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PubMed2002

Hypertension induced by blockade of ET(B) receptors in conscious nonhuman primates: role of ET(A) receptors.

The role of endothelin-B (ET(B)) receptors in circulatory homeostasis is ambiguous, reflecting vasodilator and constrictor effects ascribed to the receptor and diuretic and natriuretic responses that could oppose the hypertensive effects of ET excess. With the use of conscious, telemetry-instrumented cynomolgus monkeys, we characterized the hypertension produced by ET(B) blockade and the role of ET(A) receptors in mediating this response. Mean arterial pressure (MAP) and heart rate (HR) were measured 24 h/day for 24 days under control conditions and during administration of the ET(B)-selective antagonist A-192621 (0.1, 1.0, and 10 mg/kg bid, 4 days/dose) followed by coadministration of the ET(A) antagonist atrasentan (5 mg/kg bid) + A-192621 (10 mg/kg bid) for another 4 days. High-dose ET(B) blockade increased MAP from 79 +/- 3 (control) to 87 +/- 3 and 89 +/- 3 mmHg on the first and fourth day, respectively; HR was unchanged, and plasma ET-1 concentration increased from 2.1 +/- 0.3 pg/ml (control) to 7.24 +/- 0.99 and 11.03 +/- 2.37 pg/ml. Atrasentan + A-192621 (10 mg/kg) decreased MAP from hypertensive levels (89 +/- 3) to 75 +/- 2 and 71 +/- 4 mmHg on the first and fourth day, respectively; plasma ET-1 and HR increased to 26.64 +/- 3.72 and 28.65 +/- 2.89 pg/ml and 113 +/- 5 (control) to 132 +/- 5 and 133 +/- 7 beats/min. Thus systemic ET(B) blockade produces a sustained hypertension in conscious nonhuman primates, which is mediated by ET(A) receptors. These data suggest an importance clearance function for ET(B) receptors, one that influences arterial pressure homeostasis indirectly by reducing plasma ET-1 levels and minimizing ET(A) activation.

Animals↗
PubMed2005

Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy.

We have shown previously that the glucagon-like peptide-1 (GLP-1)-(7-36) amide increases myocardial glucose uptake and improves left ventricular (LV) and systemic hemodynamics in both conscious dogs with pacing-induced dilated cardiomyopathy (DCM) and humans with LV systolic dysfunction after acute myocardial infarction. However, GLP-1-(7-36) is rapidly degraded in the plasma to GLP-1-(9-36) by dipeptidyl peptidase IV (DPP IV), raising the issue of which peptide is the active moiety. By way of methodology, we compared the efficacy of a 48-h continuous intravenous infusion of GLP-1-(7-36) (1.5 pmol.kg(-1).min(-1)) to GLP-1-(9-36) (1.5 pmol.kg(-1).min(-1)) in 28 conscious, chronically instrumented dogs with pacing-induced DCM by measuring LV function and transmyocardial substrate uptake under basal and insulin-stimulated conditions using hyperinsulinemic-euglycemic clamps. As a result, dogs with DCM demonstrated myocardial insulin resistance under basal and insulin-stimulated conditions. Both GLP-1-(7-36) and GLP-1-(9-36) significantly reduced (P < 0.01) LV end-diastolic pressure [GLP-1-(7-36), 28 +/- 1 to 15 +/- 2 mmHg; GLP-1-(9-36), 29 +/- 2 to 16 +/- 1 mmHg] and significantly increased (P < 0.01) the first derivative of LV pressure [GLP-1-(7-36), 1,315 +/- 81 to 2,195 +/- 102 mmHg/s; GLP-1-(9-36), 1,336 +/- 77 to 2,208 +/- 68 mmHg] and cardiac output [GLP-1-(7-36), 1.5 +/- 0.1 to 1.9 +/- 0.1 l/min; GLP-1-(9-36), 2.0 +/- 0.1 to 2.4 +/- 0.05 l/min], whereas an equivolume infusion of saline had no effect. Both peptides increased myocardial glucose uptake but without a significant increase in plasma insulin. During the GLP-1-(9-36) infusion, negligible active (NH2-terminal) peptide was measured in the plasma. In conclusion, in DCM, GLP-1-(9-36) mimics the effects of GLP-1-(7-36) in stimulating myocardial glucose uptake and improving LV and systemic hemodynamics through insulinomimetic as opposed to insulinotropic effects. These data suggest that GLP-1-(9-36) amide is an active peptide.

