Sustained Rise In Blood Pressure Research Articles

Bradykinin increases blood pressure in endotoxemic rats

Despite the knowledge about the mechanisms triggered by bradykinin (BK), mainly its hypotensive effect, several aspects of biological effects of this peptide remain unclear, such as its release and action in endotoxemia. The main hypothesis of this study was that blood pressure responses to BK are impaired in experimental models of sepsis. Female Wistar rats (200–280 g) received intraperitoneal (i.p.) injections of sterile saline (1 ml/kg), or lipopolysaccharide (LPS; 1 mg/kg), and were anesthetized at 6, 24, 48, or 72 h after for direct measurement of the mean arterial pressure (MAP). The hypotensive effect of intravenous (i.v.) BK (6, 20 and 60 nmol/kg), and acetylcholine (ACh; 60 nmol/kg) were assessed before and after the treatment with prazosin (0.5 mg/kg i.v.), HOE 140 (20 nmol/kg s.c.), [Leu8]des‐Arg9‐BK (100 nmol/kg, i.v.), losartan (15 mg/kg, i.v.), Y‐27632 (0.1 mg/kg, i.v.), or indomethacin (10 mg/kg i.v.). We also evaluated the influence of endotoxemia on BK‐ and ACh‐induced vasodilation in the in vitro perfused mesenteric vascular bed obtained from both control and LPS 24 h groups. Moreover, the expression of bradykinin B2 and angiotensin II AT1 receptors, and the phosphorylated MYPT‐1 subunit of myosin phosphatase (pMYPT‐1) was detected by Western blotting in homogenates of resistance mesenteric arteries. In spite of the lack of changes in the MAP, and the hypotensive effects induced by BK and ACh remained unaltered in the LPS groups, LPS‐treated animals presented hematological evidence of systemic inflammation (i.e. leukocytosis, high levels of nitrate + nitrite), compared with the control group. Although endotoxemia have not changed the hypotensive effects induced by BK and ACh, BK‐induced hypotension in LPS treated animals (both 24 h and 48 h groups) was followed by an immediate and sustained pressor effect. For instance, the MAP increased by 9 ± 2, 18 ± 5, and 24 ± 3 mm Hg in the control group, and by 29 ± 4, 42 ± 3, and 56 ± 4 mm Hg in the LPS 24 h group, after administration of 6, 20, and 60 nmol/kg BK, respectively. This hypertensive response to BK was not reduced by the selective antagonist of the alpha‐1 adrenergic receptor prazosin, nor by the antagonist of the BK B1 receptor [Leu8]des‐Arg9‐BK, but it was vanished by HOE‐140, a selective BK B2 receptor antagonist, and losartan, an angiotensin II AT1 receptor antagonist. We also found that the hypertensive effect of angiotensin II (60 nmol/kg) was enhanced from 52 ± 5 mm Hg in control animals to 75 ± 3 mm Hg in the LPS 24 h group, an event that was fully prevented by HOE‐140. Although the cyclooxygenase inhibitor indomethacin has not had any influence on BK effects, the Rho‐associated kinase (ROCK) inhibitor Y‐27632 avoided the enhanced hypertensive effect of BK in LPS‐treated animals. Western blotting analysis revealed that B2 and AT1 receptors, and pMYPT‐1, were significantly increased in resistance arteries at 24 h after LPS, compared with samples from control animals. Notably, perfused mesenteric vascular bed obtained from the LPS 24 h group also displayed pressor responses to BK. These results disclose that in spite of the typical hypotension produced by BK in healthy animals, administration of BK in endotoxemic rats produces a biphasic effect, which is characterized by a hypotension followed by a sustained rise in blood pressure. The pressor effect of BK, induced by endotoxemia, appears to be mediated by both bradykinin B2 and angiotensin II AT1 receptors and is fully dependent on activation of ROCK.Support or Funding InformationCNPq (448738/2014‐7). This study was approved by CEUA/UFSC (PP00566).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Renal sodium handling and blood pressure changes in gestational protein-restricted offspring: Role of renal nerves and ganglia neurokinin expression.

