Mechanisms of Responses of Systemic Circulation: Role of the Endothelial Factor of Vascular Tone Control

Experimental data on the effect of NO synthase inhibition on hemodynamic changes (blood pressure, cardiac output, and peripheral resistance) induced by an increased (polyglucin infusion) or decreased (orthostasis) cardiac output are presented. Under conditions of NO synthase inhibition, the pressor effects of polyglucin and orthostatic hypotension increased by 70 and 72%, respectively. The response of peripheral resistance had a similar trend. Significance of NO secretion by vascular endothelium for the development of systemic hemodynamic responses is proposed.     

Blockade of the systemic and renal vascular actions of angiotensisn II with the 1-sar, 8-ala analogue in the rat.

To assess the characteristics of blockade induced by 1-Sar, 8-Ala angiotensin II (P113) in the rat, dose-response relationships were established for angiotensin II and blood pressure, cardiac output and renal blood flow (measured with microspheres) and calculated total peripheral resistance. P113 infused at 1.0 μg/kg/min reduced renal and systemic vascular responses to angiotensin II, but did not modify the pressor response because of compensatory increase in cardiac output. Ganglionic blockade (pentolinium tartrate 2.5 mg) uncovered a significant influence of P113 at 1.0 μg/kg/ min on pressor responses to angiotensin II. P113 at 10 μg/kg/min totally prevented the pressor and renal vascular response to 1.0 μg/kg/min of angiotensin II. P113 at 10 and 100 μg/kg/min did not influence renal blood flow, cardiac output or total peripheral resistance, and had only a transient, small influence on blood pressure. P113 did not modify the renal or systemic vascular response to norepinephrine. The failure of P113 to influence renal blood flow in the rat and the relative insensitivity of the renal vasculature to angiotensin II suggest that the vascular receptor for angiotensin II in the rat differs from that in other species including the dog, rabbit and man.     

The mechanism of beta-adrenergic receptor blockade-induced elevation of arterial blood pressure in rats

Beta-adrenergic blockade increases peripheral vascular resistances acutely and paradoxically lowers arterial blood pressure in most species but not in the rat. In this study the hypothesis has been tested of a significant participation of unopposed alpha-adrenergic mediated vasoconstriction following beta-adrenergic blockade in blood pressure regulation of conscious rats. Alpha-adrenergic blockade in propranolol-pretreated rats significantly decreased mean arterial blood pressure by 22%, heart rate by 20%, and total peripheral resistance by 14% when compared to rats treated only with propranolol, whereas cardiac output was similar in the two groups. A significant 28% reduction of coronary blood flow in rats treated with alpha- and beta-adrenergic blockers, when compared to rats treated only with propranolol, is most likely related to phentolamine's indirect effects on the coronary vasculature. Cerebrovascular and renovascular resistances were similar in these groups. All changes reported were significant at the 95% confidence level. It is concluded that the mechanism of increased blood pressure following beta-adrenergic blockade in rats is related at least in part to unmasking of unopposed alpha-receptor tone, which, however, is minimal in the coronary, cerebral and renal circulations.     

Endurance training in dogs increases vascular responsiveness to an alpha 1-agonist

The effects of endurance training on vascular responsiveness to an alpha 1-agonist and the associated changes in baroreflex modulation of heart rate and vascular resistance were studied. Graded dosages of phenylephrine were given to eight treadmill-trained dogs and to eight untrained dogs; both groups were chronically instrumented and were sedated and resting when tested. These dosages were repeated after ganglionic blockade. Aortic pressure, cardiac output, central venous pressure, peripheral resistance, and heart rate were each averaged over 30 s before injection and 90 s after injection. The slope of the peripheral resistance-dose relationship was significantly increased in trained compared with untrained dogs in both the unblocked and blocked cases [unblocked: trained 0.89, untrained 0.47; blocked: trained 4.30, untrained 2.05 (mmHg.l-1.min)/(microgram.kg-1)]. The unblocked resistance slopes were reduced with respect to the blocked slopes by 77 (untrained) and 79% (trained). The slope of the heart rate-aortic pressure response was reduced, but not significantly, by endurance training. We conclude that 6 wk of endurance training in dogs resulted in a doubling of the vascular responsiveness to an alpha 1-agonist, with no significant change in the baroreflex regulation of resistance or heart rate.     

