Vascular effects of Physalia physalis venom in the skeletal muscle of the dog

The purpose of this study was to characterize the mode of action of the venom from Portuguese man-of-war (Physalia physalis) on the skeletal muscle vascular bed of dogs anesthetized with sodium pentobarbital (35 mg/kg). Venous outflow and the blood pressure difference across the hind-limb vascular bed were used to calculate changes in resistance due to close arterial injections of the venom (0.001-1 microgram/kg). The venom consistently produced dilations that were blocked by sodium meclofenamate (5 mg/kg). Atropine (1 mg/kg), propranolol, phentolamine, cimetidine (each 2 mg/kg) or tripelennamine (2.5 mg/kg) had no significant blocking effect. The venom also produced transient dilations on vascular beds predilated with histamine or prostaglandin E1, or preconstricted with norepinephrine (each 0.01 microgram/kg) or by sympathetic stimulation (12 V, 20 Hz). These data suggest that Physalia venom dilates skeletal muscle vasculature primarily by stimulation of endogenous prostaglandin synthesis.     

Influence of prostaglandins E1 and F2alpha on pulmonary vascular resistance, isolated lobar vessels and cyclic nucleotide levels.

The effects of prostaglandins E1 (PGE1) and F2alpha) on the pulmonary vascular bed were studied in the intact dog under conditions of controlled pulmonary blood flow. PGF2alpha increased lobar arterial and venous pressure when injected or infused into the lobar, artery. The pressor response was dose-related and doses as low as 0.03 and 0.1 mug, which established concentrations of 0.1 to 0.3 ng/ml in lobar arterial blood, increased pulmonary vascular resistance. PGF2alpha also increased airway resistance in the left lower lobe. However, the effects of this substance on the vascular bed were not related to its effects on bronchomotor tone since similar pressor responses were observed in normal and nonrespiring lobes, PGE1 decreased pressure in the lobar artery and vein when infused into the lobar artery and the effects of PGE1 and PGF2alpha on the pulmonary vascular bed were similar when the lung was perfused with dextran or with blood. PGF2alpha increased isometric tension in isolated helical segments of lobar vein 3 to 5 mm in diameter but was without effect on arterial segments of the same diameter. The increase in isometric tension in the venous segments with PGF2alpha was associated with a significant increase in intracellular levels of guanosine 3',5'-monophosphate (cGMP) but no change in adenosine 3',5'-monophosphate (cAMP) levels. PGE1 decreased isometric tension in both arterial and venous segments and the decrease in tension was accompanied by a significant elevation in smooth muscle cAMP levels and a small but significant reduction in vein cGMP. Results of the present study indicate that PGF2alpha increases pulmonary resistance by constricting lobar veins and to a lesser extent vessels upstream in the precapillary bed whereas PGE1 dilates lobar veins and upstream vessels. These results suggest that PGE1-induced vasodilation may be mediated by an increase in cAMP levels while PGF2alpha-induced venoconstriction may be related to increased smooth muscle levels of cGMP.     

Endothelium-dependent responses in autogenous femoral veins grafted into the arterial circulation of the dog

Endothelium-dependent responses differ in arteries and veins of the dog. Experiments were performed to determine whether chronic grafting of veins into the arterial circulation would alter the endothelium-dependent responses of the veins. Segments of femoral veins were grafted to the femoral artery of the dog. 6 wk after surgery the venous grafts were removed from the dog, cut into rings, and suspended in organ chambers for isometric tension recording. In some rings the endothelial cells were removed. Acetylcholine and alpha 2-adrenergic agonists did not cause endothelium-dependent relaxations in venous grafts. The calcium ionophore (A23187) initiated such relaxations which were not mediated by prostanoids. Endothelium-dependent relaxations were also observed in venous grafts to ADP, thrombin, and arachidonic acid. In segments of graft where myo-intimal hyperplasia was prominent, relaxations to ADP, thrombin, and A23187 were blunted and in some segments contractions were observed. These results demonstrate the ability of the endothelium of venous grafts to initiate changes in tone of the smooth muscle.     

