Peripheral vascular responses to hypoxic hypoxia after aortic denervation

We wished to see whether aortic chemoreceptors and other vagal afferent traffic played an essential role in the circulatory adjustments to hypoxic hypoxia. Aortic chemoreceptors were denervated (AD) in one group (n = 6) of anesthetized dogs, bilateral cervical vagotomy (V) was done on a second group (n = 6), and a third group (n = 6) was sham-operated to serve as a control. Venous outflow from the left hindlimb was isolated. After a 20-min control period of ventilation with room air, the animals were ventilated for 60 min with 9% of O2 in N2. Arterial, mixed venous, and hindlimb venous blood samples were taken every 20 min. The cardiac output response to hypoxic hypoxia was attenuated at 40 and 60 min in both the AD and V groups (p less than 0.05). Hindlimb blood flow increased equally in all three groups during hypoxia. The pressor response at the onset of hypoxia (20 min) was abolished in the AD and V groups, but mean arterial pressure fell to similar levels in all three groups by 60 min of hypoxia. We concluded that reflex aortic chemoreceptor stimulation during hypoxia augmented cardiac output mostly by effects on the venous side of the circulation but played no role in skeletal muscle vascular responses to hypoxic hypoxia.     

Cutaneous vascular responses to isometric handgrip exercise during local heating and hyperthermia.

The dramatic increase in skin blood flow and sweating observed during heat stress is mediated by poorly understood sympathetic cholinergic mechanisms. One theory suggests that a single sympathetic cholinergic nerve mediates cutaneous active vasodilation (AVD) and sweating via cotransmission of separate neurotransmitters, because AVD and sweating track temporally and directionally when activated during passive whole body heat stress. It has also been suggested that these responses are regulated independently, because cutaneous vascular conductance (CVC) has been shown to decrease, whereas sweat rate increases, during combined hyperthermia and isometric handgrip exercise. We tested the hypothesis that CVC decreases during isometric handgrip exercise if skin blood flow is elevated using local heating to levels similar to that induced by pronounced hyperthermia but that this does not occur at lower levels of skin blood flow. Subjects performed isometric handgrip exercise as CVC was elevated at selected sites to varying levels by local heating (which is independent of AVD) in thermoneutral and hyperthermic conditions. During thermoneutral isometric handgrip exercise, CVC decreased at sites in which blood flow was significantly elevated before exercise (-6.5 +/- 1.8% of maximal CVC at 41 degrees C and -10.5 +/- 2.0% of maximal CVC at 43 degrees C; P < 0.05 vs. preexercise). During isometric handgrip exercise in the hyperthermic condition, an observed decrease in CVC was associated with the level of CVC before exercise. Taken together, these findings argue against withdrawal of AVD to explain the decrease in CVC observed during isometric handgrip exercise in hyperthermic conditions.     

L-Name modulates responses to adrenomedullin in the hindquarters vascular bed of the rat

Responses to synthetic human adrenomedullin (ADM), a novel hypotensive peptide recently discovered in human pheochromocytoma cells, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the hintquarters vascular bed of the rat. Under conditions of controlled hintquarters blood flow, intraarterial injections of ADM (0.01–0.3 nmol) and of CGRP (0.03–0.3 nmol) caused dose-related decreases in hindquarters perfusion pressure and decreases in systemic arterial pressure. Following administration of the nitric oxide synthase inhibitor, N^ω-nitro-L-arginine methyl ester (L-NAME), hindquarters vasodilator and systemic depressor responses to ADM were significantly decreased, whereas L-NAME did not significantly decrease the vasodilator response to CGRP in either the hindquarters or systemic vascular beds. Following administration of the cyclooxygenase inhibitor, meclofenamate, vasodilator responses to ADM and to CGRP were not significantly decreased. When the relative vasodilator activity of the two peptides was compared on a nmol basis, responses to ADM were similar to responses with CGRP in the hindquarters vascular bed, whereas ADM was 30–100 fold less potent than CGRP in decreasing systemic arterial pressure. The present data demonstrate that ADM has significant vasodilator activity in the hindquarters vascular bed of the rat, that hindquarters vasodilator and systemic vasodepressor responses to ADM, but not to CGRP, are dependent upon the release of nitric oxide from the endothelium.     

Segmental vascular responses to voltage-gated calcium channel potentiation in rat lung.