Animals↗
PubMed2003

Effect of blockade of endogenous angiotensin II on baroreflex function in conscious diabetic rats.

Little is known about baroreflex control of renal nerve sympathetic activity (RSNA) or the effect of angiotensin II (ANG II) on the baroreflex in diabetes. We examined baroreflex control of RSNA and heart rate (HR) in conscious, chronically instrumented rats 2 wk after citrate vehicle (normal) or 55 mg/kg iv streptozotocin (diabetic) before and after losartan (5 mg/kg iv) or enalapril (2.5 mg/kg iv). Resting HR and RSNA were lower in diabetic versus normal rats. The range of baroreflex control of HR and the gain of baroreflex-mediated bradycardia were impaired in diabetic rats. Maximum gain was unchanged. The baroreflex control of RSNA was reset to lower pressures in the diabetic rats but remained otherwise unchanged. Losartan decreased mean arterial pressure (MAP) and increased HR and RSNA in both groups but had no influence on the baroreflex. Enalapril decreased MAP only in normal rats, yet the increase in HR and RSNA was similar in both groups. Thus in diabetic rats enalapril produced a pressure-independent increase in HR and RSNA. Enalapril exerted no effect on the baroreflex control of HR or RSNA in either group. These data indicate that in conscious rats resting RSNA is lower but baroreflex control of RSNA is preserved after 2 wk of diabetes. At this time, the baroreflex control of HR is already impaired and blockade of endogenous ANG II does not improve this dysfunction.

Angiotensin II↗
PubMed2003

Cardiovascular responses to substance P in the nucleus tractus solitarii: microinjection study in conscious rats.

The cardiovascular effects of substance P (SP) microinjections in the nucleus tractus solitarii (NTS) were evaluated in conscious rats. We chose this model because it is an effective way to access some of the cardiovascular effects of neurotransmitters in the NTS without the inconvenience of blunting pathways with anesthetic agents or removing forebrain projections by decerebration. The cardiovascular responses to SP injections were also evaluated after chronic nodose ganglionectomy. We found that, in conscious rats, SP microinjections into the NTS induced hypertension and tachycardia. Unilateral and bilateral SP injections into the NTS caused a slow increase in blood pressure and heart rate that peaked 1.5-5 min after injection and lasted for 20-30 min. Nodose ganglionectomy increased the duration of the pressor and tachycardic effects of SP and enhanced the pressor response. These data show that SP in the NTS is involved in pressor pathways. The supersensitivity to SP seen after nodose ganglionectomy suggests that vagal afferent projections are involved in those pressor pathways activated by SP in the NTS.

Animals↗
PubMed2003

Gender differences on the effects of aging on cardiac and peripheral adrenergic stimulation in old conscious monkeys.

We examined the effects of gender and aging on cardiac and peripheral hemodynamic responses to beta-adrenergic receptor (beta-AR) stimulation in young (male = 5.9 +/- 0.4 yr old and female = 6.5 +/- 0.7 yr old) and old (male = 19.8 +/- 0.7 yr old and female = 21.2 +/- 0.2 yr old) conscious monkeys (Macaca fascicularis), chronically instrumented for measurements of left ventricular (LV) and arterial pressures as well as cardiac output. Baseline LV pressure, the first derivative of LV pressure (LV dP/dt), cardiac index, mean arterial pressure, total peripheral resistance (TPR), and heart rate in conscious monkeys were not different among the four groups. Increases in LV dP/dt in response to 0.1 microg/kg isoproterenol (Iso) were diminished (P < 0.05) in old males (+99 +/- 11%) compared with young males (+194 +/- 18%). In addition, the inotropic responses to norepinephrine (NE) and forskolin (FSK) were significantly depressed (P < 0.05) in old males. Iso-induced reductions of TPR were less (P < 0.05) in old males (-28 +/- 2%) than in young males (-49 +/- 2%). The changes of TPR in response to NE and FSK were also significantly attenuated (P < 0.05) in old males. However, the LV dP/dt responses to BAY y 5959 (15 microg. kg-1. min-1), a Ca2+ channel promotor independent of beta-AR signaling, were not significantly different between old and young males. In contrast to results in male monkeys, LV dP/dt and TPR responses to Iso, NE, and FSK in old females were similar to those observed in young females. Thus both cardiac contractile and peripheral vascular dynamic responses to beta-AR stimulation are preserved in old female but not old male monkeys. This may explain, in part, the reduced cardiovascular risk in the older female population.