BackgroundConsidering long-term changes in renal sodium handling and blood pressure in maternal protein-restricted (LP) offspring, we assumed that the development of LP hypertension results from abnormal dorsal root ganglia (DRG) neurokinin expression associated with impaired responsiveness of renal sensory receptors, promoting a reduced urinary excretion of sodium. The present study investigates whether increased blood pressure in protein-restricted offspring would be associated with changes in the DRG cells and in renal pelvic wall expression of NK1R, SP and CGRP when compared to NP offspring. In addition, we assessed the tubular sodium handling, estimated by creatinine and lithium clearances before and after bilateral renal denervation in conscious LP offspring relative to age-matched NP counterparts.MethodsDams received a normal (NP) or low-protein diet (LP) during their entire pregnancy period. Male NP or LP offspring underwent bilateral surgical renal denervation before the 8-week renal functional test and blood pressure measurements. Immunofluorescence staining in DRG cells was assessed in optical sections by confocal laser scanning microscope.ResultsThe current data demonstrated a sustained rise in blood pressure associated with a decrease in fractional excretion of sodium (FENa) by reducing post-proximal tubule sodium rejection in 16-wk old LP rats relative to age-matched NP counterparts. According to this study, bilateral renal denervation attenuated blood pressure and increased FENa in LP offspring. Furthermore, an immunohistochemical analysis showed a reduced expression of SP and CGRP in DRGs of LP when compared with NP rats. Renal pelvis of LP rats did not show a strong CGRP expression related to NP rats, whereas there was no change in SP immunostaining.ConclusionsThese observations raise the possibility that impaired DRG and pelvic neurokinin expression associated with responsiveness of renal sensory receptors in 16-wk old LP offspring are conducive to excess renal reabsorption of sodium and development of hypertension in this programmed model.

Acetaminophen use and change in blood pressure in a hypertensive population

Recent data suggest that self-reported acetaminophen use is associated with increased risk of cardiovascular events and a rise in arterial blood pressure (BP). We investigated the association between acetaminophen use and BP in a large cohort of patients with hypertension using verified prescription data. We extracted data from the UK General Practice Research Database for all hypertensive patients aged 65 years or older who were prescribed acetaminophen and had BP measured both before and during acetaminophen treatment. Patients were grouped according to whether their antihypertensive treatment remained unchanged or not during the study period. The change in SBP and DBP during acetaminophen use was determined and compared with the change in BP in a group of nonacetaminophen-exposed people identified using propensity matching. A total of 2754 acetaminophen-exposed individuals were included. BP rose slightly during the period of acetaminophen treatment wherein antihypertensive treatment was unchanged [change in SBP 1.6 [95% confidence interval (CI) 0.7-2.5) mmHg and change in DBP 0.5 (95% CI 0.1-1.0) mmHg)]. BP fell when new antihypertensive medications were prescribed. These BP changes were no different to those seen in matched nonacetaminophen-exposed individuals [between-group difference wherein antihypertensive treatment was unchanged was 0.6 (95% CI -0.6 to 1.9) mmHg and 0.5 (-0.1 to 1.1) mmHg for change in SBP and DBP, respectively]. We found no evidence of a sustained rise in blood pressure caused by acetaminophen treatment in a large population of patients with treated hypertension.

