Simulation of integrative physiology for medical education.

Medical education is founded on the understanding of physiology. While lecture materials and reading contribute to the learning of physiology, the richness and complexity of the subject suggest that more active learning methods may provide a richer introduction to the science as it applies to the practice of medicine. Simulation has been previously used in basic science to better understand the interaction of physiological systems. In the current context, simulation generally refers to interactive case studies performed with a manikin or anatomic device. More recently, simulation has grown to encompass computational simulation: virtual models of physiology and pathophysiology where students can see in a mechanistic setting how tissues and organs interact with one another to respond to changes in their environment. In this manuscript, we discuss how simulation fits into the overall history of medical education, and detail two computational simulation products designed for medical education. The first of these is an acute simulator, JustPhysiology, which reduces the scope of a large model, HumMod, down to a more focused interface. The second is Sycamore, an electronic health record-delivered, real time simulator of patients designed to teach chronic patient care to students. These products represent a new type of tool for medical and allied health students to encourage active learning and integration of basic science knowledge into clinical situations.

Systemic hemodynamic and regional blood flow changes in response to chronic reductions in uterine perfusion pressure in pregnant rats.

Preeclampsia (PE) is associated with increased total peripheral resistance (TPR), reduced cardiac output (CO), and diminished uterine and placental blood flow. We have developed an animal model that employs chronic reductions in uterine perfusion pressure (RUPP) in pregnant rats to generate a "preeclamptic-like" state during late gestation that is characterized by hypertension, proteinuria, and endothelial dysfunction. Although this animal model has many characteristics of human PE, the systemic hemodynamic and regional changes in blood flow that occur in response to chronic RUPP remains unknown. Therefore, we hypothesized that RUPP would decrease uteroplacental blood flow and CO, and increase TPR. Mean arterial pressure (MAP), CO, cardiac index (CI), TPR, and regional blood flow to various tissues were measured using radiolabeled microspheres in the following two groups of conscious rats: normal pregnant rats (NP; n = 8) and RUPP rats (n = 8). MAP was increased (132 +/- 4 vs. 99 +/- 3 mmHg) in the RUPP rats compared with the NP dams. The hypertension in RUPP rats was associated with increased TPR (2.15 +/- 0.02 vs. 0.98 +/- 0.08 mmHg x ml(-1) x min(-1)) and decreased CI (246 +/- 20 vs. 348 +/- 19 ml x min(-1) x kg(-1), P < 0.002) when contrasted with NP dams. Furthermore, uterine (0.16 +/- 0.03 vs. 0.38 +/- 0.09 ml x min(-1) x g tissue(-1)) and placental blood flow (0.30 +/- 0.08 vs. 0.70 +/- 0.10 ml x min(-1) x g tissue(-1)) were decreased in RUPP compared with the NP dams. These data demonstrate that the RUPP model of pregnancy-induced hypertension has systemic hemodynamic and regional blood flow alterations that are strikingly similar to those observed in women with PE.

ATP-mediated release of arachidonic acid metabolites from venular endothelium causes arteriolar dilation.

This study was designed to test the hypothesis that venular administration of ATP resulted in endothelium-dependent dilation of adjacent arterioles through a mechanism involving cyclooxygenase products. Forty-three male golden hamsters were anesthetized with pentobarbital sodium (60 mg/kg ip), and the cremaster muscle was prepared for in vivo microscopy. ATP (100 microM) injected into venules dilated adjacent arterioles from a mean diameter of 51 +/- 4 to 76 +/- 6 microm (P < 0.05, n = 6). To remove the source of endothelial-derived relaxing factors, the venules were then perfused with air bubbles to disrupt the endothelium. Resting arteriolar diameter was not altered after disruption of the venular endothelium (51 +/- 5 microm), and the responses to venular ATP infusions were significantly attenuated (59 +/- 4 microm, P < 0.05). To determine whether the relaxing factor was a cyclooxygenase product, ATP infusion studies were repeated in the absence and presence of indomethacin (28 microM). Under control conditions, ATP (100 microM) infusion into the venule caused an increase in mean arteriolar diameter from 55 +/- 4 to 78 +/- 3 microm (P < 0.05, n = 6). In the presence of indomethacin, mean resting arteriolar tone was not significantly altered (49 +/- 4 microm), and the response to ATP was significantly attenuated (54 +/- 4 microm, P < 0.05, n = 6). These studies show that increases in venular ATP concentrations stimulate the release of cyclooxygenase products, possibly from the venular endothelium, to vasodilate the adjacent arteriole.

