Alterations in phospholipid N-methylation of cardiac subcellular membranes due to experimentally induced diabetes in rats.

Phosphatidylethanolamine N-methylation was examined in cardiac subcellular membranes after inducing chronic experimental diabetes in rats (65 mg streptozotocin/kg, i.v.). The incorporation of radiolabeled methyl groups from S-adenosyl-L-methionine in diabetic sarcolemma was significantly depressed at all three catalytic sites (I, II, and III) of the methyltransferase system. An increase in methyl group incorporation was evident at site I without any changes at sites II and III in diabetic sarcoplasmic reticulum and mitochondria. Similar changes were also seen for the individual N-methylated lipids (monomethyl-, dimethylphosphatidylethanolamine, and phosphatidylcholine) specifically formed at each catalytic site in all cardiac membranes from diabetic animals. These alterations in N-methylation were reversible by a 14-d insulin therapy to the diabetic animals. In the presence of 10 microM ATP and 0.1 microM Ca2+, N-methylation was maximally activated at site I in both control and diabetic sarcolemma and sarcoplasmic reticulum, but not in mitochondria. Incubation of cardiac membranes with of S-adenosyl-L-methionine showed that Ca2(+)-stimulated ATPase activities in both sarcolemma and sarcoplasmic reticulum were augmented; however, the activation of diabetic sarcolemma was lesser and that of diabetic sarcoplasmic reticulum was greater in comparison with the control preparations. These results identify alterations in phosphatidylethanolamine N-methylation in subcellular membranes from diabetic heart, and it is suggested that these defects may be crucial in the development of cardiac dysfunction in chronic diabetes.

Characterization of heart sarcolemmal phospholipid methylation.

The transmethylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) was studied in rat heart sarcolemmal membrane. Kinetically, three apparent Km values for S-adenosyl-L-methionine (AdoMet) were obtained when the total [3H]methyl groups incorporation into the phospholipids was examined in the presence of 0.01-250 microM AdoMet. A first methyltransferase active site having a very low Km (0.1 microM) for AdoMet showed a partial requirement for Mg2+ and an optimum pH of 8.0 with a major formation of phosphatidyl-N-monomethylethanolamine (PMME). Both Ca2+ and K+ were inhibitory to this site. A second active site with a Km of 3.6 microM showed an optimum pH of 7.0 with predominant formation of phosphatidyl-N,N-dimethylethanolamine (PDME) and no Mg2+ requirement; in addition, transmethylation activity was also observed over a broad alkaline pH range (9-11) with an optimum at pH 10.5. This site was insensitive to Ca2+ but was stimulated by Na+, while K+ had an inhibitory effect. A third active site with a Km of 119 microM showed an optimum pH of 10.5 with major formation of PC and no Mg2+ requirement. This site was also insensitive to Ca2+ but markedly inhibited by both K+ and Na+. Under optimal conditions, the activities of all three methyltransferase sites were linear for at least 30 min of incubation and the sensitivity to the inhibitory effect of S-adenosyl-L-homocysteine was different for each site. Addition of exogenous PMME and PDME as substrates enhanced the synthesis of the corresponding methylated products by 3-5-fold and 3-8-fold, respectively. In contrast, exogenous PE failed to increase methyltransferase activity. These results provide evidence for the existence of three distinct methyltransferase active sites in rat heart sarcolemma.

Modulation of cardiac beta-adrenergic receptors by dopamine beta-hydroxylase.

Incubation of cardiac sarcolemma in the presence of dopamine beta-hydroxylase (DBH), a catecholamine biosynthetic enzyme, increased beta-adrenergic receptor density by 68% as measured by [3H]dihydroalprenolol (DHA) binding. The addition of DBH to plasma membranes isolated from brain, kidney, skeletal muscle, liver and intestine did not alter [3H]DHA binding. Cardiac alpha-receptors were unaffected under similar conditions. Since DBH is coreleased with norepinephrine, these results indicate that a functional coupling of the putative beta-adrenergic receptor with DBH may exist in cardiac muscle.

Adrenoreceptor-mediated effect of neuropeptide Y decreases cardiac inotropic responses.