We determined lung vascular responses to voltage-gated Ca2+ channel potentiation with BAY K 8644 (BAY). We anesthetized 46 rats (Sprague-Dawley; halothane and pentobarbital) and then excised and perfused their lungs at constant blood flow of 25 +/- 2 (SE) ml.kg-1.min-1 at constant airway and left atrial pressures of 5 and 6 cmH2O, respectively. Pulmonary arterial pressure (Ppa) increased from 13.3 +/- 0.3 cmH2O at baseline to 17.3 +/- 1.3 cmH2O after BAY (2.8 x 10(-6) M; n = 5; P less than 0.01). As determined by micropuncture, arteriolar and venular (Pven) pressures did not change. Increase of perfusate Ca2+ (16 x 10(-3) M; n = 8) similarly increased Ppa. NG-mono-methyl-L-arginine (2 x 10(-4) M), an inhibitor of endothelium-derived relaxing factor, augmented the pressor effect of BAY when given after (n = 4) but not before (n = 4) BAY (P less than 0.01). Prior cyclooxygenase blockade with indomethacin (5 mg/kg; n = 5) attenuated the Ppa response to BAY (P less than 0.01). None of these agents changed Pven. To confirm vasoactivity in veins, we induced smooth muscle depolarization with KCl (20 x 10(-3) M; n = 6) and receptor-mediated responses with histamine (3 x 10(-4) M; n = 7). Both of these agents increased Pven markedly (P less than 0.01). We interpret that, in rat lung, BAY causes arterial but not venous constriction, because the venous segment differs from the arterial with regard to Ca2+ channel potentiation.     

Comparison of responses to rat and human adrenomedullin in the hindlimb vascular bed of the cat

Responses to rat (r) adrenomedullin (ADM) and human (h) ADM were compared in the hindlimb vascular bed of the cat under conditions of controlled blood flow. Intra-arterial injections of rADM and hADM in doses of 0.03–1 nmol caused dose-related decreases in hindlimb perfusion pressure. In terms of relative vasodilator activity, rADM was similar to hADM. The time course of the vasodilator response and the recovery half times (T_1/2) for the vasodilator response to rADM and hADM were not significantly different. Decreases in hindlimb perfusion pressure in response to rADM and hADM were not altered by the calcitonin gene-related peptide receptor antagonist, rCGRP(8–37), at the same time, vasodilator responses to calcitonin gene-related peptide (CGRP) were significantly reduced. The T_1/2 of the vasodilator response to rADM and hADM were significantly greater after administration of the cAMP-selective, type IV phosphodiesterase inhibitor, rolipram. These data demonstrate that decreases in hindlimb perfusion pressure in response to rADM and hADM are similar and that vasodilator responses to rADM are not dependent on the activation of CGRP receptors in the hindlimb vascular bed of the cat. These data further suggest that decreases in hindlimb perfusion pressure in response to rADM are mediated by smooth muscle increases in cAMP levels.     

Indomethacin inhibits responses to all vasoconstrictors in the rat mesenteric vascular bed: Restoration of responses by prostaglandin E2

Indomethacin added to the perfusing buffer inhibited pressor responses to noradrenaline, angiotensin II, arginine vasopressin, histamine, serotonin, calcium ions and potassium ions in the male rat mesenteric vascular bed. For every pressor agent the indomethacin concentration which inhibited response amplitude by 50% was about 7 microg/ml (2.1 × 10^?5 M). With every pressor agent, prostaglandin (PG) E2 could restore normal responsiveness in indomethacin-blocked preparations even while the indomethacin was still present in the buffer. The concentration of PGE2 required was proportional to the concentration of indomethacin. Preparations completely inhibited by indomethacin needed about 5ng/ml PGE2 for complete restoration of normal responses. Aspirin and mefenamic acid could also inhibit responses to all pressor agents tested but with these drugs only a partial restoration could be achieved by PGE2.     

Segmental pulmonary vascular responses to ATP in rat lungs: role of nitric oxide

Hakim, Tawfic S., Lara Ferrario, Jeffrey C. Freedman, RobertE. Carlin, and Enrico M. Camporesi. Segmental pulmonary vascularresponses to ATP in rat lungs: role of nitric oxide. J. Appl. Physiol. 82(3): 852-858, 1997.ATP exhibits vascular pressor and depressor responses in a dose-and tone-dependent manner. The vascular site of ATP-induced contractionor dilation has not previously been characterized. Using the vascularocclusion technique, we investigated the effects of ATP in isolated rat lungs perfused with autologous blood (hematocrit = 20%) and described its action during resting and elevated tone in terms of changes inresistances of the small and large arteries and veins. During restingtone, ATP (10⁵M)

     

Peripheral changes above and below injury level lead to prolonged vascular responses following high spinal cord injury

Autonomic dysreflexia (AD) is a debilitating disorder producing episodes of extreme hypertension in patients with high-level spinal cord injury (SCI). Factors leading to AD include loss of vasomotor baroreflex control to regions below injury level, changes in spinal circuitry, and peripheral changes. The present study tested for peripheral changes below and above injury level 6 wk after a transection at the fourth thoracic spinal level. Changes in vascular conductance were recorded in the femoral, renal, brachial, and carotid arteries in response to intravenous injections of two alpha-adrenergic agonists, phenylephrine (PE; 0.03-100 microg/kg) and methoxamine (Meth; 1-300 microg/kg). Unlike PE, Meth is not subject to neuronal reuptake. Ganglionic blockade (0.6 mg/kg chlorisondamine) was used to eliminate the central component of the cardiovascular response. After ganglionic blockade, SCI animals exhibited prolonged vasoconstriction in response to PE in all blood vessels measured compared with those in intact animals (all, P < 0.035). However, the PE dose-response curves obtained after ganglionic blockade revealed no significant difference in the potency between the two groups (all, P > 0.06), indicating that the prolonged vasoconstriction was not due to supersensitivity to PE. In contrast to PE, vascular responses to Meth did not vary between intact and SCI groups (all P > 0.108). These results show the development of a widespread peripheral change producing prolonged vasoconstriction in response to PE, but not Meth, possibly due to reduced neuronal reuptake of PE after SCI. This is the first study to report such a change in blood vessels not only below but also above injury level. Interventions to correct this reduced reuptake may help limit the development of AD.     