Differential inhibition of functional dilation of small arterioles by indomethacin and glibenclamide.

Indomethacin or glibenclamide treatments attenuate functional dilation of larger-diameter "feed" arterioles paired with venules in hamster cremaster muscle. We tested the hypothesis that release of cyclooxygenase products from venules is important for functional dilation of third- and fourth-order arterioles. We also tested whether ATP-sensitive potassium channels are important during functional dilation of smaller arterioles. The microcirculation of hamster cremaster muscle was visualized with in vivo video microscopy. We measured diameter responses of third- and fourth-order arterioles paired and unpaired with venules in response to 2 minutes of muscle field stimulation (40 microseconds, 10 V, 1 Hz). Control diameters of vessels were 31+/-2 (n=19), 13+/-1 (n=12), 12+/-2 (n=12), and 10+/-1 (n=12) for paired and unpaired third-order and paired and unpaired fourth-order arterioles, respectively. In all groups, field stimulation resulted in increases in mean control diameter of >80%. Indomethacin (28 micromol/L) superfused on the preparation was used to inhibit cyclooxygenase metabolism, or glibenclamide (10 micromol/L) was used to block ATP-sensitive potassium channels. Indomethacin attenuated arteriolar vasodilations to electrical stimulation in paired third-order vessels only, whereas glibenclamide attenuated this vasodilation in all 4 groups. These results support a role for ATP-sensitive potassium channels in functional dilation of arterioles of all sizes regardless of whether or not they are paired with venules. Conversely, a role for cyclooxygenase products is limited to larger "feed arterioles" paired with venules. This study provides further evidence that venules may be the source of prostaglandin release during functional hyperemia.

Inhibition of phospholipase A2 attenuates functional hyperemia in the hamster cremaster muscle.

Arachidonic acid (AA) is the common precursor for several vasodilatory factors involved in the local control of blood flow. This study was designed to determine the role of phospholipase A2 (PLA2) and AA release in functional hyperemia in the hamster cremaster muscle. The muscle was prepared for in vivo microscopy and subjected to electrical field stimulation for 1 min. First- and second-order arterioles dilated in response from a mean diameter of 66 +/- 5 to 88 +/- 7 micrometer (n = 6). PLA2 was then inhibited with quinacrine (3 x 10(-6) M) for 60 min. PLA2 inhibition was verified by an attenuation of thrombin-induced vasodilation (2 U/ml). Quinacrine had no effect on resting arteriolar diameter but completely abolished functional hyperemia. Quinacrine also had no effect on dilation induced by superfusion of the preparation with 3 x 10(-6)-10(-5) M AA, 10(-6)-10(-4) M adenosine, or 10(-6)-10(-4) M sodium nitroprusside, ruling out nonspecific effects of quinacrine on smooth muscle contractility. These results indicate that functional hyperemia in the hamster cremaster muscle is dependent on PLA2 activation and the availability of AA.

Influence of venular prostaglandin release on arteriolar diameter during functional hyperemia.

