Autonomic control of skeletal muscle vasodilation during exercise

Despite extensive investigation, the control of blood flow during dynamic exercise is not fully understood. The purpose of this study was to determine whether beta-adrenergic or muscarinic receptors are involved in the vasodilation in exercising skeletal muscle. Six mongrel dogs were instrumented with ultrasonic flow probes on both external iliac arteries and with a catheter in a branch of one femoral artery. The dogs exercised on a treadmill at 6 miles/h while drugs were injected intra-arterially into one hindlimb. Isoproterenol (0.2 microg) or acetylcholine (1 microg) elicited increases in iliac blood flow of 89.8 +/- 14.4 and 95.6 +/- 17.4%, respectively, without affecting systemic blood pressure or blood flow in the contralateral iliac artery. Intra-arterial propranolol (1 mg) or atropine (500 microg) had no effect on iliac blood flow, although they abolished the isoproterenol and acetylcholine-induced increases in iliac blood flow. These data indicate that exogenous activation of beta-adrenergic or muscarinic receptors in the hindlimb vasculature increases blood flow to dynamically exercising muscle. More importantly, because neither propranolol nor atropine affected iliac blood flow, we conclude that beta-adrenergic and muscarinic receptors are not involved in the control of blood flow to skeletal muscle during moderate steady-state dynamic exercise in dogs.     

Immunocytochemical localization of the alpha-1B adrenergic receptor and the contribution of this and the other subtypes to vascular smooth muscle contraction: analysis with selective ligands and antisense oligonucleotides

The contribution of the alpha-1B adrenergic receptor (AR) to vascular smooth muscle contraction has been assessed using a combination of immunological, molecular biological and pharmacological approaches. A subtype-selective antibody detected alpha-1B immunoreactivity in the medial layer of the aorta, caudal, femoral, iliac, mesenteric resistance, renal and superior mesenteric arteries. Receptor protection assays and antisense oligonucleotides were used to assess the contribution of the alpha-1B AR to contraction. The alpha-1B AR was implicated in mediating the phenylephrine-induced contraction of the mesenteric resistance artery. The alpha-1D AR was implicated in mediating the contraction of the aorta, femoral, iliac and superior mesenteric arteries. Similarly, the alpha-1A AR was implicated in mediating contraction of the caudal and renal arteries. In vivo application of antisense oligonucleotides targeted to the translational start site of the alpha-1B AR had no effect on the phenylephrine-induced contraction of the femoral or renal arteries. In contrast, antisense oligonucleotides directed against the alpha-1D AR significantly inhibited the phenylephrine response in the femoral artery but had no effect on the renal artery. Application of alpha-1A AR antisense oligonucleotides inhibited the contraction of the renal artery without effect on the femoral artery. These data show that (1) alpha-1B AR immunoreactivity is widely distributed in the same peripheral arteries in which previous studies detected its mRNA, and (2) despite this distribution, receptor protection and antisense oligonucleotide studies indicate that the alpha-1B AR mediates the contraction of only the mesenteric resistance artery.     

Augmented mesenteric and renal vasoconstriction during exercise in senescent Fischer 344 rats

The purpose of this study was to test the hypothesis that vasoconstriction in the mesenteric and renal circulations is greater at both submaximal and maximal exercise intensities with advancing age. Arterial blood pressure, heart rate, and mesenteric, renal, and iliac (hindlimb) artery blood flow velocities were measured before and during graded treadmill exercise in mature (12 mo) and senescent (24 mo) male Fischer 344 rats. During treadmill running at mild, moderate, and maximal exercise intensities (approximately 45, 70, and 100% of maximal oxygen uptake), the increases in arterial pressure were similar in the mature and senescent animals, whereas heart rate rose less in the older group (P < 0.05). Mesenteric and renal flow velocities declined and vascular resistances increased from resting levels in both groups in response to graded exercise; however, the magnitudes of the increases in both mesenteric and renal vascular resistance were significantly augmented in the older rats at the moderate and maximal workloads. Hindlimb blood flow velocity increased and resistance declined from resting levels at each exercise intensity in both groups. In contrast to the visceral and renal adjustments, the magnitudes of the changes in both hindlimb flow and resistance were similar for the two age groups at all exercise intensities. These findings support the hypothesis that mesenteric and renal vasoconstriction is augmented in senescent Fischer 344 rats during exercise at moderate and maximal intensities but not at mild workloads. Despite these regional differences, the maintenance of arterial pressure is not altered at either submaximal or maximal exercise intensities with advancing age.     