Adrenocortical responses to adrenocorticotrophin in the rat

The time course of plasma adrenocorticotrophin (ACTH), adrenal cyclic AMP, adrenal corticosterone, and plasma corticosterone was measured in male Sprague-Dawley rats whose endogenous release of ACTH had been blocked (1) following rapid injections of 100 and 300 ng ACTH/100 g body weight, i.v., (2) during prolonged infusions at rates of 1, 2, and 4 ng ACTH/min per 100 g body weight, and (3) after termination of 30-min infusions at rates extending from 0.06 to 8 ng ACTH/min per 100 g body weight. Following injections, the time course of the variables is similar to the one simulated from our models of adrenal cortical secretion, including the simulation of an intermediate variable of our models of the adrenal cortex cell which was presumed to correspond to cyclic AMP. However, during prolonged infusions there is an unexpected overshoot of adrenal cyclic AMP content whereas adrenal and plasma corticosterone concentrations rise to a steady-state value without overshoot. The total amount of cyclic AMP gradually increases following the three increasing infusion rates of ACTH whereas similar levels of plasma corticosterone concentrations are reached at steady state; therefore the saturation of the adrenal cortical secretion is due to a step ulterior to cyclic AMP formation in the steroidogenesis. After 30-min infusions, plasma corticosterone concentration reaches its maximal value following a rate of ACTH input which evokes only a 4-fold increase in adrenal cyclic AMP content; however, there is a 250-fold increase of adrenal cyclic AMP with respect to control value following the higher rates of infusion of ACTH.     

Increase in rat intestinal permeability to endotoxin during hyperthermia

Victims of heat stroke exhibit several clinical features which are also encountered in endotoxaemia. In order to investigate these similarities hyperthermic rats were used to explore the possibility that high body temperature results in increased permeability of intestinal wall to endotoxin. 125I endotoxin was introduced into intestinal segments taken from non-heat exposed rats. The segments were then incubated at 37 degrees C or 45 degrees C. Intestinal segments from heat stressed rats were similarly prepared and incubated at 37 degrees C. Leakage of endotoxin from segments taken from heat stressed rats was three times greater than from those from non-heat stressed rats, as were the segments from non-heat stressed rats which were incubated at 45 degrees C. These results indicate that the intestinal membrane is damaged by heat and that an increase in outward leakage of microbial endotoxins from the gut then occurs. This might contribute to the pathophysiological picture of heatstroke.     

Fetal and placental responses to artificially induced hyperthermia in rats.

Pregnant rats were utilized to study the effect of maternal hyperthermia on fetal development. Eight groups of six to eight rats were exposed to ambient temperatures of 43-44 degrees C at various stages of pregnancy. All rats were killed on day 20 of gestation. Edema, microencephaly and microphthalmia followed heat treatment on day 4, 6, or 8 and skeletal defects occurred on day 10 of gestation. Apparently heat stress of dams after day 14 of gestation had little or no effect on embryos. Most placentas from day 6-10 treatment groups were significantly heavier than control and exhibited extensive thickening and necrosis of decidua basalis. Our results suggest that the rat is a useful model for investigating maternal hyperthermia as a possible cause of human placentophathies and fetal retardation.     

Analysis of purine- and pyrimidine-induced vascular responses in the isolated rat cerebral arteriole

Effects of extraluminal UTP were studied and compared with vascular responses to ATP and its analogs in rat cerebral-penetrating arterioles. UTP, UDP, 2-methylthio-ATP, and alpha,beta-methylene-ATP dilated arterioles at the lowest concentration and constricted them at high concentrations. Low concentrations of ATP dilated the vessels; high concentrations caused a biphasic response, with transient constriction followed by dilation. Endothelial impairment inhibited ATP- and UTP-mediated dilation and potentiated constriction to UTP but not to ATP. ATP- and 2-methylthio-ATP- but not UTP-mediated constrictions were inhibited by desensitization with 10(-6) M alpha,beta-methylene-ATP or 3 x 10(-6) M pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). PPADS at 10(-4) M abolished the UTP-mediated constriction and induced vasodilation in a dose-dependent manner but did not affect the dilation to ATP. These results suggest that in rat cerebral microvessels 1) ATP and 2-methylthio-ATP induce transient constriction via smooth muscle P(2X1) receptors in the cerebral arteriole, 2) UTP stimulates two different classes of P(2Y) receptors, resulting in constriction (smooth muscle P(2Y4)) and dilation (possibly endothelial P(2Y2)), and 3) ATP and UTP produce dilation by stimulation of a single receptor (P(2Y2)).