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PubMed1982

Haemodynamic differences in untreated hypertension and hypertension treated with various beta-adrenoceptor antagonists.

1 As a rule, hypertension progresses from an early stage with a high cardiac output (CO) and an inappropriately normal total peripheral resistance (TPR) to later stages with a normal or decreased CO and a high TPR. 2 Low CO and high TPR can be considered detrimental to the blood perfusion in the tissues and organs and thus to their functional and structural integrity. 3 Among beta-adrenoceptor antagonists, some lower blood pressure by reducing CO, thus bringing about a reactive increase in TPR. The result is that, even though blood pressure is reduced, the haemodynamic conditions commanding regional blood flow are qualitatively similar to those in untreated hypertension. To what extent these circumstances may curtail the benefit expected from blood-pressure reduction deserves careful investigation. 4 Pindolol, a beta-adrenoceptor antagonist with an appropriate degree of intrinsic sympathomimetic activity (ISA), lowers blood pressure while lowering TPR and not unduly reducing cardiac performance. These features should on theoretical grounds lead to a greater improvement in the prognosis of hypertension.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

A comparison of the effects of salbutamol, etilefrine and dextran during hypotension and low cardiac output states in rabbit.

The effects of salbutamol (25 and 50 micrograms/kg), etilefrine (50 and 200 micrograms/kg) and dextran (8 ml/kg) on cardiovascular function have been studied in the rabbit. The three drugs raised the resting cardiac output (with salbutamol producing delta max 52%, P less than 0.001, n = 5) and right heart filling pressure (RHFP, delta max from dextran 3.5 cmH2O; P less than 0.001, n = 6) and lowered total peripheral resistance (TPR, delta max from salbutamol 46%, P less than 0.001, n = 5). However, TPR rose with the 200 micrograms/kg etilefrine (P less than 0.05, n = 5). Pulse pressure rose with salbutamol (P less than 0.001, n = 6) and etilefrine (P less than 0.05, n = 6). Etilefrine raised resting BP (delta max, P less than 0.001, n = 6); salbutamol lowered resting BP (delta max, P less than 0.001, n = 6) while dextran (n = 6) had little effect on resting BP. The actions of salbutamol are mediated mainly through beta 2-adrenoceptors although the drug also has some minor beta 1-adrenoceptor action. With etilefrine, the increase in cardiac output and the reduction in TPR are mediated through beta-adrenoceptors while the increases in RHFP, blood pressure and TPR are a direct action on the alpha-adrenoceptors. However, during haemorrhage the fall in diastolic pressure produced by salbutamol was considerably reduced while the reduction in mean BP and systolic pressure (which sometimes rose) was abolished. Dextran raised BP during hypotension produced by either sympathectomy or haemorrhage but not during normotension. The reflex recovery in RHFP and the reflex tachycardia were slightly attenuated during lower body negative pressure (LBNP) after salbutamol or dextran. The reflex recovery in blood pressure was complete and the pressure sometimes exceeded the resting level by up to 10 mmHg during LBNP after salbutamol, etilefrine (50 micrograms/kg only) and dextran. The reduced TPR (presumably due to vasodilation) and the increases in cardiac output and RHFP at an adequately maintained blood pressure produced by suitable doses of the three drugs may be useful in the management of circulatory shock and related states.

Albuterol↗

PubMed1977

Responses of the cardiovascular system of the rat to noradrenaline infusions and their modification by adrenoceptor blocking agents.

1 The effects of noradrenaline upon the cardiovascular system of the rat, anaesthetized with pentobarbitone, have been investigated.2 Noradrenaline produces a dose-dependent increase in mean arterial blood pressure (MABP) which is due entirely to an increase in cardiac output; total peripheral vascular resistance (TPR) remains unchanged.3 Following beta-adrenoceptor blockade the pressor response to infused noradrenaline is enhanced and is now due mainly to an increase in TPR; the increment in cardiac output is reduced.4 After alpha-adrenoceptor blockade the pressor response is greatly reduced; the residual increase in MABP is due solely to an increase in cardiac output.5 After ganglion blockade resting cardiac output and TPR both fall, resulting in a reduction in MABP. The pressor response to noradrenaline is enhanced and is now due to increases in both TPR and in cardiac output.6 The cardiovascular response of the anaesthetized rat to noradrenaline can be explained in terms of classical alpha- and beta-adrenoceptor stimulation by the amine; the unusual form of the response may be due to an effective predominance of beta-adrenoceptor-mediated effects in this species.7 It is suggested that the failure of exogenous noradrenaline to produce a rise in TPR results from a balance between the alpha-adrenoceptor-mediated increase and beta-adrenoceptor-mediated decrease in this variable. However, this proposed balance is lost if resting vasoconstrictor tone is reduced by ganglion blockade.