Plasmodium berghei: malaria infection causes increased cardiac output in rats, Rattus rattus

Thirty-two 4-week-old male Wistar rats were infected with Plasmodium berghei malaria. On Days 12 through 14, blood volume, arterial blood pressure, right ventricular pressure, heart rate, cardiac output, stroke volume, hematocrit, and vascular resistances were determined. All of the cardiovascular parameters measured, with the exception of calculated pulmonary vascular resistance, changed progressively as the peripheral blood parasitemia increased. With a rising parasitemia, cardiac output increased, despite a reduced heart rate. The highest parasitemia of 63% was accompanied by a doubling of the normal cardiac output. The relationship between parasitemia and cardiac output can be described by the equation, cardiac output = (6.14) x % parasitemia + 452 ml/min/kg. The mean arterial blood pressure was lower than controls when parasitemia exceeded 20%, whereas systolic right ventricular pressure was elevated only at the highest parasitemias. When noninfected control rats were compared with those animals having parasitemias greater than 40%, in the infected animals, mean arterial pressure was 28% lower (P less than 0.01) and systolic right ventricular pressure rose by 21% (P less than 0.02). A 50% decline was observed in the total peripheral vascular resistance (P less than 0.01), although the pulmonary resistance was apparently unchanged. With P. berghei infection, there is also a marked anemia, an increase in plasma volume, and a 16% increase in blood volume (% body weight). It is concluded from these results that although the hemodynamic changes previously reported in the literature indicate that infection with malaria may result in focal blockages in microvessels and poor tissue perfusion, the total systemic effect, in the rat, is an increase in cardiac output secondary to a reduced peripheral resistance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasodilator tone in the llama fetus: the role of nitric oxide during normoxemia and hypoxemia

The fetal llama responds to hypoxemia, with a marked peripheral vasoconstriction but, unlike the sheep, with little or no increase in cerebral blood flow. We tested the hypothesis that the role of nitric oxide (NO) may be increased during hypoxemia in this species, to counterbalance a strong vasoconstrictor effect. Ten fetal llamas were operated under general anesthesia. Mean arterial pressure (MAP), heart rate, cardiac output, total vascular resistance, blood flows, and vascular resistances in cerebral, carotid and femoral vascular beds were determined. Two groups were studied, one with nitric oxide synthase (NOS) blocker N(G)-nitro-L-arginine methyl ester (L-NAME), and the other with 0.9% NaCl (control group), during normoxemia, hypoxemia, and recovery. During normoxemia, L-NAME produced an increase in fetal MAP and a rapid bradycardia. Cerebral, carotid, and femoral vascular resistance increased and blood flow decreased to carotid and femoral beds, while cerebral blood flow did not change significantly. However, during hypoxemia cerebral and carotid vascular resistance fell by 44% from its value in normoxemia after L-NAME, although femoral vascular resistance progressively increased and remained high during recovery. We conclude that in the llama fetus: 1) NO has an important role in maintaining a vasodilator tone during both normoxemia and hypoxemia in cerebral and femoral vascular beds and 2) during hypoxemia, NOS blockade unmasked the action of other vasodilator agents that contribute, with nitric oxide, to preserving blood flow and oxygen delivery to the tissues.     

