[Follow-up study of fetal cardiac birth defects after prenatal diagnosis and graded counseling].

Objective: To explore accurate prenatal diagnosis, full-coverage graded counseling and follow-up for the fetus with cardiac birth defects (CBD). Methods: CBD fetus diagnosed prenatal by echocardiography from January 2018 to December 2020 in Guangdong Provincial People's Hospital were enrolled. Fetal CBD was graded (Ⅰ-Ⅵ) according to prognosis and possible operation time after birth, and the classification criteria and common diseases included were proposed. After the prenatal grading counseling, the outcome of the fetus was followed-up. The induced labor rate, live birth rate, prenatal and postnatal ultrasound diagnosis coincidence rate and other indicators were calculated. The disease composition ratio, prognosis of fetus with different grades and the outcome of integrated treatment were analyzed. Results: The detection rate of fetal CBD was up to 16.2% (1 971/12 188), 30 cases of which were excluded. A total of 1 941 cases were included in this study, including 196 cases (10.1%) of gradeⅠ, 433 cases (22.3%) of gradeⅡ, 615 cases (31.7%) of grade Ⅲ, 261 cases (13.4%) of grade Ⅳ, 388 cases (20.0%) of gradeⅤ, 48 cases (2.5%) of grade Ⅵ. Grade Ⅱ and gradeⅢ (the operation time was within 1 year after birth) accounted for 54.0% (1 048/1 941). The distribution of some diseases in different grades had obvious proportion advantage, which was representative. Among 1 747 CBD fetus, 736 cases (induced labor rate 42.1%) chose to terminate pregnancy due to CBD. Of the 1 010 live births, 975 cases (96.5%) had the same prenatal and postnatal diagnosis, 3 cases were missed diagnosis and 32 cases were misdiagnosed. The diagnostic accuracy of live births with severe and complex congenital heart disease was 383 out of 389 (98.5%). A total of 258 cases have received surgery or intervention. The age at the time of surgery or intervention was different among grades（χ²=47.3，P<0.001）. With the improvement of prognosis from gradeⅠ to Ⅴ, the live birth rate increased and the induced labor rate decreased accordingly; the difference between grades was significant（χ²=623.6，P<0.001）. Conclusions: Prenatal diagnosis and graded counseling is important in the integrated model. Fetal CBD grading could refine post-natal treatment strategies, guide delivery decisions and become an evaluation standard.

Routine exercise ameliorates the metabolic side-effects of treatment with the atypical antipsychotic drug olanzapine in rats.

Second generation antipsychotic (SGA) drugs are effective treatments for psychosis. Common side-effects of SGAs include metabolic dysregulation and risk of cardiometabolic disorders. Metabolic side-effects, including glucose intolerance, can be accurately modelled in rodents. The benefits of interventions used for treating metabolic side-effects of SGAs are mostly unknown. In a 9 wk longitudinal study, female rats were given daily olanzapine (10 mg/kg s.c.) or vehicle. Animals were either sedentary or allowed 1 or 3 h daily access to a running wheel, with total wheel revolutions electronically quantified to reflect exercise intensity. Glucose tolerance tests were performed once weekly to measure glycemic control. Drug levels were measured at week 4. At week 9, abdominal fat and skeletal muscle levels of Glucose Transporter 4 (GLUT4) were measured. Exercise intensity progressively increased over time in all groups given access to running wheels; however, rats treated with olanzapine consistently exercised less than those given the vehicle. Olanzapine caused acute and persistent glucose intolerance throughout the study, which was markedly, though incompletely, ameliorated by exercise. Exercise did not affect glycemic regulation in vehicle-treated rats. Olanzapine-treated rats showed greater central adiposity. Levels of GLUT4 in skeletal muscle were higher in both groups of exercising than in sedentary rats, and GLUT4 values were negatively correlated with glucose intolerance. Routine exercise reduced olanzapine-induced glucose intolerance and increased skeletal muscle levels of GLUT 4, the insulin-responsive transporter that mediates glucose uptake into cells. The current animal model is suitable for evaluating physiological pathways involved with glucose intolerance.

