Cardiovascular responses to an isosterically modified prostaglandin analog in conscious dogs

The cardiovascular effects of oral and intravenous administration of 0.05 and 0.1 mg/kg of the isosterically modified prostaglandin (PG) analog, (+)- 4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-thiazolidinyl] propyl) benzoic acid were ascertained in conscious mongrels. After 0.05 mg/kg p.o., mean arterial pressure (MAP), obtained from indwelling catheters, fell from 105 +/- 1 to 100 +/- 4 mm Hg and total peripheral resistance (TPR) decreased from 0.062 +/- 0.006 to 0.039 +/- 0.002 mm Hg/ml/min. Cardiac output (CO), measured via electromagnetic flow probes, rose from 1.8 +/- 0.2 to 2.6 +/- 0.1 l/min and heart rate from 109 +/- 13 to 128 +/- 8 beats/min. The 0.1 mg/kg p.o. dose produced similar results. Intravenous injection of 0.1 mg/kg immediately dropped MAP from 103 +/- 6 to 58 +/- 3 mm Hg and TPR from 0.049 +/- .006 to .014 +/- .002 mm Hg/ml/min. CO climbed from 2.3 +/- 0.2 to 5.3 +/- 0.5 l/min and HR increased from 126 +/- 9 to 254 +/- 14 beats/min. Stroke volume was not affected by either oral or intravenous administration of the PG analog. Pretreatment with 100 micrograms/kg timolol blunted the CO and HR responses to 0.1 mg/kg iv of the PG analog without affecting the depressor response. Metaraminol infused during injection of 0.1 mg/kg iv of the PG analog diminished all responses. When compared to the cardiovascular effects of hydralazine and nitroprusside, the profile of the PG analog activity closely resembled that produced by the arterial vasodilator, hydralazine; in contrast, nitroprusside (which also dilates veins) reduced stroke volume, but did not significantly affect HR. In conclusion, dilation of the resistance vessels by the PG analog decreased MAP and TPR and reflexly elevated CO and HR in conscious dogs.     

Cardiovascular responses of the rat to a prostaglandin endoperoxide analog

In the anaesthetized rat, injection of the prostaglandin endoperoxide analog, U 44069, in the right ventricle is vasopressor both in the pulmonary and the systemic circulation. When a moderate dose is used, the hypertensive response of the systemic vascular bed changes in an hypotension. The toxicity seems to be cumulative. At high doses, a vascular collapse is observed sometimes with pulmonary oedema. These findings correlate with the EKG pattern typical for an acute cor pulmonale.     

Pulmonary vascular responses to angiotensin II and captopril in conscious dogs

Our objectives were to investigate the extent to which angiotensin II (ANG II) and converting-enzyme inhibition (CEI) 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 to reduce Q. The effects of ANG II infusion (60 ng X kg-1 X min-1, iv) and CEI with captopril (1 mg/kg plus 1 mg X kg-1 X h-1, iv) on pulmonary vascular P/Q plots were assessed first with the conscious dogs intact and again after combined administration of pharmacological antagonists to block sympathetic alpha- and beta-adrenergic, cholinergic, and arginine vasopressin receptors. In intact dogs, ANG II increased (P less than 0.01) the pulmonary vascular pressure gradient (pulmonary arterial pressure-pulmonary capillary wedge pressure, PAP-PCWP) over the entire range of Q studied (60-120 ml X min-1 X kg-1). Conversely, CEI decreased (P less than 0.05) PAP-PCWP at each level of Q. After administration of the autonomic nervous system and arginine vasopressin receptor antagonists, ANG II again increased (P less than 0.01) and CEI decreased (P less than 0.01) PAP-PCWP over the entire range of Q studied. Thus exogenous administration of ANG II results in active, nonflow-dependent constriction of the pulmonary circulation, and this effect is not dependent on the autonomic nervous system or increased circulating levels of arginine vasopressin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular responses to V1-vasopressinergic antagonism in conscious versus anesthetized rats

Experiments were performed to compare the possible effect of endogenous arginine vasopressin on renal hemodynamics between anesthetized, surgically stressed rats and conscious rats. Animals were instrumented with arterial and venous catheters as well as with a pulsed Doppler flow probe on the left renal artery. The rats were studied under the following conditions: (1) conscious and unrestrained; (2) anesthetized only; (3) anesthetized with minor surgical stress; and (4) anesthetized with major surgical stress. Two anesthetic agents were also compared, a mixture of ketamine (110 mg/kg i.m.) and acepromazine (1 mg/kg i.m.), and sodium pentobarbital (50 mg/kg i.p.). Baseline mean arterial blood pressure was significantly higher in pentobarbital-anesthetized rats following surgical stress compared with conscious animals, but blood pressure was not affected by ketamine-acepromazine anesthesia. After baseline measurements of blood pressure, heart rate, and renal blood flow, a specific V1-vasopressinergic antagonist (d(CH2)5Tyr(Me) arginine vasopressin, 10 mg/kg i.v.) was administered to each group. Mean arterial blood pressure, heart rate, and renal blood flow were monitored for an additional 15 min. Mean arterial blood pressure and renal blood flow decreased after V1 antagonism in ketamine-acepromazine-anesthetized rats with major surgical stress, but were not affected in pentobarbital-anesthetized animals. Heart rate and renal vascular resistance were not affected following V1 blockade with either anesthetic agent. These data suggest that arginine vasopressin plays a role in maintaining blood pressure and renal perfusion in ketamine-acepromazine-anesthetized rats following surgical stress, but does not have a significant effect on renal hemodynamics under pentobarbital anesthesia.     