Blood pressure regulation during cardiac autonomic blockade: effect of fitness

The purpose of this study was to determine the role of the autonomic nervous system's control of the heart in fitness-related differences in blood pressure regulation. The cardiovascular responses to progressive lower-body negative pressure (LBNP) were studied during unblocked (control) and full blockade (experimental) conditions in 10 endurance-trained (T) and 10 untrained (UT) men, aged 20-31 yr. The experimental conditions included beta 1-adrenergic blockade (metoprolol tartrate), parasympathetic blockade (atropine sulfate), or complete blockade (metoprolol and atropine). Heart rate, blood pressure, forearm blood flow, and cardiac output were measured at rest and -16 and -40 Torr LBNP. Forearm vascular resistance, peripheral vascular resistance, and stroke volume were calculated from these measurements at each stage of LBNP. Blood pressure was maintained, primarily by augmented vasoconstriction, equally in T and UT subjects during complete and atropine blockade. The fall in systolic and mean pressure from 0 to -40 Torr was greater (P less than 0.05) in the T subjects during the unblocked and metoprolol blockade conditions. This reduced blood pressure control during unblocked condition was attributable to attenuated vaso-constrictor and chronotropic responses in the T subjects. We hypothesize that an autonomic imbalance (elevated base-line parasympathetic activity) in highly trained subjects restricts reflex cardiac responses, which accompanied by an attenuated vasoconstrictor response, results in attenuated blood pressure control during a steady-state hypotensive stress.     

Pharmacologic tools for assessment of adrenergic nerve activity in human hypertension

Measurement of plasma norepinephrine concentration (plasma NE) has not resolved the role of the adrenergic system in the pathogenesis or maintenance of hypertension. A better picture is gained if plasma NE measurement is combined with the assessment of sympathetic drive and reactivity by the use of specific sympathetic antagonists and agonists. In mild hypertension, the decrease in heart rate and cardiac output after beta-adrenoceptor blockade correlates with the level of plasma NE. In established hypertension, the fall in blood pressure or peripheral vascular resistance after alpha-adrenoceptor blockade is related to plasma NE levels. Similarly, changes in forearm vascular resistance induced by local alpha-adrenoceptor blockage correlates with plasma NE in hypertension. Cardiovascular responsiveness to adrenergic agonists is altered in hypertension. The response to cardiac beta-receptor stimulation decreases during the course of the disease. To the contrary, vascular responses to exogenous NE increase with the progression of the hypertensive disease. Results with total autonomic blockade indicate that in some patients with early or borderline hypertension, increased sympathetic tone is involved in the maintenance of blood pressure. In established hypertension, there is no definite indication of increased sympathetic tone, but the sympathetic nervous system may nevertheless play a prominent role in the maintenance of the blood pressure. A vascular hyperreactivity to adrenergic stimulation is characteristically associated with established hypertension. The nature of this hyperreactivity has not been fully elucidated, but it is very likely that it reflects structural vascular changes in hypertension.     

The role of alpha-adrenergic receptors in carbon monoxide hypoxia

The importance of alpha-adrenergic receptors in the cardiac output and peripheral circulatory responses to carbon monoxide (CO) hypoxia was studied in anesthetized dogs. Phenoxybenzamine (3 mg/kg i.v.) was injected to block alpha-receptor activity and the data obtained were then compared with those from a previous study of CO hypoxia in unblocked animals. Values for cardiac output, hindlimb blood flow, vascular resistance, and oxygen uptake were obtained prior to and at 30 and 60 min of CO hypoxia which reduced arterial oxygen content by approximately 50%. alpha-Adrenergic blockade resulted in a lower (p less than 0.05) control value for cardiac output than observed in unblocked animals, but no differences were present between the two groups at 30 or 60 min of CO hypoxia. Similarly, limb blood flow was lower (p less than 0.05) during the control period in the alpha-blocked group but rose to the same level as that in the unblocked animals at 60 min of COH. No change in limb blood flow occurred during CO hypoxia in the unblocked group. These findings demonstrated that during CO hypoxia alpha-receptor mediated venoconstriction does not contribute to the cardiac output response and alpha-receptor mediated vasoconstriction probably does prevent a rise in hindlimb skeletal muscle blood flow.     

Alteration of systemic hemodynamics in dogs with adrenal hypertension

Arterial hypertension was reproduced in 20 dogs by suturing the adrenal glands with ligature. Arterial pressure showed a significant fall in 2 weeks; cardiac output diminished, and the general peripheral resistance displayed a sharp elevation. The phasic syndrome of hypodynamia, a reduction of the contractility index, of the volumetric rate of cardiac output, of the cardiac index, and of the rate of increase of the intraventricular pressure pointed to reduction of the myocardial contractility. Three months after the suturing there was an even greater elevation of arterial pressure, and hemodynamic shifts were analogous to the two-week hypertension period.     