Aging↗
PubMed1982

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.

Animals↗
PubMed1983

Left ventricular oxygen consumption and function in hypoxemia in conscious lambs.

The effects of hypoxemia on left ventricular myocardial blood flow, myocardial oxygen consumption, and contractile function were studied in 12 conscious newborn lambs 4-24 days after birth. Through a left thoracotomy, we placed fluid-filled catheters in the ascending aorta, coronary sinus, and left atrium. An electromagnetic flow transducer was placed around the ascending aorta, and a solid-state pressure transducer was introduced into the left ventricle. Three to four days later we measured aortic and coronary sinus blood oxygen contents, left ventricular myocardial blood flow, heart rate, aortic and left ventricular blood pressures, ascending aortic blood flow velocity, and the first derivative of left ventricular pressure (dP/dt) and ascending aortic blood flow velocity (dV/dt) during a control period and during 50 and 75% reductions in ascending aortic oxygen content. Myocardial oxygen consumption was calculated. There was no significant change in aortic or coronary sinus blood pH or CO2 tension during the study. Coronary sinus blood oxygen content and the arteriovenous difference of oxygen across the left ventricle decreased as a linear function of the aortic blood oxygen content. Myocardial blood flow increased in proportion to the reduction in aortic blood oxygen content. Myocardial oxygen consumption increased during hypoxemia but not as a function of aortic blood oxygen content. There was no significant change in left ventricular end-diastolic pressure or aortic mean blood pressure. dP/dt and dV/dt doubled during hypoxemia, but the increases did not occur as a function of the aortic blood oxygen content. In conscious, unanesthetized newborn lambs, 50 and 75% reductions of aortic blood oxygen content were associated with significant increases of left ventricular myocardial blood flow, oxygen consumption, and contractile function.

Animals↗
PubMed1983

Vasopressin and renin responses to hemorrhage in conscious, cardiac-denervated dogs.

We measured plasma arginine vasopressin (AVP) and plasma renin activity (PRA) during continuous hemorrhage in cardiac-denervated and sham-operated conscious dogs. Hemorrhage produced comparable decreases in aortic pressure, cardiac output, stroke volume, pulmonary arterial pressure, and left and right atrial pressures in each group of dogs. After 10 ml blood/kg body wt had been removed, AVP was increased in sham-operated dogs (P less than 0.05) but not in cardiac-denervated dogs. After 20 and 30 ml blood/kg body wt had been removed, AVP was increased in all dogs, but the response was markedly attenuated in cardiac-denervated dogs. Hemorrhage at 10 and 20 ml/kg caused comparable increases in PRA in each group of dogs. However, at 30 ml/kg hemorrhage the increase in PRA was significantly higher in cardiac-denervated dogs than in sham-operated dogs. Our results suggest that cardiac receptors play a dominant role in mediating the release of AVP during hemorrhage in conscious dogs. In contrast, we found no evidence for a dominant role of cardiac receptors in mediating renin secretion during hemorrhage.

Animals↗
PubMed1983

A method for evaluation of blood substitutes in the conscious animal.