The circadian melatonin rhythm and its modulation: possible impact on hypertension

In experimental rodents, surgical removal of the pineal gland, the major source of circulating melatonin, causes a gradual and sustained rise in blood pressure. Conversely, when melatonin is chronically administered to pinealectomized rodents the increment in blood pressure is ameliorated. In humans as well, the night time rise in endogenous circulating melatonin levels may be inversely related to the reduction in night time blood pressure. Among patients with hypertension, some exhibit a much greater reduction in blood pressure at night (the so-called 'extreme dippers' and 'dippers'), whereas others exhibit only a slight night time reduction in systolic and diastolic pressure ('non-dippers' and 'inverted dippers'). Longitudinal studies of these patients show that inverted dippers and non-dippers die at a faster rate than do dippers and extreme dippers. The chronic administration of melatonin to individuals with hypertension induces a measurable drop in night time systolic and diastolic blood pressure. Moreover, the higher the night time level of endogenous melatonin (estimated from urinary metabolite of melatonin, 6-hydroxymelatonin sulphate), the greater the reduction in arterial blood pressure at night. The implication of these findings is that melatonin may have utility as an antihypertensive agent.

The 5-Hydroxytryptamine1A Receptor Agonist, (+)-8-Hydroxy-2-(di-n-propylamino)-tetralin, Increases Cardiac Output and Renal Perfusion in Rats Subjected to Hypovolemic Shock

The 5-hydroxytryptamine(1A) receptor agonist, (+)-8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), raises blood pressure (BP) and venous tone in rats subjected to hemorrhagic shock. Here, BP, ascending aortic blood flow [i.e., estimate of cardiac output (CO)] and venous blood gases were measured to determine the hemodynamic effects of 8-OH-DPAT (30 nmol/kg i.v., n = 10), saline (n = 10), or an equipressor infusion of epinephrine (n = 10) in unanesthetized rats subjected to hemorrhagic shock (25 min of hypotensive hemorrhage, approximately 50 mm Hg). Renal and iliac blood flow were measured in separate groups of similarly hemorrhaged rats given the same dose of 8-OH-DPAT (n = 7) or saline (n = 6). Compared with saline treatment, 8-OH-DPAT produced a sustained rise in BP (+32 +/- 4 versus +9 +/- 2 mm Hg, 15 min after injection, P < 0.01) and CO (+27 +/- 5 versus +4 +/- 6 ml/min/kg, P < 0.01) but did not affect total peripheral resistance (TPR). Infusion of epinephrine reduced CO (-12 +/- 6 ml/min/kg, P < 0.01) and dramatically increased TPR [+0.37 +/- 0.11 versus +0.05 +/- 0.05 log (mm Hg/ml/min/kg), P < 0.01]. 8-OH-DPAT increased renal conductance (+7 +/- 1 versus +4 +/- 1 microl/min/mm Hg, P < 0.01) but did not significantly affect iliac conductance. 8-OH-DPAT attenuated further development of acidosis compared with either saline or epinephrine (-5.6 +/- 1.6 versus -13.0 +/- 2.0 versus -11.3 +/- 2.6 mmol/liter base excess 45 min after start of hemorrhage, both P < 0.01 versus 8-OH-DPAT). These data demonstrate that 8-OH-DPAT improves hemodynamics during circulatory shock, in part, through renal vasodilation and mobilizing of blood stores.

The Serotonin 5-Hydroxytryptaphan1A Receptor Agonist, (+)8-Hydroxy-2-(di-n-propylamino)-tetralin, Stimulates Sympathetic-Dependent Increases in Venous Tone during Hypovolemic Shock