Adrenergic alpha-Antagonists↗

PubMed1996

The vasoconstrictor effects of L-NAME, a nitric oxide synthase inhibitor, in pregnant rabbits.

1. We have used anaesthetized, acutely instrumented non-pregnant (NP) and late pregnant (P) New Zealand white rabbits to examine the possible role of nitric oxide (NO) in the pregnancy-induced fall of vascular tone and arterial pressure. Systemic, renal and pulmonary vascular resistance, as well as plasma concentrations of cyclic GMP (PcGMP) were compared before and after the inhibition of NO synthesis by N(G)-nitro-L-arginine methyl ester (L-NAME). 2. P rabbits had lower baseline total peripheral resistance (TPR), mean arterial pressure (MAP) and higher PcGMP than NP controls (all P < 0.05 or less). L-NAME (1, 10, 50 mg kg1, i.v.) resulted in dose-dependent elevation of TPR in both groups. However, the absolute, as well as percentage increases in TPR were greater (P < 0.05) in NP than in P rabbits. 3. Cardiac output (CO) was reduced more (P < 0.01) by NO inhibition in NP than P rabbits. Therefore, despite the smaller increase in TPR, the elevation of MAP was greater (P < 0.001) in P than NP rabbits. After L-NAME, NP rabbits developed more severe bradycardia and a greater increase of pulmonary vascular resistance which might have contributed to the more pronounced reduction of CO. 4. PcGMP increased in both groups following L-NAME, but more (P < 0.01) in NP than P rabbits. 5. Infusion of acetylcholine (ACh, 0.02 micromol l-1 kg-1) reduced MAP and TPR more (both P < 0.05) in NP than P rabbits and L-NAME reduced the ACh-induced depressor response only in NP rabbits. 6. These results suggest that the low vascular tone and arterial pressure in pregnant rabbits is not mediated by NO.

Acetylcholine↗

PubMed1982

Influences on central hemodynamics in hemorrhage of beta 2-adrenergic vascular control mechanisms.

Central hemodynamic responses evoked by standardized hemorrhage (exsanguination of 20 ml x kg bwt-1) were followed during 2 h in cats with intact and blocked vascular beta 2-adrenoceptors using the 'selective' beta 2-blocker, ICI 118, 551. In the first 10 min after bleeding blood pressure and cardiac output (CO) decreased and total peripheral resistance (TPR) increased by the same amount in the 'intact' and beta 2-blocked animals. Whereas blood pressure later on reached approximately the same hypotension level in both groups, other hemodynamic variables were distinctly different. In the 'intact' animals there was a gradual, partial recovery of stroke volume (SV) and CO in the face of a restoration to control of TPR. In the beta 2-blocked animals TPR continued to increase in the face of a maintained low CO and declining SV. The lower SV in the latter group was ascribed to abolition of beta 2-adrenergic restoration of plasma volume via absorption of tissue fluid into the circulation. The gradual decline of TPR in the 'intact' animals was attributed to beta 2-adrenergic dilator interaction with constrictor influences on the resistance vessels. It is concluded that beta-adrenergic vascular control mechanisms help to improve nutritional tissue blood flow during hemorrhage by increasing plasma volume, and hence venous return and CO, and by decreasing TPR. These reflex, beta 2-adrenergic circulatory events are similar to those aimed at in current shock therapy by transfusion and vasodilator treatment.

Adrenergic beta-Antagonists↗

PubMed2004

Vaccinia virus A36R membrane protein provides a direct link between intracellular enveloped virions and the microtubule motor kinesin.