Role of the vascular endothelium in the contractile response to prostacyclin in the isolated rat aorta

Prostacyclin (PGI2) relaxes vascular smooth muscle in several species but, in high doses, PGI2 has been reported to contract several isolated arteries. Vascular endothelium is known to be obligatory for the vasodilatory responses to acetylcholine and several other substances. We therefore investigated the contractile effect of various prostanoids on rat abdominal aorta in which the endothelium was left intact or was removed. PGI2 (4-2000 ng/ml), 6-keto-prostaglandin (PG) E1, PGE1 and PGE2 (4-800 ng/ml) contracted both intact and de-endothelialized aortic segments in a dose-dependent manner. PGI2 (8-2000 ng/ml) increased the force generated by aortic rings with intact endothelium from 77.3 +/- 24.6 to 685 +/- 99.2 mg. The response to similar doses of PGI2 in aortic rings with the endothelium removed was reduced significantly (22.7 +/- 14.1 to 260 +/- 116.4 mg). This contractile response to PGI2 in both intact and de-endothelialized aortic rings was abolished by indomethacin pretreatment (20 micrograms/ml for 30 min) and was also blocked completely by the thromboxane receptor antagonist SQ 29548 (100 ng/ml). In contrast, the thromboxane synthase inhibitor OKY 1581 (2.5 micrograms/ml) did not significantly reduce the contractile response to PGI2. Unlike PGI2, the force generated by PGE2 (4-800 ng/ml) in aortic rings with intact endothelium (0-550.0 +/- 107.2 mg) was not significantly different from that generated by aortic rings without endothelium (35.0 +/- 23.6 to 650.0 +/- 193.2 mg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Rat peritoneal neutrophils selectively relax vascular smooth muscle.

A vascular relaxing factor from oyster glycogen-elicited rat peritoneal neutrophils has been shown previously to possess a pharmacologic profile similar to that described for endothelium-derived-relaxing factor. The present experiments were designed to determine the in vitro tissue and species selectivity effects of the neutrophil-derived nitric oxide. Neutrophils (1 x 10(5) to 1 x 10(8) cells/10-ml organ chamber) were added to organ chambers filled with a physiological salt solution (37 degrees C; pH 7.4; 21% O2; 100 U/ml of superoxide dismutase) containing a ring or strip of an isolated tissue contracted with an appropriate contractile agent. Neutrophils caused relaxations in all vascular tissues tested, with the dog coronary artery being the most sensitive (IC50 approximately 1 x 10(5) cells), followed by the dog femoral artery, rabbit aorta and dog saphenous vein, respectively. In the rabbit fundic strip, approximately 1 x 10(7) cells were required to induce 50% relaxation, with 1 x 10(8) cells producing less than 35% relaxation in the dog, guinea pig and rat tracheas. In contrast, nitroprusside- and cromakalim-induced relaxations in all the smooth muscle tissues tested. The response to cromakalim was similar in all tissues with nitroprusside being more active in the vascular tissues. Methylene blue (1 x 10(-5) M) abolished the neutrophil induced relaxations in the rabbit aorta and dog femoral artery but had no effect on the responses to nitroprusside or cromakalim in the rabbit aorta, dog femoral artery or guinea pig trachea. Neutrophils, nitroprusside and cromakalim had limited effects on the spontaneously beating guinea pig right atria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of prostacyclin on vascular capacity in the dog.