[Prenatal interventional therapy in two cases with critical pulmonary stenosis or pulmonary atresia with intact ventricular septum].

Objectives: Two cases who underwent fetal pulmonary valvuloplasty (FPV) for pulmonary atresia with intact ventricular septum (PA-IVS) or critical pulmonary stenosis with intact ventricular septum (CPS-IVS) successfully were reported. The aim of the report was to explore the criteria for case selection, the technical essentials of FPV, and the postpartum outcome of the fetus. Methods: One case with PA-IVS and the other with CPS-IVS were enrolled in September 2016 and February 2017 in Guangdong General Hospital, and both cases were diagnosed with severe right ventricular dysplasia and tricuspid regurgitation by fetal echocardiogram. Parameters of right ventricle development and hemodynamics from echocardiography included tricuspid/mitral annulus (TV/MV), right ventricle/left ventricle long-axis (RV/LV), pulmonary/aortic annulus (PV/AV), tricuspid inflow duration/cardiac cycle, degree of tricuspid regurgitation (TR), blood flow direction of arterial duct and ductus venosus. Multidisciplinary team including the maternal-fetal cardiology, pediatric cardiology, cardiac surgery, obstetrics, neonatology and anesthesiology was summoned to discuss the indications and timing of PFV. Two cases underwent ultrasound-guiding trans-abdominal PFV at the 28 weeks of gestational age. Echocardiography was performed to observe the opening and closing of the pulmonary valve, and to evaluate the development of right ventricle and improvement in hemodynamics every 2-4 weeks until delivery. Results: From the technical perspective, pulmonary balloon valvuloplasty was successfully performed in these two cases. The opening of pulmonary valve improved in these two cases at 2-4 weeks after FPV. However, an obvious restenosis was detected in the first case at 5-8 weeks after FPV. In the first case, the echocardiography parameters including TV/MV, RV/LV, PV/AV and tricuspid inflow duration/cardiac cycle increased from 0.56, 0.42, 0.85,0.26 to 0.59, 0.51, 0.87, 0.32 at 5-8 weeks after FPV, respectively. However, the direction of blood flow through the arterial duct was still reverse. In the second case, TV/MV, RV/LV, PV/AV and tricuspid inflow duration/cardiac cycle ratio increased from 0.70, 0.63, 0.91,0.35 to 0.80, 0.80, 0.97, 0.42 at 5-8 weeks after FPV, respectively. The direction of blood flow through the arterial duct changed to bidirectional. Both fetuses were born alive. The first case underwent pulmonary valve commissurotomy and modified Blalock-Taussig shunt on the 8(th) day after delivery and received follow-up for 6 months. The strategy for the next-step therapy was still pending. The second case underwent transcutaneous pulmonary balloon valvuloplasty on the 19(th) day after delivery and received follow-up for 3 months. The opening of pulmonary valve improved obviously and the cardiac function was normal in the second case. Conclusions: FPV is safe and effective for fetus during the second and third trimester of pregnancy, and FPV is beneficial for the development of fetal ventricle, valve and large artery. In addition, FPV may help to avoid the postnatal surgery for isolated single ventricle, improve fetal heart failure and prevent fetal death.

Autonomic control of the venous system in health and disease: effects of drugs.

The venous system contains approximately 70% of the blood volume. The sympathetic nervous system is by far the most important vasopressor system in the control of venous capacitance. The baroreflex system responds to acute hypotension by concurrently increasing sympathetic tone to resistance, as well as capacitance vessels, to increase blood pressure and venous return, respectively. Studies in experimental animals have shown that interference of sympathetic activity by an alpha1- or alpha2-adrenoceptor antagonist or a ganglionic blocker reduces mean circulatory filling pressure and venous resistance and increases unstressed volume. An alpha1- or alpha2-adrenoceptor agonist, on the other hand, increases mean circulatory filling pressure and venous resistance and reduces unstressed volume. In humans, drugs that interfere with sympathetic tone can cause the pooling of blood in limb as well as splanchnic veins; the reduction of cardiac output; and orthostatic intolerance. Other perturbations that can cause postural hypotension include autonomic failure, as in dysautonomia, diabetes mellitus, and vasovagal syncope; increased venous compliance, as in hemodialysis; and reduced blood volume, as with space flight and prolonged bed rest. Several alpha-adrenoceptor agonists are used to increase venous return in orthostatic intolerance; however, there is insufficient data to show that these drugs are more efficacious than placebo. Clearly, more basic science and clinical studies are needed to increase our knowledge and understanding of the venous system.

