Flow-Dependent Dilation and Myogenic Constriction Interact to Establish the Resistance of Skeletal Muscle Arterioles

Objective: To test the hypothesis that the diameter of skeletal muscle arterioles is determined by the interaction of responses elicited by intravascular pressure and flow. Methods: Experiments were conducted on isolated, cannulated, first-order arterioles of cremaster muscle of male Wistar rats. The diameter of arterioles was followed by videomicroscopy. Perfusion pressures and flows were controlled. Results: In the absence of perfusate flow, increases in perfusion pressure (from 0 to 120 mm Hg), after initial dilation, elicited endothelium independent constrictions of arterioles. At 60 mm Hg of perfusion pressure, the active diameter of vessels was 84.9 ± 1.9 μm. The passive diameter of arterioles (Ca²⁺-free solution) was 150.6 ± 2.4 μm. Increases in perfusate flow resulted in a significant upward shift in the pressure—diameter curves; in the presence of perfusate flows of 20, 40, and 60 μL/min, the constriction of the vessels at a pressure of 60 mm Hg was attenuated by 25.1 ± 3.9%, 35.2 ± 3.0%, and 46.8 ± 4.4%, respectively. In contrast, the corresponding diameter of arterioles at perfusate flows of 10 to 60 μL/min was significantly reduced when perfusion pressure was increased from 60 to 80 and 100 mm Hg (at a flow of 60 μL/min) by 12.0 ± 4.3% and 37.1 ± 2.8%, respectively. Hence, both flow- and shear stress—diameter curves were significantly shifted downward when perfusion pressure increased from 60 to 100 mm Hg. Conclusion: These results demonstrate that an interplay between pressure and flow-sensitive mechanisms is an important determinant of the arteriolar resistance in skeletal muscle.     

Acute and chronic effects of nitrendipine in patients with precapillary pulmonary hypertension due to pulmonary fibrosis

Eleven patients with histologically confirmed fibrosis of the lung were investigated for the effects of the dihydropyridine calcium antagonist nitrendipine on pulmonary hemodynamics. After 5 mg of acute sublingual nitrendipine, mean pulmonary artery pressure was significantly lowered (p≤0.05) from 32 ± 3 to 29 ± 3 mmHg at rest, and significantly lowered (p≤0.05) during exercise from 55 ± 4 to 49 ± 4 mmHg. Short-term oxygen application at rest significantly reduced this parameter to 28 ± 3 mmHg(p≤0.01). Nitrendipine lowered total pulmonary vascular resistance during both rest (from 412 ± 50 to 351 ± 49 dyn?S?cm^-5; p≤0.05) and exercise (from 433 ± 61 to 383 ± 54 dyn?s?cm^-5; p≤0.05), although it did not affect pulmonary arteriolar resistance. Also, oxygen treatment at rest influenced only total pulmonary vascular resistance (reduction from 412 ± 50 to 373 ± 48 dyn?s?cm^-5; p≤0.01), but not pulmonary arteriolar resistance. Pressure-flow curves, which were derived from cardiac output at rest and during exercise and from the corresponding gradient between mean pulmonary artery pressure and pulmonary capillary wedge pressure, remained unchanged by acute medication. Since a change in arterial oxygen partial pressure was not noticed after nitrendipine, arteriovenous shunting or a worsening of ventilation perfusion relationships can be excluded. Long-term (3 weeks) treatment (double-blind parallel design) with 10 mg of nitrendipine (4 patients) once daily showed no advantage in comparison to placebo (6 patients). From these observations we conclude that the reduction of lower circulatory pressures after nitrendipine is not caused by pulmonary arteriolar vasodilation, but rather by indirect effects due to the reduction of total peripheral resistance and left ventricular filling pressure.     

