with an NADPH-regenerating system. HCN was simultaneously produced in these solutions, and addition of KCN blocked NO release. Iodine oxidized intermediate cyanoferrates and blocked nitric oxide release. KCN or iodine also blocked NO production by tissue, but had no effect upon photochemical NO release. These results show that, apart from photolysis which makes no physiological contribution, release of nitric oxide from nitroprusside, in simple solutions and in biological tissue, occurs after nitroprusside has undergone reduction and lost cyanide.

Animals↗
PubMed1991

L-cysteine selectively potentiates nitroglycerin-induced dilation of small coronary microvessels.

Nitroglycerin potently dilates large coronary arteries but has minimal effect on coronary resistance vessels. Thus, nitroglycerin is not likely to be converted to vasoactive intermediates in small coronary microvessels (less than 100 microns diameter). Because nitroglycerin biotransformation may involve sulfhydryl groups, the effect of L-cysteine on the dilation caused by nitroglycerin (1 nM to 10 microM) was examined in small (80-100 microns in diameter) and large (190-300 microns in diameter) porcine coronary microvessels. Vessels were pressurized in a no-flow state and preconstricted with acetylcholine, then visualized by means of an in vitro microvessel imaging apparatus. Under control conditions, nitroglycerin caused potent dilations of large coronary microvessels, while having minimal effects on small coronary microvessels [peak relaxations 90 +/- 3 vs. 20 +/- 7% (mean +/- S.E.M.) of preconstricted diameter, respectively]. L-Cysteine (100 microM) markedly enhanced relaxations of small coronary microvessels (peak relaxation 96 +/- 2%), while having no effect on relaxations of large coronary microvessels. Ethacrynic acid, which alkylates sulfhydryl groups, markedly inhibited relaxations of large coronary microvessels (peak relaxation = 31 +/- 9%) yet had a minimal effect on the small relaxations of small coronary microvessels to nitroglycerin. Thus, when sulfhydryl groups are made available, small coronary microvessels are markedly responsive to nitroglycerin. This suggests that small coronary microvessels normally lack the reductive capacity to convert nitroglycerin to its active metabolites. Prussian blue stains of sulfhydryl groups in large and small coronary microvessels were qualitatively similar. Thus, small coronary microvessels do not lack sulfhydryl groups but may be deficient in a critical pool necessary for nitroglycerin biotransformation.

Animals↗
PubMed1991

EDRF: nitrosylated compound or authentic nitric oxide.

Endothelium-derived factor (EDRF) from bovine aortic endothelial cells was compared to solutions of authentic nitric oxide (NO) and to solutions of the nitrosothiol S-nitroso-L-cysteine. EDRF was produced from endothelial cells by basal release or by stimulation with the calcium ionophore A23187. Biological activity was measured as relaxation of porcine coronary arteries preconstricted with prostaglandin F2 alpha, and chemical analysis was made of the nitrosyl content by measurement of NO released after chemical reduction with 1% sodium iodide in glacial acetic acid. EDRF, NO, and nitrosocysteine had identical half-lives, were all inactivated by hemoglobin and methylene blue, and were all augmented in their biological activity by superoxide dismutase. When solutions were analyzed for their biological activity as a function of the NO content (after NaI/acetic acid reduction), nitrosocysteine showed more vasodilation per amount of contained NO than did authentic NO. Solutions containing EDRF (basal release or by stimulation with A23187) subjected to the same analysis appeared similar to nitrosocysteine, and were distinct from solutions of NO. These experiments show that nitrosyl compounds other than NO can have properties very similar or identical to EDRF, and that in this system EDRF appears more similar to nitrosocysteine than to NO.

Animals↗
PubMed1991

Endothelial modulation of vascular tone: relevance to coronary angioplasty and restenosis.

