Search PubMed⌕ Search

Biomedical subjects

D G Harrison

Publications and source records attributed to D G Harrison.

At least 145 records · Page 8Linked to original sources
PubMed1989

Characteristics of canine coronary resistance arteries: importance of endothelium.

Canine coronary resistance vessels were studied in vitro to examine the role of the endothelium in modulating responses to acetylcholine, vasopressin, and thrombin and to compare these responses to those found in large epicardial vessels. Acetylcholine had no effect on passively distended microvessels; however, after preconstriction with the thromboxane analogue, U 46619 caused dose-dependent vasodilation [50% effective concentration (EC50), 0.05 microM; maximum response, 97.9 +/- 2.1% relaxation]. Large epicardial arterial rings studied in organ chambers similarly relaxed to acetylcholine (EC50, 0.07 microM; maximum response, 79 +/- 5% relaxation). Hemoglobin was utilized to inactivate endothelium-derived relaxing factor (EDRF), resulting in reversal of acetylcholine vasodilation in both the microvessels (92 +/- 3.2% reversal) and the large epicardial vessels (117 +/- 9%). Hemoglobin had no effect on passively distended or preconstricted microvessels. Vasopressin constricted resistance vessels by 22.3 +/- 5.9 microns at 500 microU/ml. Hemoglobin potentiated this response by 100%, suggesting that vasopressin elicited EDRF release. In large coronary arteries, however, vasopressin elicited endothelium-dependent dilation with maximal relaxation of 36 +/- 9% at 3,000 microU/ml. Thrombin produced endothelium-dependent relaxation of large epicardial arterial rings but only constricted coronary microvessels. The response to thrombin was not altered by hemoglobin. This study demonstrates that the endothelium of coronary microvessels, like that of larger vessels, importantly modulates vascular reactivity to selected agents. Furthermore, major differences exist between large and small coronary arteries in their response to vasopressin and thrombin.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Beta-adrenergic receptors on canine coronary collateral vessels: characterization and function.

The present studies were performed to examine the role of beta-adrenergic receptors in modulating smooth muscle tone in mature coronary collaterals. To examine the beta-adrenergic receptor population present, radioligand binding-cover slip autoradiographic studies were performed on sections of native canine coronary vessels and sections of coronary collaterals developed after placement of Ameroid constrictors. Specific binding of the nonselective beta-adrenergic antagonist [125I]iodopindolol to vascular smooth muscle in segments of both collaterals and native coronary arteries was saturable and stereospecific. Maximal binding and the potency of beta-adrenergic subtype-selective antagonists were similar in all segments. Beta-adrenergic relaxation of native coronary vessels and collateral vessels were studied in isolated organ chambers after preconstriction with prostaglandin F2 alpha. Both native coronary arteries and collateral segments demonstrated beta-adrenergic-mediated relaxation with affinities for both agonists and antagonists compatible with a mixed population of beta 1- and beta 2-adrenergic receptors. These studies indicate that during development, the new collateral vascular smooth muscle expresses a functional population of beta-adrenergic receptors, comparable to that in native vessels.

Adrenergic beta-Antagonists↗
PubMed1989

Mechanisms of abnormal endothelium-dependent vascular relaxation in atherosclerosis: implications for altered autocrine and paracrine functions of EDRF.

The present studies were performed to determine if abnormal endothelium-dependent vascular relaxation in atherosclerosis is due to decreased production or release of endothelium-derived relaxing factor (EDRF) by atherosclerotic rabbit vessels or if atherosclerotic vessels are less sensitive to the relaxing effects of EDRF. EDRF release was quantified using two approaches, by the response of bioassay detector vessels and also by the activation of guanylate cyclase within cultured endothelial cells. Using these assays, atherosclerotic vessels were found to release significantly less EDRF than normal vessels in response to both receptor- and nonreceptor-mediated stimuli. Relaxations of normal and atherosclerotic vessels to luminally applied EDRF (derived from normal rabbit aortas stimulated by the calcium ionophore, A23187) and nitric oxide, a putative EDRF, were also studied. Atherosclerotic vessels were more sensitive to EDRF than normal vessels, and equally sensitive to nitric oxide. Additional studies performed in organ chambers failed to demonstrate augmented constriction of atherosclerotic vessels in response to acetylcholine in the presence or absence of methylene blue or LY83583, compounds which inhibit the effect of EDRF. We conclude that decreased EDRF release is the principal underlying mechanism responsible for abnormal endothelium-dependent vascular relaxation in atherosclerosis.