Reflex cardiovascular changes with veratridine in the conscious dog

The present study was undertaken to examine the reflex responses of activation of cardiac sensory receptors in the conscious dog. Intracoronary (left circumflex coronary artery) injection of veratridine (0.10 micrograms/kg) reduced mean arterial pressure (-40 mmHg, P less than 0.05), heart rate (-34 beats/min, P less than 0.05), and maximum rate of rise of left ventricular pressure (LV dP/dtmax) (-419 mmHg/s, P less than 0.05). Bilateral cervical vagal cold block (BVB) eliminated the depressor and bradycardic responses of veratridine. BVB not only eliminated the negative inotropic response to veratridine but reversed it to a positive inotropic response (LV dP/dtmax increased 313 +/- 76 mmHg/s). Ganglionic blockade abolished all effects of veratridine. The bradycardia and negative inotropic effects caused by veratridine were attenuated by either atropine or metoprolol and completely eliminated by the combination of the two antagonists. Veratridine also produced a decrease in renal artery blood flow but had no effect on renal vascular resistance. In contrast, iliac blood flow was increased with veratridine, and this, combined with the depressor effect, resulted in a decrease in iliac vascular resistance (-37%), P less than 0.05). BVB abolished the changes in renal and iliac blood flow or resistance caused by veratridine. The results indicate that activation of cardiac receptors in the conscious dog elicits inhibitory reflexes to the heart and peripheral circulation that are mediated by vagal afferents. After vagotomy, veratridine elicited a reflex positive inotropic response, which may have resulted from activation of cardiac sympathetic afferent fibers.     

Contraction and endothelium dependent relaxation via alpha adrenoceptors are variable in various pig arteries

OBJECTIVE: The aim was to examine differences in the vascular response to alpha adrenoceptor stimulation on both smooth muscle and endothelium among large arteries perfusing various organs. METHODS: In ring preparations of coronary, carotid, iliac, mesenteric, and renal arteries from pigs (n = 24), the magnitudes of contraction to noradrenaline (with beta blocker), with or without endothelium, and endothelium dependent relaxation to noradrenaline (with alpha 1 and beta blocker) were compared in vitro. RESULTS: In both endothelium-intact and denuded groups, the contractions to noradrenaline were significantly smaller in coronary and carotid arteries than in iliac, mesenteric, and renal arteries. The presence of endothelium significantly suppressed the contractions in coronary and carotid arteries, but did not affect the contractions in iliac, mesenteric, and renal arteries. The endothelium dependent relaxations to noradrenaline, which were abolished by LNMMA, were more prominent in coronary and carotid arteries than in iliac, mesenteric, and renal arteries. CONCLUSIONS: The contractions via alpha adrenoceptors were small, and endothelium dependent relaxations via alpha 2 adrenoceptors were large, in the coronary and carotid arteries, which perfuse the vital organs (heart and brain), as compared with those in iliac, mesenteric, and renal arteries. These results suggest that in the state of activation of the sympathetic nervous system, arterial tone in response to alpha adrenoceptor stimulation may be regulated not only by alpha adrenoceptors on vascular smooth muscle but also by those on endothelium, through release of endothelium derived relaxing factor (EDRF) via alpha 2 adrenoceptors.     

Prolonged systemic and regional haemodynamic effects of intracerebroventricular angiotensin II in conscious sheep

