Pamela A.C. Watt

Pulse Pressure and Resistance Artery Structure in the Elderly

There has been recent interest in the possibility that resistance vessel structural adaptation in hypertension may be more closely related to pulse pressure than to other blood pressure parameters. We investigated the relation between blood pressure and resistance vessel structure in a group of subjects from an age group (older than 60 years) in which a widening of pulse pressure is a typical finding and characterized blood pressure parameters using 24-hour ambulatory blood pressure monitoring. We studied resistance vessels retrieved from biopsies of skin and subcutaneous fat taken from the gluteal region of 32 subjects under local anesthesia (age, 70 +/- 1 years [mean +/- SEM], 21 of whom were hypertensive and 11 normotensive. Media-lumen ratio was higher in the hypertensive than the normotensive subjects (18.6 +/- 1.6% versus 12.8 +/- 1.2%, P < .01) and correlated with age (r = .44, P < .05), clinic systolic pressure (r = .35, P < .05), 24-hour systolic pressure (r = .40, P < .05), and 24-hour pulse pressure (r = .56, P < .001). Stepwise multivariate regression analysis identified clinic and 24-hour pulse pressure as the only significant predictors of media-lumen ratio independent of age, other parameters of clinic blood pressure, and blood pressure variability (R2 = 41%, P < .05). These findings confirm those from animal models of hypertension in demonstrating the importance of pulse pressure in relation to cardiovascular structural adaptation and have important implications for the goals of treatment of hypertension in the elderly.

Endothelium-dependent relaxation in resistance vessels from the spontaneously hypertensive rats.

The endothelium-dependent vasodilator acetylcholine was used to observe relaxation responses of noradrenaline-contracted mesenteric resistance vessels from 3-, 6-, 12- and 18-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Relaxation responses were greater than normal in the 3-week-old SHR but the pattern of response was different in the 6-18-week-old SHR compared with the WKY. In these older animals, low concentrations of acetylcholine relaxed SHR and WKY vessels to a similar extent, but high concentrations (greater than 10(-7) mol/l) caused the partially relaxed vessels to contract again. Indomethacin enhanced relaxation in the 12-week-old SHR and reduced the difference between the SHR and WKY. The reduction in acetylcholine-induced, endothelium-dependent relaxation in SHR suggested that a functional change occurred, causing the vessels to release a vasoconstrictor factor that opposes the action of endothelium-derived relaxing factor.

Contraction and relaxation of human internal mammary artery after intraluminal administration of papaverine

The internal mammary artery has become the conduit of choice for coronary artery bypass grafting. Intraluminal papaverine treatment during operation reduces vasospasm and facilitates anastomosis. However, it has been suggested that papaverine may cause intimal damage, and accordingly we have investigated endothelial damage by comparing the responsiveness of internal mammary arteries before and after intraluminal exposure to papaverine (15 mg/mL). Control and papaverine-treated segments of internal mammary artery were obtained from 13 patients undergoing coronary artery bypass grafting and mounted as ring preparations in an organ bath. Cumulative dose contractions to noradrenaline were performed, and the dose producing a half maximal response was determined. Relaxation studies of submaximally contracted arteries were performed using the endothelium-dependent vasodilators acetylcholine and bradykinin and the endothelium-independent vasodilator sodium nitroprusside. In the human internal mammary artery the use of intraluminal papaverine increased the lumen size by 20% (p less than 0.05), and the contractions elicited by noradrenaline were significantly less in the papaverine group than in the control group (p less than 0.05). Endothelium-dependent relaxation to acetylcholine or bradykinin was not affected by papaverine treatment. Endothelium-independent relaxation was the same in both groups, with almost 100% relaxation achieved by sodium nitroprusside. These results indicate that intraluminal papaverine treatment during coronary artery bypass grafting causes a reduction of smooth muscle contraction and does not impair endothelium-dependent relaxation.

The effect of insulin on the vascular reactivity of isolated resistance arteries taken from healthy volunteers.

SummaryImpaired reactivity of the resistance vasculature may contribute to the development of diabetic microangiopathy by altering microvascular haemodynamics. This study investigates the acute effects of insulin on the contractility and relaxation properties of isolated human resistance arteries (<300 Μm internal diameter) taken from gluteal subcutaneous fat of 33 (18 male: 15 female) normotensive healthy volunteers (supine blood pressure 115.6±1.6/ 70.0±1.5 mm Hg [mean±SEM], with no family history of hypertension or diabetes mellitus. Resistance arteries were mounted in a small vessel myograph to measure isometric tension. Contractile responses to noradrenaline were reduced after incubation in 1 mU/ml of insulin for 20 min (p<0.01; Group 1). Increasing concentrations of insulin were found to reduce the contractile response to noradrenaline in a dose-dependent manner (Group 2; 0.1 mU/ml by 8% [p<0.01], 1 mU/ml by 17% [p<0.02] and 10 mU/ml by 22% [p< 0.01]). Sensitivity to insulin (ED50) only decreased at the highest concentration of insulin. However, acetycholine-induced relaxation was not altered by insulin (Group 2). Time control studies (Group 3) showed that contractile and relaxation responses over the 4-h study period were unchanged. Furthermore, the length of time the vessels were exposed to insulin did not progressively impair responses (Group 4). These findings suggest that insulin may induce abnormalities in vascular smooth muscle contractility, a factor that may contribute to or exacerbate the abnormal haemodynamics observed in the capillary microcirculation of numerous vascular beds in diabetes.