Effects of mental stress on insulin-mediated glucose metabolism and energy expenditure in lean and obese women

The effects of the sympathetic activation elicited by a mental stress on insulin sensitivity and energy expenditure (VO(2)) were studied in 11 lean and 8 obese women during a hyperinsulinemic-euglycemic clamp. Six lean women were restudied under nonselective beta-adrenergic blockade with propranolol to determine the role of beta-adrenoceptors in the metabolic response to mental stress. In lean women, mental stress increased VO(2) by 20%, whole body glucose utilization ([6,6-(2)H(2)]glucose) by 34%, and cardiac index (thoracic bioimpedance) by 25%, whereas systemic vascular resistance decreased by 24%. In obese women, mental stress increased energy expenditure as in lean subjects, but it neither stimulated glucose uptake nor decreased systemic vascular resistance. In the six lean women who were restudied under propranolol, the rise in VO(2), glucose uptake, and cardiac output and the decrease in systemic vascular resistance during mental stress were all abolished. It is concluded that 1) in lean subjects, mental stress stimulates glucose uptake and energy expenditure and produces vasodilation; activation of beta-adrenoceptors is involved in these responses; and 2) in obese patients, the effects of mental stress on glucose uptake and systemic vascular resistance, but not on energy expenditure, are blunted.     

Haemodynamic Effects of Salbutamol in Patients Needing Circulatory Support after Open-heart Surgery

The effects of substituting an infusion of salbutamol for isoprenaline were studied in 12 patients needing circulatory support after valve replacement surgery. The cardiac output rose while the heart rate remained unaltered. There was a reduction in systemic vascular resistance, and though the oxygen uptake tended to rise the increase in cardiac output was proportionately greater so that the arteriovenous oxygen difference fell.It is suggested that the drug is of value for two reasons. It causes a selective reduction in peripheral arteriolar resistance, which avoids peripheral pooling, but permits limited myocardial work to be used to generate flow rather than pressure, and the increase in cardiac output is not accompanied by a corresponding rise in oxygen uptake.     

Gas exchange and oxygen transport during long term hypothermia following a hypothermal apnea in rats

The data obtained show that, at the initial stages of hypothermia, a decrease in the oxygen consumption and carbon dioxide production, cardiac output, and heart rate occurred in accordance with the temperature coefficient. Suppression of the tissue gas exchange was unrelated to disorders in the lung gas exchange but determined rather by a progressing weakening of heart activity, decrease in the cardiac output, and increase in the general vascular peripheral resistance.     

The adrenergic mechanisms are involved in the pulmonary hemodynamics changes following experimental myocardial ischemia in rabbits

In acute experiments in anesthetized rabbits the changes of the pulmonary hemodynamics following myocardial ischemia in the region of the descendent left coronary artery were studied in control animals and after the blockade of alpha-adrenoreceptors by phentolamine or N-cholinoreceptors of autonomic ganglia by hexamethonium. Following myocardial ischemia in control animals the pulmonary artery pressure and flow decreased, the pulmonary vascular resistance was elevated not significantly, the cardiac output decreased more than pulmonary artery flow. Following myocardial ischemia after the blockade of alpha-adrenoreceptors the pulmonary artery flow and cardiac output decreased in the same level and the pulmonary vascular resistance was decreased. In these conditions the pulmonary artery pressure decreased more than in control animals, meanwhile the pulmonary artery flow was decreased in the same level as in the last case. Following myocardial ischemia after the blockade of N-cholinoreceptors the pulmonary hemodynamics changes were the same as they were following myocardial ischemia in the control rabbits, the cardiac output decreased more than pulmonary artery flow. The disbalance of the cardiac output and pulmonary artery flow changes in the case of myocardial ischemia was caused by the pulmonary vessel reactions following activations of the humoral adrenergic mechanisms.     