Effects of drugs on body venous tone, as reflected by mean circulatory filling pressure.

The venous system is supremely important in the control of cardiac output. Drugs which affect the venous system have profound effects on haemodynamics. This review comments on the methods available for the determination of venous compliance, resistance, and unstressed volume and describes the mean circulatory filling pressure (MCFP) technique, its usefulness and limitations. The MCFP technique involves the measurement of central venous pressure during brief (5-7 s) circulatory arrest. Mathematically, MCFP is inversely proportional to vascular compliance while experimentally, it is a primary determinant of venous return. The MCFP technique provides a reproducible and relatively non-traumatic means for the estimation of body venous tone in conscious and anaesthetised animals. Drugs examined by this technique include alpha and beta adrenoceptor agonists and antagonists, ganglionic blockers, vasoactive peptides (endothelin, vasopressin, angiotensin, neuropeptide Y), and vasodilators (hydralazine, nitroprusside, glyceryl trinitrate, calcium antagonists, and MCI-154).

Effect of chronic treatment of spontaneously hypertensive rats with D 600.

The effects of chronic treatment of spontaneously hypertensive rats (SHR) with methoxyverapamil (D 600) on blood pressure (BP) and on the in vitro contractile response of aortic and portal vein strips of rats were examined. D 600, prepared as the free base and dissolved in sesame oil, was injected subcutaneously daily into SHR to maintain the systolic blood pressure (SBP) at less than 130 mm Hg for 24 hours after injections. The dose required increased progressively from 4 to 8.5 mg/day/rat. As controls, normotensive rats (WKY) and untreated SHR received daily injections of the vehicle. After 2 weeks, aortic and portal vein strips were prepared from each rat for studies of cumulative dose-response curves to norepinephrine (NE) in Krebs' solution containing normal (2.5 mM) and low (0.2 and 0.4 mM) calcium (Ca). Chronic treatment with D 600 restored to control values the ordinarily depressed contractile response to NE and increased the ED50 values for NE (i.e., the NE dose that produces 50% of the maximum response) of aortic strips from SHR in nord-mal and low Ca. Portal veins from SHR showed increased spontaneous activity, supernormal responses to NE, and decreased ED50 values for NE that were all exaggerated by chronic D 600 treatment. These results imply that SHR developed a tolerance to D 600 associated with enhanced contractility of vascular smooth muscles.

The dopamine transporter gene and Parkinson's disease in a Chinese population.

We studied a variable number tandem repeat polymorphism within the dopamine transporter gene (DAT) for an association with Parkinson's disease in a Chinese population. Five alleles were detected, consisting of 6, 8, 9, 10, and 11 copies of the 40 base pair repeat sequence. The 10-copy allele was most common, accounting for 90% of alleles. There were no significant differences between the patients and the control subjects in the distribution frequencies of the alleles or genotypes. Therefore, this polymorphism is not associated with Parkinson's disease in Chinese populations.

Alpha 1b-adrenoceptors mediate renal tubular sodium and water reabsorption in the rat.