Endothelium-dependent modulation of resistance vessel contraction: studies with NG-nitro-l-arginine methyl ester and NG-nitro-l-arginine

1 The effect of NG‐nitro‐l‐arginine methyl ester (l‐NAME) and NG‐nitro‐l‐arginine (l‐NOARG) on noradrenaline (NA)‐induced contractility and acetylcholine (ACh)‐induced endothelium‐dependent relaxation was studied in rat mesenteric resistance arteries. 2 Third order branches of mesenteric arteries were dissected and mounted on two forty micron wires in a Mulvany myograph. 3 Incubation with l‐NAME and l‐NOARG (10 μm) caused a time‐dependent shift in the 50% response to NA (ED50) (0.01 μm‐10 μm) but was not associated with an increase in the maximum contractile response. 4 l‐NAME and l‐NOARG (10 μm) caused a time‐dependent inhibition of ACh (1 μm)‐induced relaxation with a maximum effect after 120 min. 5 Following endothelium removal, incubation with either l‐NAME or l‐NOARG caused no significant shift in the ED50, although the residual relaxation response to ACh (1 μm) was further attenuated. 6 Incubation with the cylco‐oxygenase inhibitor, indomethacin, enhanced the relaxation to ACh and reduced the inhibitory effects of l‐NAME and l‐NOARG. 7 In conclusion, l‐NAME and l‐NOARG are potent inhibitors of acetylcholine‐induced endothelium‐dependent relaxation in mesenteric resistance arteries. The shift in ED50 associated wtih these inhibitors suggests a probable role for the endothelium in modulating the contractility of the resistance vasculature.

Vasoconstrictor actions of endothelin-1 in human resistance vessels.

The contractile response to endothelin-1 was studied in isolated human resistance vessels in the presence and absence of extracellular calcium. Endothelin-1 was 1000-fold more potent than noradrenaline, with an ED50 of 6.5 +/- 1.26 x 10(-9) mol/l compared with 2.1 +/- 0.7 x 10(-6) mol/l. Calcium depletion by repeated stimulation with noradrenaline in a calcium-free medium attenuated but did not prevent a sustained contraction in response to endothelin-1 (30% of control). On re-adding calcium to the bath a full contraction immediately occurred. These experiments suggest that an endothelin-1-induced contraction is largely dependent on the presence of extracellular calcium, but a partial contraction can be induced in a calcium-free medium and this may be dependent on mobilization of intracellular calcium from a store not affected by repeated noradrenaline stimulation.

Inhibition of Endothelium-Dependent Relaxation by Free Hemoglobin in the Human Internal Thoracic Artery

Hemolysis and postoperative hypertension are well recognized complications of cardiopulmonary bypass (CPB). The rise in the concentration of total and free hemo globin is directly related to the duration of CPB. It is well established that free hemoglobin binds and inactivates endothelium-derived relaxing factor, and the authors have studied the effects of low concentrations of free hemoglobin on the endothelium-dependent and endothelium-independent relaxation of the human internal thoracic artery (ITA). In the presence of free hemoglobin the endothelium-dependent relaxation induced by acetylcholine was reduced by 80% with 0.5 μM free hemoglobin (P< 0.01) and by 52% with 0.1 μM free hemoglobin (P<0.05). Sodium nitroprusside, endothelium indepen dent, produced relaxation of almost 100%. These results indicate that relatively low concentrations of free hemoglobin significantly inhibit endothelium-dependent but not endothelium-independent relaxation. This may influence blood flow in the ITA and may be a contributory factor in postoperative hypertension.

EFFECT OF CHRONIC ISCHEMIA ON HUMAN SMALL ARTERIES

Critical limb ischemia (CLI) is the term used to describe chronic ischemia which is of a severity to endanger the whole or part of the leg. It is generally caused by advanced atherosclerotic peripheral vascular disease producing an occlusion of a large artery or arteries in the leg. The hemodynamic consequences are increased resistance at the proximal obstruction with a reduction in distal perfusion pressure and blood flow to the peripheral circulation (1).