Indomethacin treatment or removal of the venular endothelium will attenuate functional arteriolar vasodilation in the hamster cremaster muscle. We tested the hypothesis that prostanoid release from venular endothelial cells was responsible for the functional vasodilation of the paired arteriole. The hamster cremaster muscle was prepared for in vivo microscopy and stimulated for 1 minute (10 V, 40 microsec, 1 Hz). Before a second muscle stimulation, the venular endothelium was removed by perfusing the venule with several air bubbles. A third muscle stimulation was performed during prostaglandin inhibition (28 micromol/L indomethacin superfusion). Arterioles (n = 9, 55+/-5 microm) dilated 25+/-4% during the initial muscle stimulation. After removal of the endothelium from the paired venules, there was no effect on resting arteriolar diameters (53+/-4 microm), but the functional arteriolar dilation was attenuated to 15+/-5% (P<.05). The additional indomethacin treatment had a significant effect on resting diameter (50+/-4 microm) but did not alter the magnitude of the functional vasodilation (11+/-4%, P>.05). In a second set of experiments, the order of the experimental protocol was reversed. Muscle stimulation resulted in a 23+/-2% increase in diameter (47+/-2 to 57+/-2 microm). Indomethacin treatment significantly attenuated the functional dilation to 8+/-3% (45+/-2 to 48+/-2 microm). Arteriolar diameter was significantly smaller after disruption of the venular endothelium with air bubbles (40+/-2 microm), but there was no effect on the functional vasodilation, 8+/-3% increase in diameter (to 43+/-2 microm). These results suggest that the arteriolar dilatory response to muscle stimulation is mediated, in part, by prostanoid release from the venular endothelium.

Reduced cardiac contractile responsiveness to isoproterenol in obese rabbits.

Although obesity is characterized by increased sympathetic nervous system activity, there is often a paradoxical reduction in cardiovascular end-organ response to sympathetic stimulation. Mechanisms involved in reduced sympathetic responsiveness in obesity have not been well characterized. Therefore, we determined cardiac contractile responsiveness to beta-stimulation in the obese rabbit model using both isolated heart (IH) and isolated papillary muscle (IPM) preparations. Female New Zealand White rabbits were fed control (IH: n=9; IPM: n=6) or 10% fat diets (IH: n=9; IPM: n=7) for 12 weeks. Contractile responsiveness in the IH was determined using a modified Langendorff preparation to evaluate the dose-response relationship between isoproterenol and 1) peak developed pressure/g of left ventricular wet weight and 2) maximal rate of pressure development (+dP/dt/P). Contractile responsiveness in the IPM was determined using right ventricular papillary muscles to evaluate the dose-response relationship between isoproterenol and (1) peak developed tension (T)/mm2 cross-sectional area (CSA) and (2) maximal rate of tension development (dT/dt/CSA). In the IH, baseline and maximum developed pressure/g were reduced in obese rabbits by 37% and 31%, respectively (P< or =.05). In the IPM, baseline and maximum T/CSA responses were reduced in obese rabbits by 59% and 33%, respectively (P< or =.05). Potency of isoproterenol as reflected by the EC50 did not differ between lean and obese animals in either preparation. These results demonstrate that left ventricular contractility in obesity is reduced at baseline and in response to stimulation with isoproterenol and suggest that decreased responsiveness to beta-stimulation may be a factor in the obesity-related systolic dysfunction.

Role of nitric oxide, adenosine, and ATP-sensitive potassium channels in insulin-induced vasodilation.

The resistance of various tissues to the vasodilator and metabolic effects of insulin may be an important risk factor in the genesis of hypertension observed in several pathological states. Because of this, it is important to understand the mechanisms by which insulin causes vasodilation. Because insulin is known to raise metabolism, one mechanism by which insulin causes vasodilation could be through metabolic vasodilation. Recently, however, it has been suggested that the insulin-induced vasodilation is mediated by the release of endothelium-derived nitric oxide. Using a model of muscle microcirculation (hamster cremaster), we examined the interactions between insulin, nitric oxide, and tissue metabolism to understand the potential mechanisms by which insulin causes vasodilation. Topical application of insulin (200 microU/mL) to the cremaster resulted in significant increases in arteriolar diameter. Second-order arteriolar diameter increased from 69.6 +/- 6 to 79.8 +/- 5 microns and fourth-order arteriolar diameter from 11.3 +/- 1 to 15.1 +/- 2 microns (n = 8). During nitric oxide synthase inhibition, topical application of insulin caused significant vasodilation in both second- and fourth-order arterioles. In contrast, both adenosine receptor antagonism and blockade of ATP-sensitive potassium channels prevented insulin-induced increases in arteriolar diameter. Our findings suggest a role for increased tissue metabolism, particularly the metabolite adenosine, in mediating insulin-induced vasodilation.

Functional hyperemia in striated muscle is reduced following blockade of ATP-sensitive potassium channels.

