Cardiovascular effects of oxymetazoline and UK14,304 in conscious and pithed rats

Relatively selective alpha 2-adrenoceptor agonists have proven useful in a variety of therapeutic situations including hypertension, glaucoma and withdrawal from opiate addiction. In particular, oxymetazoline (OXY) and UK14,304 (UK) have been used in subclassifying alpha 2-adrenoceptors and imidazoline receptors. We evaluated the cardiovascular effects of OXY and UK in conscious and pithed rats in the presence and absence of efaroxan (EFA), idazoxan (IDA) and rauwolscine (RAU). Both OXY or UK (1, 5 and 10 micrograms/kg, i.v.) increased blood pressure (BP) and reduced heart rate (HR) in conscious rats. In pithed rats, OXY and UK each increased BP to a greater extent than that observed in conscious rats, but HR was not affected. BP increases following sympathetic nerve stimulation in the pithed rats were not affected by OXY but were reduced by UK at 0.1 Hz and 0.3 Hz. HR responses to nerve stimulation in pithed rats were reduced after OXY at all frequencies, but only at 0.1 Hz following UK. EFA, IDA and RAU inhibited the pressor responses of UK, with EFA being most potent. OXY-induced pressor responses were inhibited by all three antagonists, RAU being the least potent. HR responses to either OXY or UK were not affected by the antagonists. Taken together, the data suggest that: 1) alpha 2-adrenoceptors contribute less to the vascular response to OXY than to UK based upon the antagonistic effect of RAU; 2) prejunctional I1 receptors maybe more prevalent in the heart than in vascular tissue based upon the response to OXY in pithed rats. Thus, the heterogeneity among receptors mediating cardiac and vascular responses are complex.     

Cardiovascular responses of conscious rats to carotid body chemoreceptor stimulation by intravenous KCN

This multicentre, double-blind, randomised, crossover study compared the efficacy, safety and tolerability of subcutaneous sumatriptan (6 mg and 12 mg) with placebo in 134 in-patients with cluster headache. Headache improvement to mild or no pain at 5, 10 and 15 min after treatment was recorded. At 10 min, headache relief was reported by 25% (placebo), 49% (6 mg) and 63% (12 mg) of patients and at 15 min the results were 35% (placebo), 75% (6 mg) and 80% (12 mg) (p < 0.001 for all comparisons with placebo). The 12 mg dose was not significantly better than the 6 mg dose and was associated with more adverse events. The 6 mg dose is therefore recommended for the acute treatment of cluster headache.     

Cardiovascular and sympathetic effects of proadrenomedullin NH2-terminal 20 peptide in conscious rats

Proadrenomedullin NH2-terminal 20 peptide (PAMP) and adrenomedullin (AM), which are derived from the same gene, are novel vasodilative peptides and have been shown to exhibit hypotensive action in anesthetized animals. To avoid the modification via anesthesia, we investigated the effects of intravenously administered PAMP on mean arterial pressure, heart rate (HR), and renal sympathetic nerve activity (RSNA) relative to those of AM in conscious unrestrained rats. We also examined whether the arterial baroreceptor reflex was altered with the two peptides. Intravenous injection of rat PAMP (rPAMP) (10, 20 and 50 nmol/kg) and rat AM (rAM) (0.3, 1.0 and 3.0 nmol/kg) similarly elicited dose-related hypotension accompanied by increases in HR and RSNA. However, the responses to rPAMP were less potent in magnitude and shorter in duration than those to rAM. Moreover, rAM facilitated baroreflex control, whereas rPAMP attenuated it. These findings indicate that although PAMP, as well as AM, may play an important role as a circulating hormone in the systemic circulation of conscious rats, the two peptides derived from an identical origin might have different mechanisms responsible for their cardiovascular and RSNA actions.     