Cardiocirculatory and myocardial energetic effects of prostaglandin E1 in severe left ventricular failure due to chronic coronary heart disease

The cardiocirculatory actions of brief (69 ± 5 minutes) infusions of prostaglandin E₁ were evaluated in nine chronic coronary heart disease patients with severe left ventricular (LV) failure caused by previous myocardial infarction. Prostaglandin E₁ infusion did not alter heart rate (HR) and produced modest declines in mean systemic blood pressure (BP) (85 ± 6 to 76 ± 5 mm Hg, p < 0.025) and LV filling pressure (19 ± 3 to 15 ± 2 mm Hg, p < 0.01). Simultaneously, prostaglandin E₁ augmented LV pump function raising cardiac index from 1.9 ± 0.2 to 2.5 ± 0.2 L/min/m² (p < 0.005), elevating stroke index from 28 ± 2.4 to 35 ± 2.9 ml/beat/m² (p < 0.01), and increasing stroke work index from 26 ± 4.3 to 30 ± 4.4 gm·m/m² (p < 0.02). Additionally, total systemic vascular resistance decreased from 1862 ± 192 to 1282 ± 100 dynes-sec-cm^?5 (p < 0.02) and double product LV aerobic index of HR · systolic BP diminished from 9492 ± 666 to 8278 ± 493 (p < 0.02). Concomitantly, in the forearm, vascular resistance fell, blood flow rose, and venous tone remained unchanged. These results indicate that prostaglandin E₁ is a potent systemic arteriolar dilator with markedly beneficial effects on cardiac function in chronic coronary patients having severe ischemic LV failure refractory to conventional therapy.     

Pressure effects on the flow behavior of sickle (HbSS) red cells in isolated (ex-vivo) microvascular system

The effect of varying arterial perfusion pressure (P_a) on flow behavior of human normal (HbAA) and sickle (HbSS) erythrocytes was evaluated in isolated rat mesoappendix vasculature. Red cell velocity (V_rbc) and wall shear rate in single arterioles (i.d. 20.4 ± 4.5 μm, $\text{X}$ and SD) were determined and total peripheral vascular resistance (PRU) calculated. The vasculature initially perfused with Ringer's solution was then perfused with red cells suspended (HCT 2%) in the same medium. At P_a of 100 mm Hg, oxy HbSS cells resulted in higher (50%) PRU and lower V_rbc (7.1 ± 2.2 mm/sec) and wall shear rates (1800 ± 490 sec^?1) than those recorded with HbAA cells which show a more rapid microvascular passage, i.e., V_rbc (14.4 ± 2.8 mm/sec) and wall shear rates (3810 ± 360 sec^?1). At the same P_a, partial deoxygenation (PO₂ 40 mm Hg) of HbSS cells caused marked (300%) increase in PRU, and decrease in V_rbc (3.2 ± 0.9 mm/sec), and wall shear rates (820 ± 440 sec^?1). During stepwise decrement of P_a (100-30 mm Hg), PRU for oxy HbSS cells remains elevated but the overall trend is similar to that for HbAA cells and Ringer's perfusion. At P_a of 30 mm Hg, oxy HbSS cells caused some microvascular obstruction. In contrast, with decrement in P_a below 80 mm Hg partially deoxy HbSS cells resulted in progressive increase in PRU and drastic decrease in V_rbc, coupled with progressive capillary obstruction and stasis. An increased propensity of these cells to cause irreversible vasoocclusion is demonstrated when low-pressure conditions prevail.     

Intravascular pressure distribution and dimensional analysis of microvessels in hamsters with renovascular hypertension

Microvascular pressures and dimensional analysis (wall and lumen diameters) were measured in the branching network of arterioles and venules in the cheek pouch of both normotensive (NT) and hypertensive (HT) hamsters before and after vasodilating with nitroprusside (10^?4M). The Grollman technique was used to induce renovascular HT in 15 hamsters and 12 others were sham operated. The microcirculation of the cheek pouch was evaluated 10–26 days later using intravital microscopy after anesthetization with pentobarbital. Systemic blood pressure (direct catheterization) and microvascular pressure (Servo-Null system with micropipets) were measured. In the HT hamsters (133 ± 3 mm Hg), all arteriolar microvascular pressures were increased by 15–26% as compared to the NT hamsters (113 ± 4 mm Hg). However, pressures in small venules (10–20 μm) were decreased by 50–60%. Lumen diameters in first-order arterioles (90–120 μm) and in the venules of HT hamsters decreased. Vasodilation reduced systemic and microvascular pressures and increased lumen diameters to the same extent in both NT and HT hamsters. These results indicate that in HT hamsters arteriolar pressures are elevated and that there is a large drop in pressure across the capillaries which includes small arterioles and venules. These elevated arteriolar pressures do not appear to be due to structural hypertrophy with encroachment on lumen diameters.     