1. The haemodynamic mechanisms by which infusion of angiotensin II (AngII), either into the lateral cerebral ventricles (i.c.v.) or intravenously (i.v.), increased arterial pressure were studied in conscious sheep. 2. Sheep were previously fitted with flow probes for measurement of cardiac output and coronary, mesenteric, renal and iliac blood flows. 3. Intracerebroventricular AngII (10 nmol/h for 1 h) increased arterial pressure by 11 +/- 4 mmHg (P < 0.001) due to vasoconstriction, predominantly in the mesentric vasculature. These effects developed over 30 min and took 2 h to return to control. Following the infusion renal conductance increased continuously for 3 h, resulting in a parallel increase in renal blood flow (to 75 +/- 18 mL/min above control, P < 0.001). 4. Intracerebroventricular AngII increased plasma vasopressin from 0.8 +/- 0.3 to 7.2 +/- 1.8 pg/mL (P, 0.01), and reduced plasma renin concentration from 0.9 +/- 0.3 to < 0.4 nmol/L/h. 5. The pressor effect of i.v. AngII (5, 10, 25, 50 nmol/h) also depended on peripheral vasoconstriction, but the pattern of responses was different. The greatest degree of vasoconstriction occurred in the renal, followed by the mesentric and iliac vascular beds; these effects were rapid in onset and offset. 6. In conclusion, the pressor responses to both i.c.v. and i.v. angiotensin depended on peripheral vasoconstriction, but there were contrasting regional haemodynamic changes. ICV AngII caused a prolonged pressor response, mainly due to mesentric vasoconstriction possibly partly due to vasopressin release, and following the infusion there was a pronounced, long-lasting renal vasodilatation. In contrast, i.v. AngII caused vasoconstriction preferentially in the renal vascular bed and its effects were short lasting.     

Influence of corticotropin-releasing factor on pancreatic and islet blood flow in different regions of the rat pancreas

Corticotropin-releasing factor (CRF) has previously been shown to selectively dilate the mesenteric vascular bed, without affecting other vascular beds. Pancreatic blood flow and islet blood flow were therefore measured separately with a microsphere technique in the two regions of the rat pancreas perfused by the superior mesenteric artery (SMA) or celiac artery (CA) respectively. Intravenous infusion of CRF (0.25 microgram/kg b.w./min) caused an increase in both whole pancreatic blood flow and islet blood flow in the region of the pancreas perfused by the SMA. The fraction of whole pancreatic blood flow diverted through the islets in this part of the pancreas was, however, unaffected by CRF infusion (approximately 10%). CRF did not change either pancreatic or islet blood flow in the CA-perfused part of the pancreas, and did not affect the release of insulin.     

Hemodynamic actions of insulin in rat skeletal muscle: evidence for capillary recruitment

Insulin-induced increases in blood flow are hypothesized to enhance overall glucose uptake by skeletal muscle. Whether the insulin-mediated changes in blood flow are associated with altered blood flow distribution and increased capillary recruitment in skeletal muscle is not known. In the present study, the effects of insulin on hemodynamic parameters in rat skeletal muscle in vivo were investigated. Mean arterial blood pressure, heart rate, femoral blood flow, hind leg vascular resistance, and glucose uptake were measured in control and euglycemic insulin-clamped (10 mU x min(-1) x kg[-1]) anesthetized rats. Blood flow distribution within the hind leg muscles was assessed by measuring the metabolism of 1-methylxanthine (1-MX), an exogenously added substrate for capillary xanthine oxidase. Insulin treatment had no effect on heart rate but significantly increased arterial blood pressure (12 mmHg) and femoral blood flow (80%) and decreased hind leg vascular resistance (31%). Changes were similar in magnitude and in time of onset to those reported in humans. Insulin treatment increased hind leg glucose uptake approximately fourfold and also increased hind leg 1-MX metabolism by 50%, suggesting increased exposure to endothelial xanthine oxidase. To ascertain whether the increased 1-MX metabolism was simply due to increased bulk femoral blood flow, epinephrine was infused at a dose (0.125 microg x min(-) x kg[-1]) chosen to match the insulin-induced increase in femoral blood flow. This dose of epinephrine had no significant effects on arterial blood pressure or heart rate but increased femoral blood flow and lowered hind leg vascular resistance to a similar extent as insulin. Epinephrine did not significantly alter 1-MX metabolism as compared with control animals. These results demonstrate that insulin increases total hind leg blood flow and metabolism of 1-MX, suggesting a recruitment of capillary blood flow in rat hind leg not mimicked by epinephrine.     