The vascular endothelium importantly modulates many biochemical and physiologic properties of the vascular wall, including the release of potent vasoactive factors, maintenance of an anticoagulant state and modulation of vascular growth by the release of both proliferative and antiproliferative substances. Prominent among these endothelial roles is the production of a potent vasodilator or family of vasodilators termed the endothelium-derived relaxing factor, one of which has been identified to be nitric oxide or a closely related compound. Several diseases that commonly occur in patients undergoing coronary angioplasty alter many facets of endothelial function and may predispose to adverse clinical sequelae of angioplasty, including immediate thrombosis, restenosis and vascular spasm. Several features of the endothelium-derived relaxing factor, how it is altered by pathologic processes and how these considerations relate to the immediate and late postangioplasty periods are discussed.

Angioplasty, Balloon, Coronary↗
PubMed1991

Hypertension and the coronary circulation. With special attention to endothelial regulation.

Calcium channel antagonists are commonly used to treat chronic hypertension. Several studies of intact vascular tissues suggest that these agents may impair the production of the endothelium-derived relaxing factor and alter endothelium-dependent vascular relaxation. These studies are difficult to interpret because the calcium channel antagonist may have direct effects on vascular smooth muscle. In our study, a chemiluminescence assay was used to measure the release of nitrogen oxides from bovine aortic endothelial cells (BAEC) grown in monolayer. Under basal conditions, the release of nitrogen oxides was 0.2 nmol/100 mg protein and was increased approximately two-fold by 0.1 micrograms, bradykinin. Incubations with diltiazem, verapamil, and nifedipine for 60 min did not influence the basal and bradykinin-stimulated release of nitrogen oxides by BAEC. These data illustrate that the production of the endothelium-derived relaxing factor is not altered by the calcium channel antagonist, and are compatible with an absence of L-type calcium channels in vascular endothelial cells. Chronic hypertension produces myriad adverse effects in the coronary circulation. After coronary occlusion, infarct size, expressed as a function of myocardial mass perfused, is increased by 33%, and the wavefront of infarction from subendocardium to subepicardium is hastened. Both chronic and acute hypertension produce numerous abnormalities of coronary flow regulation. These include impairments of autoregulation, changes in vascular responsiveness, and alterations of endothelial cell function. Many of these may worsen the clinical consequences of ischemic heart disease, either by producing structural alterations of the coronary vasculature, or equally importantly, by altering coronary vascular responsiveness to either mechanical or neurohumoral stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Role of the endothelium in modulation of the acetylcholine vasoconstrictor response in porcine coronary microvessels.

STUDY OBJECTIVE: The aim was to investigate the role of the endothelium in modulating the acetylcholine response in porcine coronary microvessels and compare the results with simultaneously studied large coronary arteries. DESIGN: Coronary microvessels [104 (SEM 3.3) microns; range 38-150] were removed from fresh porcine hearts and studied in vitro during no flow constant pressure conditions. Endothelium derived relaxing factor (EDRF) activity and the role of the endothelium in modulating the acetylcholine response in microvessels was assessed by measuring changes in intraluminal diameter using a video tracking device. Large coronary arteries were simultaneously studied using conventional isometric ring techniques. EXPERIMENTAL MATERIAL: Fresh porcine hearts were obtained from a local slaughterhouse. MEASUREMENTS AND MAIN RESULTS: Acetylcholine was a potent vasoconstrictor (EC50 = 0.17 microM) of passively distended microvessels. The effects of EDRF were studied by either inactivation with haemoglobin or inhibition of EDRF synthesis with N-omega-nitro-L-arginine. Preconstricted microvessels exposed to either N-omega-nitro-L-arginine or haemoglobin constricted further, consistent with basal release of EDRF. Neither drug affected passively distended microvessels. The acetylcholine vasoconstrictor response was potentiated after exposure of microvessels to either drug. Atropine, but not indomethacin, blocked the acetylcholine response in microvessels. As with microvessels, acetylcholine was a vasoconstrictor (EC50 = 0.3 microM) of large coronary arteries. In contrast to microvessels, indomethacin antagonised acetylcholine vasoconstriction in vessels with intact endothelium. Bioassay experiments using indomethacin-treated large epicardial donor artery segments showed basal release of EDRF but no EDRF release in response to acetylcholine. CONCLUSIONS: The results show the microvessels and large coronary arteries are similar in their vasoconstrictor response to acetylcholine, that both release EDRF basally, and that vasoconstriction to acetylcholine is importantly modulated by the endothelium. In large arteries, acetylcholine does not stimulate EDRF release and, in contrast to microvessels, a cyclo-oxygenase product influences the vasoconstrictor action of acetylcholine.