Since the discovery of prostacyclin (PGI2) in 1976, there has been great interest in its vascular effects and potential clinical applications. High infusion rates of PGI2 markedly depress arterial blood pressure both in animal studies and in clinical trials. This fall in pressure may result entirely from a decrease in arterial resistance. However, it is possible that the administration of PGI2 may decrease ventricular filling due to an increase in vascular capacity. To investigate whether or not PGI2 affects vascular capacity, we infused PGI2 intraarterially at both 10 and 25 micrograms/min into 15 dogs on total cardiopulmonary bypass. These infusions were associated with a 25 +/- 3 mmHg decrease in arterial pressure and an increase in vascular capacity of 155 +/- 29 ml (SE, P less than 0.005). This increase in capacity was greater (P less than 0.02) than the increase of 23 +/- 42 ml resulting from infusions of nitroglycerin into eight dogs at 2 mg/min, which produced a decrease in arterial pressure of 23 +/- 4 mmHg, which was the maximal effect that could be achieved. Neither bilateral cervical vagotomy nor beta adrenergic blockade with propranolol significantly diminished the increase in vascular capacity associated with infusions of PGI2. The results from studies in four eviscerated dogs indicated that PGI2 acts on both splanchnic and extrasplanchnic capacity vasculature. To compare the direct effects of PGI2 with those of nitroglycerin and nitroprusside on venous tone, we used an isolated canine spleen preparation. Infusions of PGI2 (100 mcg/min) increased spleen weight in this preparation by 9.0 +/- 2.4% (n = 10, P less than 0.001); this increase was significantly greater than increases of 3.6 +/- 2.2% (P less than 0.001) and 3.5 +/- 2.3% (P less than 0.001) caused by high dose infusions of nitroglycerin (1 mg/min) and nitroprusside (400 micrograms/min), respectively. Thus, PGI2 substantially increases vascular capacity by a mechanism that appears to involve a direct action on vascular smooth muscle. Furthermore, these results suggest that PGI2 might be useful in clinical conditions in which an increase in vascular capacity is indicated.     

Selective antagonism of the intesinal stimulatory effects of morphine by isoproterenol prostalglandin E1 and theophylline.

Contractions induced by graded intraaterial bolus doses of morphine and acetylcholine were measured in isolated segments of dog intestine perfused via the vasculature with Kreb's solution. Addition of the alpha and beta adrenergic receptor agonist, norepinephrine (0.2 mug/ml) to the perfusion solution decreased the magnitude of contractor responses to acetylcholine slightly and to morphine considerably. The pure alpha adrenergic receptor agonist, methoxamine (50 mug/ml), and the pure beta adrenergic receptor agonist, isoproterenol (5 mug/ml), produced similar effects; marked inhibition of responses to morphine and barely discernable inhibition of responses to acetylcholine. The mild inhibitory effects of these adrenergic amines on responses to acetylcholine are attributed to actions on neural and possibly non-neural adrenergic receptors. Perfusion of intestinal segments with Kreb's solution containing prostaglandin E1 (1 mug/ml) or theophylline (180 mug/ml) resulted in marked decreases in responses to morphine but had no significant effects on responses to acetylcholine. Patterns of inhibition similar to those seen with morphine have been observed previously with 5-hydroxytryptamine, which may mediate the intestinal stimulatory effects of morphine. Since isoproterenol, prostaglandin E1 and theophylline share in common the ability to elevate or maintain intracellular levels of cyclic adenosine monophosphate, the intestine stimulatory effects of morphine may result from 5-hydroxytryptamine-mediated interference with smooth muscle inhibitory actions of cyclic adenosine monophosphate.     

Thyrotropin-releasing hormone receptor activation in the spinal cord increases blood pressure and sympathetic tone to the vasculature and the adrenals

Cardiovascular and regional hemodynamic effects of the intrathecal (i.t.) administration of a thyrotropin-releasing hormone (TRH) analog, MK-771 (L-pyro-2-aminoadipyl-histidyl-thiazolidine-4-carboxamide), were studied in rats. MK-771 (0.01-5.0 micrograms i.t.) caused dose-related increases in mean arterial pressure (MAP) and heart rate (HR). TRH (10 micrograms i.t.), but not TRH-free acid, produced similar cardiovascular effects. The MAP response to MK-771 (i.t.) remained primarily intact after cervical spinal cord transection, whereas the HR response was attenuated (37% of control). The MAP response to MK-771 was blocked by peripheral administration of pentolinium or phentolamine, and was partially attenuated by adrenalectomy. The HR response was reduced by pentolinium or atropine. Assessment of changes in regional blood flow and vascular resistance with the radioactive microsphere technique showed that MK-771 increased total peripheral resistance and vasoconstricted cutaneous, skeletal muscle, adrenal, renal and intestinal vascular beds. Cardiac output and stroke volume were not altered. MK-771 had no effect on vascular resistance locally or in other central nervous system structures. However, blood flow was elevated by MK-771 in spinal cord and brain. These data show that TRH receptor activation in the thoracic spinal cord, presumably in the intermediolateral cell column, elevated MAP by increased sympathetic activity to the peripheral vasculature and the adrenals. However, the HR response to TRH receptor activation required a supra-spinal component and was mediated in part by vagal inhibition.     