Relationship between splanchnic, peripheral and cardiac haemodynamics in liver cirrhosis of different degrees of severity

OBJECTIVE: To investigate the relationships between changes in splanchnic and systemic haemodynamics in liver cirrhosis. DESIGN AND METHODS: Abdominal and peripheral duplex-Doppler sonography and Doppler echocardiography were performed in 42 cirrhotic patients with (group A, ascitic) or without ascites (group NA, non-ascitic) and in a control group of 36 healthy volunteers. RESULTS: There were significant differences (P < 0.05 at ANOVA) between the three groups in portal vein flow velocity (controls, groups NA and A, respectively, 29.2, 21.4 and 20.0 cm/s), portal diameter (9.3, 12.2 and 12.0 mm), superior mesenteric artery (SMA) resistance index (RI) (0.889, 0.854 and 0.816), femoral artery RI (0.988, 0.974 and 0.945), mean arterial pressure (MAP) (101.4, 102.0 and 87.3 mmHg), peripheral vascular resistance (1579, 1404 and 1094 dyn/cm5/s) and cardiac index (CI) (2.91, 3.46 and 3.77 l/min/m2). Multiple regression analysis identified renal interlobular- and SMA RI (respectively, r = -0.58 and r = 0.51) in group A as the two regional vascular beds correlated to MAP. CONCLUSION: The deterioration of the cirrhotic hyperdynamic circulation in the presence of ascites and the correlation between MAP and mesenteric and renal resistances are consistent with the peripheral arterial vasodilation hypothesis. The positive correlation between MAP and SMA RI in ascitic patients shows a link between this region and the general circulation. This seems to suggest that splanchnic hyperafflux plays a part in the formation of ascites.     

Beneficial effects of prostaglandin E1 on ischemic colitis following surgery on the abdominal aorta

To determine the effects of prostaglandin E1 (PGE1) on the intestinal circulation, an experimental dog model of ischemic colitis following abdominal aortic reconstruction was made by ligating the inferior mesenteric artery (IMA) and the internal iliac artery, with the creation of a 50% stenosis in the superior mesenteric artery (SMA). The parameters of enteric ischemia included the blood flow of the SMA, the tissue blood flow in the small intestine and left colon, the mean stump pressure of the IMA (IMAP), and the IMAP/mean systemic blood pressure ratio. With the continuous infusion of 10 ng/kg per minute of PGE1 into the descending thoracic aorta, these values increased significantly on the seventh postoperative day compared with those on the day of operation. These results thus suggest that the continuous intraarterial infusion of PGE1 may reduce ischemic changes in the colon following abdominal aortic reconstruction.     

Regional hemodynamic effects of dopamine in the sick preterm neonate

OBJECTIVE: To study the effects of dopamine on renal, mesenteric, and cerebral blood flow in sick preterm neonates. Study design: The pulsatility index was used to assess the dopamine-induced changes in renal, mesenteric, and cerebral blood flow by means of color Doppler ultrasonography in 23 nonhypotensive preterm neonates (birth weight: 981 +/- 314 g; postnatal age: <2 days). Dopamine was given at a dose of 6.1 +/- 3.0 microgram/kg per minute to combat oliguria, impaired peripheral perfusion, or both. Blood flow velocity measurements were made before and during dopamine administration, with each patient serving as his or her own control subject. RESULTS: Dopamine significantly increased blood pressure and urine output. Dopamine decreased the pulsatility index in the renal artery (2.98 +/- 1.18 vs 1.68 +/- 0.45; P <.05) while the pulsatility index in the superior mesenteric and medial cerebral artery was not affected. Thus renal blood flow increased while mesenteric and cerebral blood flow remained unchanged during dopamine treatment. The increase in renal blood flow was independent of the blood pressure changes. CONCLUSIONS: These findings suggest a functionally mature renal, but not mesenteric, vasodilatory dopaminergic response in the preterm neonate. The observations also indicate the lack of an effect of low- to medium-dose dopamine on cerebral hemodynamics in the nonhypotensive preterm neonate.     