Physiological evaluation of new and potential blood replacement agents has not kept pace with the development of such agents. Current procedures involve partial or total blood replacement in the anesthetized animal. This introduces the variable of anesthesia and eliminates the ability to observe behavior changes during blood replacement. Clinically, many patients receive blood or will receive artificial agents while sedated or under anesthesia, whereas others will be conscious. It is essential that evaluative studies be performed on the awake animal using procedures that are nontraumatic and nonrestrictive. A technique for isovolumic exchange perfusion utilizing an indwelling, heparin-coated, double-lumen catheter in the right atrium of a conscious rat is described. This animal model system permits continuous pre- and postperfusion monitoring. Nearly total blood replacement with perfluorochemical blood substitutes causes no discerniable discomfort or adverse reactions in the animal. Such animals thrive and replace missing hematologic components in 1-3 wk. The technique described can, with minimal modification, be used for isovolumic exchange perfusion of larger animals.

Animals↗
PubMed1983

Reflex cardiovascular responses to chemoreceptor stimulation in conscious dogs with cardiac hypertrophy.

Carotid chemoreceptor reflex activation (CCRA) has been previously shown to result in intense alpha-adrenergic peripheral vasoconstriction, a biphasic coronary vascular response characterized by an early vasodilation and a late alpha-adrenergic vasoconstriction, and a cholinergic increase in cardiac cycle length in normal conscious dogs. In the present study, we investigated the extent to which these reflex cardiovascular responses to CCRA are modified after the development of pressure-overload right ventricular (RV) hypertrophy induced by chronic (9-12 mo) pulmonary arterial stenosis. With heart rate constant and respiration allowed to vary spontaneously, the magnitude of the late CCRA-induced (intracarotid nicotine) increase (P less than 0.01) in right coronary resistance was markedly attenuated (P less than 0.01) in conscious dogs with RV hypertrophy [0.29 +/- 0.07 (SE) mmHg X ml-1 X min] compared with normal dogs (1.87 +/- 0.36). When respiration was controlled to eliminate pulmonary inflation reflex activation, the late CCRA-induced increase (P less than 0.01) in right coronary resistance was still found to be depressed (P less than 0.01) in the RV hypertrophy group (1.11 +/- 0.20 mmHg X ml-1 X min) compared with normal dogs (3.65 +/- 0.75). This late CCRA-induced right coronary vasoconstriction was not potentiated by beta-adrenergic receptor blockade but was abolished (P less than 0.01) by alpha-adrenergic receptor blockade. In contrast to the depressed right coronary vasoconstriction, the CCRA-induced alpha-adrenergic constriction (P less than 0.01) of the iliac arterial vascular bed was similar in both groups, and the cholinergic increase (P less than 0.01) in cardiac cycle length was enhanced (P less than 0.01) in the RV hypertrophy group compared with normal dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

PGE2 does not act at carotid sinus to raise arterial pressure in conscious sheep.

Conscious chronically instrumented adult female sheep were used to determine whether direct action of prostaglandin E2 (PGE2) on the carotid sinus baroreceptors contributes to the pressor response observed during infusion of PGE2 into the common carotid artery (CCA). During infusion of PGE2 into the CCA caudal to an intact carotid sinus, into the CCA caudal to a denervated carotid sinus, and into the external carotid artery, mean arterial pressure (MAP) rose 17, 22, and 17 mmHg, respectively (P less than 0.01). Heart rate (HR) rose 6, 6, and 8 beats/min, respectively (P less than 0.05). Cardiac output (CO) was also measured by indicator dilution using indocyanine green. In these experiments with infusion of PGE2 into the external carotid artery, MAP rose 15 mmHg (P less than 0.01), HR increased 6 beats/min (P less than 0.05), CO did not change, and total peripheral resistance (TPR) increased 23% (P less than 0.01). With infusion of PGE2 past a denervated carotid sinus, MAP rose 20 mmHg (P less than 0.01), HR rose 4 beats/min (P less than 0.05), CO did not change, and TPR increased 29% (P less than 0.01). There were no statistically significant differences in MAP or HR responses when PGE2 was infused past an intact carotid sinus, past a denervated carotid sinus, or beyond the carotid sinus. There is no evidence that direct action of PGE2 on carotid sinus baroreceptors either augments or inhibits the observed pressor effect of intracarotid PGE2. Intracarotid PGE2 acts rostral to the carotid sinus to increase MAP, HR, and TPR in conscious sheep.