1. It is known that activation of alpha 1-adrenoceptors causes renal vasoconstriction and increased tubular Na+ and water reabsorption, with the alpha 1a-subtype mediating the constrictor effect. 2. This study examines which subtype of alpha 1-adrenoceptors mediates tubular Na+ and water reabsorption in pentobarbitone-anaesthetized rats. In order to avoid systemic effects, phenylephrine (0.3 to 30 micrograms kg-1), methoxamine (0.1-10 micrograms kg-1) and vehicle were infused into the right renal artery (via the suprarenal artery) of three groups of rats. Two other groups of rats were continuously infused with the irreversible selective alpha 1b-adrenoceptor antagonist, chloroethylclonidine (3 mg kg-1 h-1) for 1 h, prior to the construction of dose-response curves to phenylephrine or methoxamine. Another group was continuously infused with the irreversible selective alpha 1a-adrenoceptor antagonist, SZL-49 (10 micrograms kg-1 h-1) for 1 h, prior to the construction of dose-response curves to phenylephrine. Mean arterial pressure (MAP), heart rate (HR), urine flow, Na+ and K+ excretion, and urine osmolality were monitored. 3. Phenylephrine and methoxamine did not affect MAP or HR but dose-dependently and significantly decreased urine flow, urine osmolality as well as Na+ excretion and, slightly increased K+ excretion, although this was significant only for phenylephrine. 4. The antidiuretic, antinatriuretic and kaliuretic effects of phenylephrine were abolished by pretreatment with chloroethylclonidine, but were not inhibited by SZL-49. The inhibitory effects of methoxamine on urine flow and Na+ excretion were also almost totally abolished by chloroethylclonidine. 5. Our results show that alpha 1b-adrenoceptors mediate renal tubular Na+ and water reabsorption.

Possible dependence of pressor and heart rate effects of NG-nitro-L-arginine on autonomic nerve activity.

1. The effects of NG-nitro-L-arginine (L-NNA) on mean arterial pressure (MAP) and heart rate (HR) were investigated in conscious rats. 2. Intravenous bolus cumulative doses of L-NNA (1-32 mg kg-1) dose-dependently increased MAP. Both mecamylamine and phentolamine increased MAP responses to L-NNA, angiotensin II and methoxamine. Propranolol, reserpine, atropine and captopril did not affect MAP response to L-NNA. 3. A significant negative correlation of HR and MAP responses to L-NNA was obtained in control rats but not in rats pretreated with reserpine or mecamylamine. Significant negative correlations also occurred in the presence of atropine, propranolol, phentolamine or captopril. 4. A single i.v. bolus dose of L-NNA (32 mg kg-1) raised MAP to a peak value of 53 +/- 3 mmHg and the effect lasted more than 2 h; the rise and recovery of MAP were accompanied by significant decrease and increase in HR, respectively. While both phentolamine and mecamylamine increased peak MAP response to L-NNA, mecamylamine abolished the biphasic HR response and phentolamine potentiated the bradycardiac component of HR. 5. Blockade of the autonomic nervous and renin-angiotensin systems did not attenuate the pressor effects of L-NNA. However, the biphasic HR response to L-NNA is mediated via modulation of autonomic nerve activities.

Cardiovascular effects of injections of vasopressin into the nucleus tractus solitarius in conscious rats.

The effects of injections of arginine vasopressin (AVP) into the nucleus tractus solitarius (NTS) on mean arterial pressure (MAP), heart rate (HR) and plasma concentrations of noradrenaline and adrenaline were investigated in conscious, unrestrained rats. Injection of 2 ng AVP into the NTS significantly increased MAP but not plasma catecholamine concentrations, while injection of 10 ng AVP significantly increased MAP and plasma noradrenaline and adrenaline levels. Neither dose of AVP produced any change in HR. The vehicle did not affect MAP, HR or plasma catecholamine levels. Injection of a specific pressor antagonist of AVP, d(CH2)5Tyr-(Me)AVP (10 ng), did not change MAP, HR or plasma noradrenaline or adrenaline levels. These results suggest that the NTS is a central site of the pressor action of AVP. However, since the injection of the AVP antagonist did not reduce MAP or plasma noradrenaline or adrenaline levels, it suggests that AVP does not act tonically at the NTS to influence sympathoadrenal outflow.

The effects of noradrenaline, B-HT 920, methoxamine, angiotensin II and vasopressin on mean circulatory filling pressure in conscious rats.