Adjuvant treatment of hypovolemic shock with vasoconstrictors is controversial due to their propensity to raise arterial resistance and exacerbate ischemia. A more advantageous therapeutic approach would use agents that also promote venoconstriction to augment perfusion pressure through increased venous return. Recent studies indicate that 5-hydroxytryptophan (5-HT)(1A) receptor agonists increase blood pressure by stimulating sympathetic drive when administered after acute hypotensive hemorrhage. Given that venous tone is highly dependent upon sympathetic activation of alpha(2)-adrenergic receptors, we hypothesized that the 5-HT(1A) receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), would increase venous tone in rats subject to hypovolemic shock through sympathetic activation of alpha(2)-adrenergic receptors. Systemic administration of 8-OH-DPAT produced a sustained rise in blood pressure (+44 +/- 3 mm Hg 35 min after injection, P < 0.01 versus saline) and mean circulatory filling pressure (+4.2 +/- 0.7 mm Hg, P < 0.01 versus saline) in conscious rats subjected to hypovolemic shock. An equipressor infusion of epinephrine failed to influence mean circulatory filling pressure (MCFP). Ganglionic blockade, alpha(1)-, or peripheral alpha(2)-adrenergic receptor blockade prevented the rise in MCFP observed with 8-OH-DPAT, but only alpha(1)-adrenergic receptor blockade diminished the pressor effect of the drug (P < 0.01). 8-OH-DPAT raises blood pressure in rats in hypovolemic shock through both direct vascular activation and sympathetic activation of alpha(1)-adrenergic receptors. The sympathoexcitatory effect of 8-OH-DPAT contributes to elevated venous tone through concurrent activation of both alpha(1)- and alpha(2)-adrenergic receptors. The data suggest that 5-HT(1A) receptor agonists may provide an advantageous alternative to currently therapeutic interventions used to raise perfusion pressure in hypovolemic shock.

Found in translation: neural feedback from exercising muscles

Found in translation: neural feedback from exercising muscles

Symposium

Symposium

Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep.

Cerebral hypothermia has been shown to reduce damage from experimental hy-poxia-ischemia if started shortly after reperfusion. However, in the newborn infant it may not be feasible to determine prognosis so soon after exposure to asphyxia. The aim of this study was to determine whether head cooling, delayed until shortly before the onset of postasphyxial seizure activity, is neuroprotective. Unanesthetized near-term fetal sheep in utero were subjected to 30 minutes of cerebral ischemia. Later, at 5.5 hours, they were randomized to either cooling (n = 7) or sham cooling (n = 10) for 72 hours. Intrauterine cooling was induced by circulating cold water through a coil around the fetal head. The water temperature was titrated to reduce fetal extradural temperature from 39.1 +/- 0.1 degreesC to between 30 degreesC and 33 degreesC, while maintaining esophageal temperature >37 degreesC. Cerebral cooling suppressed the secondary rise in cortical impedance (a measure of cytotoxic edema), but did not prevent delayed seizures, 8 to 30 hours after ischemia. Transient metabolic changes including increased plasma lactate and glucose levels were seen with a moderate sustained rise in blood pressure. This severe cerebral insult resulted in depressed residual parietal electroencephalographic activity after 5 days recovery (-14.2 +/- 1.5 decibels), associated with a watershed distribution of neuronal loss (eg, 94 +/- 4% in parasagittal cortex and 77 +/- 4% in the lateral cortex). Hypothermia was associated with better recovery of electroencephalographic activity (-8.9% +/- 1.8 decibels) and substantially reduced neuronal loss in the parasagittal cortex (46 +/- 13%), the lateral cortex (9 +/- 4%), and other regions except the cornu ammonis sectors 1 and 2 of the hippocampus. Delayed selective head cooling begun before the onset of postischemic seizures and continued for 3 days may have potential to significantly improve the outcome of moderate to severe hypoxic-ischemic encephalopathy.

Cardiorespiratory and Neuromuscular Effects of Freshwater Cyanophyte Anabena flosaquae in Rats

Anatoxin-a, recognised as a potent toxin warfare agent, is considered as a weapon of mass destruction due to its lethal anticholinesterase activity. The intravenous administration of cell-free extract of Anabena flosaquae UTEX-2383(anatoxin-a) produced a transient vasodepressor response followed by a sustained rise in blood pressure. The vasodepressor effect was potentiated by physostigmine and antagonised by atropine and bilateral vagotomy, suggesting the involvement of cholinergic system. On the contrary, the vasopressor response was antagonised by hexamethonium prazosin and hemicholinium-3, indicating that the toxin stimulates the sympathetic system through the release of catecholamines from nerve endings. Prolonged apnoea with attendant bronchoconstriction was observed corresponding to bradycardia and vasppressor response which remained unaltered by atropine while antagonised by bilateral vagotomy. The extract when administered intra-arterially did not modify the apnoea induced by veratridine; but phenyldiguanide potentiated the bronchoconstriction, indicating the involvement of pulmonary vagal afferents. The extract produced a dose- and time-dependent blockade of indirect muscle twitch recorded from gastrocnemius muscle. The neuromuscular blockade was potentiated by neostigmine but unaltered by DTC.