Previous work demonstrated that intracellular enveloped vaccinia virus virions use microtubules to move from the site of membrane wrapping to the cell periphery. The mechanism and direction of intracellular virion movement predicted that viral proteins directly or indirectly interact with the microtubule motor protein kinesin. The yeast two-hybrid assay was used to test for interactions between the light chain of kinesin and the cytoplasmic tails from five viral envelope proteins. We found that the N-terminal tetratricopeptide repeat region of the kinesin light chain (KLC-TPR) interacted with the cytoplasmic tail of the viral A36R protein. A series of C- and N-terminal truncations of A36R further defined a region from residues 81 to 111 that was sufficient for interaction with KLC-TPR. Interactions were confirmed by using pull-down assays with purified glutathione S-transferase (GST)-A36R and (35)S-labeled KLC-TPR. The defined region on A36R for interaction with kinesin overlaps the recently defined region (residues 91 to 111) for interaction with the A33R envelope protein. The yeast three-hybrid system was used to demonstrate that expression of A33R interrupted the interaction between A36R and KLC-TPR, indicating that the binding of A36R is mutually exclusive to either A33R or kinesin. Pull-down assays with purified GST-A36R and (35)S-labeled KLC-TPR in the presence of competing A33R corroborated these findings. Collectively, these results demonstrated that the viral A36R protein interacts directly with the microtubule motor protein kinesin and that the viral protein A33R may regulate this interaction.

Animals↗

PubMed1993

Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase.

Oncogenic activation of the met (hepatocyte growth factor/scatter factor) receptor tyrosine kinase involves a genomic rearrangement that generates a hybrid protein containing tpr-encoded sequences at its amino terminus fused directly to the met-encoded receptor kinase domain. Deletion of Tpr sequences abolishes the transforming ability of this protein, implicating this region in oncogenic activation. We demonstrate, by site-directed mutagenesis and coimmunoprecipitation experiments, that a leucine zipper motif within Tpr mediates dimerization of the tpr-met product and is essential for the transforming activity of the met oncogene. By analogy with ligand-stimulated activation of receptor tyrosine kinases, we propose that constitutive dimerization mediated by a leucine zipper motif within Tpr is responsible for oncogenic activation of the Met kinase. The possibility that this mechanism of activation represents a paradigm for a class of receptor tyrosine kinase oncogenes activated by DNA rearrangement is discussed.

3T3 Cells↗

PubMed2000

Enhanced transformation by a plasma membrane-associated met oncoprotein: activation of a phosphoinositide 3'-kinase-dependent autocrine loop involving hyaluronic acid and CD44.

A Met-hepatocyte growth factor receptor oncoprotein, Tpr-Met, generated by chromosomal rearrangement, fuses a protein dimerization motif with the cytoplasmic domain of the Met receptor, producing a cytosolic, constitutively activated tyrosine kinase. Although both the Met receptor and the Tpr-Met oncoprotein associate with the same substrates, activating mutations of the Met receptor in hereditary papillary renal carcinomas have different signaling requirements for transformation than Tpr-Met. This suggests differential activation of membrane-localized pathways by oncogenic forms of the membrane-bound Met receptor but not by the cytoplasmic Tpr-Met oncoprotein. To establish which pathways might be differentially regulated, we have localized the constitutively activated Tpr-Met oncoprotein to the membrane using the c-src myristoylation signal. Membrane localization enhances cellular transformation, focus formation, and anchorage-independent growth and induces tumors with a distinct myxoid phenotype. This correlates with the induction of hyaluronic acid (HA) and the presence of a distinct form of its receptor, CD44. A pharmacological inhibitor of phosphoinositide 3' kinase (PI3'K), inhibits the production of HA, and conversely, an activated, plasma membrane-targeted form of PI3'K is sufficient to enhance HA production. Furthermore, the multisubstrate adapter protein Gab-1, which couples the Met receptor with PI3'K, enhances Met receptor-dependent HA synthesis in a PI3'K-dependent manner. These results provide a positive link to a role for HA and CD44 in Met receptor-mediated oncogenesis and implicate PI3'K in these events.

Adaptor Proteins, Signal Transducing↗

PubMed1994

Simple method for comparing reliability of two serum tumour markers in breast carcinoma.