Acetylcholine↗
PubMed1991

Release of intact endothelium-derived relaxing factor depends on endothelial superoxide dismutase activity.

Endothelium-derived relaxing factor (EDRF) is rapidly inactivated by radicals. Endothelial cells possess several antioxidant defense mechanisms. It is not clear which intrinsic antioxidant defense systems are important to preserve the release of biologically active EDRF. We impaired antioxidant defense in normal vascular tissue by inhibiting catalase activity with 3-amino-1,2,4-triazole (AT), superoxide dismutase with diethyldithiocarbamate (DETC), and by reducing glutathione content via inhibiting glutathione synthesis with L-buthionine-(S,R)-sulfoximine (BSO). Pretreatment of rabbit aorta in vitro with DETC markedly reduced endothelium-dependent relaxation in response to acetylcholine and calcium ionophore A23187 and, to a lesser extent, reduced endothelium-independent relaxation in response to nitroprusside. Pretreatment of cultured bovine aortic endothelial cells (BAEC) with DETC did not alter release of nitrogen oxides (measured by chemiluminescence), but, the effluent of pretreated cells showed marked depression in vasodilator activity (measured by bioassay). Pretreatment of rabbit aorta in vitro with AT did not alter endothelium-dependent and -independent relaxations. Pretreatment of BAEC with BSO did not alter the release of nitrogen oxides or the vasodilator activity. These results suggest that endothelial superoxide dismutase activity, but not catalase or glutathione, is necessary for the release of biologically active EDRF. An imbalance of the intrinsic superoxide dismutase and the production of superoxide anions may therefore predispose to impaired endothelium-dependent relaxations and alter vascular reactivity.

Acetylcholine↗
PubMed1991

Capillary growth and geometry during long-term hypertension and myocardial hypertrophy in dogs.

Angiogenic response of the myocardial capillary bed to long-term (7 mo) renovascular hypertension (one-kidney, one-clip) was assessed in eight mongrel dogs and compared with seven control dogs. Image analyses of histological sections from four transmural specimen sites of left ventricular (LV) free wall were performed. While mean cross-sectional cardiocyte area increased in all transmural layers (epi-endo) in dogs with LV hypertrophy (LVH), the greatest increases occurred in the inner layers. Although capillary length density was significantly lower in two of the four transmural regions of LVH dogs, these decrements were much less than the lateral expansion of cardiocytes as indicated by cross-sectional areas. Calculations of total capillary length indicate that approximately one-fifth of the capillary bed in LVH dogs was formed during the 7-mo period of hypertension in hypertrophied hearts. Capillary volume and surface densities in LVH dogs decreased to a greater extent due to a larger population of capillaries with lumen diameters less than 4 microns. Capillary volume density in LVH dogs was remarkably similar across the wall despite large transmural differences in cardiocyte hypertrophy. LVH did not alter the log SD of capillary domains, a measure of the heterogeneity of spacing, or capillary orientation (degree or anisotropy). These data support several important conclusions regarding long-term hypertension-induced LVH in dogs. First, although capillary growth does not fully compensate for the increase in LV mass, a myriad of new capillaries are formed as indicated by a substantial increase in total capillary length. This growth minimizes the increase in intercapillary distance characteristic of LVH.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