Effects of autonomic blockade on cardiac function at rest and during upright exercise in humans

The cardiac function was studied by radionuclide cardiography in eight healthy subjects at rest and during submaximal upright exercise before and after autonomic blockade with metoprolol and atropine. At rest the median stroke volume was reduced by 21% during autonomic blockade (P less than 0.01), but cardiac output was maintained by a concomitant increase in heart rate. The systolic blood pressure was reduced from 120 to 105 mmHg (P less than 0.01), and left ventricular ejection fraction was reduced from 61 to 56% (P less than 0.05). After autonomic blockade the heart rate reached during exercise was the same. Stroke volume and cardiac output were maintained through cardiac dilation. The increase in left ventricular end-diastolic volume was 31 vs. 10% during control conditions (P less than 0.01). The systolic blood pressure was reduced from 174 to 135 mmHg (P less than 0.01). Left ventricular ejection fraction was reduced from 75 to 67% (P less than 0.05), but the increase from rest to exercise was preserved. Total peripheral resistance was reduced by 17% (P less than 0.05). These findings suggest that the heart possesses intrinsic mechanisms to maintain cardiac output during submaximal upright exercise. End-diastolic dilation results in a preserved stroke volume despite a reduced contractility.     

Effects of dihydroergotamine on hemodynamic molsidomine actions in anesthetized dogs

In pentobarbital-anesthetized mongrel dogs the intravenous actions of 0.50 mg/kg molsidomine on pulmonary artery and left ventricular (LV) end-diastolic pressures and internal heart dimensions (preload), left ventricular systolic and peripheral blood pressures, and total peripheral resistance (afterload), as well as on heart rate, dP/dt, stroke volume, and cardiac output (heart performance) were studied for 2 h. Hemodynamic molsidomine effects were influenced by increasing amounts of intravenously infused dihydroergotamine solution (DHE, 1-64 micrograms X kg-1 X min-1). Molsidomine decreased preload, stroke volume, and cardiac output for over 2 h but decreased ventricular and peripheral pressures for 45 min. Systemic vascular resistance showed a tendency to decrease while heart rate and LV dP/dtmax were not altered. DHE infusion reversed molsidomine effects on the preload and afterload of the heart. The diminished stroke volume was elevated so that cardiac output also increased. Total peripheral resistance increased while heart rate fell in a dose-dependent fashion. The LV dP/dtmax remained unchanged until the highest dose of 64 micrograms X kg-1 X min-1 DHE elevated the isovolumic myocardial contractility. These experiments indicate that DHE can reverse the intravenous molsidomine effects on hemodynamics. Most likely, this is mediated through peripheral vasoconstriction of venous capacitance vessels, thereby affecting molsidomine's action on postcapillary beds of the circulation.     

Effects of physical training and detraining on resting cardiovascular parameters in albino rats

The time course of shifts induced by physical training in the resting cardiovascular parameters was investigated in swim-trained albino rats. Measurements were performed weekly, both during a 14-weeks training period and 5 weeks after cessation of regular swimming. Cardiac output (dye dilution) blood pressure (electromanometry) and heart rate (ECG) were measured under intraperitoneal urethan anesthesia. In comparison with non-exercising controls, rats at the end of the training period displayed lower heart rate, smaller stroke volume and cardiac output, and a higher peripheral resistance. The early phase of regular training, however, was characterized by an elevated cardiac output, heart rate and stroke volume, and by a decreased peripheral resistance. After discontinuation of regular training, cardiac output was elevated as well, but this was brought about only by the increased stroke volume, because resting heart rate was still lower than in the controls. Blood pressure did not change during the whole experimental period. Considering that similar shifts have been reported in humans, the changes in the resting cardiovascular status may be responsible for the similar complaints and symptoms often observed in undertrained athletes or in athletes who had interrupted high intensity regular training.     

Endogenous substance P modulates human cardiovascular regulation at rest and during orthostatic load.