Cardiovascular effects of verapamil enantiomer combinations in conscious dogs

We examined the systemic and coronary hemodynamic effects of five combinations of R- and S-verapamil enantiomers (R/S; 100/0, 90/10, 80/20, 50/50, and 20/80%, respectively) in conscious dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dt, subendocardial segment length, coronary blood flow velocity, and aortic blood flow. Dogs received escalating doses (0.1, 0.2, and 0.4 mg kg(-1)) of each verapamil combination over 2 min at 30 min intervals on different experimental days and peak changes in hemodynamics were recorded 2 min after each dose. All verapamil combinations increased heart rate, mean aortic blood flow, and coronary blood flow velocity and decreased calculated systemic and coronary vascular resistance. Alterations in coronary hemodynamics were most pronounced with 20/80 R/S verapamil. Racemic and 20/80 R/S verapamil decreased mean arterial and left ventricular systolic pressure, in contrast to combinations with greater concentrations of the R enantiomer. Left ventricular function was unchanged during administration of 100/0, 90/10, and 80/20 R/S verapamil. Direct negative inotropic and lusitropic effects occurred with 50/50 and 20/80 R/S verapamil. The high dose of 20/80 R/S verapamil also increased left ventricular end-diastolic pressure and the regional chamber stiffness constant, consistent with diastolic dysfunction. The results indicate that combinations of R- and S-verapamil produce differential hemodynamic and left ventricular functional effects in conscious, unsedated dogs that are dependent on the relative ratio of these enantiomers.     

Alpha 2-adrenoceptor-mediated antisecretory effect of hypoxia in conscious rats

Gastric acid secretion is suppressed, resulting in a significant rise in gastric pH, when conscious rats are exposed to hypoxia (Yamaji et al., 1996). When adrenal medullectomized rats were exposed to moderate (10.5% O2) hypoxia for 3 h, gastric acid secretion was restored to nearly the level in normoxia by the adrenal medullectomy. In severe (7.6% O2) hypoxia, the operation also caused an increase in the level of gastric acid output, although the extent was lower than that under 10.5% O2 hypoxic conditions. Gastric pH was normalized by the operation even with 7.6% O2 hypoxia. Similar results were obtained when reserpine, which causes an adrenergic discharge, was administered. When an alpha 2-adrenoceptor blocking agent, yohimbine, was administered, the inhibitory effect of 10.5% and 7.6% O2 hypoxia on gastric acid secretion was almost completely removed. However, neither prazosin (an alpha 1-adrenoceptor blocker) nor propranolol (a beta-adrenoceptor blocker) showed any significant effects on gastric acid output in hypoxia. These results indicate that acute hypoxia stimulated the adrenergic response from the adrenal medulla, and that gastric acid secretion was consequently suppressed through alpha 2-adrenoceptor.     

Hypotensive effects of peptide T in conscious rats

1. The present study investigated the effects of peptide T on mean arterial blood pressure (MAP) in conscious normotensive Sprague-Dawley (SD) rats, spontaneously hypertensive rats (SHR) and two-kidney one-clip (2K1C) hypertensive rats. 2. Peptide T was infused via the left jugular vein at a rate of 1 mg/kg per h in SD, SHR and 2K1C rats and then at doses of 0.1, 0.25, 0.5, 1 and 5 mg/kg per h in SHR, with 0.9% saline as a sham control in SHR and 2K1C. Mean arterial pressure was measured directly before, during and after infusion. 3. Peptide T (1 mg/kg per h) decreased blood pressure in both SHR (P < 0.01) and 2K1C (P < 0.05). In normotensive SD rats the fall in MAP approached statistical significance (P = 0.06). The effect of peptide T was not significantly different in normotensive compared with hypertensive rats. Saline infusion had no effect. The blood pressure lowering effect of peptide T appeared to be dose-dependent in SHR.     

