Decrease In Peripheral Vascular Resistance Research Articles

Neurocardiogenic Syncope and Related Disorders of Orthostatic Intolerance

Received September 14, 2004; revision received January 31, 2005; accepted March 9, 2005. “We shall not cease from exploration and the end of all our exploring will be to arrive where we started and know the place for the first time” — —T.S. Eliot, Four Quartets Syncope, defined as transient loss of consciousness and postural tone with spontaneous recovery, has both challenged and perplexed physicians since the dawn of recorded time. The earliest written accounts come from Hippocrates, and the word syncope itself is derived from an old Greek term meaning “to cut short” or “interrupt.” Recurrent episodes of syncope may result from a large number of different disorders, all of which cause a transitory reduction in cerebral blood flow sufficient to disturb the normal functions of the brain. Over the last 2 decades, considerable attention has been given to types of syncope that occur due to a centrally mediated (or “reflex”) fall in systemic blood pressure, a condition that has been referred to as vasovagal (and later neurocardiogenic) syncope. However, research into the nature of this disorder revealed that it is but one aspect of a broad and varied group of disturbances in the normal functioning of the autonomic nervous system (ANS), each of which may result in orthostatic intolerance, hypotension, and ultimately syncope. Continued investigations into the nature of these similar yet different disorders has led to the development of a system of classification that attempts to more accurately reflect our understanding of these conditions and their interrelationships.1 The present system of classification has proven both functional and clinically relevant and includes a group of disorders that most investigators have thought to be principally autonomic in nature. Because both the cardiologist and the cardiac electrophysiologist frequently are expected to both diagnose and treat these conditions, the following …

The development of haemodynamics in the extracranial cerebral arteries of healthy preterm and term neonates

To investigate the development of cerebral haemodynamics in healthy preterm and term newborns, a prospective colour duplex sonography study was performed in 113 neonates at 32 to 42 weeks of postmenstrual age. In the extracranial internal carotid arteries (ICAs) and vertebral arteries (VAs), luminal diameters and angle-corrected flow velocities were measured. Flow volumes and waveform parameters were calculated. There were no side-to-side or gender-related differences for any of the parameters measured. A marked increase of luminal diameters, end-diastolic and time-averaged flow velocities and flow volumes with postmenstrual age was found in both ICA and VA ( p ≤ 0.0001). Peak systolic velocity did not vary with age, thus, leading to a significant decrease of the resistance and pulsatility indices with rising postmenstrual age. Reference data for flow velocities, waveform parameters, luminal diameters and flow volumes of both ICA and VA are provided for different groups of postmenstrual age. In conclusion, the marked increase in cerebral blood flow volume with postmenstrual age is due to a rise in the luminal diameter of extracranial cerebral arteries and a decrease in peripheral vascular resistance. (E-mail: martin.schoening@med.uni-tuebingen.de)

Congenital Heart Diseases With Right-to-Left Shunts

Tetralogy of Fallot comprises a constellation of cardiac findings that share the following common anatomic abnormalities (Fig. 1): a large malaligned ventricular septal defect (VSD), overriding of the aorta over the septal defect, right ventricular outflow obstruction, and right ventricular hypertrophy. The anatomic spectrum of TOF is diverse and includes other variants such as pulmonary stenosis (TOF-PS), pulmonary atresia (TOF-PA), or absent pulmonary valve (TOF-APV). The pathophysiology of TOF depends, primarily, on the degree of right ventricular outflow tract obstruction (RVOTO) and, secondarily, on the status of the systemic vascular resistance relative to the degree of right ventricular obstruction. The patients can be fully saturated or severely cyanotic depending on the ratio of pulmonary to systemic blood flow. In a Tetralogy spell (tet spell), or hypoxic spell, the infants experience episodes of severe hypoxemia and acidemia. The responsible factors may be increase in RVOTO and increase in oxygen requirement, decrease in peripheral vascular resistance, contraction of the right ventricular infundibulum, closure of the ductus arteriosus, or development of physiologic anemia.