Influence of central command and ergoreceptors on the splanchnic circulation during isometric exercise

The splanchnic circulation can make a major contribution to blood flow changes. However, the role of the splanchnic circulation in the reflex adjustments to the blood pressure increased during isometric exercise is not well documented. The central command and the muscle chemoreflex are the two major mechanisms involved in the blood pressure response to isometric exercise. This study aimed to examine the behaviour of the superior mesenteric artery during isometric handgrip (IHG) at 30% maximal voluntary contraction (MVC). The pulsatility index (PI) of the blood velocity waveform of the superior mesenteric artery was taken as the study parameter. A total of ten healthy subjects [mean age, 21.1 (SEM 0.3) years] performed an IHG at 30% MVC for 90 s. At 5 s prior to the end of the exercise, muscle circulation was arrested for 90 s to study the effect of the muscle chemoreflex (post exercise arterial occlusion, PEAO). The IHG at 30% MVC caused a decrease in superior mesenteric artery PI, from 4.84 (SEM 1.57) at control level to 3.90 (SEM 1.07) (P = 0.015). The PI further decreased to 3.17 (SEM 0.70) (P = 0.01) during PEAO. Our results indicated that ergoreceptors may be involved in the superior mesenteric artery vasodilatation during isometric exercise.     

Human lactoferrin receptor activity in non-encapsulated Haemophilus influenzae

We recently reported that attenuation of vasoactive agent-induced calcium signal and cell contraction of mesangial cell by insulin-like growth factor 1 (IGF-1), observed in normal mesangial cells, is totally abolished in spontaneously hypertensive rat (SHR) mesangial cells. This phenomenon might be related to the well-known aberrant regulation of SHR glomerular hemodynamics. Since it has been reported that in vivo IGF-1 infusion increases renal plasma flow (RPF) and glomerular filtration rate (GFR), we examined whether the modulation of renal function by IGF-1 is altered in SHR. We performed in vivo renal clearance studies using eight-week-old SHR and control Wistar Kyoto rats (WKY) before and after IGF-1 (5 micrograms/kg) infusion into the left renal artery for 20 minutes. Mean arterial pressure was not affected by IGF-1 in both WKY and SHR. In WKY, IGF-1 increased GFR and RPF, and decreased renal vascular resistance (RVR). However, GFR, RPF, and RVR were not altered by IGF-1 in SHR, while systemic infusion of angiotensin II antagonist, CV-11974, increased GFR and RPF. The present data show that the modulation of renal hemodynamics by IGF-1 is absent in SHR. This might be related the pathophysiology of the development of hypertension.     

Identification of HLA-A2-restricted epitopes of the tumor-associated antigen MUC2 recognized by human cytotoxic T cells

BACKGROUND: Dopexamine is a specific dopaminergic and beta2-adrenergic agonist. Using newborn piglets, we have previously shown that (1) dopexamine increases cardiac output and mesenteric blood flow; (2) indomethacin reduces mesenteric blood flow. METHODS: Ultrasonic blood flow probes were placed around the ascending aorta, cranial mesenteric artery, and a renal artery of 0 to 2-day-old and 2-week-old piglets. Animals of each age were grouped (5 to 8 animals per group) and subjected to one of three experimental protocols: (1) 0.4 mg/kg indomethacin infusion, (2) 10 microg/kg/min dopexamine infusion begun 10 minutes before indomethacin, or (3) no treatment. RESULTS: Control animals demonstrated no significant alterations in mesenteric blood flow. Compared with baseline, indomethacin produced significant (P< .05, analysis of variance) declines in cranial mesenteric artery blood flow in 0 to 2-day old (37.2+/-5.7 mL/min v 17.9+/-3.7 mL/min at 90 min), and 2-week-old (80.2+/-12.5 mL/min v 29.7+/-5.7 mL/min at 90 minutes) piglets. In both animal groups treated with dopexamine before indomethacin, the decreases in cranial mesenteric artery blood flow were eliminated (38.4+/-7.6 mL/min at baseline v 36.5+/-6.8 mL/min at 90 minutes in 0 to 2 day olds; 79.9+/-10.0 mL/min at baseline v 77.5+/-14.7 mL/min in 2 week olds). Indomethacin-induced declines in renal blood flow were similarly abrogated by dopexamine. CONCLUSION: Dopexamine may prove of clinical benefit when a neonate is considered a candidate for indomethacin therapy.     