Effect of changes in vascular tone on the haemodynamic characteristics of the portal vascular bed of the isolated perfused rat liver

The effect of altered vascular tone on the haemodynamic characteristics of the intrahepatic portal vascular bed was studied in the isolated perfused rat liver preparation. The relationship between portal venous inflow (Q) and portal perfusion pressure (P) was determined in the presence of a maximally effective concentration of a vasoconstrictor agent (noradrenaline, NA_max, 3 × 10^?5mol/L), an intermediate concentration (NA_med, 1 × 10^?6mol/L) or a vasodilator agent (papaverine, PAP, 6 × 10^?4mol/L). At flow rates greater than 20 mL/min, the pressure-flow relationship could be regarded as linear (P < 0.001), with mean values for the extrapolated intercept with the pressure axis (P_o) of 6.8 ± 0.9 mmHg for NA_max, 4.5 ± 0.5 mmHg for NA_med, and 1.65 ± 0.05 mmHg for PAP-treated preparations. Over the full flow range (0–70 mL/min), in both NA- and PAP-treated preparations, portal vascular conductance (G = Q/P) was related directly to perfusion pressure. Thus, G = C.P, where C is a constant (mean values for NA_max, NA_med, and PAP-treated preparations were 0.0090 ± 0.0020, 0.023 ± 0.005, and 0.26 ± 0.02 mL/min per g per mmHg², respectively). It is concluded that both C and P_o may be useful indices of tone in the isolated perfused rat liver, and that analysis of hepatic portal haemodynamics in this manner may have considerable practical value in studies of the action of vasoactive agents.     

Partitioning of Pulmonary Vascular Resistance in Primary Pulmonary Hypertension

Objectives. This study sought to determine the site of increased pulmonary vascular resistance (PVR) in primary pulmonary hypertension by standard bedside hemodynamic evaluation.Background. The measurement of pulmonary vascular pressures at several levels of flow (Q) allows the discrimination between active and passive, flow-dependent changes in mean pulmonary artery pressure (Ppa), and may detect the presence of an increased pulmonary vascular closing pressure. The determination of a capillary pressure (Pc′) from the analysis of a Ppa decay curve after balloon occlusion allows the partitioning of PVR in an arterial and a (capillary + venous) segment. These approaches have not been reported in primary pulmonary hypertension.Methods. Ppa and Pc′ were measured at baseline and after an increase in Q induced either by exercise or by an infusion of dobutamine, at a dosage up to 8 μg/kg body weight per min, in 11 patients with primary pulmonary hypertension. Reversibility of pulmonary hypertension was assessed by the inhalation of 20 ppm nitric oxide (NO), and, in 6 patients, by an infusion of prostacyclin.Results. At baseline, Ppa was 52 ± 3 mm Hg (mean value ± SE), Q 2.2 ± 0.2 liters/min per m², and Pc′ 29 ± 3 mm Hg. Dobutamine did not affect Pc′ and allowed the calculation of an averaged extrapolated pressure intercept of Ppa/Q plots of 34 mm Hg. Inhaled NO had no effect. Prostacyclin decreased Pc′ and PVR. Exercise increased Pc′ to 40 ± 3 mm Hg but did not affect PVR.Conclusions. These findings are compatible with a major increase of resistance and reactivity at the periphery of the pulmonary arterial tree.     

Favorable effects of hydralazine on the hemodynamic response to isometric exercise in chronic severe aortic regurgitation