The effects of vasoactive substances on mean circulatory filling pressure (MCFP), an index of total body venous tone, were determined in conscious rats. Cumulative doses of saline (0.9% w/v NaCl solution), methoxamine (alpha 1-adrenoceptor agonist), B-HT920 (alpha 2-adrenoceptor agonist) noradrenaline and vasopressin, and individual doses of angiotensin II (AII), were infused into the rats. Mean arterial pressure (MAP), MCFP and heart rate (HR) were determined before and during the plateau responses to infusions of the vasoactive substances. The infusions of all the agonists caused a dose-dependent increase in MAP and a decrease in HR. The infusion of saline affected neither MAP nor HR. The infusions of saline and methoxamine did not affect MCFP while the infusions of B-HT 920, noradrenaline and AII increased MCFP. MCFP was slightly increased during the infusion of high doses of vasopressin. It was concluded that receptors for the alpha 2-adrenoceptor agonist and AII are involved in the control of venous tone. Receptors for the alpha 1-adrenoceptor agonist and vasopressin are not important for the control of venous tone.

Halothane inhibits the pressor effect of diphenyleneiodonium.

1. We have recently found that diphenyleneiodonium (DPI), a novel inhibitor of nitric oxide (NO) synthase, causes pressor and tachycardic responses in pentobarbitone- but not halothane-anaesthetized rats. The present study investigated the mechanism by which halothane suppresses the pressor response of DPI. The effects of halothane on the pressor response of DPI were also compared with those of other anaesthetic agents. 2. In conscious rats, i.v. bolus injections of DPI (0.025- 1.6 mg kg-1) caused dose-dependent increases in mean arterial pressure (MAP), with ED90 of 0.07 +/- 0.01 mg kg-1 and maximal rise of MAP (Emax) of 59 +/- 2 mmHg. While ketamine potentiated Emax without altering the ED50 and pentobarbitone increased the ED50 without changing Emax of the pressor response to DPI, chloralose, urethane and ethanol displaced the curve to the right and potentiated Emax. In contrast, halothane (0.5-1.25%) dose-dependently and non-competitively reduced the pressor responses to DPI. 3. Intravenous bolus injection of a single dose of DPI (1.6 mg kg-1) caused immediate and large increases in plasma noradrenaline and adrenaline, as well as MAP in conscious rats. Halothane (1.25%) almost completely inhibited these increases. 4. The results suggest that DPI causes a pressor response in conscious rats by activating the sympathetic nervous system and halothane abolishes this pressor response by inhibiting activities of the sympathetic nervous system. The results also show that influences of anaesthetics must be taken into consideration when evaluating pressor response of vasoactive agents.

In vivo venodilator action of fenoldopam, a dopamine D(1)-receptor agonist.

The effects of the dopamine D(1)-receptor agonist fenoldopam were compared with those of the D(2)-receptor agonist R(-)-propylnorapomorphine and vehicle on mean arterial pressure (MAP), mean circulatory filling pressure (MCFP, the driving force of venous return), arterial resistance (R(a)), venous resistance (R(v)), heart rate (HR) and cardiac output (CO) in groups of thiobutabarbitone-anaesthetized rats pre-treated with i.v. injection of mecamylamine (3.7 micromol kg(-1)) and continuously infused with noradrenaline (6.8 nmol kg(-1) min(-1)). The vehicle did not alter any haemodynamic variables. All doses of fenoldopam (0.5, 2 and 16 microgram kg(-1) min(-1)) reduced MAP, R(a) and R(v), and increased CO. At the highest dose, fenoldopam also increased HR and reduced MCFP. All doses of R(-)-propylnorapomorphine (0.5, 2 and 16 microgram kg(-1) min(-1)) increased MAP but did not significantly alter CO, R(v) and MCFP. Both R(a) and HR were increased by the highest dose of R(-)-propylnorapomorphine. Our results indicate that fenoldopam reduces MAP and MCFP, and markedly increases CO through reductions of arterial and venous resistances. The effects of fenoldopam in dilating arterial resistance and capacitance vessels were similar. In contrast, R(-)-propylnorapomorphine elevates MAP through an increase in arterial resistance but has minimal effects on CO, MCFP and venous resistance. Both drugs have a small direct, positive chronotropic action at the highest dose.

Venous versus arterial actions of diethylamine/nitric oxide (DEA/NO) complex and S-nitroso-N-acetylpenicillamine (SNAP) in vivo.