This study was designed to determine the role of ATP-sensitive potassium channels in the control of the arteriolar diameter during functional hyperemia. The hamster cremaster muscle was prepared for in vivo microscopy and stimulated electrically for 1 min before and after topical application of 10 microM glibenclamide to block ATP-sensitive potassium channels. Glibenclamide treatment resulted in a small, though not significant, decrease in resting arteriolar diameter (P > 0.05). Glibenclamide almost completely inhibited the vasodilation of the first-order and the third-order arterioles in response to topical application of 1 microM cromakalim (P < 0.05). During muscle stimulation, the first-order arterioles dilated from 69 +/- 3 to 89 +/- 3 microns (n = 7), and the third-order arterioles dilated from 16 +/- 1 to 35 +/- 2 microns (n = 7). In this set of experiments glibenclamide treatment resulted in a significant decrease (approximately 4 microns) in the resting diameters of the first-order arterioles, but had no significant effect on the resting diameter of third-order arterioles. Glibenclamide treatment significantly attenuated the vasodilation associated with muscle contraction to 72 +/- 3 and to 21 +/- 3 microns, respectively (P < 0.05). These results suggests that ATP-sensitive potassium channels are an important mediator in the vasodilatory response to muscle stimulation in the hamster cremaster muscle.

Hemodynamic alterations in hypertensive obese rabbits.

There is little information on changes in overall and regional hemodynamics in obesity-associated hypertension. Therefore, the purpose of this study was to determine alterations in overall and regional blood flows and resistances in adipose and nonadipose tissues in a new model of obesity-associated hypertension in rabbits. Sixteen female New Zealand White rabbits were fed either a maintenance or high-fat diet; after 8 to 12 weeks cardiac output and regional blood flows were measured with the use of radioactive microspheres. Obese rabbits (5.22 +/- 0.14 versus 3.66 +/- 0.04 kg) had higher blood pressure (113 +/- 3 versus 95 +/- 1 mm Hg), cardiac output (812 +/- 59 versus 593 +/- 47 mL/min), and heart rate (269 +/- 12 versus 219 +/- 9 beats per minute) and lower overall peripheral resistance (0.14 +/- 0.01 versus 0.17 +/- 0.01 mm Hg/[mL/min]) than lean rabbits. Compared with lean controls, obese rabbits had higher weights of the ventricles, kidneys, liver, ovaries, adrenals, diaphragm, and spleen. Absolute blood flows were greater in the ventricles, kidneys, lungs, and ovaries, but differences were minimized when flows were normalized for organ weight. Adipose tissue flow per gram weight was significantly lower and resistance higher in obese rabbits. However, calculated total adipose tissue flow was higher in obese rabbits (86 versus 45 mL/min). Absolute resistances were lower in the left ventricle, kidneys, and large intestine, but when resistances were indexed for organ weight, kidney resistance tended to be higher in obese rabbits. These results indicate that even short periods of obesity-associated hypertension result in marked overall and regional hemodynamic changes.

Influence of the renal nerves on sodium excretion during progressive reductions in cardiac output.

The purpose of this study was to elucidate the role of the renal nerves in promoting sodium retention during chronic reductions in cardiac output. In five dogs, the left kidney was denervated and the urinary bladder was surgically divided to allow separate 24-h urine collection from the innervated and denervated kidneys. Additionally, progressive reductions in cardiac output were achieved by employing an externally adjustable occluder around the pulmonary artery and by servo-controlling right atrial pressure (control = 0.9 +/- 0.2 mmHg) at 4.7 +/- 0.1, 7.5 +/- 0.1, and 9.8 +/- 0.2 mmHg for 3 days at each level. At the highest level of right atrial pressure, the 24-h values for mean arterial pressure (control = 97 +/- 3 mmHg) and cardiac output (control = 2,434 +/- 177 ml/min) were reduced approximately 25 and 55%, respectively; glomerular filtration rate fell by approximately 35% and renal plasma flow by approximately 65%. However, despite the sodium retention induced by these hemodynamic changes, there were no significant differences in renal hemodynamics or sodium excretion between the two kidneys during pulmonary artery constriction. In contrast, after release of the pulmonary artery occluder on day 9, sodium excretion increased more (approximately 28% during the initial 24 h) in innervated than in denervated kidneys. These results suggest that the renal nerves are relatively unimportant in promoting sodium retention in this model of low cardiac output but contribute significantly to the short-term elimination of sodium after partial restoration of cardiac output and mean arterial pressure.