Acetylcholine↗
PubMed1989

Vasopressin and the mature coronary collateral circulation.

In isolated vascular rings, we have shown that mature coronary collateral vessels are highly responsive to the vasoconstrictor effects of vasopressin. The purpose of the present study was to determine the effect of concentrations of vasopressin encountered in pathophysiologic states on the collateral circulation in vivo. We studied eight open-chest anesthetized dogs with mature coronary collateral vessels 3-6 months after placement of an ameroid constrictor on the left circumflex coronary artery. The left anterior descending coronary artery was perfused at constant pressure, and peripheral coronary pressure was monitored continuously throughout each experiment. At baseline and during intracoronary infusion of vasopressin, which resulted in concentrations ranging from 8 +/- 3 to 1,340 +/- 327 microM/ml, we measured regional myocardial perfusion with radiolabeled microspheres. At baseline, regional myocardial perfusion to the collateral-dependent myocardium and to the normally perfused myocardium was similar; however, during vasopressin infusion, collateral-dependent zone flow decreased by 49 +/- 14% whereas normal zone flow decreased by only 9 +/- 9% (p less than 0.0005, normal zone perfusion vs. collateral perfusion). Vasopressin increased transcollateral resistance by 242 +/- 95% above baseline but produced a more modest increase in normal zone resistance (15 +/- 10%). The subendocardial to subepicardial perfusion ratio increased by 28 +/- 12% in the normal zone in response to vasopressin but decreased by 18 +/- 11% in the collateral-dependent zone. These data show that mature coronary collateral vessels are responsive to the vasoconstrictor effects of vasopressin at concentrations encountered in various pathophysiologic states.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Coronary angiogenesis during long-term hypertension and left ventricular hypertrophy in dogs.

Many studies have documented that during the development of left ventricular hypertrophy (LVH) coronary vascular growth lags behind that of cardiac muscle. To ascertain whether significant growth of coronary resistance vessels occurs with long-standing hypertension and LVH, we studied dogs with Goldblatt (one-kidney, one-clip) hypertension seven months after surgery. Left ventricular minimal coronary vascular resistance (LV MCVR) was derived from adenosine-induced maximal flow measured with 15 microns microspheres. Morphometric data were based on perfuse-fixed hearts arrested in diastole. Hypertension and LVH were associated with a 46% increase in left ventricular weight/body weight ratio (LVH, 6.73 +/- 0.31; control, 4.62 +/- 0.30), no significant change in LV MCVR/100 g, and a reduction in total LV MCVR (LVH, 0.11 +/- 0.02 mm Hg/ml/min; control, 0.15 +/- 0.02 mm Hg/ml/min). Arterial and arteriolar wall/lumen ratios were virtually identical in the two groups. Arteriolar (lumen diameter less than 200 microns) numerical densities (arteriolar profiles/mm2) were also similar for the two groups even when analyzed according to lumen diameter size class and by ventricular location (epimyocardium, midmyocardium, and endomyocardium). Moreover, the relative frequency distribution of any arteriolar size class was similar for both groups. Because MCVR and arteriolar density were normal, this study provides new evidence that angiogenesis during long-term LVH in this model is of sufficient magnitude to enable the cross-sectional area of the coronary resistance vessels to increase in proportion to the increase in left ventricular mass.

Animals↗
PubMed1989

Vascular responses to leukocyte products in atherosclerotic primates.

Little is known about the possible role of leukocytes in the pathogenesis of vasospasm. We hypothesized that vasoactive products released by leukocytes might produce constriction of atherosclerotic arteries. To test this hypothesis, we infused fmet-leu-phe (fMLP), a peptide that activates leukocytes to release their vasoactive products, into the perfused hind limb of normal and atherosclerotic cynomolgus monkeys. Infusion of fMLP did not change resistance of large arteries in normal monkeys. In contrast, fMLP produced pronounced constriction of large arteries in atherosclerotic monkeys. To determine whether leukotrienes, platelet-activating factor, or prostaglandin E2 (PGE2), which are released by leukocytes, may contribute to leukocyte-induced vasoconstriction in atherosclerotic monkeys, we injected leukotriene D4, platelet-activating factor, and PGE2 intra-arterially into the perfused hind limb. Leukotriene D4 and platelet-activating factor had minimal effects on large arteries in both normal and atherosclerotic monkeys. PGE2 produced marked constriction of large arteries in atherosclerotic, but not normal, monkeys. Thus, pronounced constriction in atherosclerotic, but not normal, arteries during infusion of fMLP suggests that products released by leukocytes may mediate vasoconstriction in atherosclerotic vessels. Vasoconstrictor responses to PGE2 are profoundly potentiated by atherosclerosis, which suggests that PGE2 may contribute to leukocyte-induced vasoconstriction.