A postmarketing, open-label study to evaluate the tolerability and effectiveness of replacing standard-formulation doxazosin with doxazosin in the gastrointestinal therapeutic system formulation in adult patients with hypertension

Background: The antihypertensive doxazosin works to decrease perivascular muscular tone, causing vasodilatation and hence a decrease in peripheral vascular resistance. To prevent the sharp decrease in blood pressure (BP), syncope, and other postural effects that may occur at the beginning of therapy with this drug, the dose must be adjusted. A new formulation, doxazosin gastrointestinal therapeutic system (GITS), allows slow release of the active agent so therapeutic serum levels are reached within 24 hours, rendering dose adjustment unnecessary and eliminating any first-dose effects.Objectives: The goals of this study were to evaluate the tolerability and effectiveness of (1) using doxazosin in the standard and new GITS formulations in adult patients with hypertension who either had uncontrolled or newly diagnosed disease, and (2) replacing standard-formulation doxazosin with doxazosin in the GITS formulation.Methods: This was a postmarketing, open-label, noncomparative, multicenter clinical study covering primary care patients diagnosed with essential uncontrolled arterial hypertension (AHT). Subjects could be patients who were undergoing drug therapy before enrollment or those diagnosed with AHT and/or treated for the disease for the first time on entering the study. The study covered a period of 6 to 9 months, divided into 2 phases. Phase 1 involved a minimum of 3 and maximum of 6 months of treatment with standard-formulation doxazosin. Phase 2 commenced with the changeover from standard-formulation doxazosin to the GITS formulation and lasted 12 weeks. The principal study variables included BP and the development of adverse events (AEs). At every visit, the patients were asked by an investigator whether they had suffered any AEs since the previous contact.Results: Of the total of 4512 patients initially enrolled, 3537 (78.4%) completed the study. A total of 285 patients were excluded for failing to comply with the inclusion criteria, leaving 4227 patients for analysis. In most instances, premature withdrawal from the study (16.3% [690/4227]) was due to loss to follow-up (37.2% [257/690]), followed by the development of AEs (27.8% [192/690]). Fifty-nine percent (2493/ 4226) of patients analyzed were men and 41.0% (1733/4226) were women (sex data not recorded for 1 patient), with a mean age of 62.4 years (SD, 10.6). Among the patients participating, 54.8% (2316/4227) presented with some type of associated disease. The percentage of patients undergoing monotherapy was 70.7% (2987/4227); the remainder (29.3% [1240/4227]) underwent a combined-therapy regimen using another antihypertensive drug in conjunction with doxazosin. The mean initial systolic and diastolic BPs were 160 ± 10.63 mm Hg and 95.26 ± 7.21 mm Hg, respectively. Reduction in systolic BP was 20.9 mm Hg in phase 1 and 3.8 mm Hg in phase 2. In the case of diastolic BP, the reduction was 13.3 mm Hg in phase 1 and 2.6 mm Hg in phase 2. The percentage of patients with controlled disease was 47.9% (1891/3949) by the end of phase 1 and 63.4% (2242/3537) by the end of phase 2. A total of 322 (7.6%) patients presented with 343 AEs, 37 (0.9%) of which were deemed severe (0.6% in phase 1 and 0.3% in phase 2). Limitations included the following: (1) the design of this study did not allow comparison of the 2 formulations regarding effectiveness or tolerability; (2) the patients who remained in the study after phase 1 were those less susceptible to toxicity from doxazosin; and (3) it is probable that the nonresponders were more likely to drop out of the study.Conclusions: Doxazosin in the standard formulation was effective and well tolerated for the purpose of lowering BP. Patients who tolerated the standard formulation also tolerated the switch to the GITS formulation. Finally, this substitution did not negatively impact the effectiveness of treatment of AHT.