AIMS: To compare the two breast tumour markers, CA15-3 and mucinous-like carcinoma associated antigen (MCA), using Receiver Operating Characteristic (ROC) curve analysis. METHODS: One hundred and ninety six patients "presenting" with breast carcinoma had serum CA15-3 and MCA concentrations measured. RESULTS: Using these markers as indicators of stage IV disease at the recommended laboratory level, true positive rates (TPR) and false positive rates (FPR) were obtained as follows: CA15-3 TPR = 75%, FPR = 7.4%, MCA TPR = 80%, FPR = 59.1%. By increasing the CA15-3 cutoff level to 45 U/ml, a TPR and FPR of 75% and 0.6%, respectively were obtained. By increasing the MCA cutoff level to 23 U/ml, a TPR and FPR of 65% and 2.3%, respectively, were obtained. CONCLUSIONS: Using ROC curve analysis shows that CA15-3 is a superior indicator of metastatic breast disease than MCA at recommended laboratory levels, and by altering the cutoff points, the specificity and sensitivity for both these markers can be improved.

Antigens, Neoplasm↗

PubMed1984

Beta 2-adrenergic vascular control in hemorrhage and its influence on cardiac performance.

Cardiac output (CO), heart rate, stroke volume (SV), and total peripheral resistance (TPR) were followed in anesthetized cats with intact and selectively blocked beta 2-adrenoceptors. SV and CO decreased and TPR increased initially after bleeding in both groups. After this, animals with intact beta 2-adrenoceptors showed gradual recovery of SV and CO and gradual restoration to control of the initially raised TPR. In beta 2-blocked animals SV and CO instead remained low and TPR high. These patterns of response occurred after mild, moderate, and severe bleeding. Separate experiments indicated that the restoration of TPR with intact beta 2-adrenoceptors mainly can be attributed to beta 2-adrenergic dilator interaction with the vasoconstrictor influences. The previously described beta 2-adrenergic control of plasma volume in hemorrhage (Acta Physiol. Scand. 116: 175-180, 1982) suggests that the increases in SV and CO with intact beta 2-adrenoceptors, in turn, probably are indirect effects on cardiac performance due to improved cardiac filling. A synthesis of present and previous findings thus suggests the existence of a beta 2-adrenergic vascular control in hemorrhage favoring tissue perfusion via decreased resistance and via increased plasma volume and hence SV and CO.

Adrenergic beta-Antagonists↗

PubMed1986

Hemodynamic changes during onset of high-sodium one-kidney figure-8 renal hypertension.

The hemodynamic changes associated with the onset of one-kidney, figure-8, renal-wrap hypertension were monitored in rats fed a high-sodium diet. In addition, the hemodynamic contributions of the sympathetic nervous system (SNS) and arginine vasopressin (AVP) were assessed during the 1st week of hypertension. Renal wrapping caused mean arterial pressure (MAP) to increase significantly from 108 +/- 4 to 140 +/- 4 mmHg on day 5 after renal surgery. The hypertension was associated with a significant bradycardia and no significant change in cardiac output (CO), as measured with an electromagnetic flow probe. Total peripheral resistance (TPR) was significantly elevated to 140% above control value on day 5 after renal surgery. Ganglionic blockade caused similar decreases in MAP and TPR in normotensive and hypertensive animals. Sympathetic blockade after pretreatment with a specific vascular antagonist of AVP, [1-beta-mercapto-beta, beta-cyclopentamethylene propionic acid), 2-(O-methyl)tyrosine]Arg8-vasopressin ([d(CH2)5Tyr(Me)]AVP), caused a greater depressor response in the renal-wrapped animals as compared with the effect of ganglionic blockade alone in these animals. The effect of [d(CH2)5Tyr(Me)]AVP alone on the hemodynamics was not different between the two groups of rats. After ganglionic blockade pretreatment, [d(CH2)5Tyr(Me)]AVP caused a significant decrease in MAP and TPR in the renal-wrapped animals. In addition, the difference in MAP and TPR between the two groups of rats was eliminated after combined blockade of AVP and the SNS. The results of this study indicated that the onset of hypertension was a result of an activation of neurohumoral mechanisms to increase TPR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Role of vasopressin in the cardiovascular response to hypoxia in the conscious rat.