Cardiovascular responses to melanocortin 4-receptor stimulation in conscious unrestrained normotensive rats

In the present studies, we used a non-selective melanocortin MC3/4 receptor agonist (HP228) and a novel selective melanocortin MC4 receptor (MC4-R) agonist (MK-cpd1) to study the cardiovascular, temperature, locomotor and feeding responses to melanocortin receptor stimulation in comparison to sibutramine in rats instrumented with a telemetry transmitter. Moreover, norepinephrine turnover rates in heart and brown adipose tissue were determined. HP228 (1, 3 and 10mg/kg, i.p.) reduced 24h food intake dose-dependently and increased heart rate and mean arterial pressure (maximal differences: +60+/-8beats/min and +8+/-1mmHg, means+/-S.E.M., p<0.001 and p<0.01, respectively). After 10mg/kg HP228 showed a three-fold increase in norepinephrine turnover in the heart. The selective MC4-R agonist MK-cpd1 tended to decrease 24h food intake only at the highest dose tested (10mg/kg, i.p., p=0.06) and increased both heart rate (+17+/-4 and +22+/-5beats/min at 3 and 10mg/kg, p<0.01) and mean arterial pressure (+4+/-1mmHg at 10mg/kg, p<0.05). Sibutramine reduced food intake at all doses tested (1, 3 and 10mg/kg, i.p.). It did not change mean arterial pressure significantly, and increased heart rate only at the highest dose tested (+36+/-6beats/min, p<0.05). If also observed in humans, the pharmacological profile of MC4-R agonists would not offer a significant therapeutic advantage over currently used appetite suppressants such as sibutramine.     

Arterial baroreceptors control plasma vasopressin responses to graded hypotension in conscious dogs

We studied the role of cardiac and arterial baroreceptors in the reflex control of arginine vasopressin (AVP) and renin secretion during graded hypotension in conscious dogs. The dogs were prepared with Silastic cuffs on the thoracic inferior vena cava and catheters in the pericardial space. Each experiment consisted of a control period followed by four periods of inferior vena caval constriction, during which mean arterial pressure (MAP) was reduced in increments of approximately 10 mmHg. The hormonal responses were measured in five dogs under four treatment conditions: 1) intact, 2) acute cardiac denervation (CD) by intrapericardial infusion of procaine, 3) after sinoaortic denervation (SAD), and 4) during combined SAD+CD. The individual slopes relating MAP to plasma AVP and plasma renin activity (PRA) were used to compare the treatment effects using a 2 x 2 factorial analysis. There was a significant (P < 0.01) effect of SAD on the slope relating plasma AVP to MAP but no effect of CD and no SAD x CD interaction. In contrast, the slope relating PRA and MAP was increased (P < 0.05) by SAD but was not affected by CD. These results support the hypothesis that stimulation of AVP secretion in response to graded hypotension is primarily driven by unloading arterial baroreceptors in the dog.     

Physiological responses to low dose infusions of atrial peptide in conscious dogs

Mongrel dogs prepared with chronic catheters in their femoral artery and vein and urinary bladder received 60 minute infusions of atrial peptide ranging from 5 to 100 ng/kg/min. Infusion of atrial peptides caused dose dependent increases in plasma atrial peptide concentration with doses of 25 ng/kg/min or less increasing plasma concentrations to levels observed in normal animals during stimulation of endogenous atrial peptide secretion. Atrial peptide infusion at doses of 10 ng/kg/min and above caused significant decreases in mean arterial pressure which were not accompanied by statistically significant changes in heart rate. Atrial peptide infusion at doses of 25 ng/kg/min and above increased urinary sodium excretion and urine flow rate. Atrial peptide infusion was without effect on plasma vasopressin, ACTH and corticosterone concentrations. However, atrial peptide infusion resulted in dose dependent decreases in plasma aldosterone concentration and plasma renin activity, but the decreases were only significant with the high physiologic (25 ng/kg/min) and pharmacologic doses (50 & 100 ng/kg/min). These data show that atrial peptide infusions in conscious dogs have minimal effects when infused in small doses that mimic endogenous atrial peptide release. At higher doses, significant effects on the cardiovascular, renal and endocrine systems can be observed but their physiological significance is unclear.     