We studied the effects of diethylamine/NO complex (DEA/NO) and S-nitroso-N-acetylpenicillamine (SNAP), relative to those of sodium nitroprusside (SNP) and nitroglycerin (NTG), on mean arterial pressure (MAP), mean circulatory filling pressure (MCFP), arterial resistance (Ra), venous resistance (Rv), heart rate (HR), cardiac output (CO) and stroke volume (SV) in groups of Inactin-anaesthetized rats pre-treated with i.v. mecamylamine (3.7 micromol kg(-1)) and noradrenaline (6.8 nmol kg(-1) min(-1)). Doses of each that reduced MAP by 30%, 80% and the lowest dose that maximally reduced MAP were examined to allow a comparison of the compounds' dilator actions at equivalent effective depressor doses. DEA/NO (4, 32 and 256 microg kg(-1) min(-1)), SNAP (4, 32 and 256 microg kg(-1) min(-1)) and SNP (8, 32 and 128 microg kg(-1) min(-1)) caused similar dose-dependent reductions in MAP and Ra, and increases in CO and SV. NTG (0.2, 0.8 and 6.4 microg kg(-1) min(-1)) dose-dependently reduced Ra, and increased CO and SV, but lowered MAP only at the highest dose. DEA/NO, SNAP and SNP but not NTG lowered MCFP with efficacy: DEA/NO > SNAP > SNP. All four drugs reduced Rv with efficacy: DEA/NO approximately equal to SNAP > SNP approximately equal to NTG. Therefore, all compounds lowered Ra and Rv. DEA/NO, SNAP and SNP but not NTG reduced MCFP. The pharmacological profiles of DEA/NO and SNAP resemble SNP more than NTG.

Adrenalectomy abolishes antagonism of alpha-adrenoceptor-mediated hypotension by a beta-blocker in conscious rats.

1. The effects of a single bolus injection of propranolol, atenolol or ICI 118,551, non-selective beta-, selective beta 1- and selective beta 2-adrenoceptor antagonists, respectively, on mean arterial pressure (MAP) and plasma catecholamine concentrations were examined in seven groups of conscious and unrestrained adrenalectomized rats receiving a continuous infusion of the alpha-adrenoceptor antagonist phentolamine. In all rats adrenaline was undetectable in the plasma four days after adrenalectomy. 2. In the first three groups, phentolamine significantly decreased MAP and increased the plasma concentrations of noradrenaline. The injection of propranolol, atenolol or ICI 118,551 in Groups I, II and III, respectively, caused a small increase in MAP and a small, but not significant, decrease in plasma noradrenaline concentrations. 3. Groups IV, V and VI were given a continuous infusion of adrenaline for 1 h prior to the infusion of phentolamine, followed by a bolus injection of propranolol, atenolol or ICI 118,551, respectively. Group VII was treated similarly to IV, but was also given daily cortisone replacement after adrenalectomy. Adrenaline slightly, but not significantly, decreased MAP while phentolamine significantly decreased MAP and increased plasma noradrenaline concentrations in all groups. A subsequent injection of a beta-blocker caused a significant increase in MAP in each group and a slight decrease in the plasma level of noradrenaline which reached statistical significance in group VII. The pressor effect of propranolol was significantly greater in the cortisone-treated rats (Group VII) than in Group IV. 5. The results suggest that adrenaline and adrenocortical steroids are both involved in the antagonism of alpha-adrenoceptor-induced hypotension by a beta-blocker.

A comparison of the inhibitory effects of sodium nitroprusside, pinacidil and nifedipine on pressor response to NG-nitro-L-arginine.