Previous experiments have demonstrated that hypoxia stimulates the release of arginine vasopressin in conscious animals including the rat. The present study was designed to test whether AVP may exert a vasoconstrictor influence during hypoxia at varying levels of CO2. Systemic hemodynamics were assessed in conscious rats for 30 min under hypocapnic hypoxic, isocapnic hypoxic, hypercapnic hypoxic, and room air conditions. Progressive effects on heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR) were observed with varying CO2 under hypoxic conditions. Hypocapnic hypoxia [arterial PO2 (PaO2) = 32 Torr; arterial PCO2 (PaCO2) = 22 Torr] caused HR and CO to rise and TPR to fall. Isocapnic hypoxia (PaO2 = 36 Torr; PaCO2 = 35 Torr) was associated with no significant changes in HR and CO or TPR, whereas hypercapnic hypoxia (PaO2 = 35 Torr; PaCO2 = 51 Torr) caused HR and CO to fall and TPR to rise. Room air time control experiments were associated with no change in measured hemodynamic variables. To determine the possible role of circulating AVP on these cardiovascular responses, additional experiments were performed where the specific V1-vasopressinergic antagonist d(CH2)5Tyr(Me)AVP (10 micrograms/kg iv) was administered at the midpoint of hypoxic exposure. Antagonist administration had no effect on hypocapnic hypoxic animals or animals breathing room air; however, blood pressure and TPR were significantly reduced by d(CH2)5Tyr(Me)AVP in both isocapnic and hypercapnic hypoxic animals. The heart rate response to hypoxia at the various CO2 levels was unaffected; however, cardiac output and stroke volume were increased after V1-antagonism in the isocapnic and hypercapnic hypoxic animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2001

Mechanisms mediating NTS P2x receptor-evoked hypotension: cardiac output vs. total peripheral resistance.

We have previously shown that P2x purinoceptor activation in the subpostremal nucleus tractus solitarius (NTS) produces dose-dependent decreases in mean arterial pressure (MAP), heart rate, efferent sympathetic nerve activity, and significant peripheral vasodilation. However, the relative roles of cardiac output (CO) and total peripheral resistance (TPR) in mediating this depressor response are unknown. Bradycardia does not necessarily result in decreased CO, because, with the greater filling time, stroke volume may increase such that CO may be unchanged. We measured changes in CO (via a chronically implanted flow probe on the ascending aorta) and MAP in alpha-chloralose- and urethane-anesthetized male Sprague-Dawley rats in response to microinjection of the selective P2x purinoceptor agonist alpha,beta-methylene ATP (25 and 100 pmol/50 nl) into the subpostremal NTS. TPR was calculated as MAP/CO. At the low dose of NTS P2x purinoceptor agonist, the reduction in MAP was primarily mediated by reductions in TPR (-31.3 +/- 3.3%), not CO (-8.7 +/- 1.7%). At the high dose, both CO (-34.4 +/- 6.6%) and TPR (-40.2 +/- 2.5%) contribute to the reduction in MAP. We conclude that the relative contribution of CO and TPR to the reduction in MAP evoked by NTS P2x purinoceptor activation is dependent on the extent of P2x purinoceptor activation.

Adenosine Triphosphate↗

PubMed1991

Hemodynamic responses to acute volume expansion in Dahl salt-sensitive rats.