Hemodynamic, hormonal, and renal effects of intracerebroventricular adrenomedullin in conscious sheep

Adrenomedullin, the recently described vasodilator that exhibits potent hypotensive actions when administered systemically, is also found in the central nervous system, suggesting a role for adrenomedullin as a neurohormone. However, only a limited number of studies have examined the central effects of adrenomedullin. Therefore, we have examined the integrative hemodynamic, renal, and hormonal effects of intracerebroventricular (I.C.V.) adrenomedullin in conscious sheep. Eight surgically prepared sheep received I.C.V. infusions of adrenomedullin at two doses (2 ng/kg x min followed immediately by 20 ng/kg x min each for 90 min) in a vehicle-controlled study. Water deprivation for 48 h before control infusion resulted in sheep drinking 2617 +/- 583 ml in the 90-min period following reintroduction of water. On the adrenomedullin day, drinking was halved to 1392 +/- 361 ml (P < 0.05). Adrenomedullin had no significant effect on urinary volume and sodium excretion. Plasma adrenomedullin levels remained unchanged during control infusions but were elevated by the end of I.C.V. adrenomedullin infusions (P < 0.001). Plasma ANP levels were also increased approximately 50% (P < 0.05). Plasma levels of both ACTH and cortisol were also increased 3- to 4-fold in response to I.C.V. adrenomedullin (P < 0.05). There was no significant difference in arterial pressure, heart rate, or cardiac output between study days. In conclusion, adrenomedullin within the central nervous system may have at least two roles: modulation of the hypothalamo-pituitary-adrenal axis and protection against fluid overload.     

Cardiovascular and behavioural effects of intracerebroventricularly administered tachykinin NK3 receptor antagonists in the conscious rat

1. In the conscious rat, three tachykinin NK3 receptor antagonists, namely SR142801 ((S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)pro pyl)-4-phenylpiperidin-4-yl)-N-methylacetamide), R820 (3-indolylcarbonyl-Hyp-Phg-N(Me)-Bzl) and R486 (H-Asp-Ser-Phe-Trp-beta-Ala-Leu-Met-NH2) were assessed against the intracerebroventricular (i.c.v.) effects induced by senktide, a selective NK3 receptor agonist, on mean arterial blood pressure (MAP), heart rate (HR) and motor behaviour. 2. Senktide (10-650 pmol per animal; i.c.v; n = 4-16) at the lowest dose caused a significant fall in MAP (-10 +/- 6 mmHg), while at the highest doses (100 and 650 pmol), senktide caused a rise in MAP (9 +/- 3 and 12 +/- 1 mmHg, respectively) when compared to vehicle. The intermediate doses (25 and 65 pmol) had no effect on MAP. The highest two doses caused a tachycardia of 62 +/- 15 and 88 +/- 8 beats min(-1), respectively. The dose of 65 pmol had a biphasic effect on HR, an initial bradycardia of 47 +/- 12 beats min(-1) followed by a tachycardia of 46 +/- 14 beats min(-1). The lowest doses caused either a rise of 52 +/- 10 beats min(-1) (25 pmol) or no effect (10 pmol) on HR. All doses of senktide caused similar increases in face washing, sniffing and wet dog shakes except at the dose of 100 pmol, when wet dog shakes were more than double those observed with the other doses. 3. The antagonist SR142801 (100 pmol -65 nmol per animal; i.c.v.; n = 6-8) caused increases in MAP at the highest two doses (6.5 and 65 nmol) while HR, dose-dependently, increased (23 +/- 6 to 118 +/- 26 beats min[-1]) and the onset dose-dependently decreased. The (R)-enantiomer, SR142806 (100 pmol - 65 nmol per animal; i.c.v.; n = 6-8) only caused rises in MAP (13 +/- 2 mmHg) and HR (69 +/- 11 beats min[-1]) at the highest dose. These drugs had no apparent effect on behaviour, except for the highest dose of SR142801 which increased sniffing. The antagonist R820 (650 pmol - 6.5 nmol per animal; i.c.v.; n = 6) had no effect on MAP or HR and only increased sniffing behaviour at 6.5 nmol. At 650 pmol (n = 6), R486 had no effect on any variable, but at 3.25 nmol, i.c.v. (n = 4) a delayed tachycardia and a significant increase in all behavioural variables were observed. 4. The cardiovascular responses induced by 6.5 nmol SR142801 and 25 pmol senktide were inhibited by R820 (6.5 nmol, 5 min earlier i.c.v.). In contrast, R820 failed to affect the central cardiovascular and behavioural responses induced by 10 pmol [Sar9, Met(O2)11]substance P, a NK1 receptor selective agonist. The senktide-induced behavioural changes were not inhibited by R820 (6.5 nmol, i.c.v.) while R486 (650 pmol, i.c.v.) blocked both the cardiovascular and behavioural responses to 25 pmol senktide. A mixture of antagonists for NK1 (RP67580; 6.5 nmol) and NK2 (SR48968; 6.5 nmol) receptors injected i.c.v. did not affect the cardiovascular response to SR142801. Cross-desensitization was shown between the central responses to SR142801 and senktide, but not between SR142801 and [Sar9, Met(O2)11]substance P. 5. The antagonists SR142801 and SR142806 (6.5-650 nmol kg(-1); n = 5-7), given i.v., did not evoke any cardiovascular or behavioural changes, except a delayed bradycardia for SR142806 (650 nmol kg[-1]), and also failed to inhibit the increase in MAP evoked by senktide (4 nmol kg(-1), i.v.). However, at the highest dose, both drugs slightly reduced the senktide-induced tachycardia. 6. Although the present data are consistent with the in vitro pharmacological bioassays and binding data, showing that SR142801 is a poor antagonist at rat peripheral NK3 receptors, they suggest that SR142801 has a partial agonist action at these receptors centrally. A separation of the cardiovascular and behavioural effects mediated by central NK3 receptor activation was achieved with SR142801 and R820 but not with R486. These results could be explained by the existence of NK3 receptor subtypes in the rat or by the differential activation and inhibition of the same receptor protein linked to the production of different second messengers. Differences in the pharmacokinetic or pharmacodynamic properties of the antagonists cannot be excluded at this time.     