Substance P (SP) is a peptide neurotransmitter identified in many central and peripheral neural pathways. Its precise role in human physiology has been difficult to elucidate. We used the selective neurokinin 1 (NK1) antagonist aprepitant as a pharmacological probe to determine the role of endogenous SP in human cardiovascular regulation. We performed a randomized, double-blind, placebo-controlled, crossover trial in healthy subjects. Blockade of endogenous NK1 receptors reduced resting muscle sympathetic activity 38% (P=0.002), reduced systemic vascular resistance by 25% (P=0.021), and increased cardiac index by 47% (P=0.006). This constellation of changes did not, however, alter either blood pressure or heart rate in the supine position. NK1 antagonism also raised orthostatic heart rate change by 38% (P=0.023), although during the incremental postural adjustment on the tilt table neither heart rate nor blood pressure was altered significantly. Despite a mildly attenuated vagal baroreflex with SP blockade, the depressor and pressor responses to nitroprusside and phenylephrine did not differ compared with placebo, suggesting other compensatory mechanisms. NK1 blockade manifests as a decrease in muscle sympathetic nerve activity and systemic vascular resistance. Our study suggests SP exerts a tonic enhancement of sympathetic outflow to some cardiovascular structures via its modulation of the NK1 receptor. Most likely, this ubiquitous neurotransmitter exerts effects at multiple sites that, in the aggregate, are relatively well compensated under many circumstances but may emerge with perturbations. This study is consistent with a role for SP afferents in supporting peripheral vascular resistance.     

PEG-albumin supraplasma expansion is due to increased vessel wall shear stress induced by blood viscosity shear thinning

We studied the extreme hemodilution to a hematocrit of 11% induced by three plasma expanders: polyethylene glycol (PEG)-conjugated albumin (PEG-Alb), 6% 70-kDa dextran, and 6% 500-kDa dextran. The experimental component of our study relied on microelectrodes and cardiac output to measure both the rheological properties of plasma-expander blood mixtures and nitric oxide (NO) bioavailability in vessel walls. The modeling component consisted of an analysis of the distribution of wall shear stress (WSS) in the microvessels. Our experiments demonstrated that plasma expansion with PEG-Alb caused a state of supraperfusion with cardiac output 40% above baseline, significantly increased NO vessel wall bioavailability, and lowered peripheral vascular resistance. We attributed this behavior to the shear thinning nature of blood and PEG-Alb mixtures. To substantiate this hypothesis, we developed a mathematical model of non-Newtonian blood flow in a vessel. Our model used the Quemada rheological constitutive relationship to express blood viscosity in terms of both hematocrit and shear rate. The model revealed that the net effect of the hemodilution induced by relatively low-viscosity shear thinning PEG-Alb plasma expanders is to reduce overall blood viscosity and to increase the WSS, thus intensifying endothelial NO production. These changes act synergistically, significantly increasing cardiac output and perfusion due to lowered overall peripheral vascular resistance.     

Cyclooxygenase blockers inhibit ethanol-induced pulmonary vasoconstriction in lambs

We investigated the mechanism of ethanol-induced pulmonary vasoconstriction in lambs, by a pharmacological approach. We chronically instrumented 28 lambs to determine whether phentolamine (alpha-block), propranolol (beta-block), promethazine and cimetidine (H1- and H2-block), high-dose indomethacin, or low- and high-dose meclofenamate (cyclooxygenase block) altered the vasoconstriction. Ethanol alone increased pulmonary vascular resistance from 0.14 to 0.49 Torr.ml-1.kg-1.min (U). Only indomethacin (7-8 mg/kg po) and high-dose meclofenamate (7-8 mg/kg iv) abolished the pulmonary vascular response to ethanol infusion. Pulmonary vascular resistance was 0.14 U after ethanol plus indomethacin and was 0.2 U after ethanol plus high-dose meclofenamate (P = NS vs. base line). Low-dose meclofenamate (2 mg/kg) attenuated the vasoconstrictor response. Systemic vascular resistance increased moderately after ethanol and had a similar pattern of inhibition by cyclooxygenase blockade. Cardiac output and heart rate decreased nearly significantly after ethanol (P less than 0.06), a tendency that was also ablated by cyclooxygenase inhibition. Thus the acute cardiocirculatory response to ethanol involves an intact prostaglandin synthase system in lambs. To our knowledge, these data are the first documentation that cyclooxygenase enzyme blockade can eliminate the acute cardiac and vascular effects of ethanol in a whole-animal system.