Animals↗
PubMed1985

Atriopeptins: renal-specific vasodilators in conscious dogs.

Conscious dogs were instrumented to study the effects of atriopeptins (I, II, III) on renal, iliac, mesenteric, and coronary blood flow. Intravenous injection of atriopeptins II and III caused a dose-related increase in renal blood flow, whereas atriopeptin I had no effect. Atriopeptins II and III at 5 micrograms/kg increased renal blood flow 27 +/- 5.0% from 252 +/- 29 ml/min and 18 +/- 2.9% from 238 +/- 32 ml/min and reduced renal vascular resistance 24 +/- 3.2% from 0.431 +/- 0.048 mmHg X ml-1 X min and 15.1 +/- 1.2% from 0.443 +/- 0.023 mmHg X ml-1 X min, respectively. Atriopeptin I, II, or III exerted no significant effect on systemic arterial pressure, heart rate, coronary, mesenteric, or iliac blood flows. Doses of nitroglycerin (25 micrograms/kg) that increased renal blood flow (28 +/- 5.0%) to a degree comparable to atriopeptins II and III also caused increases in coronary, iliac, and mesenteric blood flows and produced falls in systemic blood pressure and a reflex tachycardia. Thus in the conscious dog, atriopeptins II and III are potent selective renal vasodilators that do not exhibit systemic hemodynamic effects in contrast to nitroglycerin, a nonselective vasodilator. Cleavage at the carboxy terminal end of these peptides to yield atriopeptin I abolishes the renal vasodilator action entirely.

Anesthesia↗
PubMed1985

Hemodynamic effects of arginine vasopressin in conscious water-deprived rats.

By means of a specific antagonist [d(CH2)5AVP] of the vasoconstrictor activity of arginine vasopressin (AVP), we studied whether the vasoconstrictor effect of AVP contributed to the blood pressure control during water deprivation in conscious rats. After 24 h of dehydration plasma AVP rose from 3.5 +/- 0.5 to 11.2 +/- 2.0 fmol/ml. Intravenous injection of 5 micrograms/kg d(CH2)5AVP reduced total peripheral resistance. Since cardiac output rose simultaneously, mean arterial blood pressure remained unchanged. In rats with sinoaortic deafferentation (SAD) 4 wk before water deprivation, d(CH2)5AVP caused a reduction of total peripheral resistance and of mean arterial pressure, whereas cardiac output remained unchanged. Consequently, mean arterial pressure fell. No hemodynamic changes were observed in hydrated control rats with and without SAD. It is concluded that the vasoconstrictor activity of AVP plays an important role in maintaining blood pressure during water deprivation in conscious rats. After AVP blockade, arterial pressure fell only in SAD rats as intact rats maintain arterial pressure via acute increase cardiac output.

Animals↗
PubMed1985

Apparent reduction in baroreflex sensitivity to adenosine in conscious dogs.

Relative effects of equihypotensive doses (-35 mmHg) of adenosine (5.0 mumol/kg) and nitroglycerin (25 micrograms/kg) on heart rate and, therefore, baroreflex sensitivity were studied in conscious dogs. Nitroglycerin increased heart rate 133 +/- 24% from 78 +/- 5.5 beats/min, whereas adenosine increased heart rate only 79 +/- 16% from 78 +/- 5.2 beats/min (P less than 0.01). Injection of nitroglycerin during combined beta-adrenergic and muscarinic receptor blockades caused arterial pressure to fall 38 +/- 3.4% from 107 +/- 3.2 mmHg without any significant change in heart rate (3.8 +/- 3.8 from 162 +/- 9.2 beats/min). During combined beta-adrenergic and muscarinic receptor blockades adenosine also reduced arterial pressure 45 +/- 2.7% from 106 +/- 2.9 mmHg but unexpectedly reduced heart rate as well by 37 +/- 1.7% from 160 +/- 9.7 beats/min. This bradycardia reflected an effect on the sinoatrial (SA) node rather than an induction of heart block, since the R-R interval increased by 70 +/- 7.8% from 371 +/- 20 ms (P less than 0.01), while the P-R interval increased only 13 +/- 2.3% from 97 +/- 7.2 ms (P less than 0.05) with no electrocardiographic evidence of nonconducted beats. Arterial plasma adenosine levels were 43 +/- 5 nmol/ml at this time. Adenosine also caused bradycardia during muscarinic blockade alone (-43 +/- 3.4% from 201 +/- 6.4 beats/min) and following bilateral vagal section (-33 +/- 1.9% from 151 +/- 5.9 beats/min). In summary, adenosine appears to alter normal baroreflex function in the conscious dog by reducing the tachycardia that normally follows a fall in systemic arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1985