Hemodynamic and norepinephrine responses to pacing-induced heart failure in conscious sinoaortic-denervated dogs

Brändle, Marian, Kaushik P. Patel, Wei Wang, andIrving H. Zucker. Hemodynamic and norepinephrine responses topacing-induced heart failure in conscious sinoaortic-denervated dogs.J. Appl. Physiol. 81(4):1855-1862, 1996.The present study was undertaken to determinethe effects of chronic sinoaortic (baroreceptor) denervation (SAD) on the hemodynamic and sympathetic alterations thatoccur in the pacing-induced model of congestive heart failure. Twogroups of dogs were examined: intact(n = 9) and SAD(n = 9). Both groups of dogs werestudied in the control (prepace) state and each week after theinitiation of ventricular pacing at 250 beats/min. After the pacemakerwas turned off, hemodynamic and plasma norepinephrine levels returnedtoward control levels in the prepaced state and after 1 and 2 wk ofpacing. However, by 3 wk all hemodynamic and norepinephrine levelsremained relatively constant over the 10-min observation period withthe pacemaker off. With the pacemaker off, left ventricularend-diastolic pressure went from 2.7 ± 1.4 (SE) mmHg during theprepace state to 23.2 ± 2.9 mmHg in the heart failure state inintact dogs (P < 0.01). Leftventricular end-diastolic pressure increased to 27.1 ± 2.2 mmHgfrom a control level of 4.2 ± 1.9 mmHg in SAD dogs(P < 0.0003). Mean arterial pressuresignificantly decreased in intact and SAD dogs. Resting heart rate wassignificantly higher in SAD dogs and increased to 135.8 ± 8.9 beats/min in intact dogs and 136.1 ± 6.5 beats/min in SAD dogs.There were no significant differences in the hemodynamic parametersbetween intact and SAD dogs after pacing. Plasma norepinephrine wassignificantly lower in intact than in SAD dogs before pacing (197.7 ± 21.6 vs. 320.6 ± 26.6 pg/ml;P < 0.005). In the heart failurestate, plasma norepinephrine increased significantly in both intact(598.3 ± 44.2 pg/ml) and SAD (644.0 ± 64.6 pg/ml) groups. Therewere no differences in the severity or the magnitude of the developedheart failure state in SAD vs. intact dogs. We conclude from these datathat the arterial baroreflex is not the sole mechanism for the increasein sympathetic drive in heart failure.

     

Role of splanchnic constriction in governing the hemodynamic responses to gravitational stress in conscious dogs

Octreotide is a somatostatin analog that constricts the splanchnic circulation, thereby improving orthostatic tolerance. We tested the hypotheses that octreotide improves orthostatic tolerance by 1)increasing cardiac filling (right atrial) pressure via reductions in vascular capacity; 2) by causing an upward (i.e., cranial) shift of the hydrostatic indifferent point; and 3) by increasing arterial pressure via a reduction in total vascular conductance. Studies were carried out in acepromazine-sedated, hexamethonium-treated atrioventricular-blocked conscious dogs lightly restrained in lateral recumbency. Beat-by-beat cardiac output was held constant via computer-controlled ventricular pacing at rest and during 30 s of 30° head-up tilt. Octreotide (1.5 μg/kg iv) raised right atrial pressure by 0.5 mmHg and raised mean arterial pressure by 11 mmHg by reducing total vascular conductance (all P < 0.05). Right atrial pressure fell by a similar amount in response to tilting before and after octreotide, thus there was no difference in location of the hydrostatic indifferent point. These data indicate that octreotide improves orthostatic tolerance by decreasing total vascular conductance and by increasing cardiac filling pressure via a reduction in unstressed vascular volume and not by eliciting a cranial shift of the location of the hydrostatic indifferent point.     

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.     

Systemic and renal hemodynamic responses to vascular blockade of vasopressin in conscious dogs with ascites

A role for arginine vasopressin has been implicated in the compensatory control of arterial blood pressure in several animal models with reported increases in plasma levels of arginine vasopressin. A threefold elevation in plasma vasopressin has been reported in conscious dogs following constriction of the inferior vena cava. In the present study, infusion of the arginine vasopressin antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-O-methyltyrosine] Arg8-vasopressin into conscious dogs with chronic caval constriction did not decrease mean arterial blood pressure. However, the dose of infused antagonist completely blocked the pressor response to 2 micrograms of exogenous vasopressin. Also the antagonist produced no effect on heart rate, plasma renin activity, or urinary volume and electrolyte excretions. A slight, transient increase (P less than or equal to 0.05) was observed in creatinine clearance and in PAH clearance following antagonist infusion, suggesting a possible decrease in renal vascular resistance. These data suggest that the direct vasoconstrictor actions of vasopressin contribute minimally, if at all, to blood pressure maintenance following chronic caval constriction. Alternatively, blockade of endogenous vasopressin receptors at the level of peripheral arterioles may have resulted in no depressor response due to a masking of this response by other compensatory hormonal and neural pressor systems.