Effects of dopamine (DA) and SKF 82526, a selective DA1-receptor agonist, on vascular resistances in the canine forelimb

This study was performed to determine the presence of vascular dopamine (DA1) receptors in the canine forelimb. Local i.a. infusions of DA (2, 4 or 8 micrograms base/min) produced cutaneous and skeletal muscle vasoconstriction in the forelimb comparable to that produced by local i.a. infusions of norepinephrine (0.5, 1 or 4 micrograms base/min). In the cutaneous vasculature, DA produced large artery, small vessel and large vein constrictions. The small vessels and large veins constricted proportionately more than the large arteries. The pattern of constriction produced by DA along the cutaneous vascular tree was similar to that produced by norepinephrine. The forelimb vasoconstriction produced by both DA and norepinephrine was abolished completely by treatment with phentolamine, indicating that both agents produce vasoconstriction mediated by stimulation of alpha adrenoceptors. The failure of DA to produce vasodilation after phentolamine suggests that there are no vascular or DA1-subtype DA receptors in the canine forelimb vasculature. The local i.a. infusion of SKF 82526, a selective DA1-receptor agonist, for 3 min produced cutaneous and skeletal muscle dilation which could be antagonized by either sulpiride or phentolamine. This neurogenic dopaminergic vasodilation produced by SKF 82526 (25, 50 or 100 micrograms base/min) was converted into vasoconstriction after ganglionic blockade. Inasmuch as SKF 82526 does not activate presynaptic or DA2-subtype DA receptors, the neurogenic vasodilation caused by SKF 82526 may be due to a dopaminergic inhibition of ganglionic transmission. Whereas the results of our study fail to provide any evidence for the presence of vascular DA (DA1) receptors in the canine forelimb, they show that SKF 82526, a DA1-receptor agonist, produces neurogenic vasodilation probably by activating ganglionic DA receptors.     

Effects of prostaglandins B2 and B1 on the pulmonary circulation in the intact dog.

The effects of prostaglandins (PG) B2 and B1 on the pulmonary circulation were studied in the intact spontaneously breathing dog under conditions of controlled blood flow using right heart and transseptal catheterization techniques to isolate and perfuse the left lower lung lobe. Infusion of PGB2 and PGB1 into the left lower lung lobe increased lobar arterial and lobar venous pressure but had no significant effect on left atrial pressure. PGB2 and PGB1 increased pressure gradients between the lobar artery and lobar small vein and between the lobar small vein and the left atrium. PGB2 and PGB1 increased isometric tension in isolated helical segments of lobar vein (3-5 mm diameter) but had little or no effect on lobar arterial segments of the same size. These results indicate that in the intact dog prostaglandins of the B series increase pulmonary vascular resistance by constricting lobar veins and to a lesser extent vessels upstream to lobar small veins, presumably small lobar arteries. PGB2 and PGB1 both produced large increases in pulmonary vascular resistance in the dog with PGB2 being about 10 times as potent as PGB1. It is concluded that PGB2 is one of the most potent pressor substances in the canine pulmonary vascular bed.     