The purpose of this study is to evaluate hemodynamic responses to acute volume expansion in chronically instrumented, conscious Dahl salt-sensitive (Dahl-S) and Dahl salt-resistant (Dahl-R) rats that have been maintained on either 0.45% NaCl, 1% NaCl, or 7% NaCl (5 days) intakes. Total peripheral resistance (TPR), but not arterial pressure, was increased by 5 days of 7% NaCl in Dahl-S (P less than 0.05) but not in Dahl-R. In Dahl-S, but not in Dahl-R, right atrial pressure increased with increasing dietary NaCl (P less than 0.05). On the 0.45% NaCl intake, atrial pressure did not differ in the two strains, whereas on both the 1 and 7% NaCl diets atrial pressure was higher in Dahl-S than in Dahl-R (P less than 0.05). In response to acute extracellular fluid volume expansion, arterial pressure did not change, and cardiac output increased in Dahl-S and in Dahl-R. On the 0.45% NaCl intake, TPR decreased (P less than 0.01) similarly in response to volume expansion in both strains; however, on the 1% NaCl intake TPR decreased in Dahl-R (P less than 0.05) but not in Dahl-S. In contrast, in animals fed 7% NaCl for 5 days, TPR decreased acutely in Dahl-S (P less than 0.01) but not in Dahl-R. These observations suggest that cardiopulmonary baroreflex activity is impaired in Dahl-S on a 1% NaCl intake, possibly as a consequence of elevated right atrial pressure. This alteration of the cardiopulmonary baroreflex may contribute to increased TPR in Dahl-S on a high-NaCl intake.

Animals↗

PubMed1993

Total autonomic blockade eliminates the attenuated pressor response to angiotensin II in pregnant rats.

Pressor responses to angiotensin II (ANG II) are markedly attenuated in reflex-intact pregnant animals, a phenomenon widely attributed to intrinsic changes in vascular reactivity. To test the hypothesis that gestational augmentation of neural reflex activity contributes importantly to this phenomenon, changes in mean arterial pressure (MAP), cardiac output (CO), and total peripheral resistance (TPR) were compared during constant infusion (25-400 ng.kg-1.min-1) of ANG II in conscious virgin and pregnant rats, using a model of total autonomic blockade (chlorisondamine chloride and methscopolamine bromide), with restoration of baseline hemodynamics by infusion of norepinephrine. Basal CO was higher and TPR lower in pregnant (CO 121.8 +/- 3.8 ml/min; TPR 0.78 +/- 0.04 mmHg.ml-1.min) compared with virgin (CO 95.9 +/- 3.9 ml/min; TPR 1.05 +/- 0.08 mmHg.ml-1.min) rats (P < 0.005). Pressor responses to ANG II were similar in both groups of reflex-blocked animals due to comparable changes in TPR and CO (not significant by repeated-measures analysis of variance). Other experiments demonstrated that changes in MAP after bolus administration of ANG II did not differ in areflexic virgin and gravid rats. Thus in the absence of autonomic control ANG II has similar effects on systemic resistance in pregnant and nonpregnant rats, suggesting that reflex neural mechanisms contribute significantly to gestational changes in pressor responsiveness. These data further suggest that pregnancy is not accompanied by a generalized decrease in vascular reactivity to all pressor agents.

Angiotensin II↗

PubMed2001

Paradoxically enhanced endothelin-B receptor-mediated vasoconstriction in conscious old monkeys.

BACKGROUND: We investigated the effects of aging on the responses to endothelin (ET) in conscious old (19.8+/-0.6 years) and young adult (6.8+/-0.3 years) monkeys and compared these results with those of other vasoconstrictors, eg, phenylephrine (PE) and angiotensin II (Ang II). METHODS AND RESULTS: The monkeys (Macaca fascicularis) were chronically instrumented. Baseline total peripheral resistance (TPR) was not different between the 2 groups. As expected, TPR rose less (P<0.05) with PE (5 microgram/kg) in old monkeys (34+/-3%) than in young monkeys (57+/-6%); TPR also rose less with Ang II. Surprisingly, TPR rose more (P<0.05) with endothelin-1 (ET-1, 25 ng. kg(-1). min(-1)) in old monkeys (36+/-6%) than in young monkeys (10+/-2%). An ET(B) receptor agonist, sarafotoxin (S6c, 30 ng. kg(-1). min(-1)) was administered in the presence of an ET(A) receptor antagonist, BQ-123 (1 mg/kg). Under these conditions, TPR increased more (P<0.05) in old monkeys (59+/-10%) than in young monkeys (31+/-4%). In the presence of nitric oxide synthase (NOS) inhibition with N(W)-nitro-L-arginine methyl ester (60 mg/kg), vasoconstriction induced by S6c no longer differed with age, because it was enhanced in young monkeys (P<0.05) (68+/-9% versus 31+/-4%) but not in old monkeys (58+/-6% versus 59+/-10%). Thus, after NOS inhibition, vasoconstrictor responses to ET were no longer enhanced in old monkeys. CONCLUSIONS: Peripheral vasoconstriction (PE and Ang II) is reduced in old monkeys, as expected. Paradoxically, vasoconstriction induced by ET-1 was actually enhanced in old monkeys, which appears to be a result of impaired endothelium-dependent vasodilation, which with ET-1 should involve the ET(B) receptor.