976-12 Reduced Reflex Vagal Activity in Patients with AV Nodal Reentrant Tachycardia Compared to Patients with Atrioventricular Reentrant Tachycardia

Decreased heart rate variability, a manifestation of reduced tonic vagal activity. has been reported following radiofrequency catheter ablation (RFCA) for AV nodal reentrant tachycardia (AVNRT). Disruption of parasympathetic fibers in the posteroseptal region is the proposed mechanism. Baroreflex sensitivity (BRS). an index of reflex vagal activity. has not been evaluated in patients with AVNRT. We studied BRS prior to and immediately following RFCA in 20 patients with AVNRT(age 13–65 years, mean 42; 15 females. 5 males). Fourteen patients with atrioventricular reentrant tachycardia (AVRT) and free wall accessory pathways (age 14–46 years. mean 25; 6 females. 8 males) were evaluated as controls (RFCA site far from posteroseptal region I. BRS (msec/mmHg) was assessed with continuous femoral artery blood pressure (BP) and ECG recordings during the bolus administration of phenylephrine (400 μg). BRS was calculated as the slope of the change in cycle length vs the change in systolic BP during the first sustained rise in BP. At baseline. prior to RFCA. mean BRS for patients with AVNRT was significantly less than for patients with AVRT (8.3 ± 5.9 vs 22.1 ± 10.3; P &lt; 0.0002). This difference remained significant when controlled for age (p &lt; 0.0002) and male gender (p &lt; 0.0003). but not for female gender (p &lt; 0.09). Following RFCA there was no significant change in BRS for patients with AVNRT (9.3 ± 7.6) or AVRT (17.3 ± 9.6) compared to pre-RFCA values. This comparison remained insignificant when controlled for age or gender. These results suggest that in the baseline state, patients with AVNRT have lower reflex vagal activity than patients with AVRT. Reduced reflex vagal activity may contribute to the development of sustained AVNRT in patients with dual AV nodal physiology. RFCA did not alter BRS in either patient group.

Inhibitory actions of diphenyleneiodonium on endothelium-dependent vasodilatations in vitro and in vivo.

1. This study examined the in vitro and in vivo inhibitory effects of diphenyleneiodonium (DPI), a novel inhibitor of nitric oxide (NO) synthase, on endothelium-dependent vasodilatations. 2. DPI (3 x 10(-8)-3 x 10(-6) M) concentration-dependently inhibited acetylcholine (ACh)-induced relaxation in preconstricted rat thoracic aortic rings, with an IC50 of 1.8 x 10(-7) M and a maximal inhibition of nearly 100%. DPI (3 x 10(-6) M) also completely inhibited the relaxation induced by the calcium ionophore, A23187 but not by sodium nitroprusside (SNP). The inhibitory effect of DPI (3 x 10(-7) M) on ACh-induced relaxation was prevented by pretreatment with NADPH (5 x 10(-3) M) and FAD (5 x 10(-4) M) but not L-arginine (L-Arg, 2 x 10(-3) M). Pretreatment with NADPH did not alter the inhibitory effect of NG-nitro-L-arginine on ACh-induced relaxation. 3. The inhibitory effect of DPI on ACh-induced relaxation in the aortae lasted > 4 h after washout. In contrast to pretreatment, post-treatment (1 h later) with NADPH (5 x 10(-3) M) reversed only slightly the inhibitory effect of DPI. 4. In conscious rats, DPI (10(-5) mol kg-1) inhibited the depressor response to i.v. infused ACh, but not SNP. However, it caused only a transient pressor response which was previously shown to be due completely to sympathetic activation. 5. Thus, DPI is an efficacious and 'irreversible' inhibitor of endothelium-dependent vasodilatation in vivo and in vitro. The mechanism of the inhibition may involve antagonism of the effects of FAD and NADPH, co-factors of NO synthase. However, unlike the N0-substituted arginine analogues (another class of NO synthase inhibitors), DPI-induced suppression of endothelium-dependent vasodilatation in vivo does not lead to a sustained rise in blood pressure.