Effect of glucagon on hepatic circulation in the pig

The effect of intravenous injection of 50 mug/kg of glucagon on the hepatic circulation of the pig was studied in 12 animals. Glucagon caused an arterial pressure reduction of 11 mm Hg after two minutes and 7 mm Hg after ten minutes. The portal pressure and blood flow were not altered. The superior mesenteric arterial flow decreased by 12%. The hepatic arterial blood flow increased by 80% after two minutes and by 58% after ten minutes. There was no difference in response when anesthesia was achieved with small intravenous doses of thiopental (Pentothal) sodium or 70% nitrous oxide in oxygen and tubocurarine chloride.     

Changes in intestinal vascular diameter during norepinephrine vasoconstrictor escape

The hypothesis that escape from norepinephrine-induced vasoconstriction in the intestine is due to relaxation of initially constricted vessels was tested in 18 anesthetized cats. Intestinal blood flow was measured by an electro magnetic probe on the superior mesenteric artery. Intestinal submucosal and muscle arterioles and small mesenteric arteries were studied by in vivo microscopy with an image-splitting technic. Continuous recordings of mesenteric flow and vessel diameter were made during the infusion into the superior mesenteric artery of norepinephrine (NE) at a rate of 1-2 mug/min for 3 min. Mesenteric flow decreased soon after the NE infusion began but then escaped. Microscopically, arterial constriction and escape were noted in submucosal, muscle, and mesenteric vessels with a time course similar to that for flow. Arteriovenous anastomoses were not seen. These findings support the hypothesis that escape from Ne-induced vasoconstriction is due to relaxation of initially constricted vessels.     

Effects of nitric oxide synthase inhibition and endothelin ETA receptor blockade on haemodynamics in hypertensive rats

1. The objectives of the present study were to study regional differences in haemodynamics between spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats induced by the nitric oxide synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA) and the endothelin ETA receptor antagonist BQ 123 in vivo in tissues known to be important for blood pressure (BP) regulation (heart, kidney and skeletal muscle). Furthermore, the effect of acetylcholine (ACh) infusion (2 micrograms/kg per min) was examined after L-NMMA or BQ 123. The microsphere method was used for determinations of cardiac index (CI) and regional haemodynamics. 2. NG-Monomethyl-L-arginine (20 mg/kg) increased BP (26-48%; P < 0.01) and reduced CI in both rat strains. BQ 123 (1 mg/kg) reduced BP slightly (-4 to 11%; P < 0.05). 3. NG-Monomethyl-L-arginine significantly increased myocardial and skeletal muscle vascular resistance in SHR only; however, in the kidney, L-NMMA reduced blood flow and increased vascular resistance in both rat strains. 4. BQ 123 induced minor changes in regional haemodynamics that were not significantly different between the two strains. 5. Acetylcholine following BQ 123 induced an increase in myocardial blood flow in WKY rats, but decreased blood flow in SHR. Acetylcholine following L-NMMA reduced myocardial blood flow in both strains. 6. Acetylcholine following BQ 123 induced renal vasodilation in WKY rats but, following L-NMMA, ACh did not induce renal vasodilation in either rat strain. In contrast, L-NMMA did not abolish the vasodilation of acetylcholine in skeletal muscle in WKY rats. 7. In conclusion, the contribution of nitric oxide to basal vessel tone was not impaired in the heart, skeletal muscle and kidney in SHR. Antagonism of ETA receptors caused similar haemodynamic responses in both rat strains in these organs. Furthermore, NOS inhibition, but not ETA blockade, blunted the expected ACh-induced vasodilation in the heart and kidney in WKY rats, but not in skeletal muscle in both strains.     

ETA receptor-mediated role of endothelin in the kidney of DOCA-salt hypertensive rats

Renal effects of FR139317, an endothelin ETA receptor antagonist, were examined using anesthetized normotensive and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The intravenous bolus injection of FR139317 (10 mg/kg) produced a slight decrease in mean blood pressure (MAP; -13%) in the control rats and this hypotension was accompanied by a moderate renal vasodilation (renal vascular resistance: RVR; -12%). In the DOCA-salt hypertensive rat, FR139317 had a more pronounced hypotensive effect (MAP; -26%) accompanied by a potent renal vasodilation (RVR; -33%). FR139317 significantly increased renal blood flow only in the DOCA-salt rats. In contrast, FR139317 produced a significant decrease in urine flow and urinary sodium excretion only in control rats. Northern blot analysis revealed that the renal prepro endothelin-1 (ET-1) mRNA level was significantly increased in DOCA-salt hypertensive rats. Thus, it seems likely that endogenous ET-1 is responsible for the maintenance of DOCA-salt-induced hypertension. We also suggest that at least in part, ET-1 and ETA receptors are involved in renal hemodynamic abnormalities in DOCA-salt-induced hypertension. The augmentation of renal ET-1 production may possibly have a function in the development and maintenance of DOCA-salt-induced hypertension.     