The hemodynamic effects of isometric exercise and the response to hydralazine therapy were evaluated in 11 patients with chronic, severe aortic regurgitation (AR). Isometric exercise produced a significant increase in heart rate (from 78 ± 11 to 93 ± 19 beats/min [mean ± standard deviation], p < 0.05), mean blood pressure (from 83 ± 8 to 104 ± 20 mm Hg, p < 0.05), mean right atrial pressure (from 3 ± 2 to 7 ± 5 mm Hg, p < 0.05) and mean pulmonary artery wedge pressure (from 12 ± 7 to 18 ± 10 mm Hg, p < 0.05). Small and insignificant changes were seen in cardiac index (from 3.4 ± 0.8 to 3.9 ± 1.0 liters/min/m²), systemic vascular resistance (from 1,097 ± 257 to 1,171 ± 284 dynes s cm^?5), pulmonary vascular resistance (from 120 ± 76 to 130 ± 89 dynes s cm^?5) and stroke volume index (from 44 ± 10 to 43 ± 12 ml/m²). After oral hydralazine administration (100 to 300 mg), hemodynamic values during isometric exercise were: Heart rate increased further, to 105 ± 14 beats/min (p < 0.05), mean blood pressure was 102 ± 16 mm Hg (difference not significant [NS]) cardiac index increased markedly, to 5.2 ± 1.4 liters/min/m² (p < 0.05), stroke volume index increased to 49 ± 12 ml/m² (p < 0.05), right atrial pressure decreased slightly, to 5 ± 5 mm Hg (NS), pulmonary artery wedge pressure decreased to 14 ± 7 mm Hg (p < 0.05), systemic vascular resistance decreased to 903 ± 288 dynes s cm^?5 (p < 0.05), and pulmonary vascular resistance changed to 100 ± 66 dynes s crrr^?5 (NS). Thus, isometric exercise in patients with chronic severe AR is associated with only a slight and insignificant increase in systemic vascular resistance, but a marked increase in pulmonary artery wedge pressure. Direct arteriolar vasodilation with hydralazine results in a significant attenuation of pulmonary artery wedge pressure increase during isometric exercise and leads concomitantly to a significant augmentation of stroke volume and cardiac output. These findings substantiate the value of hydralazine therapy in patients with chronic, severe AR.     

The effect of coronary inflow pressure on coronary vascular resistance in the isolated dog heart

The shape of the coronary arterial pressure-flow relationship results from the interaction of a number of poorly understood physiological factors. Experiments in which coronary inflow and outflow pressures were coupled so that driving pressure was held constant showed that changes in inflow or outflow pressures altered coronary blood flow: coronary vascular resistance varied inversely with changes inflow pressure below 50 mm Hg and with changes in outflow pressure below 80 mm Hg. The magnitude of the influence of inflow pressure on resistance also depended on the fixed level of outflow pressure, the influence being large when the outflow pressure was low, and small when it was high. Inflow and outflow pressures, then, are two physiological factors which are determinants of the shape of the pressure-flow relationship, and their interaction contributes to the degree of curvature found in a particular relationship. These findings suggest that the use of linear regression in the interpretation of pressure-flow relationships results in poor estimation of resistance and zero-flow pressure. Other experiments measuring regional coronary blood flow using radionuclide-labeled microspheres resulted in the same inverse relationship between inflow pressure and resistance, regardless of mural depth, indicating that inflow pressure may influence resistance by distending vessels, rather than by causing sequential cessation of perfusion in successive transmural layers.     

Prostacyclin therapy in patients with congestive heart failure

The acute hemodynamic effects of intravenous prostacyclin (PGI₂), in doses of 22 ± 11 ng/kg per min were studied in nine patients with severe congestive heart failure refractory to digitalis and diuretic drugs. After prostacyclin infusion, mean (±standard deviation) pulmonary capillary wedge pressure decreased from 21.0 ± 7.9 to 15.0 ± 6.6 mm Hg (p < 0.001), mean arterial pressure from 98.9 ± 12.8 to 76.2 ± 7.0 mm Hg (p < 0.001), systemic vascular resistance from 2,574 ± 384 to > 1,368 ± 283 dynes s cm^?5 (p < 0.001), pulmonary vascular resistance from 1,008 ± 451 to 443 ± 135 dynes s cm^?5 (p < 0.001) and pulmonary arteriolar resistance from 330 ± 111 to 189 ± 73 dynes s cm^?5 (p < 0.001). Heart rate increased from 78 ± 21 to 82 ± 24 beats/min (p = not significant [NS]), cardiac index from 2.0 ± 0.37 to 3.2 ± 0.59 liters/min per m² (p < 0.001) and stroke index from 27.6 ± 8.69 to 42.0 ± 0.62 cc/m² (p < 0.001). With prostacyclin, moreover, coldness of the limbs and face disappeared, and patients felt warmth and mild flushing of the face. After prostacyclin, plasma norepinephrine levels, renin activity and aldosterone concentrations rose from 824 ± 375 to 880 ± 468 pg/ml (NS), 0.68 ± 1.36 to 0.95 ± 1.21 ng/ml per h (NS), and 6.64 ± 2.50 to 6.38 ± 2.88 ng/dl (NS), respectively, while plasma epinephrine increased from 140 ± 80 to 250 ± 154 pg/ml (p < 0.025).     