1. The inhibitory effects of sodium nitroprusside (SNP), a nitric oxide (NO) donor, on mean arterial pressure (MAP) responses to NG-nitro-L-arginine (L-NNA) (NO synthase inhibitor), angiotensin II (AII) and noradrenaline (NA) were compared with those of pinacidil (KATP channel opener) and nifedipine (L-type calcium antagonist) in conscious, unrestrained rats. 2. Intravenous bolus injections of L-NNA (1-64 mg kg-1), AII (0.02-1.28 micrograms kg-1) and NA (0.25-16 micrograms kg-1) dose-dependently increased MAP to similar maxima. Intravenous infusions of SNP (1, 4 and 16 micrograms kg-1 min-1) dose-dependently increased ED20S of L-NNA, AII and NA. However, the maximum response evoked by L-NNA, but not by AII nor NA, was dose-dependently reduced by SNP. Moreover, the inhibitory effect of SNP on the pressor response to L-NNA ceased when the infusion of SNP was terminated. 3. Pinacidil (80 micrograms kg-1 min-1 for 30 min followed by 5 micrograms kg-1 min-1) increased ED50S of L-NNA, AII and NA but did not decrease the maximum responses to any of these agents. 4. Nifedipine (1 mg kg-1 min-1) non-selectively reduced maximum responses to L-NNA, AII and NA to similar levels and increased ED50S of AII and NA but not L-NNA. 5. The results show that SNP causes a selective, non-competitive and reversible inhibition of the pressor response to L-NNA. This inhibition by SNP is unlikely to be related to hypotension, the opening of ATP-sensitive potassium channels or blockade of L-type calcium channels.

Vascular pharmacology of methylene blue in vitro and in vivo: a comparison with NG-nitro-L-arginine and diphenyleneiodonium.

1. The vascular effects of the soluble guanylyl cyclase inhibitor, methylene blue as well as the nitric oxide (NO) synthase inhibitors, NG-nitro-L-arginine (L-NOARG) and diphenyleneiodonium (DPI) were studied in rat isolated aortic rings and conscious, unrestrained rats. 2. Acetylcholine (ACh) and sodium nitroprusside (SNP) caused concentration-dependent relaxation of preconstricted aortic rings. Both methylene blue (1 x 10(-5) M) and L-NOARG (3 x 10(-5) M) abolished ACh-induced relaxation; however, methylene blue but not L-NOARG shifted the concentration-response curve of SNP to the right. 3. In conscious rats, i.v. infusion of methylene blue (1.1 x 10(-5) mol kg-1 min-1), at a concentration which reduced the aortic tissue level of cyclic GMP by 50%, did not significantly alter mean arterial pressure (MAP) and heart rate (HR). In contrast, i.v. bolus injection of L-NOARG (1.5 x 10(-4) mol kg-1) markedly increased MAP and decreased HR. 4. Both ACh and SNP dose-dependently decreased MAP in conscious rats. Methylene blue did not alter the magnitude or duration of ACh- or SNP-induced depressor responses. L-NOARG, on the other hand, significantly though incompletely, reduced the magnitude and duration of the depressor response to ACh but not SNP. The depressor response to ACh or SNP was not altered by pretreatment with indomethacin (1.4 x 10(-5) mol kg-1) or capsaicin (3.3 x 10(-4) mol kg-1). 5. NG-nitro-L-arginine methyl ester (L-NAME) also caused dose-dependent increases in MAP in conscious rats. Both methylene blue and DPI (1 x 10-5 mol kg-1) selectively shifted the dose-pressor response curve of L-NAME to the right.6. These results suggest that: (1) the inhibition of endogenous NO biosynthesis does not necessarily lead to pressor response in vivo, (2) L-NOARG may not produce pressor response solely via the inhibition of endogenous endothelial NO biosynthesis, and (3) the depressor responses to ACh and SNP may not involve the release of NO or prostanoids or afferent nerve transmitters.

Effects of calcitonin gene-related peptide receptor antagonists on renal actions of adrenomedullin.

1. Adrenomedullin is a novel vasoactive peptide which is produced in the lungs, ventricle, kidneys, heart and adrenal medulla. Adrenomedullin shows homology to calcitonin gene-related peptide (CGRP) and has similar pharmacological actions to CGRP. 2. This study examined the dose-response effects of adrenomedullin (rat, 11-50) on mean arterial pressure (MAP), heart rate (HR), renal blood flow (RBF), glomerular filtration rate (GFR) and renal tubular electrolyte excretion in Inactin-anaesthetized Sprague Dawley rats. The possible involvement of CGRP receptors in actions of adrenomedullin was also examined via renal arterial injection of a CGRP receptor antagonist, CGRP (8-37) (1 or 10 nmol kg-1) or [Tyr0]CGRP(28-37) (3 or 30 nmol kg-1), starting 15 min prior to the administration of adrenomedullin. 3. Renal arterial infusion (0.001 to 1 nmol kg-1) of adrenomedullin did not alter MAP, HR and renal K+ excretion but dose-dependently increased RBF and arterial conductance, GFR, urine flow and Na+ excretion. 4. The renal actions of adrenomedullin were not blocked by either the low or the high dose of CGRP(8-37) or [Tyr0]CGRP(28-37). 5. The results show that adrenomedullin causes renal vasodilatation, increments in GFR, diuresis and natriuresis. The renal actions of adrenomedullin are not mediated via the activation of CGRP1 receptors.