Pressor effects following microinjection of 5‐HT1A receptor agonists into the raphe obscurus of the anaesthetized rat

1. The effects of electrical stimulation and microinjections (90 nl) of the 5-HT1A receptor agonists, flesinoxan and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), and glutamate into the raphe obscurus on blood pressure, heart rate and phrenic nerve activity (central inspiratory drive) were investigated in rats anaesthetized with alpha-chloralose. 2. Electrical stimulation of the raphe obscurus caused a rise in blood pressure which was associated with bradycardia, while glutamate (2.7 nmol) caused only a rise in blood pressure. 3. Flesinoxan (1.3 nmol) and 8-OH-DPAT (0.7 nmol) increased blood pressure by 9 +/- 1 and 14 +/- 2 mmHg, respectively and did not affect heart rate. For both agonists the effect on blood pressure was shown to be dose-dependent; again no effect on the heart rate was observed over the dose-ranges chosen. 4. Microinjections of the non-selective 5-HT1A receptor antagonists, (+/-)-pindolol (2.7 nmol) or methiothepin (5.2 nmol), into the raphe obscurus prevented the increase in blood pressure caused by microinjection of flesinoxan. However, (+/-)-pindolol caused a sustained rise in blood pressure of 15 +/- 1 mmHg while methiothepin caused a transient rise in blood pressure. Neither drugs affected heart rate. The ability of methiothepin to attenuate the pressor effect of flesinoxan was found to be partially reversed after 30 min. 5. It is suggested that activation of 5-HT1A receptors within the raphe obscurus can cause sympatho-excitation.

Angiotensin II

The consequence of a sustained rise in blood pressure is an adaptive change in the structure of the heart and the vasculature. In humans, the left ventricle, aorta, and medium-sized arteries undergo hypertrophy whereas the changes in resistance vessels are unclear at present. Recent studies suggest that left ventricular hypertrophy is a better predictor of stroke or cardiac risk than age or blood pressure. Therefore, the cellular mechanisms that bring about these structural alterations to the circulation in hypertension are the subject of intense research at this time. The main factor was assumed to be the pressure load imposed on the wall of the left ventricle and the arteries. However, recent work has suggested that pressor hormones can act as growth factors in vascular tissues by pressure-independent actions. This article examines the cellular mechanisms activated by angiotensin II that could be involved in producing growth and the evidence available that this nonpressor role is important in vitro and in vivo.

Endothelial derived relaxing factor controls renal hemodynamics in the normal rat kidney.

These studies were conducted in the conscious, chronically catheterized rat to determine whether the endothelial derived relaxing factor (EDRF) controls renal function in the normal state. Administration of the EDRF synthesis inhibitors N-monomethyl-L-arginine (NMA; 100 mg/kg body weight) or N-nitro-L-arginine methylester (NAME; 10 mg/kg body wt) led to a large, sustained rise in blood pressure, a large rise in renal vascular resistance, a fall in renal plasma flow, a relatively slight reduction in glomerular filtration rate, and a consequent rise in filtration fraction. In addition, a marked natriuresis occurred because of a reduction in the fractional reabsorption of sodium. In separate studies, a continuous infusion of excess L-arginine (300 mg/kg body wt bolus followed by 50 mg/kg body wt per min) attenuated the NMA- or NAME-induced rise in blood pressure and reversed the renal hemodynamic effects such that a significant rise in renal plasma flow was seen. L-Arginine alone produced a selective renal vasodilation and large increases in sodium excretion. These observations support earlier suggestions that tonic release of EDRF controls the basal blood pressure and also show that renal function in the normal unstressed rat is markedly influenced by EDRF. These studies suggest that, in addition to controlling renal plasma flow, EDRF may have other, complex actions at the glomerulus. The natriuresis seen after acute inhibition of EDRF with NMA or NAME was probably the result of a pressure natriuretic response to the abrupt rise in blood pressure and also, perhaps, reflects removal of an EDRF influence to directly enhance sodium reabsorption somewhere in the nephron.