Comparison of hemodynamic responses to nifedipine and nitroprusside in severe chronic congestive heart failure

The hemodynamic effects of 20 to 40 mg of oral nifedipine were compared with those of intravenous nitroprusside in 11 patients with severe chronic congestive heart failure (CHF). In each patient, both drugs were administered to produce similar reduction of systemic vascular resistance (SVR) (29 ± 13% with nifedipine and 29 ± 12% with nitroprusside, difference not significant [NS]). At this comparable decrease in systemic vascular resistance, significant differences in hemodynamic responses to both drugs were noted: Nifedipine caused a smaller increase in cardiac index (20 ± 20% vs 40 ± 24%, p < 0.02) and a larger decrease in mean blood pressure than nitroprusside (16 ± 9% vs 8 ± 10%, p < 0.05). In addition, nifedipine produced a smaller decrease in mean pulmonary artery wedge pressure (13 ± 24% vs 36 ± 21%, p < 0.001) and pulmonary vascular resistance than nitroprusside (6 ± 42% vs 26 ± 46%, NS. Mean right atrial pressure decreased with nitroprusside, from 10 ± 7 to 5 ± 3 mm Hg (p < 0.05), but not with nifedipine (10 ± 7 mm Hg before and after nifedipine administration, NS). Left ventricular stroke work index increased with nitroprusside (20 ± 8 to 27 ± 9 g-m/m², p < 0.05), but did not change with nifedipine (21 ± 9 vs 21 ± 10 g-m/m², NS). These data show that nifedipine has an arteriolar dilatatory action in patients with CHF. However, compared with nitroprusside, nifedipine had a significantly larger hypotensive effect and had a lesser effect on right and left ventricular filling pressure, cardiac output and left ventricular function.     

Oxygen sensitivity of vascular smooth muscle. I. In vitro studies

The mechanical responses of isolated arterial smooth muscle strips to alterations in bathing solution oxygen tension (PO₂) were investigated to determine the extent to which diffusion of oxygen limits in vitro contractile performance of vascular smooth muscle. Isometric tension was measured for 17 isolated hog carotid artery strips suspended in a physiological salt solution aerated with gas mixtures of varying PO₂. Strip thickness varied between 0.017 and 0.053 cm. Strips were stimulated with 10^?6M norepinephrine (bath concentration), and PO₂ was alternately varied between control and lower levels while the steady-state mechanical tensions were recorded at each PO₂ level. For each strip studied, there was a PO₂ below which the mechanical tension declined from the control level. This PO₂ varied with strip thickness, ranging from 15 mm Hg for a strip 0.017 cm thick to 240 mm Hg for one 0.053 cm thick. The data were consistent with the assumption that diffusion limited the oxygen supply to the smooth muscle cells. Extrapolation of these data to the thickness of arteriolar walls (10 μm) indicates that the smooth muscle cells would not be affected by the changes in oxygen tension at levels above 2 ± 6 mm. Hg. Since the PO₂'s found at this level of the microcirculation are probably greater than 20 mm Hg, it follows that oxygen per se cannot exert a direct influence on blood flow regulation by altering vascular tone unless the arteriolar smooth muscle possesses a special sensitivity to oxygen or the flow is intermittent.     

Effect of basal epicardial tone on endothelium-independent coronary flow reserve measurement

Increased basal epicardial tone may attenuate the coronary flow reserve (CFR) by causing vasodilatation of resistance vessels. We examined the effect of basal epicardial tone on the endothelium-independent CFR measurements in subjects with nonobstructive coronary disease. Patients underwent evaluation of endothelium-independent CFR using adenosine (18–36 μg) and endothelium-dependent CFR using acetylcholine (10⁻⁶M-10⁻⁴M), both administered intracoronary. CFR to adenosine, presented as the ratio of Doppler flow velocities post- and pre-adenosine, was measured at baseline and after intracoronary nitroglycerin (200 μg). Nitroglycerin increased the coronary artery diameter by 19.7 ± 2.5%, and decreased the coronary vascular resistance from 3.0 ± 0.2 mm Hg/ml/min to 1.8 ± 0.1 mm Hg/ml/min (p < 0.0001). The response to adenosine at baseline and after nitroglycerin was similar (CFR ratio of 2.52 ± 0.09 and 2.57 ± 0.10, respectively, p = NS). The effect of nitroglycerin on the response to adenosine did not correlate with coronary endothelial function (r² = 0.06, p = 0.13). The basal epicardial tone does not affect CFR measurements in patients with angina and nonobstructive coronary disease. Cathet. Cardiovasc. Diagn. 44:392–396, 1998. © 1998 Wiley-Liss, Inc.     