Ganglionic blockade in conscious dogs with chronic caval constriction.

Chronic constriction of the thoracic inferior vena cava decreases venous return and cardiac output, increases the secretion of renin and aldosterone, and produces sodium retention with ascites and edema formation. The arterial pressure is maintained at normotensive levels in this caval model by an increase in total peripheral resistance. The objective of the present study was to compare renal and hemodynamic responses to ganglionic blockade in the conscious thoracic caval dog to responses obtained in another low-output model, the chronic sodium-deplete dog, and also to the responses obtained in the normal sodium-replete dog. The control base-line pressures averaged 103 +/- 2, 110 +/- 3, and 110 +/- 3 mmHg, respectively, in the sodium-replete, sodium-deplete, and thoracic caval dogs (P greater than 0.05). Ganglionic blockade in the conscious dog with caval constriction resulted in a sustained 20- to 30-mmHg fall in the arterial pressure; a sustained fall of 20 mmHg occurred in the sodium-deplete dogs. In contrast, ganglionic blockade failed to decrease the blood pressure at any time in the normal sodium-replete animals. Effective renal blood flow and creatinine clearance failed to demonstrate sustained changes after ganglionic blockade in any group of dogs; renal sodium excretion increased only in the normal sodium-replete dogs. These results suggest an enhanced contribution of the sympathetic nervous system to blood pressure maintenance in both the sodium-deplete and the caval dogs. Although the data fail to demonstrate an important contribution of the adrenergic system in the chronic sodium retention in these two experimental models, decreases in renal perfusion pressure may have blunted any potential natriuresis in these animals following ganglionic blockade.

Animals↗
PubMed1986

Effect of vasopressin and phenylephrine on arterial pressure and heart rate in conscious dogs.

The effect of arginine vasopressin (AVP) and phenylephrine (PE) infusions on mean arterial pressure (MAP) and heart rate (HR) were compared in conscious dogs with all autonomic receptors intact (I), during muscarinic blockade (MB) and during ganglionic blockade (GB). After either MB or GB, the dose-MAP response curve for AVP and PE was shifted to the left of the I response curve; a greater shift was observed with AVP than with PE. The MAP threshold after GB for AVP and PE occurred at 10 and 50% of the threshold dose observed during the I response, respectively. Not only did the MAP threshold occur at a lower dose after MB and GB, but also the slope of the response curve was steeper than that of the I response. Comparing the amount of drug necessary to increase MAP 25 mmHg above control for PE and AVP before and after GB, the intact PE response required 4.3 +/- 1.0 (P less than 0.01) times more drug than during GB versus the intact AVP required 16.8 +/- 2.8 (P less than 0.01) times more drug than during GB. The baroreflex control of HR when all receptors were intact was 3.4 +/- 0.4 (P = 0.001) times more sensitive during AVP compared with PE; no differences were observed after MB. There were no significant changes in HR to AVP or PE after GB, thus indicating a lack of a direct effect of these agents on the HR. Our results show that MB and GB equally potentiate the pressor effects of AVP and PE, and the augmentation was much greater for AVP than for PE. The difference in the potentiation of these two vasoconstrictors is consistent with the finding that the baroreflex sensitivity during AVP was enhanced compared with PE. We have postulated that, in the resting conscious dog, AVP increases the sensitivity of the baroreflex primarily by producing a greater level of parasympathetic tone to the heart in response to a given pressure stimulus.