Animals↗
PubMed1988

Influence of risk area size and location on native collateral resistance and ischemic zone perfusion.

To examine the effect of risk area size on collateral resistance and ischemic region perfusion, we produced different sized risk areas by occluding either the left anterior descending (LAD) or the circumflex (Cx) coronary artery at different sites. The most proximal occlusion of the LAD and Cx produced risk areas of 43 +/- 5 and 36 +/- 2% of left ventricular (LV) mass, respectively, whereas distal LAD and Cx occlusions produced risk areas of 13 +/- 2 and 17 +/- 2% of LV weight, respectively. Although total collateral flow was highest to the largest risk areas, collateral flow per 100 g of ischemic myocardium was 80% higher to the small LAD risk area compared with the large LAD risk area and 43% higher to the small Cx risk area compared with the large Cx risk area. Collateral resistance, calculated from the transcollateral pressure and perfusion per 100 g of myocardium was significantly lower in the small risk areas than in the large ones. We examined the effect of risk area location on collateral perfusion and resistance. Small risk areas (6% LV mass) were created near the base and at the apex of 10 hearts. Collateral flow per 100 g was 60% higher and transcollateral resistance per 100 g 50% lower at the apex than at the base. These experiments show that collateral resistance is influenced both by ischemic region size and location. Small risk areas receive more collateral flow per mass of tissue than large risk areas, and apical risk areas receive greater quantities of collateral flow than those located at the base.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

The effect of hypertension and left ventricular hypertrophy on the lower range of coronary autoregulation.

These studies were performed to test the hypothesis that left ventricular hypertrophy arising as a complication of chronic hypertension is associated with impaired coronary autoregulation. Twelve dogs with hypertension and left ventricular hypertrophy (one-kidney, one-clip model) and 11 normal dogs were instrumented and subsequently studied while conscious. Circumflex pressure, measured with an intracoronary catheter, was adjusted to 100, 75, and 40 mm Hg with a hydraulic occluder that was placed proximally. At each circumflex pressure, myocardial perfusion was measured with radioactive microspheres. Reduction of circumflex pressure over this range did not significantly alter heart rate, left atrial pressure, or arterial pressure. In normal dogs, reduction of circumflex pressure did not alter total myocardial perfusion or the transmural distribution of perfusion. In contrast, in dogs with hypertension and left ventricular hypertrophy, circumflex subendocardial perfusion decreased 46% when pressure was decreased from 100 to 40 mm Hg (p less than .05 compared with normal). Autoregulation was quantified for each third of myocardium with the use of autoregulatory gain values (1 = perfect autoregulation; 0 = the absence of autoregulation). For pressure changes of 100 to 75 mmHg, values for autoregulatory gain were near unity for all layers of myocardium in both groups of animals. When pressure was decreased from 75 to 40 mm Hg, values for autoregulatory gain among the normal and hypertensive groups were, respectively: for subepicardium 1 +/- 0.2 (mean +/- SE) vs 0.9 +/- 0.2 (p = NS), for the midwall 0.8 +/- 0.2 vs 0.5 +/- 0.2 (p = NS), and for the subendocardium 0.8 +/- 0.1 vs 0.1 +/- 0.2 (p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Responsiveness of iliac collateral vessels to constrictor stimuli in atherosclerotic primates.

This study was performed to examine, first, the protective effects and responses of collateral vessels of the hind limb in normal and atherosclerotic monkeys and, second, the effects of chronic arterial occlusion on the development of atherosclerosis. The iliac artery was ligated on one side in cynomolgus monkeys. Sixteen months later, we recorded the pressure gradient across the limb collaterals and measured blood flow with microspheres. Collateral conductance was fivefold greater after chronic ligation of the iliac artery than after acute ligation. Despite dilatation or growth of collateral vessels after chronic ligation, iliac pressure was reduced distal to the ligation. Blood flow to the limb was normal after chronic ligation in both normal and atherosclerotic monkeys. Collateral vessels constricted in response to infusion of phenylephrine and serotonin in normal and atherosclerotic monkeys. Thus, one conclusion of this study is that collateral vessels restore limb blood flow to normal after chronic vascular occlusion in both normal and atherosclerotic monkeys, but the protective effects of collateral vessels may be compromised by vasoconstrictor stimuli. Morphometric measurements indicated that occlusion of the iliac artery reduced proliferation of atherosclerotic intima distal to the occlusion in the cholesterol-fed monkeys. Thus, a second conclusion of this study is that atherosclerosis is attenuated below an arterial occlusion.