Subtypes of endothelin receptors that mediate venous effects of endothelin-1 in anaesthetized rats.

1. The subtypes of endothelin receptors that mediate the effects of endothelin-1 (ET-1) on mean arterial pressure (MAP), heart rate (HR), mean circulatory filling pressure (MCFP), arterial resistance (RA), cardiac output (CO) and venous resistance (RV) were characterized in 9 groups of pentobarbitone-anaesthetized rats via the injection of ET-1 in the absence and presence of bosentan (Ro 47-0203, ETA- and ETB-receptor antagonist), PD 142893 (ETA- and ETB-receptor antagonist) or FR 139317 (ETA-receptor antagonist), as well as injection of the ETB-receptor agonist, IRL 1620. 2. Cumulative i.v. bolus injections of ET-1 or IRL 1620 (0.5, 1 and 2 nmol kg-1) dose-dependently increased MAP (ET: by 22, 34 and 44; IRL: 8, 17 and 28 mmHg), RA (ET: 62, 108 and 162; IRL: 51, 63 and 86% over baseline), RV (ET: 70, 132 and 179; IRL: 81, 89 and 98% over baseline) and MCFP (ET: 1.1, 1.8 and 1.9; IRL: 0.9, 1.0 and 1.2 mmHg) and reduced CO (ET: -18, -35 and -44; IRL: -24; -26; -25% below baseline). Equimolar doses of ET-1 and IRL 1620 caused similar initial transient depressor responses. Saline did not modify any haemodynamic variables in the time-control group. 3. Bosentan (10 mg kg-1, i.v.) inhibited ET-induced increases in MAP, RV, RA and MCFP and decrease in CO. PD 142893 (22 mg kg-1, i.v.) abolished ET-induced changes on MAP, RV, RA and CO, but did not alter effects on MCFP. Bosentan alone did not cause haemodynamic changes, but PD 142893 alone elevated MCFP (0.9 +/- 0.3 mmHg at 1 h after injection) and did not alter other variables. Both antagonists abolished the initial depressor effects of ET-1. 4. FR 139317 (1 mg kg-1, i.v.) partially inhibited the increases in MAP, RV, RA and MCFP and decreases in CO elicited by ET-1, but did not alter the transient depressor response of ET-1. 5. The results show that both ETA- and ETB-receptors mediate the arterial and venous constrictor effects of ET-1. Bosentan is more efficacious than PD 142893 in inhibiting the venous effects of ET-1.

Effects of anipamil on cardiovascular status and regional blood flow in anaesthetized rats.

1. Anipamil, a long-acting analogue of verapamil, was tested at 1, 2.5 and 5 mg kg-1 i.v. for its effects on cardiovascular status and blood flow in different organs and vascular beds in rats anaesthetized with pentobarbitone. 2. Blood flow was determined by microsphere (57Co or 113Sn) injection before, and 1 h after, administration of anipamil at the above doses. 3. Anipamil produced a dose-dependent fall in blood pressure and heart rate. This was associated with a fall in peripheral resistance. At the highest dose there was, in addition, evidence of myocardial depression. 4. Both blood flow and conductance (flow corrected for blood pressure) were notably increased by anipamil in heart, liver and skeletal muscle beds, but were decreased, especially at the high doses, in kidneys, intestine and spleen. 5. The profile of the actions of anipamil on haemodynamic performance and flow was consistent with its proposed calcium antagonist actions. This profile was similar to that of verapamil.