Effects of a specific antidiuretic agonist on cardiac output and its distribution in intact and anephric dogs

1. The specific antidiuretic agonist [4-valine, 8-D-arginine]vasopressin (VDAVP) was administered intravenously to seven conscious dogs at a rate of 10 ng min-1 kg-1. Cardiac output (aortic electromagnetic flowmeter), mean arterial pressure and regional blood flows (radioactive microspheres) were measured before and after 30 min of infusion. 2. Mean arterial pressure fell from 89.9 +/- 4.5 (mean +/- SEM) to 82.3 +/- 5.9 mmHg and cardiac output increased from 115.4 +/- 8.7 to 163.0 +/- 14.4 ml min-1 kg-1. Total peripheral resistance decreased from 41.6 +/- 3.7 to 27.8 +/- 3.6 units and heart rate increased from 79.2 +/- 5.9 to 123.2 +/- 5.9 beats/min. Blood flow increased significantly in the myocardium, fat and skeletal muscle vascular bed. 3. In another group of six dogs subjected to a similar protocol 24 h after bilateral nephrectomy, mean arterial pressure fell from 102.2 +/- 5.3 to 82.7 +/- 3.4 mmHg and cardiac output increased from 125.6 +/- 3.0 to 171.2 +/- 4.0 ml min-1 kg-1. Total peripheral resistance decreased from 39.3 +/- 3.4 to 23.4 +/- 1.3 units and heart rate increased from 84 +/- 4.9 to 113.3 +/- 4.3 beats/min. The increase in cardiac output and the fall in total peripheral resistance did not differ significantly between intact and anephric dogs. Regional blood flow responses differed in some respects in the two groups studied, but there was no evidence that the vasodilatory action of VDAVP depended on the presence of the kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vascular actions of TA 3090, a novel analog of diltiazem: interaction with endothelium-dependent relaxation in canine femoral and coronary arteries

The effects of a new 1,5-benzothiazepine calcium antagonist, TA 3090 (an analog of diltiazem), were analyzed in isolated canine femoral and coronary arteries suspended in organ chambers or studied in a bioassay system. TA 3090 (10(-9) to 10(-4) M) caused comparable relaxations in arterial rings with and without endothelium contracted by prostaglandin F2 alpha. Coronary arteries were more sensitive to the Ca++ antagonist. In both preparations, TA 3090 was more potent than diltiazem. In femoral (but not coronary) artery rings with endothelium, acetylcholine (10(-8) M) inhibited relaxations to TA 3090. Previous treatment of femoral or coronary arteries with TA 3090 (10(-6) M) had no effect on endothelium-dependent relaxations to acetylcholine. In a bioassay system, TA 3090 (2 x 10(-7) M) caused partial reversal of acetylcholine-induced relaxation in perfused femoral arteries and superfused coronary arterial rings. The dihydropyridine enantiomer (-)-202,791 did not affect acetylcholine-induced relaxations and did not prevent the reversal by TA 3090. These data indicate that, in addition to a direct action on vascular smooth muscle, this novel benzothiazepine Ca(++)-antagonist interferes with the synthesis/release of endothelium-derived relaxing factor stimulated by acetylcholine in canine femoral arteries. These findings, which are similar to those obtained with d-cis-diltiazem, support the hypothesis that a specific benzothiazepine-dependent mechanism(s) can suppress the production of endothelium-derived relaxing factor in endothelial cells.     

Effects of prostaglandin E1 on canine nasal vascular and airway resistances

We have developed a technique which can measure directly and simultaneously changes in both nasal vascular and airway resistances in the dog. Nasal vascular resistance was measured by either direct monitoring of the arterial inflow or a change in the perfusion pressure of the nasal vascular bed with blood flow maintained constant. Nasal airway resistance was measured by a rhinomanometric method. Intra-arterial infusion of prostaglandin (PG) E1 at the rate of 1 ml/min in doses of 0.001 to 10 micrograms/min caused a dose-dependent decrease in both nasal vascular and airway resistances. When compared with the control, the average maximal effect of PGE1 on vascular resistance was -38.4%, whereas on airway resistance it was -16.4%. The present studies demonstrate that PGE1 has significant vasodilatatory activity in the canine nasal vascular bed and suggest that the vascular and airway responses to PGE1 may be due to a decrease in inflow and outflow vascular resistance and/or opening of arteriovenous anastomoses.     