Cardiovascular effects produced by R-(+)-8-hydroxy-2-(di-n-propylamino) tetralin in the preoptic area of conscious rats

The effect of ancrod-induced defibrinogenation on thrombosis and bleeding time was determined in anesthetized rats. Functional plasma fibrinogen levels were reduced 42, 71, 94 and 93% by ancrod doses of 5, 10, 20 and 30 U/kg, respectively, while a 2.5 U/kg dose was without significant effect. Ancrod inhibited vena cava thrombosis induced by partial stasis of blood flow combined with mild vascular injury. Thrombus weight was decreased 85 and 93% by the 10 and 20 U/kg doses, but was unaffected at lower doses. In contrast, ancrod doses of up to 30 U/kg did not significantly decrease carotid artery thrombi formed in response to oxidative transmural vessel injury. Ancrod caused a dose-dependent increase in bleeding time measured by puncturing small mesenteric arteries with a hypodermic needle. The bleeding time increase was approximately 38% in response to the 2.5 and 5 U/kg doses, and 182% in response to the 10 U/kg dose. These studies demonstrate that ancrod-induced reductions in plasma fibrinogen more effectively inhibit venous compared to arterial thrombosis, although these activities require doses that also increase bleeding time in small arteries.     

Autonomic mechanisms in the acute cardiovascular effects of cocaine in conscious rats