INCREASED NO-MEDIATED AND REDUCED TxA2-DEPENDENT RESPONSES IN SKELETAL MUSCLE ARTERIOLES IN PREGNANCY

The contribution of skeletal muscle microvessels to pregnancy-induced decrease in peripheral vascular resistance and its underlying mechanisms are not fully understood. We aimed to test the hypothesis that pregnancy enhances arteriolar dilation and reduces constriction by increasing NO-mediation and decreasing reactivity to TxA2. Thus, changes in diameter of isolated, pressurized gracilis muscle arterioles (d: ∼180 μm) of non-pregnant (NP) and pregnant (P) rabbits to vasoactive agents were measured by videomicroscopy. Acetylcholine (ACh) elicited significantly greater dilations in P than in NP arterioles that could be inhibited by l-NAME, a NO synthase blocker. Dilations to the NO donor SNP did not differ between P and NP arterioles. Constrictions to norepinephrine and the TxA2 receptor agonist U46619 were significantly attenuated in P as compared to NP arterioles. l-NAME increased norepinephrine-induced arteriolar constrictions eliminating the difference between responses of NP and P arterioles. l-NAME enhanced constrictions to U46619 in P and NP arterioles, but the constrictions were still greater in NP vessels. The number of vascular TxA2 receptors—characterized by the TxA2 analog [125I]-BOP in aortic membrane preparations—was significantly less in P as compared to NP rabbits (NP: 284±83, P: 62±14 fmol/mg protein, p<0.01). Thus, pregnancy up-regulates endothelial NO- and down regulates TxA2-mediation of responses of skeletal muscle arterioles. These changes in the local regulation of microvascular tone are likely to favor a dilated state of skeletal muscle arterioles, which may contribute to the decreased peripheral vascular resistance during normal pregnancy.

The Influence of Inhaled Nitric Oxide on Cerebral Blood Flow and Metabolism in a Child with Traumatic Brain Injury

The Influence of Inhaled Nitric Oxide on Cerebral Blood Flow and Metabolism in a Child with Traumatic Brain Injury

Pharmacological evidence for the activation of potassium channels as the mechanism involved in the hypotensive and vasorelaxant effect of dioclein in rat small resistance arteries.

The hypotensive and vasorelaxant effect of dioclein in resistance mesenteric arteries was studied in intact animals and isolated vessels, respectively. In intact animals, initial bolus administration of dioclein (2.5 mg kg(-1)) produced transient hypotension accompanied by an increase in heart rate. Subsequent doses of dioclein (5 and 10 mg kg(-1)) produced hypotensive responses with no significant change in heart rate. N(G)-nitro-L-arginine methyl ester (L-NAME) did not affect the hypotensive response. In endothelium-containing or -denuded vessels pre-contracted with phenylephrine, dioclein (5 and 10 mg kg(-1) produced a concentration-dependent vasorelaxation (IC(50)=0.3+/-0.06 and 1.6+/-0.6 microM, respectively) which was not changed by 10 microM indomethacin. L-NAME (300 microM) produced a shift to the right. Dioclein was without effect on contraction of vessels induced by physiological salt solution (PSS) containing 50 mM KCl and the concentration dependence of dioclein's effect on phenylephrine induced contraction was shifted to the right in vessels bathed in PSS containing 25 mM KCl. Tetraethylammonium (10 mM) and BaCl(2) (1 mM) increased the IC(50) for dioclein-induced vasorelaxation without affecting the maximal response (E(max)). Charybdotoxin (100 nM), 4-aminopyridine (1 mM) and iberiotoxin (100 nM) increased the IC(50) and reduced the E(max). Apamin (1 microM) reduced the E(max) without affecting the IC(50). Dioclein produced a hyperpolarization in smooth muscle of mesenteric arteries with or without endothelium (7.7+/-1.4 mV and 12.3+/-3.6 mV, respectively). In conclusion dioclein lowered arterial pressure probably through a decrease in peripheral vascular resistance. The underling mechanism implicated in the vasorelaxant effect of dioclein appears to be the opening of K(Ca) and Kv channels and subsequent membrane hyperpolarization.