Intrarenal haemodynamics in rats during haemorrhagic hypotension

Abstract. Previous studies of intrarenal haemodynamics by wash-out with inert gas suggested that haemorrhagic hypotension (HH) in the dog causes a redistribution of intrarenal blood flow with a patchy cortical hypoperfusion, mainly due to an increased concentration of circulating catecholamines. In the present experiments intrarenal haemodynamics were studied by the same methods in the rat during prolonged HH with a mean arterial BP of 51 mm Hg. Under these conditions inert gas wash-out studies showed a decrease in compartment I (CP I) flow fraction (“cortical flow fraction”) from 81.5% to 43.2% of total renal blood flow (RBF). CP I blood flow dropped from 3.13 ml/min. to 0.63 ml/min. per g kidney weight. Total renal vascular resistance increased by a factor of 1.2 as compared with control conditions. These changes in intrarenal haemodynamics were considerably smaller than those observed in the dog under comparable conditions. In contrast to observations in the canine kidney no patchy areas of cortical hypoperfusion occurred in the rat, and there was no evidence of stratification of cortical blood flow during HH. Instead, there was an even reduction in cortical blood flow from the subcapsular area to the cortico-medullary border as indicated by inert gas wash-out studies and ⁸⁵krypton autoradiographs. The meaning and pathogenesis of the observed differences between both species remains to be defined. It is suggested that in the rat the reaction of the renal vasculature to sympathoadrenal stimuli and/or to angiotensin might be different from that in the dog.     

Subcutaneous and muscle blood flow during dopamine infusion in man

Subcutaneous fat tissue and skeletal-muscle blood flow was measured in six male volunteers using the local 133Xe-washout method. Measurements were obtained before and during intravenous dopamine infusion in non-pressor (1 microgram kg-1 min-1) and pressor infusion rates (3-6 micrograms kg-1 min-1). During non-pressor infusion rate the systolic and diastolic arterial pressure and heart rate remained unchanged. When pressor dose dopamine was infused the systolic and mean arterial pressures increased significantly, whereas the diastolic pressure and the heart rate were left unchanged. The blood flow increased progressively from control values in both subcutis (control: 2.9 +/- 0.2, non-pressor: 5.0 +/- 1.6, pressor: 9.1 +/- 0.4 ml min-1 100 g-1, mean +/- SEM) and in skeletal muscle (control: 1.2 +/- 0.2, non-pressor: 1.5 +/- 0.2, pressor: 1.9 +/- 0.4 ml min-1 100 g-1, mean +/- SEM) and was significantly different from baseline values at any dopamine infusion rate. Side-effects were observed only at pressor dose infusion. It is concluded that dopamine in humans seems to possess vasodilatoric properties in subcutaneous fat tissue, and in skeletal muscles.     

Comparison of the alpha adrenoceptor activity of dopamine, ibopamine and epinine in the pulmonary circulation of the dog

The ability of dopamine, ibopamine and epinine to elicit alpha adrenoceptor-mediated vasoconstriction was studied in the in situ, autoperfused pulmonary circulation of the open-chest anesthetized dog. Animals were pretreated with propranolol to eliminate beta adrenoceptor-mediated relaxation of the pulmonary vasculature. Heparinized blood was withdrawn from the left femoral artery and transferred via a peristaltic pump to the pulmonary arterial branch supplying the left diaphragmatic lobe of the lung. The flow rate of the pump was adjusted so that mean pulmonary perfusion pressure in the lobe was equal to resting diastolic pulmonary artery pressure (10 +/- 1 mm Hg). Under conditions of constant left atrial pressure and pulmonary blood flow, intralobar administration of dopamine, ibopamine and epinine elicited dose-dependent increases in perfusion pressure of the lobe, reflecting increases in pulmonary vascular resistance. Prazosin (100 micrograms/kg i.v.), a selective alpha-1 adrenoceptor antagonist, inhibited the pulmonary vasopressor responses to dopamine, ibopamine and epinine. Rauwolscine (100 micrograms/kg i.v.), a selective alpha-2 adrenoceptor antagonist, inhibited pulmonary pressor responses to dopamine and epinine without altering significantly the pulmonary vasoconstrictor response to ibopamine. These data indicate that dopamine and epinine stimulate both postjunctional vascular alpha-1 and alpha-2 adrenoceptors to elicit pulmonary vasoconstriction in the dog, whereas ibopamine, when injected directly into the pulmonary circulation, stimulates primarily postjunctional vascular alpha-1 adrenoceptors. However, when ibopamine was administered intraduodenally, both prazosin and rauwolscine were found to inhibit the resulting pulmonary vasopressor response. This finding is consistent with the hypothesis that ibopamine is converted to its active metabolite epinine, which stimulates both pulmonary vascular alpha-1 and alpha-2 adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pressure-flow relationships of the pulmonary circulation during endotoxin infusion in intact dogs.