We studied the differential involvement of central dopaminergic activation and autonomic nervous system regulatory mechanisms in the cardiovascular responses to cocaine in conscious rats. Sprague-Dawley rats, Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were instrumented with catheters in the jugular vein and abdominal aorta at least 5 days before the experiment. Intravenous administration of cocaine (0.1-3.0 mg/kg) caused a dose-dependent increase in blood pressure that was biphasic, with a large and rapid increase peaking at 10 s, followed by a mild sustained pressor response. Pressor responses to cocaine were significantly greater in SHR when compared to WKY rats. However, pretreatment with dopamine D1 receptor antagonist SCH 23390 or the D2 receptor antagonist raclopride did not influence the effects of cocaine. Pretreatment with the alpha-adrenoceptor antagonist phentolamine or the ganglion blocker pentolinium blocked the peak response and reversed the more sustained response into a depressor effect. While pretreatment with propranolol alone did not alter the responses to cocaine, in rats pretreated with phentolamine and propranolol neither a pressor response nor a depressor response was observed. In conclusion, cocaine administration caused marked, but short lasting pressor responses that were mediated by sympathetic activation and alpha-adrenoceptor vasoconstriction with little involvement of central dopaminergic mechanisms. The rapid return of blood pressure towards baseline may be mediated by sympathoinhibition and beta-adrenoceptor-mediated vasodilatation, the latter of which being particularly prominent when alpha-adrenoceptor activation was prevented.     

Somatosensory evoked potentials during hypoxia and hypocapnia in conscious humans

PURPOSE: The objective of the study was to evaluate the effects of moderate hypoxia and hypocapnia on the latency and amplitude of cortical somatosensory evoked potentials (SSEPs) in conscious human subjects. METHODS: In ten volunteers the amplitude and latency of the cortical somatosensory evoked potentials were recorded during stimulation of the left posterior tibial nerve. Measurements of SSEPs and respiratory variables were made breathing ambient air, air containing a reduced oxygen percentage (17% O2, 14% O2 (n = 6) or 11% O2 (n = 10)), and again during voluntary hyperventilation breathing ambient air (PETCO2 = 20 mmHg, n = 10). RESULTS: Hypoxia (11% O2) caused mild stimulation of ventilation (P < 0.05) but had no effects on the latency or amplitude of the SSEP. Lesser degrees of hypoxia had no effects. Hyperventilation caused a small (2-4%) decrease) in the latency of the SSEP and an increase in the amplitude of the SSEP (P < 0.05). CONCLUSIONS: These findings in conscious subjects were consistent with previous observations in anaesthetized humans and anaesthetized dogs and show that the decrease in latency of the SSEP associated with hypocapnia is not due to changes in the depth of anaesthesia. These effects of hypocapnia may contribute to small variations in the latency of the SSEP when monitoring is performed during surgery, but are unlikely to be large enough to be of clinical concern.     

Chronic nitric oxide synthase inhibition and carotid artery distensibility in renal hypertensive rats

The goal of the present study was to examine the viscoelastic properties of the carotid artery in genetically identical rats exposed to similar levels of blood pressure sustained by different mechanisms. Eight-week old male Wistar rats were examined 2 weeks after renal artery clipping (two-kidney, one clip [2K1C] Goldblatt rats, n = 53) or sham operation (n = 49). One half of the 2K1C and sham rats received the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 1.48 mmol/L) in their drinking water for 2 weeks after the surgical procedure. Mean blood pressure increased significantly in the 2K1C-water (182 mm Hg), 2K1C-L-NAME (197 mm Hg), and sham-L-NAME (170 mm Hg) rats compared with the sham-water rats (127 mm Hg). Plasma renin activity was not altered by L-NAME but significantly enhanced after renal artery clipping. A significant and similar increase in the cross-sectional area of the carotid artery was observed in L-NAME and vehicle-treated 2K1C rats. L-NAME per se did not modify cross-sectional area in the sham rats. There was a significant upward shift of the distensibility-pressure curve in the L-NAME- and vehicle-treated 2K1C rats compared with the sham-L-NAME rats. L-NAME treatment did not alter the distensibility-pressure curve in the 2K1C rats. These results demonstrate that the mechanisms responsible for artery wall hypertrophy in renovascular hypertension are accompanied by an increase in arterial distensibility that is not dependent on the synthesis of nitric oxide.     