Iliac Arteriovenous Fistula With Renal Insufficiency, Ascites, Hepatomegaly, and Abnormal Liver Test Results

Iliac Arteriovenous Fistula With Renal Insufficiency, Ascites, Hepatomegaly, and Abnormal Liver Test Results

NO donors for the regulation and treatment of preeclampsia diseases

Endothelially derived nitric oxide (NO) regulates vasodilatation via relaxation of the smooth muscle cells and inhibits platelet aggregation in addition to a number of other biological processes. Animal experiments have provided evidence for increased NO production in the normal pregnancy. This contributes to the decrease in peripheral vascular resistance and to the increased glomerular filtration rate. Inhibition of NO synthesis is associated with a preeclampsia-like syndrome in various animal species. In vivo and in vitro data in the human pregnancy have indicated that NO deficiency contributes to the vasoconstriction seen in preeclampsia. However, due to the short half-life time of NO, pharmacological application is only possible by NO-donating drugs such as glycerol trinitrate (GTN, “nitroglycerine”), isosorbide dinitrate (ISDN), isosorbide mononitrate (ISMN) or S-nitrosoglutathion (GSNO). There is limited experience with the use of NO donors in human pregnancy; yet no teratogenic or embryotoxic effects are reported. According to current knowledge, transdermal application of GTN in pregnancy is safe with only minor effects on maternal blood pressure and without compromising the uteroplacental perfusion in patients with preeclampsia. Up to now only one prospective randomized trial has been conducted on the prophylaxis of preeclampsia by NO donors in women at high risk for development of the disease. However, the sample size of this study was too small to allow final conclusions. There are no randomized trials on the therapy of preeclampsia by NO donors reported in the literature. Therefore, it is that the use of NO donors be evaluated in the prophylaxis and therapy of preeclampsia only recommended in the context of clinical trials.

Differential Expression of Inducible Nitric Oxide Synthase in Septic Shock

During cardiopulmonary bypass (CPB), the septic patient has markedly decreased peripheral vascular resistance as a consequence of endotoxin release from microorganisms. This decrease in peripheral vascular resistance is the result of endotoxin-induced nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS). iNOS and eNOS are responsible for the synthesis of NO because of various stimuli, including the bacterial endotoxin, lipopolysaccharide (LPS). We tested the hypothesis that a differential expression of iNOS among human endothelial cells and murine macrophage is dependent upon exposure to endotoxin and various pro-inflammatory cytokines. Using a human endothelial cell line, ECV-304 and murine macrophage cell line, RAW 264.7, we quantified the expression of iNOS with specific FITC-conjugated antibodies using fluorescence activated cell sorter (FACS) and NO production with a Bioxytech nitric oxide spectrophotometric assay. This in vitro septic model utilized LPS supported with species-specific interferon-γ, interleukin-1β, and tumor necrosis factor-α. The cell types were stimulated for 8 hours with combinations of the cytokines mentioned. The FACS data demonstrated a significant stimulus-dependent increase in iNOS expression among the macrophage groups; however, the stimulated endothelial cells showed no significant change in iNOS expression. The nitric oxide production data demonstrated significant increases in NO production among macrophage stimulated groups; whereas, endothelial stimulated groups exhibit no significant change. We conclude that NO secreted during septic shock is the result of activated macrophage, not the endothelium. The clinical relevance is that the more severe the infectious process, the lower the PVR may be during CPB because of increased NO production from activated macrophage.

Cardiovascular adaptation to pregnancy: the role of altered vascular structure

The cardiovascular system undergoes remarkable adaptive changes in pregnancy. Through a complex network of interrelated pathways the physiological response to the conceptus ensures an adequate blood supply and oxygen gradient to meet the demands of the feto-placental unit whilst maintaining normal maternal blood pressure. This is achievable because the increase in maternal cardiac output and blood volume which characterise normal pregnancy occur with an associated and profound decrease in peripheral vascular resistance. Longitudinal studies using Doppler ultrasound and echocardiography indicate that the decline in peripheral vascular resistance occurs very early and data from the pregnant baboon and pregnant women suggest that this is the stimulus which activates the renin-angiotensin aldosterone axis and the resultant rise in plasma volume.