Endothelium-derived relaxing factor (nitric oxide) has a tonic vasodilating action on coronary collateral vessels

Objectives. We sought to determine whether endothelium-derived relaxing factor (nitrix oxide) exerts a tonic vasodilating effect on coronary collateral channels developed in response to myocardial ischemia.Background. Although the coronary collateral circulation is known to react to several vasoactive agents, the role of endogenously produced nitric oxide is unclear.Methods. Coronary collateral channels were induced in the left circumflex artery bed of 12 chronically instrumented dogs by either ameroid implantation or repeated occlusion of the left circumflex coronary artery. With the native circumflex artery occluded, aortic and circumflex pressures and microsphere flows were measured before and after systemic administration of N^G-nitro-l-arginine methyl ester, an arginine analogue known to block the synthesis of nitric oxide.Results. N^G-nitro-l-arginine methyl ester increased mean aortic pressure from a mean ± SEM of 92 ± 4 to 114 ± 4 mm Hg, whereas pressure in the occluded circumflex artery decreased from 61 ± 4 to 55 ± 4 mm Hg. The increase in aortic-circumflex pressure gradient (from 31 ± 4 to 59 ± 5 mm Hg) was accompanied by a decrease in flow in the circumflex bed (from 1.31 ± 0.14 to 1.09 ± 0.15 ml/min per g), resulting in an increase in coronary collateral resistance averaging 173 ± 37% (from 26 ± 4 to 64 ± 9 mm Hg/ml per min per g, p < 0.01). The increase in collateral resistance could be partially reversed by administration of l-arginine.Conclusions. We conclude that nitric oxide normally exerts a substantial tonic dilating effect in coronary collateral vessels. Disease-induced alterations in endothelial function may limit collateral perfusion importantly.     

Effects of α1-Blockade on the Forearm Vascular Resistance Responses to Lower Body Negative Pressure in Young Borderline Hypertensives

To determine whether α₁-blockade affects the forearm vascular resistance responses to lower body negative pressure (LBNP) in borderline hypertensives, six hypertensives (HTN; mean arterial pressure [MAP] = 109.9 ± 1.7 mm Hg, mean ± SE) and seven normotensives (NTN; MAP = 81.5 ± 1.4 mm Hg) underwent exposures of LBNP at pressures of −10, −20, and −40 mm Hg during systemic α₁-receptor blockade (BLK) and during placebo (PLA). Resting forearm vascular resistance (FVR) was greater in HTN than in NTN during PLA (34.8 ± 5.4 v 17.5 ± 3.1 units; P < .05), but not during BLK (28.1 ± 5.2 v 25.3 ± 9.9 units). When expressed as a percentage of resting FVR, LBNP evoked an increased FVR (P < .001) that did not differ significantly between BLK and PLA in either group. FVR was higher (P < .001) in HTN than in NTN throughout both trials; at −40 mm Hg of LBNP during BLK, the increase in FVR was greater (P < .05) in HTN than in NTN (131 ± 42 v 48 ± 15%). MAP (relative to resting) was maintained throughout LBNP during PLA but, at −40 mm Hg, was lower (P < .01) during BLK for both groups. HR was elevated in BLK and was increased at −40 mm Hg (P < .01) for each group in each trial. This increase was greater during BLK (P < .05). These data suggest that borderline hypertensives have a greater vasoconstrictor response to LBNP than do normotensives and α₁-blockade does not appear to attenuate this response.     