Aging↗

PubMed1988

Effect of intravertebral angiotensin II on cardiac output and its distribution in conscious dogs.

Intravertebral infusion of angiotensin II (Ang II) increases mean arterial pressure (MAP), but the contribution of cardiac output (CO) and total peripheral resistance (TPR) to this increase is unclear. In the present study, the effects of Ang II infusion on CO and regional blood flow was determined by the microsphere technique in eight conscious, chronically catheterized dogs. Ang II was infused into both vertebral arteries at 0.33 and 1.0 ng/kg/min, and intravenously at 0.66, 2.0 and 5.0 ng/kg/min. Intravertebral infusion of Ang II at 0.33 ng/kg/min increased MAP by increasing CO without changing TPR or peripheral plasma Ang II concentration. MAP also was increased with intravertebral infusion of Ang II at 1.0 ng/kg/min, but this resulted from small increases in both CO and TPR. In contrast, intravenous infusion of Ang II at 2.0 and 5.0 ng/kg/min increased MAP by increasing TPR in association with a decrease in CO. The increase in CO with intravertebral infusion of Ang II at 0.33 ng/kg/min was distributed primarily to the muscles, kidneys, heart, and brain. Intravenous infusion of Ang II at 5.0 ng/kg/min and, to a lesser extent, 2.0 ng/kg/min decreased blood flow to the skin, splanchnic region, and kidneys. These data indicate that the increase in MAP produced by a low intravertebral dose of Ang II results from an increase in CO, which is distributed primarily to the muscle, kidney, heart, and brain. In contrast, the increase in MAP produced by a higher intravertebral dose of Ang II results from increases in CO and TPR. This latter action is apparently due to a peripheral action of Ang II to increase resistance in the skin, splanchnic, and renal circulations.

Angiotensin II↗

PubMed2001

Acute gender-specific hemodynamic and inotropic effects of 17beta-estradiol on rats.

Estrogen has cardioprotective effects. In addition to beneficial effects on lipid metabolism, estrogen affects the vascular tone and may reduce endothelial dysfunction. In the present study, we examined acute gender-specific hemodynamic and inotropic effects of 17beta-estradiol (17beta-E) versus the control situation in open-chest rats. In addition to measurements in the intact circulation, myocardial function was examined on the basis of isovolumic registration independent of peripheral vascular effects. Regarding the dose-dependent and gender-specific effects of 17beta-E, in female rats, 17beta-E (50, 100, or 200 ng/kg) increased cardiac output (CO) (26%, 43%, and 59% versus control animals) as a result of reduction in total peripheral resistance (TPR) (-13%, -18%, and -24%) without any effect on myocardial contractility (isovolumic left ventricular systolic pressure, -1%, 0%, and -6%). These vascular effects are less pronounced in male rats (for 200 ng/kg 17beta-E: CO, 34%; TPR, -14%). We investigated gender-specific effects of 200 ng/kg 17beta-E after pretreatment with the estrogen receptor (ER) antagonist ICI 182,780. ER blockade reduced the effects of estrogen in female rats (CO, 29%; TPR, -17%) and male rats (CO, 19%; TPR, -11%). Regarding the effects of 200 ng/kg 17beta-E after pretreatment with N(G)-nitro-L-arginine methyl ester, NO synthesis inhibition completely prevented the acute vascular effects of estrogen in female rats (CO, -4%; TPR, 1%). In addition, immunohistochemical staining revealed no gender-specific differences of the vascular ER distribution. 17beta-E caused an acute dose-dependent and gender-specific reduction in the afterload. ERs are involved in both genders in this vasodilative effect that is mediated by NO. This NO-mediated effect may explain in part the cardioprotective effect of estrogen.

Animals↗