Sudden death: mechanisms of resistance under acute emotional stress in rats and rabbits

Sudden death was shown to be, for some individuals, a typical outcome of conflict situations producing emotional stress. Animal populations, judging by their responses to standard conflict situations, can be subdivided into two distinct groups of individuals predisposed or resistant to sudden death under emotional stress. Arterial hypertension, hypotension, and heart failure are the reactions typical of the stress-sensitive animals. The main cause of sudden death under emotional stress is the abrupt decrease in peripheral vascular resistance. Adrenal hormones are crucial to the mechanisms of sudden death under emotional stress. Midbrain reticular formation is also involved in these mechanisms. Selected behavioral and cardiovascular variables were shown to be of great importance in predicting the animals’ resistance to emotional stress. Analyses showed group differences in the brain contents of norepinephrine, delta-sleep inducing peptide (DSIP), substance P (SP), and, β-endorphin between the rats resistant and predisposed to emotional stress. Resistance of rats to emotional stress considerably increased after administration of SP and DSIP. These data indicate that resistance of animals to sudden death under emotional stress is a result of a complex integration of peptides and neurotransmitters in the brain.

Microvascular endothelial cell control of peripheral vascular resistance during sepsis.

To determine the endothelial-dependent control of decreased peripheral vascular resistance in skeletal muscle microvessels during evolving sepsis. Acute (4 hours, n=7), established (24 hours, n=7), or chronic (72 hours, n=8) infection was induced in Sprague-Dawley rats (150-175 g) by injecting Escherichia coli and Bacteroides fragilis (1 x 10(9) colony-forming units for both) into a subcutaneous sponge. Control animals were injected with an isotonic sodium chloride solution and analyzed at the same time points: (n=6-8 per group). Dilation in response to the topically applied endothelial-dependent agonist acetylcholine (ACH) (1 x 10(-9) to 1 x 10(-5) mol/L) was measured in inflow first-order (A1) and precapillary fourth-order (A4) arterioles in cremaster muscle in vivo with videomicroscopy. Acetylcholine dose-response curves were used to determine vascular reactivity by calculating the concentration of ACH necessary to elicit 50% of the maximal dilator response. In vivo reactivity of striated muscle microvessels to the dilation agonist ACH during acute, established, and chronic infection. A1 vessels were unresponsive to all doses of ACH at all time points. A4 vessels showed an increased dilator response during short-term treatment, which deteriorated over time to depressed dilation during chronic infection. Precapillary A4 vessels have increased dilator reactivity during early sepsis, which progresses to depressed levels with chronic infection. A1 microvessels remain dilated and are not substantially influenced by endothelial dilator mechanisms initiated by ACH. Maximum dilation of the large A1 vessels appears to contribute to the decrease in peripheral vascular resistance noted during systemic infection.

Efficacy of venlafaxine (Efexor®) in patients with bipolar affective disorder. Results of a pharmacoepiderniological investigation in usual psychiatry care setting