BACKGROUND AND METHODS: We aimed to characterize the effects of an endotoxin insult (Escherichia coli 0127:B8) on the relationships between pulmonary vascular pressure and flow in intact dogs. To achieve this goal, multipoint plots of total pressure gradient, arterial pressure gradient, and venous pressure gradient vs. flow were generated by graded inflation of a right atrial balloon, which was used to vary flow. The partitioning of the total pressure decrease across the pulmonary vasculature (total pressure gradient = pulmonary arterial pressure-pulmonary artery occlusion pressure [PAOP]) into gradients across pulmonary arterial (arterial pressure gradient = pulmonary arterial pressure--effective capillary pressure) and pulmonary venous (venous pressure gradient = effective capillary pressure--PAOP) regions was assessed by a waveform mathematical analysis of the pulmonary arterial pressure profile during arterial occlusion, with computation of both PAOP and effective pulmonary capillary pressures. Slopes and extrapolated pressure intercepts from linear regression fits to the pulmonary vascular pressure/flow plots were determined in seven dogs after a 2-hr endotoxic infusion interval and were compared with the corresponding values that characterized a similar group of sham-operated dogs. RESULTS: Under normal conditions, the extrapolated pressure intercept for pulmonary arterial pressure gradient was virtually 0 mm Hg; for total pulmonary arterial pressure gradient and pulmonary venous pressure gradient, the mean extrapolated pressure intercepts were substantially positive: 2.4 +/- 0.2 and 2.1 +/- 0.3 mm Hg, respectively. Endotoxin infusion at 0.25 micrograms/kg/min significantly increased the pressure intercepts from 2.4 to 8.7 and from 2.1 to 8.3 mm Hg of total pressure gradient and venous pressure gradient vs. flow, respectively. This infusion produced a minor, nonsignificant change in the intercept of arterial pressure gradient vs. flow, whereas it increased its slope significantly (p less than .05) from 0.036 to 0.081 mm Hg/mL/min/kg. CONCLUSIONS: These data suggest that endotoxin's effects on vascular resistance are exerted at two different loci such that these effects are additive. These endotoxin-induced effects consisted of increased vascular resistance of the arterial segment and appearance of a Starling resistor at the venous side of the pulmonary circulation, which acted as the relevant back-pressure to flow.     

Dog model to study the effects of pharmacologic agents on the peripheral circulation: effects of milrinone