Effects of a K+ATP channel opener, lemakalim, on systemic, coronary and regional vascular dynamics in conscious dogs: comparison with nifedipine, adenosine, nitroglycerin and acetylcholine

The systemic, coronary and regional vascular responses to the K+ATP channel opener lemakalim were compared to other potent vasodilators (i.e., nifedipine, adenosine, nitroglycerin and acetylcholine). Experiments were performed in 12 conscious dogs 2 to 4 weeks after implantation of aortic catheters and flow probes on the ascending aorta, left circumflex coronary, celiac, mesenteric, renal and iliac arteries, and solid-state miniature pressure gauges in the left ventricular cavity. Dose-response curves induced by bolus injection (i.v.) were examined. For doses that reduced total peripheral resistance by 22%, lemakalim reduced celiac (-28 +/- 2%), mesenteric (-24 +/- 3%), renal (-17 +/- 3%) and iliac (-18 +/- 3%) vascular resistances (i.e., by amounts similar to those observed with the other vasodilators, except for adenosine, which increased renal resistance). At these doses, lemakalim induced a greater decrease (-52 +/- 3%) (P < .05) in coronary resistance, as compared with nifedipine (-35 +/- 3%), adenosine (-38 +/- 3%), nitroglycerin (-25 +/- 2%) and acetylcholine (-32 +/- 3%). However, when near maximal vasodilation was elicited, adenosine elicited the greatest (P < .05) decrease in coronary resistance (-81 +/- 1%), as compared with lemakalim (-74 +/- 2%), nifedipine (-67 +/- 2%), nitroglycerin (-63 +/- 2%) and acetylcholine (-72 +/- 1%). Both the time to maximal increases in regional blood flow and the time for recovery in all vascular beds were significantly prolonged for lemakalim compared with the other vasodilators. Thus, the K+ATP channel opener lemakalim dilates the coronary bed out of proportion to other vascular beds, is relatively more potent at lower doses than other vasodilators and exhibits a delayed and more prolonged action in all regional vascular beds.     

The effect of angiotensin AT1 receptor blockade in the brain on the maintenance of blood pressure during haemorrhage in sheep

The effect of systemic or intracerebroventricular (ICV) infusion of the angiotensin AT1 receptor antagonist losartan on blood pressure during hypotensive haemorrhage was investigated in five conscious sheep. Mean arterial pressure (MAP) was measured during haemorrhage (15 mL kg-1 body wt). Losartan (1 or 0.33 mg h-1) was given to sheep by ICV, intravenous or intracarotid administration, beginning 60 min before and continuing during the haemorrhage. During control infusion of ICV artificial cerebrospinal fluid, MAP was maintained until 13.16 +/- 0.84 mL kg-1 blood loss, when a rapid reduction of at least 15 mmHg in arterial pressure occurred (the decompensation phase). ICV infusion of losartan at 1 mg h-1 caused an early onset of the decompensation phase after only 9.8 +/- 0.8 mL kg-1 of blood loss compared with control. Intravenous infusion of losartan (1 mg h-1) also caused an early onset (P < 0.05) of the decompensation phase at 10.2 +/- 1.0 mL kg-1 blood loss. This dose of losartan inhibited the pressor response to ICV angiotensin II, but not to intravenously administered angiotensin II, indicating that only central AT1 receptors were blocked. Bilateral carotid arterial administration of losartan at 0.33 mg h-1 caused an early onset of the decompensation phase during haemorrhage at 11.06 +/- 0.91 mL kg-1 blood loss (P < 0.05), which did not occur when infused by intravenous or ICV routes. The results indicate that an angiotensin AT1-receptor-mediated mechanism is involved in the maintenance of MAP during haemorrhage in sheep. The locus of this mechanism appears to be the brain.