Background: The antihypertensive doxazosin works to decrease perivascular muscular tone, causing vasodilatation and hence a decrease in peripheral vascular resistance. To prevent the sharp decrease in blood pressure (BP), syncope, and other postural effects that may occur at the beginning of therapy with this drug, the dose must be adjusted. A new formulation, doxazosin gastrointestinal therapeutic system (GITS), allows slow release of the active agent so therapeutic serum levels are reached within 24 hours, rendering dose adjustment unnecessary and eliminating any first-dose effects.Objectives: The goals of this study were to evaluate the tolerability and effectiveness of (1) using doxazosin in the standard and new GITS formulations in adult patients with hypertension who either had uncontrolled or newly diagnosed disease, and (2) replacing standard-formulation doxazosin with doxazosin in the GITS formulation.Methods: This was a postmarketing, open-label, noncomparative, multicenter clinical study covering primary care patients diagnosed with essential uncontrolled arterial hypertension (AHT). Subjects could be patients who were undergoing drug therapy before enrollment or those diagnosed with AHT and/or treated for the disease for the first time on entering the study. The study covered a period of 6 to 9 months, divided into 2 phases. Phase 1 involved a minimum of 3 and maximum of 6 months of treatment with standard-formulation doxazosin. Phase 2 commenced with the changeover from standard-formulation doxazosin to the GITS formulation and lasted 12 weeks. The principal study variables included BP and the development of adverse events (AEs). At every visit, the patients were asked by an investigator whether they had suffered any AEs since the previous contact.Results: Of the total of 4512 patients initially enrolled, 3537 (78.4%) completed the study. A total of 285 patients were excluded for failing to comply with the inclusion criteria, leaving 4227 patients for analysis. In most instances, premature withdrawal from the study (16.3% [690/4227]) was due to loss to follow-up (37.2% [257/690]), followed by the development of AEs (27.8% [192/690]). Fifty-nine percent (2493/ 4226) of patients analyzed were men and 41.0% (1733/4226) were women (sex data not recorded for 1 patient), with a mean age of 62.4 years (SD, 10.6). Among the patients participating, 54.8% (2316/4227) presented with some type of associated disease. The percentage of patients undergoing monotherapy was 70.7% (2987/4227); the remainder (29.3% [1240/4227]) underwent a combined-therapy regimen using another antihypertensive drug in conjunction with doxazosin. The mean initial systolic and diastolic BPs were 160 ± 10.63 mm Hg and 95.26 ± 7.21 mm Hg, respectively. Reduction in systolic BP was 20.9 mm Hg in phase 1 and 3.8 mm Hg in phase 2. In the case of diastolic BP, the reduction was 13.3 mm Hg in phase 1 and 2.6 mm Hg in phase 2. The percentage of patients with controlled disease was 47.9% (1891/3949) by the end of phase 1 and 63.4% (2242/3537) by the end of phase 2. A total of 322 (7.6%) patients presented with 343 AEs, 37 (0.9%) of which were deemed severe (0.6% in phase 1 and 0.3% in phase 2). Limitations included the following: (1) the design of this study did not allow comparison of the 2 formulations regarding effectiveness or tolerability; (2) the patients who remained in the study after phase 1 were those less susceptible to toxicity from doxazosin; and (3) it is probable that the nonresponders were more likely to drop out of the study.Conclusions: Doxazosin in the standard formulation was effective and well tolerated for the purpose of lowering BP. Patients who tolerated the standard formulation also tolerated the switch to the GITS formulation. Finally, this substitution did not negatively impact the effectiveness of treatment of AHT.

Systemic and renal hemodynamic changes in the luteal phase of the menstrual cycle mimic early pregnancy.

Blood pressure decreases during early pregnancy in association with a decrease in peripheral vascular resistance and increases in renal plasma flow and glomerular filtration rate. These early changes suggest a potential association with corpora lutea function. To determine whether peripheral vasodilation occurs following ovulation, we studied 16 healthy women in the midfollicular and midluteal phases of the menstrual cycle. A significant decrease in mean arterial pressure in the midluteal phase of the cycle (midfollicular of 81.7 +/- 2.0 vs. midluteal of 75.4 +/- 2.3 mmHg, P < 0.005) was found in association with a decrease in systemic vascular resistance and an increase in cardiac output. Renal plasma flow and glomerular filtration rate increased. Plasma renin activity and aldosterone concentration increased significantly in the luteal phase accompanied by a decrease in atrial natriuretic peptide concentration. Serum sodium, chloride, and bicarbonate concentrations and osmolarity also declined significantly in the midluteal phase of the menstrual cycle. Urinary adenosine 3',5'-cyclic monophosphate (cAMP) excretion increased in the luteal compared with the follicular phase, whereas no changes in urinary cGMP or NO2/NO3 excretion were found. Thus peripheral vasodilation occurs in the luteal phase of the normal menstrual cycle in association with an increase in renal plasma flow and filtration. Activation of the renin-angiotensin-aldosterone axis is found in the luteal phase of the menstrual cycle. These changes are accompanied by an increase in urinary cAMP excretion indicating potential vasodilating mediators responsible for the observed hemodynamic changes.

Signalling pathways in bradykinin- and nitric oxide-induced hypotension in the normotensive rat; role of K+-channels.