Animals↗
PubMed1986

Systemic and regional hemodynamic effects of leukotrienes D4 and E4 in the conscious rat.

The effect of leukotrienes (LTs) D4 and E4 on systemic and regional hemodynamic variables were studied in the conscious rat (n = 5-9). Renal (R), mesenteric (M), and hindquarter (HQ) blood flow (BF) were monitored by directional pulsed Doppler velocimetry, and mean arterial blood pressure (MAP) and heart rate were recorded through a catheter in the femoral artery. In a separate series of experiments, cardiac index (CI) was measured by the thermodilution method. Systemic injection of LTD4 or LTE4 (0.1-10 micrograms/kg) produced dose-dependent pressor responses; BF in the M, HQ, and R vessels declined, due to increased vascular resistance (VR) at the following order: M much greater than HQ greater than R. Low doses of LTD4 or LTE4 produced vasodilation in the HQ area. Infusion of LTD4 (3 micrograms X kg-1 X min-1) for 10 min produced progressive and pronounced vascular constriction in the M and HQ regions along with reduction in BF. The LTD4 infusion also markedly decreased CI with a concomitant rise in total peripheral resistance index (TPRI). Indomethacin (5 mg/kg iv) pretreatment did not modify any of the hemodynamic effects of LTD4 or LTE4. FPL 55712 (10 mg/kg iv) and LY 171883 (30 mg/kg iv), two different LT-receptor antagonists, partially blocked the constriction effects of these LTs. LY 171883, but not FPL 55172, blocked the HQ vasodilation produced by LTE4. LY 171883 alone increased HQ-BF and reduced HQ-VR. These data indicate that LTD4 and LTE4 are potent constrictors of the M vascular bed, but at low doses they also produce dilation of the HQ blood vessels. Furthermore, no escape from the effects of prolonged infusion of the LTs was demonstrated in this species. Finally, the hemodynamic responses to LTD4 and LTE4 in the conscious rat are independent of cyclooxygenase products of LTs and are only partially blocked by FPL 55712 or LY 171883. These studies taken together suggest a differential distribution of multiple LT receptors in the rat vasculature.

Acetophenones↗
PubMed1986

Pulmonary vasoactive effects of exogenous and endogenous AVP in conscious dogs.

Our objectives were to investigate the extent to which both exogenously administered and endogenously released arginine vasopressin (AVP) exert a direct, vasoactive influence on the pulmonary circulation of conscious dogs. Multipoint pulmonary vascular pressure-cardiac index (P/Q) plots were constructed during normoxia in conscious dogs by stepwise constriction of the thoracic inferior vena cava (IVC) to reduce Q. In intact dogs, AVP infusion (7.6 ng X kg-1 X min-1 iv) increased (P less than 0.01) plasma AVP from 2.3 +/- 0.4 to 280 +/- 23 pg/ml, and increased (P less than 0.01) the pulmonary vascular pressure gradient (pulmonary arterial pressure minus pulmonary capillary wedge pressure, PAP-PCWP) over the entire range of Q studied. Following administration of autonomic nervous system antagonists and a converting-enzyme inhibitor, exogenous AVP again increased (P less than 0.01) PAP-PCWP over the entire range of Q. Generation of P/Q plots via IVC constriction resulted in systemic hypotension (58 +/- 4 mmHg) and a concomitant increase (P less than 0.01) in endogenous AVP release from 2.1 +/- 0.2 to 109 +/- 22 pg/ml. Following administration of the specific AVP receptor antagonist [d(CH2)5]AVP (10 micrograms/kg iv), systemic arterial pressure, but not PAP - PCWP, was decreased to significantly lower levels as Q was reduced during IVC constriction. A similar response was observed in dogs pretreated with the neurohumoral blockers. Thus exogenous administration of AVP results in active, non-flow-dependent pulmonary vasoconstriction. This effect is not dependent on reflex activation of the autonomic nervous system or on the increased production of angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