Endothelium‐dependent Vasodilation in Myogenically Active Mouse Skeletal Muscle Arterioles: Role of EDH and K+ Channels

As smooth muscle cell (SMC) membrane potential (E_m) is critical for vascular responsiveness, and arteriolar SMCs are depolarized at physiological intraluminal pressures, we hypothesized that myogenic tone impacts on dilation mediated by endothelium‐derived hyperpolarization (EDH). Studies were performed on cannulated mouse cremaster arterioles [diameter, 33±2 μm (n=23) at 60 mmHg; SMC Em ‐34.6±1.2 mV (n=7)]. Myogenic activity was assessed as tone developed in response to intraluminal pressure. Functional observations were related to mRNA, protein expression, and anatomy. Acetylcholine concentration‐response curves showed a modest shift following indomethacin (10 μM) and L‐NAME (100 μM), although maximal vasodilation was achieved. Residual dilation was removed by apamin (1 μM) in combination with TRAM‐34 (1 μM) or charybotoxin (0.1 μM), indicating the requirement of small (S) and intermediate (I) calcium‐activated potassium channels (K_Ca). Charybdotoxin, but not TRAM‐34, caused vasoconstriction, presumably through the inhibition of SMC BK_Ca. Expression of SK3 and IK1 was confirmed by immunohistochemistry and polymerase chain reaction, while myoendothelial junctions were common, suggesting a high degree of cell coupling. Also consistent with a role for endothelial K_Ca channels, acetylcholine increased endothelium [Ca²⁺]_i. Apamin and TRAM‐34 similarly blocked EDH‐mediated dilation at intraluminal pressures of 30 and 90 mmHg, suggesting that in mouse arterioles, SK_{Ca ‐} and IK_{Ca ‐} mediated mechanisms predominate and operate independently of physiological levels of myogenic activation.     

Inhibition by diltiazem of pressure-induced afferent vasoconstriction in the isolated perfused rat kidney

The renal hemodynamic response to calcium entry blockade depends on the neural, hormonal and physiologic determinants influencing basal renal vascular tone. The effects of perfusion pressure per se on the renal vascular response of the rat kidney to diltiazem were evaluated using normal kidneys and hydronephrotic kidneys perfused extracorporally. In isolated perfused normal kidneys, diltiazem did not alter perfusate flow or glomerular filtration rate (GFR) when administered at a perfusion pressure of 100 mm Hg. In contrast, when diltiazem was administered at a perfusion pressure of 150 mm Hg, the calcium antagonists caused a striking increase in GFR, which was accompanied by an increase in renal perfusate flow. In the isolated perfused hydronephrotic rat kidney, elevation of perfusion pressure was associated with an increase in renal vascular resistance and a reduction in afferent arteriolar diameter. Diltiazem abolished the pressure-induced constriction of afferent arterioles and caused an increase in renal perfusate flow in hydronephrotic kidneys perfused at pressures above 100 mm Hg. These findings suggest that in the setting of increased renal perfusion pressure, diltiazem's effects on GFR are mediated in part by an inhibition of pressure-induced constriction of the afferent arteriole.     

Evaluation of blood pressure and baroreflex sensitivity by radial artery tonometry versus finger arteriolar photoplethysmography

BackgroundPublished normative data of noninvasive blood pressures (BPs) and autonomic modulations have been primarily derived from the finger arteriole using the Finapres (Ohmeda Co., Englewood, CO), a device that is no longer manufactured. Currently, beat-to-beat BP are obtained from the radial artery using the Colin tonometer.MethodsWe compared BP and autonomic parameters in a crossover design between the two devices in 29 subjects during seated rest and a 0.1-Hz breathing protocol. In addition, we tested whether finger arteriolar BP differences were due to pressure changes exerted by the radial tonometer.ResultsUniformly, BP measured at the radial artery were significantly higher than those from the finger arteriole. Radial BP (106 ± 19.5 mm Hg) were higher than finger arteriolar BP (95.8 ± 13.7 mm Hg) (P < .005). Tonometric baroreflex sensitivity (BRS) (24.0 ± 18 msec/mm Hg) was higher compared to photoplethysmographic BRS (12.0 ± 7.7 msec/mm Hg; P < .0003). Systolic BP (radial artery) (115 ± 25 mm Hg) were higher compared to finger arteriolar BP (97.7 ± 19 mm Hg; P < .0025) during breathing, as was BRS (25.9 ± 11.6 msec/mm Hg v 21.5 ± 11.6 msec/mm Hg; P < .05). Differences in the low frequency systolic BP (LF_SBP), representative of sympathetic vasomotor modulation, between the two methods, whether absolute, normalized, or log-transformed were not observed.ConclusionsThere were no differences in arteriolar BP values in the presence or absence of radial artery tonometric pressure. These findings indicate that differences exist in systolic BP and BRS using the tonometer (radial artery) versus the Finapres (Ohmeda Co.) (finger arteriole). Furthermore, these differences are not due to pressure exerted by the radial artery tonometer that supplies blood to the finger arteriole.     