Overall hemodynamic studies after the chronic inhibition of endothelial-derived nitric oxide in rats.

Previous studies have demonstrated that an acute intravenous administration of nitro-L-arginine methyl ester (L-NAME) causes a sustained hypertension and widespread vasoconstriction. However, little information is available regarding the chronic effect of L-NAME on circulatory hemodynamics. Therefore, the purpose of the present study was to characterize both the systemic and regional hemodynamics after the chronic inhibition of endothelium-derived nitric oxide in male Sprague Dawley rats. The rats were divided into two groups: control (n = 8) and L-NAME (n = 8). The rats in the control group received only tap water and the rats in the L-NAME group received oral L-NAME solution at a dose of 0.1 mg/mL in the drinking water ad libitum. Four weeks after L-NAME or tap water treatment the rats were anesthetized with inactin, and mean arterial blood pressure, cardiac output, and individual organ flows were measured. Cardiac output and individual organ flows were measured using radioactive microspheres. Chronic administration of L-NAME resulted in a significant increase in mean arterial blood pressure from a control value of 118 +/- 4 mm Hg to 174 +/- 8 mm Hg (P < .01). Cardiac output decreased from a control value of 29 +/- 2 mL/min/100 g to 20 +/- 2 mL/min/100 g (P < .01) and total peripheral resistance increased from a control value of 4.3 +/- 0.3 mm Hg/mL/min/100 g to 9.7 +/- 1.4 mm Hg/mL/min/100 g (P < .01). In addition, chronic L-NAME treatment resulted in a widespread vasoconstriction and decrease in regional blood flows.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the needle technique for producing an arteriovenous fistula.

The purpose of the present study were to evaluate the needle technique of creating an arteriovenous (a-v) fistula and to quantitatively determine the hemodynamic responses in rats with three different fistula sizes. The fistula was made in male Sprague-Dawley rats between the aorta and vena cava below the renal arteries by using 20-, 18-, and 16-gauge angiocath needles. Five weeks after a sham operation or creation of an a-v fistula, mean arterial blood pressure (MAP), right atrial pressure, shunt flow, cardiac index, systemic flow, individual organ flows, and heart weight were quantitatively determined. All flow measurements were made using radioactive microspheres. The flow to the lungs was used as a measure of shunt flow. The shunt flow in the 20-, 18-, and 16-gauge fistula animals was significantly increased from a value of 2 +/- 1% (SE) to 50.0 +/- 0.1, 78 +/- 3, and 76 +/- 3% of total cardiac output, respectively. Average cardiac index in the 20-, 18-, and 16-gauge fistula animals increased by 105, 270, and 250%, respectively, compared with control. Right atrial pressure and heart weight were increased in proportion to the size of the fistula. MAP in the control and 20-, 18-, and 16-gauge fistula animals was 122 +/- 5, 126 +/- 3, 118 +/- 3, and 111 +/- 4 mmHg, respectively. There were no significant differences in MAP or systemic flow among any of these groups. The calculated total peripheral resistance in all fistula groups was significantly decreased compared with control.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of endothelium-derived relaxing factors in arteriolar dilation during muscle contraction elicited by electrical field stimulation.