1. Bradykinin and nitric oxide (NO) are potent hypotensive agents. In the present study, the role of K+-channels in the signalling pathways responsible for their hypotensive action was investigated in normotensive, anaesthetized rats. The rats were treated with ion-channel inhibitors before administration of bradykinin (2.8, 5.6, 28 and 56 nmol kg(-1), i.v.) followed in some of the protocols by nitroprusside (1.1, 3.5, 7, 14, and 28 nmol kg(-1), i.v.). 2. No attenuation of the hypotensive response to bradykinin was detected for inhibitors of the Na-K-Cl-cotransporter (30 micromol kg(-1) furosemide), the ATP-sensitive K+-channel (40 micromol kg(-1) glibenclamide), high conductance Ca2+-activated K+-channel (180 micromol kg(-1) tetraethylammonium, 54 micromol kg(-1) tetrabutylammonium, 35 nmol kg(-1) iberiotoxin, 35 nmol kg(-1) charybdotoxin) or the low conductance Ca2+-activated K+-channel (74 nmol kg(-1) apamin). 3. However, the voltage-sensitive K+-channel (I(A)) inhibitor 4-aminopyridine (4.05-40.5 micromol kg(-1)) induced a concentration-dependent (P<0.0001) attenuation of the hypotensive response (P<0.0001). Bradykinin had no effect on heart rate in anaesthetized rats and this observation was not altered by pretreatment with 4-aminopyridine. 4. 4-Aminopyridine (53 micromol kg(-1)) also significantly attenuated the hypotensive response to nitroprusside (P<0.0003) without altering the heart rate concentration-response curve. Of the two Ca2+-activated K+-channel inhibitors tested on nitroprusside-induced hypotension, tetrabutylammonium induced a slight attenuation (P<0.0101), whereas iberiotoxin had no effect. 5. We therefore concluded that, although the acute hypotensive response to bradykinin in the normotensive rat is not mediated through nitric oxide synthesis, the hypotensive response to both agents was mediated through opening of voltage-sensitive K+-channels (I(A)), resulting in a decrease in peripheral vascular resistance.

Papaverine injection into the hindlimb circulation stimulates ventilation in sheep

To test the hypothesis, previously suggested by Huszczuk et al. (1993), that distention of the peripheral microvascular network could, per se, stimulate ventilation, the ventilatory effects of papaverine-induced muscular vasodilation were studied in ten anaesthetized sheep. Because systemic action of papaverine may involve the arterial baro- and chemoreceptors, the animals were surgically prepared for a reversible isolation of the hindlimb circulation. Papaverine injection (1–2 mg/kg) into the arterial inflow of the isolated limbs provoked a 13 ± 6 sec-delayed increase in V̇ e by 1.8 ± 0.2 L min −1 ( p < 0.01) with a concomitant decrease in peripheral vascular resistance and no decrease in the systemic arterial blood pressure. Identical control injection into a jugular vein prior to the hindlimb circulatory separation yielded an increase of V̇ e by 4.95 ± 0.58 L min −1 with a latency of 21 ± 2 sec and a coinciding moderate decrease of the systemic arterial pressure. The present data suggest that papaverine injection into the hindlimb circulation can stimulate ventilation independently of its possible effects on the arterial baro- or chemoreceptors, supporting the hypothesis that muscular vasodilation could contribute to the control of breathing through a neural link.

Renovascular hypertension and insulin sensitivity.