Kainic acid on the rat ventral medullary surface depresses hypoxic and hypercapnic ventilatory responses

Kainic acid, topically applied to the ventral surface of the medulla immediately caudal to the trapezoid body in the urethane/chloralose anaesthetised rat, led to a depression of ventilation and a sustained rise in blood pressure; ventilatory responses to hypercapnia (10% carbon dioxide) and hypoxia (11% oxygen) were slightly depressed. Widespread application of kainic acid to an area at and slightly rostral to the rootlets of the hypoglossal nerve produced a stimulation of ventilation and an unsustained rise in blood pressure. Apnea ensued 12–28 min after application. Ventilatory responses to hypercapnia and hypoxia were markedly attenuated; more discrete bilateral application revealed two regions, one immediately rostral and lateral to the hypoglossal rootlets and the other over the point of exit of the hypoglossal nerve rootlets, which specifically contributed to the diminution of the chemosensory responses. These results raise questions about the medullary circuitry which mediates the chemoreflex regulation of breathing.

Pharmacological activity of N-methyl-carbamylcholine, a novel acetylcholine receptor agonist with selectivity for nicotinic receptors

N-Methyl-carbamylcholine (also called N-methyl-carbachol) is an analogue of the mixed muscarinic-nicotinic acetylcholine receptor agonist, carbachol. Previous studies have provided evidence that radiolabelled N-methyl-carbachol can bind selectively to nicotinic acetylcholine receptors in rat brain. To determine whether N-methyl-carbachol acts as an agonist or an antagonist at nicotinic and/or muscarinic receptor sites, the present study examined the pharmacological activity of this compound on some cholinergically innervated tissues. N-Methyl-carbachol, like carbachol, depolarized rat isolated sympathetic ganglia and these effects were inhibited by a nicotinic antagonist, d-tubocurarine, but not by a muscarinic antagonist, atropine. Exposure of rat sympathetic ganglia to N-methyl-carbachol blocked the compound action potential generated in ganglia by stimulation of the pre-ganglionic trunk; this effect of N-methyl-carbachol was likely due to desensitization of the nicotinic response. N-Methyl-carbachol, like carbachol, stimulated the release of [ 3H]noradrenaline from cultured adrenal medullary cells that had been pre-loaded with [ 3H]noradrenaline; these effects were largely inhibited by a nicotinic antagonist, mecamylamine, while atropine produced less blockade. N-Methyl-carbachol contracted the frog isolated rectus abdominis muscle and the effect was completely blocked by d-tubocurarine. By contrast, contracture of the rectus abdominis produced by carbachol was partially inhibited by either atropine or d-tubocurarine. N-Methyl-carbachol, like carbachol, contracted the rat isolated ileum and these effects were completely blocked by atropine; however, N-methyl-carbachol was about 42 times less potent than carbachol for this effect. Intravenous injection of N-methyl-carbachol, like nicotine, to the rat produced a transient decrease followed by a more sustained rise in blood pressure while carbachol produced only a sustained decrease in blood pressure. The effects of N-methyl-carbachol and nicotine on blood pressure were blocked by pretreatment of the animal with a nicotinic antagonist, hexamethonium. N-Methyl-carbachol, like nicotine, stimulated the release of [ 3H]dopamine from rat striatal synaptosomes, pre-loaded with [ 3H]dopamine; release induced by either N-methyl-carbachol or nicotine was inhibited by mecamylamine but not by atropine. In rat cerebral cortical slices pre-loaded with [ 3H]inositol, carbachol, but not N-methyl-carbachol, stimulated the accumulation of [ 3H]inositol-1-phosphate, an effect blocked by atropine but not by mecamylamine. Behavioural effects of intracerebroventricular administration of N-methyl-carbachol to rats included reversible hind-limb splaying, impaired gait, respiratory depression and hypoactivity at early times after drug injection; these effects were blocked by pretreatment of animals with mecamylamine but were unaffected by pretreatment with a muscarinic antagonist, scopolamine. Thus the overall profile of activity indicates that N-methyl-carbachol is a relatively selective agonist acting at nicotinic acetylcholine receptors. These results suggest that the structures of muscarinic and nicotinic receptors may differ in the regions which recognize the amino terminal end of compounds such as carbachol or N-methyl-carbachol.