Perfusion of Single Tumor Microvessels: Application to Vascular Permeability Measurement

Objective: To develop a new method for determining the relative importance of convection versus diffusion in macromolecular transport across tumor microvessel walls. Methods: The human colon adenocarcinoma LS174T was transplanted in the dorsal skinfold chamber in a severe combined immunodeficient (SCID) mouse. The vasculature at the tumor surface was exposed by carefully removing the glass window of the chamber. A tumor microvessel was randomly selected, which was ～20–40 μm in diameter, embedded in the connective tissue 10–12 μm below the surface of the tumor. The vessel was cannulated with a micropipette and perfused with fluorescein isothiocyanate (FITC)-labeled bovine serum albumin (BSA) at different perfusion pressures. The fluorescence intensity was recorded on videotapes via a video system attached to the fluorescence microscope for offline analysis. The apparent vascular permeability was determined based on the time-dependence of fluorescence intensity and the vessel diameter. Results: The apparent vascular permeability of single vessels to FITC-labeled BSA was quantified at perfusion pressures of 20–45 cmH₂O. The pressure dependence of vascular permeability in LS174T tumors was heterogeneous. On average, there was no correlation between the apparent vascular permeability and the perfusion pressure in the range of 20–35 cmH₂O (p= 0.73), even though the apparent permeability increased significantly when the pressure was increased from 20 to 45 cmH₂O (p= 0.008). Conclusions: These results indicate that convection in the transvascular transport of albumin is not significant in non-peripheral regions of solid tumors in which the pressure difference across the vessel wall is small or even negligible. In addition to the permeability studies, this preparation can be used to study cell-cell interactions in single tumor vessels under defined flow conditions.     

Endothelin-1 released by vascular smooth muscle cells enhances vascular responsiveness of rat mesenteric arterial bed exposed to high perfusion flow

Vasodilation of resistance vessels ensues in response to increased perfusion flow to maintain tissue perfusion. The flow-induced vasodilation is mainly dependent on nitric oxide (NO), which also regulates vascular responsiveness to vasoconstrictors. Besides NO, however, high flow increases endothelin-1 (ET-1) production from endothelial cells. It is likely, therefore, that the interaction between NO and ET-1 may play a critical role in the control of arterial vascular tone under high perfusion flow.In this study, the vascular responsiveness (VR) to high flow rate and the role of ET-1 released by vascular smooth muscle cells (VSMC) were evaluated in isolated and in vitro-perfused mesenteric arteries (MA). MA were perfused at constant (3.5 mL/min; CPF) and increased flow rate (4.5, 5.5, 6.5 mL/min; IPF). VR was evaluated by infusing norepinephrine (NE; 5 μmol/L) and potassium chloride (KCl; 80 mmol/L). Mesenteric vascular resistance (MVR), ET-1, and cGMP release were measured under different flow rates. The role of endothelium-derived ET-1 was evaluated by perfusing MA with phosphoramidon (endothelin converting enzyme inhibitor), whereas the role of other endothelium-derived vasoactive substances was excluded by measuring VR in MA without endothelium. Finally, ETA and ETB receptor antagonists were perfused in disendothelized MA. In the IPF group of intact MA, MVR dropped (P < .05) and both ET-1 and cGMP increased in the perfusate (P < .05). VR was enhanced by high flow after NE (101 ± 9 v 56 ± 12 mm Hg in CPF, P < .005) and KCl (119 ± 12 v 51 ± 10 mm Hg in CPF, P < .005) and it was unaffected by either phosphoramidon or endothelium removal. On the contrary, BQ-610 abolished the flow-dependent increase in VR. No further additive effect was achieved with BQ-788. In conclusion, in MA, high flow reduces MVR and concurrently enhances VR, likely through VSMC-derived ET-1.