We tested the hypothesis that the status of the renin-angiotensin-aldosterone system affects insulin sensitivity. Insulin sensitivity (by the euglycaemic insulin clamp technique) was measured in eight patients with angiographically proven renovascular hypertension and in eight normotensive subjects matched for age, gender, body mass index and glucose tolerance. In the patients, insulin sensitivity was measured both at baseline and following 7 days of ACE inhibition. Following glucose ingestion, patients and controls showed similar insulin and glucose responses. Insulin infusion (7 pmol min-1 kg-1) promoted similar glucose utilization in the hypertensives and normotensives: 24.8 +/- 2.3 vs. 26.0 +/- 3.0 mumol min-1 kg-1 respectively. One week of ACE inhibition caused a 20 +/- 4 mmHg decrease in mean blood pressure and a 20 +/- 6% decrease in peripheral vascular resistance. Plasma angiotensin II concentrations dropped from 24.6 +/- 6.3 to 13.5 +/-5.0 pg mL-1 (P < 0.05) and plasma aldosterone from 17 +/- 4 to 9 +/- 2 ng dL-1 (P < 0.05), and plasma renin activity doubled (from 1.6 +/- 0.3 to 3.4 +/- 1.7 ng mL-1 h-1, P < 0.02). Nevertheless, insulin sensitivity was unchanged (before, 24.8 +/- 2.3; after 25.8 +/- 2.2 mumol min-1 kg-1, P = Ns). During insulin infusion, forearm blood flow did not change from baseline in either set of studies. Also, the antinatriuretic (before, -26 +/- 18; after, -22 +/- 14%) and antikaliuretic (before: -36 +/- 13%, after -39 +/- 11%) action of the hormone was unaffected by the therapy. In conclusion, renovascular hypertension is not associated with insulin resistance. Furthermore, a selective, drastic reduction of the renin-angiotensin-aldosterone system activity and vascular tone does not alter insulin action on glucose and electrolyte metabolism.

Elevated plasma adrenomedullin level in hyperthyroidism.

Adrenomedullin is a recently discovered peptide that was first purified from phaeochromocytoma tissue and has marked vasodilatory activity, causing hypotension. In thyrotoxicosis, various haemodynamic changes are observed, including an increase in cardiac output and heart rate with a concomitant decrease in peripheral vascular resistance. To evaluate the mechanism underlying these haemodynamic changes in thyrotoxicosis, we measured the plasma adrenomedullin concentration in thyrotoxic patients with Graves' disease. The plasma concentration of adrenomedullin was elevated in hyperthyroid patients (14.7 +/- 5.7 pmol L-1) compared with euthyroid control subjects (5.6 +/- 1.3 pmol L-1) (P < 0.001). The correlation between the plasma adrenomedullin concentration and serum free thyroid hormone levels was marginally significant. The mean blood pressure was relatively low in the face of an elevated plasma adrenomedullin level. Adrenomedullin may therefore be responsible for the vasodilatation observed in thyrotoxicosis.

Effects of isovolemic hemodilution on hemodynamics, cerebral perfusion, and cerebral vascular reactivity.

To verify the hemorheological effects of isovolemic hemodilution on hemodynamics and cerebral perfusion of normal humans, we tested the efficacy of isovolemic hemodilution in systemic hemodynamics and cerebral bood flow augmentation and its influences in vascular reserve. Isovolemic hemodilution was studied in a total of 13 normal healthy subjects. Regional cerebral blood flow was measured by the xenon-enhanced CT method. Cerebral vascular activity was measured by acetazolamide challenge. These measurements, in association with hemorheological and hemodynamic monitoring, were analyzed before and after isovolemic hemodilution with low-molecular-weight dextran. Our results showed significant change in hemodynamic parameters after isovolemic hemodilution, including tachycardia, a 24% increase of cardiac index, and decrease of peripheral vascular resistance. Both left and right heart work index increased as a consequence of increased cardiac index. Regional cerebral blood flow increased 35.0 +/- 2.5% at 3 hours after hemodilution and 20.2 +/- 3.9% at 1 week after hemodilution. Cerebral vascular reactivity decreased from 32.1 +/- 4.1% to 25.3 +/- 4.0% after hemodilution, implicating a certain degree of vasodilation in the process of hemodilution. The whole procedure of hemodilution was completed in 52 +/- 6 minutes, and the subjects did not report discomfort during the procedure. Isovolemic hemodilution in subjects with normal cerebral perfusion can augment cerebral blood flow efficiently in a rapid fashion, and this effect can last for at least a week. The mechanism of flow augmentation may be partially attributed to vasodilation, which could be manifested as tachycardia, increased cardiac output, and decreased cerebral vascular reactivity.