A new method of measuring renal function in conscious rats without the use of radioisotopes

The purpose of the current experiment was to develop fast and accurate assays for measuring glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). An enzymatic method was developed for the determination of inulin, and a colorimetric method was developed for determination of p-aminohippurate (PAH) in the plasma and urine of rats. These assays are easily automated and do not require the use of radioisotopes or corrosive chemicals. Glomerular filtration rate was measured by the clearance of inulin, and effective renal plasma flow was measured by the clearance of PAH. Blood pressure, heart rate, and renal function (urine volume, electrolytes, GFR, and ERPF) were measured in conscious rats for 1.5 h prior to drug treatment and for 3 h after treatment. Baseline renal function was compared to historical data. Acute changes in GFR and ERPF following administration of the vasoconstrictor peptide endothelin-1 (ET-1) were accurately measured with results similar to those obtained with older methodologies. These new methods offer many advantages over previously described methods by eliminating the use of radioisotopes and harsh chemicals. In addition, these methods can be used with an automated instrument with high accuracy and precision. Therefore, these new methods can be used to accurately determine GFR and ERPF and are sensitive enough to detect acute changes in GFR and ERPF in conscious animals.     

The renal effects of melatonin in intact and epiphysectomized rats

Epiphysectomy in adult pubescent Wistar rats causes polyuria and Na uresis at the expense of the increased rate of the glomerular filtration and sodium filtration charge. Melatonin in a dose of 4.31 mkM/100 g of the body weight increased the glomerular filtration of both sodium and water and stimulated the sodium tubular transport in rats with intact epiphysis and did not normalize changes of the nephron excretory activity after epiphysectomy.     

Effects of angiotensin-converting enzyme inhibition on renal adaptations to acute furosemide administration in conscious rats

Understanding the developmental steps in megakaryocyte differentiation requires information regarding the microenvironmental influences which direct or permit the growth and differentiation of these cells. The megakaryocyte microenvironment, like other lineages, is a complex structure comprised of the various megakaryocytic cells, the extracellular matrix (ECM) surrounding them, and the hematopoietic stromal cells which elaborate both growth factors and ECM. As a result, definition of the minimal essential requirements for megakaryocyte development is difficult. The intricacies of megakaryocyte development are further complicated by the cellular heterogeneity of both mature megakaryocytes and their precursors, as well as a differential responsiveness of these cells to hematopoietic growth factors. This review focuses on defining the various subpopulations of megakaryocytic cells and examining their functional distinctions and in vitro responsiveness to various stimuli.     

Prostaglandins maintain renal vasodilation and hyperfiltration during chronic nitric oxide synthase blockade in conscious pregnant rats

Rats demonstrate renal vasodilation and hyperfiltration in pregnancy. Because both NO and cGMP biosynthesis are increased in gravid rats and because acute administration of NO synthase inhibitors abrogates renal vasodilation and hyperfiltration, NO most likely mediates the renal circulatory changes of gestation. In the present study, we tested the effect of chronic inhibition of NO synthase on effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) in chronically instrumented, conscious, gravid rats. Because gestation is a relatively long-term condition, we postulated that chronic withdrawal of NO would result in sustained inhibition of renal vasodilation and hyperfiltration. Contrary to our hypothesis, the renal circulatory changes of pregnancy were maintained during chronic blockade of NO synthase. That is, subcutaneous administration of 10 micrograms/min N omega-nitro-L-arginine methyl ester (NAME) for 48 hours did not significantly reduce GFR in either virgin or pregnant rats; thus, hyperfiltration persisted in the latter despite chronic NO synthase blockade. In contrast, ERPF was reduced and effective renal vascular resistance (ERVR) increased in both groups of rats during NAME administration but in a parallel fashion, such that renal vasodilation persisted in the gravid animals despite chronic inhibition of NO synthase. However, with superimposition of acute prostaglandin synthesis inhibition (meclofenamate, 10 mg/kg IV), renal vasodilation and hyperfiltration were abolished; ie, the combined treatments of chronic NO synthase blockade and acute prostaglandin synthesis inhibition led to the equalization of GFR, ERPF, and ERVR in conscious virgin and pregnant rats. Inhibition of prostaglandin synthesis alone had little affect on the renal circulation, as previously reported. In summary, prostaglandins are recruited to maintain renal vasodilation and hyperfiltration during chronic NO synthase blockade in conscious pregnant rats.     