OBJECTIVE: To determine the contribution of either endothelium-derived nitric oxide (EDNO) or prostaglandins in the functional vasodilation of first-order arterioles of the hamster cremaster muscle. METHODS: First-order arterioles dilated from 72 +/- 3 microns to 93 +/- 4 microns in response to contraction of the cremaster muscle for 1 min (n = 7). After EDNO inhibition by topical application of 10 microM NW-nitro-L-arginine methyl ester (L-NAME), the resting diameter decreased to 66 +/- 3 microns and functional dilation was attenuated to 75 +/- 3 microns (P < 0.05). When the arteriolar diameter was returned to the control values by the addition of sodium nitroprusside, an NO donor, into the superfusion solution (n = 7), functional dilation was similar to that observed before EDNO inhibition (91 +/- 3 microns vs. 89 +/- 3 microns, P > 0.05). To evaluate whether the vasoconstrictor effect of L-NAME on functional dilation is same as other vasoconstrictors, norepinephrine was applied on the cremaster muscle to induce a vasoconstriction (72 +/- 2 to 66 +/- 1 micron, n = 7) equivalent to L-NAME. RESULTS: Norepinephrine treatment attenuated functional dilation to 77 +/- 3 microns which was to a level similar to L-NAME treatment (P > 0.05). Inhibition of prostaglandin synthesis by topical application of indomethacin (28 microM) resulted in no significant changes in the resting diameter but functional vasodilation was attenuated from 89 +/- 2 to 81 +/- 3 microns (n = 7, P < 0.05). CONCLUSIONS: These results suggest that EDNO is important for the resting tone of arterioles and that prostaglandins are important in modulating the functional dilation of the first-order arterioles in the hamster cremaster muscle.

Role of venular endothelium in control of arteriolar diameter during functional hyperemia.

This study was designed to determine the importance of the venular endothelium in the vasodilation of adjacent arterioles during functional hyperemia. The hamster cremaster muscle was prepared for in vivo microscopy. Two silver-silver chloride electrodes were placed across the pedicle of the cremaster muscle, and a square-wave pulse (10 V amplitude, 1 ms duration, and 1 Hz frequency) was used to elicit muscle contraction. Muscle stimulation for 1 min resulted in a vasodilation of the first-order arterioles from 74 +/- 2 to 91 +/- 2 microns (n = 9, P < 0.05). After perfusion of the venule with air to disrupt the venular endothelium, there was no significant effect on the resting diameter, 73 +/- 3 microns, but the vasodilation associated with the muscle stimulation was significantly attenuated to 82 +/- 3 microns (P < 0.01). After completion of these experiments, the disruption of venular endothelium was confirmed by electron microscopy. The functional vasodilation of arterioles adjacent to venules with an intact endothelium (venules in which air did not enter) was retained after air perfusion (n = 6). These results suggest that the presence of the venular endothelium is important for the arteriolar vasodilation during functional hyperemia. We propose that the venular endothelium releases a relaxing factor responsible for a portion of the functional arteriolar vasodilation.

Role of EDRFs in the control of arteriolar diameter during increased metabolism of striated muscle.

This experiment was designed to determine the role that the release of endothelium-derived relaxing factors (EDRFs), endothelium-derived nitric oxide (EDNO), or prostaglandins have in the control of arteriolar vasodilation during an increased metabolic rate in striated muscle. A silicone stopcock grease dam was placed across the distal portion of the cremaster muscle of pentobarbital-anesthetized hamsters to localize the application of the metabolic stimulator 2,4-dinitrophenol (DNP). Application of DNP (10 mM) to the distal region resulted in significant increases in red cell velocity (from 6 +/- 1 to 10 +/- 2 mm/s) and arteriolar diameter (from 75 +/- 3 to 91 +/- 5 microns) (P < 0.05; n = 6) in the first-order arterioles located approximately 11 mm upstream from the silicone dam. Administration of N omega-nitro-L-arginine methyl ester (L-NAME; 2 mg iv) resulted in significant vasoconstriction of the first-order arterioles and a significant decrease in the vasodilator response to acetylcholine (1 microM). Addition of sodium nitroprusside (380 microM) to the superfusion solution during L-NAME treatment resulted in a return of arteriolar diameter to control levels. DNP treatment during L-NAME and sodium nitroprusside treatment did not inhibit the arteriolar vasodilation [75 +/- 3 to 87 +/- 4 microns (P > 0.05)] after a significant increase in red cell velocity from 7 +/- 1 to 11 +/- 1 mm/s. Before indomethacin treatment, DNP treatment resulted in an increase in arteriolar diameter from 72 +/- 3 to 90 +/- 3 microns, preceded by an increase in red cell velocity from 6 +/- 1 to 10 +/- 1 mm/s.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic and regional hemodynamics after nitric oxide synthase inhibition: role of a neurogenic mechanism.