Effect of lower body positive pressure on blood pressure, plasma atrial natriuretic factor concentration, and sodium and water excretion in healthy volunteers and cardiac transplant recipients.

The effect of one hour (40 mmHg) lower body positive pressure on blood pressure, plasma atrial natriuretic factor concentration, and urinary sodium and water excretion was studied in 10 healthy volunteers and seven cardiac transplant recipients. Both groups showed a sustained rise in blood pressure and plasma atrial natriuretic factor concentration. The healthy volunteers had a diuresis during the period of lower body positive pressure and a small natriuresis in the subsequent hour. In contrast, lower body positive pressure had no significant effect on urinary sodium and water excretion in the cardiac transplant group. The data suggest that cardiac innervation is not important as a mediator of the haemodynamic response to lower body positive pressure but is necessary for the renal response. Furthermore, small physiological rises in plasma atrial natriuretic factor concentrations do not cause a brisk natriuresis as has been reported with pharmacological plasma concentrations.

Mechanism of action of the anti-shock effect of CCK-8: influence of CCK antagonists and of sympatholytic drugs.

In an experimental model of haemorrhagic shock that causes 100% mortality in rats within 30 min, the intravenous bolus injection (20 micrograms/kg) of sulfated cholecystokinin octapeptide (CCK-8) induces a prompt and sustained rise in blood pressure and pulse amplitude, all treated animals still surviving at the end of the experiment (2 h). This effect of CCK-8 is completely blocked by reserpine (5 mg/kg i.p.), significantly antagonized by prazosin (0.1 mg/kg i.v.) and yohimbine (1 mg/kg i.v.), and unaffected by practolol (15 mg/kg i.v.) and proglumide (0.2 mg/kg i.v.); it is completely antagonized by the intravenous (0.01-0.05 mg/kg), but not by the intracerebroventricular (0.002 mg/kg) injection of the 'peripheral' CCK antagonist, L-364,718. The present data indicate that the cardiovascular effects of CCK-8 in haemorrhagic shock involve peripheral CCK receptors, and require the functional integrity of the sympathetic nervous system.

Interactive roles of monovalent and divalent cations in pathogenesis of hypertension caused by alcohol.

Subjects whose daily alcohol intake varied from less than 22 g to over 88 g were studied. They differed in their mean systolic and diastolic blood pressures compared with those of controls who were teetotallers. The association between alcohol consumption and blood pressure was independent of age. Ex-alcohol users who were much older than current alcohol users had lower systolic and diastolic blood pressures. The association of body mass index with sustained raised blood pressure was apparent. When body mass index was eliminated as a variable there was an appreciable residual effect on mean arterial pressure. Alcohol users and controls did not differ in mean plasma sodium concentration. Red blood cell intracellular sodium concentration, however, was higher in beer drinkers than in controls. On the other hand, red blood cell intracellular concentration of magnesium in beer drinkers was decreased. It is suggested that definite interactions between sodium, magnesium, and calcium ions may have some vital roles in the sustained rise in blood pressure in alcohol users.