Animals↗
PubMed1987

Serotonin and experimental vascular disease.

We have examined effects of atherosclerosis on constrictor responses to serotonin in several vascular beds. In normal monkeys, serotonin produces modest constriction of large arteries. In atherosclerotic monkeys, vasoconstrictor responses to serotonin are greatly potentiated in the limb, cerebral, and mesenteric circulation. The findings may be pertinent to the pathogenesis of vasospasm, which is an important complication of atherosclerosis. Platelets release serotonin when they aggregate. If platelets aggregate at atherosclerotic lesions and release serotonin, and vasoconstrictor responses to serotonin are greatly potentiated in atherosclerotic arteries, serotonin may be an important mediator of vasospasm. To determine whether treatment of atherosclerosis alters vascular responses, atherosclerotic monkeys were fed a low-cholesterol diet for 18 months. This treatment produced marked improvement in vascular lesions, but maximal vasodilator responses were not consistently improved by treatment of atherosclerosis. We speculated that fibrosis of the vessel may prevent improvement of vasodilator responses in vessels with fixed lesions. In contrast, we have found recently that dietary treatment of atherosclerosis abolishes hyperresponsiveness to serotonin in the limb. We conclude that atherosclerosis potentiates vasoconstrictor responses to serotonin and these abnormalities are reversible by dietary treatment of atherosclerosis.

Animals↗
PubMed1987

Relative importance of hypertension after coronary occlusion in chronic hypertensive dogs with LVH.

We have shown that there was a 50% increase in infarct size and a threefold increase in the incidence of sudden death following coronary occlusion in dogs with hypertension and left ventricular hypertrophy (LVH). To further investigate this problem, we separated the effects of hypertension from those of LVH by decreasing arterial pressure either by renal anastomosis or intravenous administration of nitroprusside in dogs with chronic renal hypertension and LVH. In 123 conscious dogs, the circumflex coronary artery was acutely occluded. Hemodynamics were monitored, myocardial perfusion was measured with labeled microspheres, the risk area was defined by postmortem angiography, and infarct size was determined pathologically 48 h after occlusion. The incidence of sudden death following acute coronary occlusion decreased dramatically in dogs with LVH if the arterial pressure was decreased with either nitroprusside or renal anastomosis. In addition, if arterial pressure was decreased with nitroprusside or renal anastomosis, infarct size in dogs with LVH was not augmented. In conclusion, normotension induced by renal anastomosis or nitroprusside returned infarct size and the incidence of sudden death in dogs with chronic hypertension and LVH toward control values. Thus it is likely that hypertension, as opposed to LVH, is the critical factor responsible for the increase in infarct size and the high incidence of sudden death observed in dogs with hypertension and LVH following sudden coronary occlusion.

Animals↗
PubMed1987

Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis.

Atherosclerosis results in impaired relaxation to acetylcholine, thrombin, and the calcium ionophore A23187, all agents that require the presence of endothelium. We now report that dietary treatment of atherosclerosis in monkeys not only produces morphological improvement of the atherosclerotic lesion but restores endothelium-dependent vascular relaxation to normal. Because the intima remains thickened after regression of atherosclerosis, these studies suggest that intimal thickening which is present in both atherosclerotic vessels and after regression of atherosclerosis does not prevent the endothelium-derived relaxing factor from reaching the underlying vascular smooth muscle.

Animals↗
PubMed1987

Alterations of vascular reactivity in atherosclerosis.