The study tested the hypothesis that the increase in blood pressure and decrease in cardiac output after nitric oxide (NO) synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME) was partially mediated by a neurogenic mechanism. Rats were anesthetized with Inactin (thiobutabarbital), and a control blood pressure was measured for 30 min. Cardiac output and tissue flows were measured with radioactive microspheres. All measurements of pressure and flows were made before and after NO synthase inhibition (20 mg/kg L-NAME) in a group of control animals and in a second group of animals in which the autonomic nervous system was blocked by 20 mg/kg hexamethonium. In this group of animals, an intravenous infusion of norepinephrine (20-140 ng/min) was used to maintain normal blood pressure. L-NAME treatment resulted in a significant increase in mean arterial pressure in both groups. L-NAME treatment decreased cardiac output approximately 50% in both the intact and autonomic blocked animals (P < 0.05). Autonomic blockade alone had no effect on tissue flows. L-NAME treatment caused a significant decrease in renal, hepatic artery, stomach, intestinal, and testicular blood flow in both groups. These results demonstrate that the increase in blood pressure and decreases in cardiac output and tissue flows after L-NAME treatment are not dependent on a neurogenic mechanism.

Angiotensin and ANP secretion during chronically controlled increments in atrial pressure.

The primary objective of this study was to determine whether angiotensin II (ANG II) has direct effects on the atrium to chronically stimulate the secretion of atrial natriuretic peptide (ANP) by actions that are independent of its vasoconstrictor and fluid-retaining effects that increase ANP secretion indirectly by raising atrial pressure. In five dogs, right atrial pressure (RAP) was controlled at approximately 5.5 mmHg above control levels for 8 days by employing an externally adjustable occluder around the pulmonary artery and a servo-control system, and plasma levels of ANG II were fixed at either normal (days 1-3 and 7-8) or high (days 4-6) physiological concentrations by chronic infusion of captopril+ANG II. When plasma ANG II was maintained at normal levels during servo-control of RAP, plasma ANP concentration increased five- to sixfold and sodium balance was achieved at a reduced arterial pressure (-14 mmHg). In contrast, despite increased plasma levels of ANP, the high rate of ANG II infusion produced marked sodium retention during the initial 24 h; however, the antinatriuresis was not sustained because the servo-control system partially deflated the pulmonary artery occluder to prevent fluid-induced increments in RAP. Moreover, in the absence of a change in RAP, high plasma levels of ANG II did not influence plasma ANP concentration. These findings indicate that the plasma levels of ANP achieved in heart failure increase renal excretory capability and allow fluid balance to be achieved at a substantial fall in mean arterial pressure as long as there is minimal involvement of the renin-angiotensin system.(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of venular flow in control of arteriolar diameter in hamster cremaster muscle.

These experiments tested the hypothesis that an intact venular flow is important for the control of upstream arteriolar diameter during an increase in metabolism. A silicone stopcock grease dam was placed across the distal portion of the cremaster muscle to localize treatment of the metabolic stimulator 2,4-dinitrophenol (DNP). Thus only the distal area would have an increased metabolic rate, with the proximal area of the cremaster having a normal metabolic rate. During DNP treatment, the first-order venule, approximately 5 mm proximal to the Silastic dam, was occluded to prevent the transport of metabolites. DNP treatment (10 mM) resulted in a significant increase in the arteriolar diameter from 75 +/- 3 to 90 +/- 4 microns (n = 7, P < 0.05), 12.1 +/- 0.3 mm upstream from the distal region. After venular occlusion, arteriolar diameter decreased to 78 +/- 3 microns (P < 0.05). As an additional test of our hypothesis we altered the experimental sequence. DNP treatment during venular occlusion did not affect arteriolar diameter, but after release of the occlusion there was a significant increase in arteriolar diameter from 78 +/- 3 to 91 +/- 4 microns (P < 0.05). These results suggest that an intact venular flow is necessary for control of arteriolar diameter during an increased metabolic rate caused by DNP treatment, providing evidence for the significance of the venular-arteriolar diffusion of vasoactive metabolites.