Pharmacological stimulation of arterial chemoreceptors in conscious rats produces differential responses in renal cortical and medullary blood flow

1. There have been no previously published data regarding intrarenal blood flow distribution in acute whole-body hypoxic hypoxia and/or arterial chemoreceptor stimulation in normoxic mammals. 2. Cortical and medullary blood flows were measured simultaneously before and in response to pharmacological stimulation of peripheral arterial chemoreceptors by i.v. injection of almitrine bismesylate (0.25 mg/kg). 3. Arterial chemoreceptor excitation reduced cortical blood flow but only in innervated kidneys. An effect on medullary blood flow was observed in neither innervated nor denervated kidneys. 4. These data indicate that renal cortical and medullary blood flows react differently to arterial chemoreceptor stimulation.     

Cardiovascular effects of nitric oxide and adenosine in the nucleus tractus solitarii of rats

It has been shown that nitric oxide (NO) is synthesized in the central nervous system as well as in vascular endothelial cells. We recently reported that NO was involved in central cardiovascular regulation, modulated the baroreflex, and was involved in a reciprocal release with excitatory amino acids in the nucleus tractus solitarii (NTS) of rats. We also reported previously that adenosine increased the release of glutamate in the NTS. The purpose of the present study was to investigate the possible interaction of NO and adenosine in the NTS. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure was monitored intra-arterially. Unilateral microinjection of L-arginine (3.3 nmol/60 nL) into the NTS produced decreases in blood pressure and heart rate. Microinjection of adenosine (2.3 nmol/60 nL) also produced depressive and bradycardic effects. These cardiovascular effects were attenuated by prior administration of the specific adenosine receptor antagonist DPSPX (0.92 nmol). Similarly, prior administration of NO synthase inhibitor NG-monomethyl-L-arginine or NG-nitro-L-arginine methyl ester significantly attenuated the depressive and bradycardic effects of adenosine. These results demonstrate a reciprocal attenuation of adenosine receptor antagonist and NO synthase inhibitor on L-arginine and adenosine responses, respectively, in the NTS and implicate an interaction between NO and adenosine in central cardiovascular regulation.     

Interrelationship of cardiovascular effects, plasma levels of nicorandil, and vascular cGMP formation in conscious rats

OBJECTIVE: To determine the reproducibility of duplex Doppler waveform analysis and fetal cardiac interventricular septal thickness measurement and to compare these parameters in matched pregnancies with and without well-controlled maternal Type 1 diabetes at 18-20 weeks of gestation. DESIGN: A prospective blind twin cohort study and a blinded inter-observer and intra-observer agreement study. SETTING: A tertiary referral prenatal diagnostic unit within a university hospital. RESULTS: Good inter- and intra-observer agreement was found for the measurement of transvalvular peak flow velocities and the duration of ventricular ejection in the fetal heart. Inter-observer agreement for aortic flow acceleration rate was poor. M-mode measurement of interventricular septal thickness showed moderate reproducibility. The mean (SD) width of the interventricular septum in the fetuses of well controlled diabetic women was 2 1 mm (0.2 mm), and was significantly greater (P=0.01) when compared with the corresponding value in matched controls [1.9 mm (0.2 mm)]. No cardiac functional differences were evident. CONCLUSIONS: On-screen video analysis of Doppler cardiac flow waveforms and M-mode measurement of intraventricular septal thickness demonstrated good reproducibility. The fetuses of well controlled diabetic pregnancies demonstrated signs of altered cardiac morphology early in pregnancy, before any evident alterations in cardiac function.