To study the effects of an inotropic agent, milrinone, on the entire cardiovascular system, we developed an intact dog model to assess the responses of the heart, arterial and venous circulations. At a dose that increased left ventricular dP/dt by 30% (P less than .001) from 2033 +/- 133 to 2688 +/- 140 mm Hg/sec, milrinone caused a decrease (P less than .001) in mean aortic pressure from 88.4 +/- 3.5 to 73.1 +/- 3.0 mm Hg and cardiac output from 148.0 +/- 14.6 to 134.5 +/- 13.9 ml/kg/min. Heart rate increased (P less than .01) from 124 +/- 8 to 135 +/- 8 beats/min. Systemic vascular resistance did not change. Right atrial pressure and left ventricular end-diastolic pressure decreased (P less than .01). Total blood volume did not change but central blood volume decreased (P less than .01) from 26.1 +/- 0.9 to 22.3 +/- 0.5 ml/kg. After milrinone administration, mean circulatory filling pressure decreased (P less than .01) by 30% from 7.4 +/- 0.4 to 5.0 +/- 0.2 mm Hg. Vascular or venous compliance increased (P less than .05) slightly from 1.96 +/- 0.4 to 2.20 +/- 0.1 ml/mm Hg/kg. This was accompanied by an increase (P less than .01) in unstressed vascular blood volume of 3.3 +/- 0.6 ml/kg. Arterial compliance also increased (P less than .05). In summary, milrinone produces an increase in inotropy, arterial vasodilatation and venodilatation as evidenced by the increased venous compliance and unstressed vascular volume.(ABSTRACT TRUNCATED AT 250 WORDS)     

Systemic hemodynamic and regional blood flow effects of LY141865, a selective dopamine receptor agonist

Intravenous infusion of LY141865 (20 micrograms/kg) lowered systemic vascular resistance in anesthetized dogs resulting in a fall in mean arterial blood pressure. These effects require an intact nervous system and involve dopamine receptors as they were abolished by hexamethonium or sulpiride pretreatment. LY141865 does not appear to interact with adrenergic receptors because it did not increase diastolic blood pressure or cardiac rate of normal or hexamethonium-treated dogs, and yohimbine pretreatment did not antagonize its systemic vasodilator and hypotensive actions. Hemodynamic analysis demonstrated that infusion of LY141865 (20 and 100 micrograms/kg i.v.) resulted in persistent arterial hypotension due solely to reduced systemic vascular resistance; aortic blood flow index was maintained. LY141865 produced slight bradycardia and sustained increments in stroke volume index at the highest tested dose. Left ventricular filling pressure was unchanged by LY141865. Regional blood flows to heart, stomach, colon, small intestine, kidneys and marrow-laden bone were not changed during hemodynamic alterations produced by LY141865, although evidence of arteriovenous shunting of blood was observed in skin and skeletal muscle. Comparable systemic vasodilation and arterial hypotension induced by infusion of nitroglycerin reduced gastric and colonic blood flows, but did not produce detectable shunting. The composite data are interpreted to be a reflection of the ability of LY141865 to interact with DA2 dopamine receptors and thereby inhibit neurogenic release of norepinephrine. The present results and known oral efficacy of LY141865 lend further support for the development and use of dopamine receptor agonists for the treatment of cardiovascular disease.     

Intrarenal Haemodynamics in Rats during Haemorrhagic Hypotension*

Abstract. Previous studies of intrarenal haemodynamics by wash-out with inert gas suggested that haemorrhagic hypotension (HH) in the dog causes a redistribution of intrarenal blood flow with a patchy cortical hypoperfusion, mainly due to an increased concentration of circulating catecholamines. In the present experiments intrarenal haemodynamics were studied by the same methods in the rat during prolonged HH with a mean arterial BP of 51 mm Hg. Under these conditions inert gas wash-out studies showed a decrease in compartment I (CP I) flow fraction (“cortical flow fraction”) from 81.5% to 43.2% of total renal blood flow (RBF). CP I blood flow dropped from 3.13 ml/min. to 0.63 ml.‘min. per g kidney weight. Total renal vascular resistance increased by a factor of 1.2 as compared with control conditions. These changes in intrarenal haemodynamics were considerably smaller than those ob served in the dog under comparable conditions. In contrast to observations in the canine kidney no patchy areas of cortical hypoperfusion occurred in the rat, and there was no evidence of stratification of cortical blood flow during HH. Instead, there was an even reduction in cortical blood flow from the subcapsular area to the cortico-medullary border as indicated by inert gas wash-out studies and “krypton autoradiographs. The meaning and pathogenesis of the observed differences between both species remains to be defined. It is suggested that in the rat the reaction of the renal vasculature to sympatho-adrenal stimuli and/or to angiotensin might be different from that in the dog.