We have previously found that vascular relaxation to acetylcholine and thrombin is markedly impaired in vessels from monkeys with diet-induced atherosclerosis. In the present study, we found that both normal and atherosclerotic vessels relaxed completely to the calcium ionophore A23187, which stimulates release of the endothelium-derived relaxing factor by nonreceptor-mediated mechanisms. Atherosclerotic vessels, however, were less sensitive to this agent. The finding that responses to the calcium ionophore were impaired in atherosclerosis suggests that abnormal endothelium-dependent relaxation in atherosclerotic vessels is not related entirely to alterations of thrombin and muscarinic receptors but may also be due to abnormal endothelium-derived relaxing factor production or transfer from the endothelium to the underlying vascular smooth muscle. Neither normal nor atherosclerotic iliac arteries constricted in response to acetylcholine when studied in the nonpreconstricted state. Constriction to acetylcholine in these vessels was not unmasked by removal of the endothelium. Thus, the smooth muscle of iliac vessels from monkeys contains few functioning muscarinic receptors. Impaired relaxation of atherosclerotic vessels to acetylcholine is not due to enhanced muscarinic-mediated constriction or to production of an endothelium-derived constricting factor. In vivo studies were performed to determine if alpha-adrenergic coronary vascular constriction is enhanced in the presence of atherosclerosis. In anesthetized monkeys, myocardial oxygen consumption was increased by two mechanisms, aortic occlusion and phenylephrine infusion. During both aortic occlusion and phenylephrine infusion, decreases in coronary vascular resistance were similar in control and atherosclerotic monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1987

Alterations in the coronary circulation in hypertrophied ventricles.

During the past decade our understanding of the complex interaction between cardiac muscle and coronary vascular growth has increased substantially. Some types of cardiac hypertrophy, for example, left ventricular hypertrophy secondary to hyperthyroidism, are associated with increased coronary vascular growth. However, in most animal preparations of hypertrophy and in several clinical types of hypertrophy of the left and/or right ventricles, pathologic cardiac enlargement impairs the ability of the coronary circulation to allow normal increases and perfusion in response to intense dilator stimuli. In general, clinical studies have demonstrated far more profound abnormalities than studies in experimental animals. These observations provide a plausible explanation of why patients with hypertrophied ventricles often exhibit signs and symptoms of myocardial ischemia in the absence of coronary obstructive disease. The recent observation that experimentally produced left ventricular hypertrophy secondary to renal hypertension augments infarct size and the incidence of sudden lethal arrhythmias has additional implications relevant to the interaction between cardiac hypertrophy and myocardial perfusion. Although coronary reserve is impaired in many types of pathologic hypertrophy, the anatomic or biochemical basis for these observations remains elusive.

Animals↗
PubMed1986

Coronary obstructive lesions: assessing their physiological significance in humans.

For more than two decades cardiologists and cardiac surgeons have estimated the physiologic significance of coronary lesions by measuring percent stenosis of the obstructive vascular segment from coronary angiograms. Such measurements, when performed without computer-based analysis, are associated with substantial variability between observers, as well as within a single observer. In addition, recent intraoperative measurements of coronary reserve in individual obstructed vessels of patients with multivessel coronary disease performed with a suction Doppler probe indicate that, in the intermediate range (10% to 90% diameter stenosis), percent stenosis measurements of coronary lesions by angiography correlates poorly with coronary reserve. These studies suggest that the physiologic significance of coronary obstructions cannot be accurately assessed by visual interpretation of coronary angiograms. More sophisticated and accurate approaches are needed for assessing the physiologic significance of coronary obstructions preoperatively.

Coronary Disease↗
PubMed1986

Studies of functional site of origin of native coronary collaterals.

Studies were performed to determine the pressure at the origin of the native coronary collaterals (Pstem) and thus assess the contribution of collaterals arising from proximal conduit coronary vessels vs. those arising from distal microvessels. Nine isolated blood-perfused dog hearts were studied. Aortic pressure was maintained at 80 mmHg. Collateral flow to the circumflex perfusion field was measured (radioactive microspheres) repeatedly before and after successive 25-micron nonradioactive microsphere embolization of the circumflex vasculature. After each microembolization, collateral flow decreased and peripheral coronary pressure (PCP) increased. After all embolizations collateral flow decreased from an initial value of 17 +/- 4 to 2 +/- 0.4 ml X min-1 X 100 g-1 and PCP increased from an initial value of 15 +/- 3 to 65 +/- 3 mmHg. The relationship between decreasing collateral flow and increasing PCP was linear with a pressure intercept of 74 +/- 3 mmHg. This pressure intercept predicts the PCP that would be observed if microembolization produced complete cessation of collateral flow. Accordingly, this pressure intercept allowed an accurate estimate of Pstem. This estimate of Pstem was similar to left anterior descending pressure (75 +/- 2 mmHg). These studies show that Pstem may be accurately estimated by measuring pressure in a nonoccluded large epicardial vessel. The contribution of microvascular anastomoses to total collateral flow is likely small.

Animals↗