The effect of neuropeptide Y on the number and affinity of catecholamine receptors in the ventricular myocardium was investigated. Receptor binding studies showed that incubation of cardiac membrane in the presence of neuropeptide Y (NPY, 10(-7) M) decreased the number of alpha/beta-adrenoceptor binding sites (Bmax) without affecting the affinity (KD) of these receptors. Although not able to modulate the contractility by itself, NPY was able to decrease the positive inotropic effects of phenylephrine and isoproterenol in the isolated, perfused myocardium. Ca2+/Mg(2+)-ATPase activity, measured from the sarcolemma, sarcoplasmic reticulum and myofibrils, was unaltered whereas the activity of sarcolemmal Na+/K(+)-ATPase was decreased when NPY was included in the media. On the other hand, NPY was shown to increase the phosphoinositide-phospholipase C associated with the sarcolemma. These findings support the hypothesis that NPY modulates postsynaptic adrenergic receptors in the myocardium and can affect the adrenergic-induced, inotropic response.

Dexamethasone for the prophylaxis of radiation-induced emesis: a National Cancer Institute of Canada Clinical Trials Group phase III study.

PURPOSE: To investigate the efficacy of dexamethasone as a prophylactic antiemetic for patients receiving fractionated radiotherapy to the upper abdomen in a randomized controlled trial. PATIENTS AND METHODS: One hundred fifty-four patients planned to receive fractionated radiotherapy to fields involving the upper abdomen (minimum total dose, 20 Gy; minimum number of fractions, five) were randomized to receive prophylactic dexamethasone (2 mg orally three times a day [tid], starting in the morning of first treatment and continuing until after their fifth treatment) or placebo. The primary end point of the study was the proportion of patients free from emesis during the study period. Secondary end points included a quality-of-life assessment using the core questionnaire of the European Organization for Research and Treatment of Cancer and side effects of dexamethasone therapy in this population of patients. RESULTS: Fifty-four (70%) out of 75 patients receiving dexamethasone had complete protection versus 37 (49%) out of 75 patients on placebo (P = .025). Most emetic episodes occurred during the initial phase of treatment. Although there was no difference in global quality of life between the two sets of patients, patients receiving dexamethasone had less nausea and vomiting and less loss of appetite but more insomnia. CONCLUSION: Dexamethasone 2 mg tid seems to be an effective prophylactic antiemetic in this situation. Side effects were acceptable, but there seemed to be no overall effect on global quality of life.

Prophylaxis of radiation-associated mucositis in conventionally treated patients with head and neck cancer: a double-blind, phase III, randomized, controlled trial evaluating the clinical efficacy of an antimicrobial lozenge using a validated mucositis scoring system.

PURPOSE: Mucositis occurs in almost all patients treated with radiotherapy for head and neck cancer. The aim of this multicenter, double-blind, prospective, randomized trial was to evaluate the clinical efficacy of an economically viable antimicrobial lozenge (bacitracin, clotrimazole, and gentamicin [BcoG]) in the alleviation of radiation-induced mucositis in patients with head and neck cancer. PATIENTS AND METHODS: One hundred thirty-seven eligible patients were randomized to treatment with either antimicrobial lozenge (69 patients) or placebo lozenge (68 patients). The primary end point of the study was the time to development of severe mucositis from the start of radiotherapy. Secondary end points included severity and duration of mucositis, pain measurement, radiation therapy interruption, and quality of life. Mucositis was scored using a validated mucositis scoring system. RESULTS: Toxicity profiles were similar between the two arms of the study. The median time to development of severe mucositis from the start of radiotherapy was 3.61 weeks on BCoG and 3.96 weeks on placebo (P =.61). There were no statistically significant differences between the arms in the extent of severe mucositis as measured by physician, in oral toxicities as recorded by patients, or in radiotherapy delays. CONCLUSION: This study was conducted on the basis of a pilot study that demonstrated the BCoG lozenge to be tolerable and microbiologically efficacious. A validated mucositis scoring system was used. However, in this group of patients treated with conventional radiotherapy, the lozenge did not impact significantly on the severity of mucositis. Whether such a lozenge would be beneficial in treatment situations where rate of severe mucositis is higher (ie, in patients treated with unconventional fractionation or with concomitant chemotherapy) is unknown.

Beneficial effects of verapamil in diabetic cardiomyopathy.

It has been suggested that the occurrence of an intracellular Ca2+ overload may result in the development of diabetic cardiomyopathy, which is associated with depletion of high-energy phosphate stores and a derangement of ultrastructure and cardiac dysfunction. Accordingly, the effects of verapamil, a Ca2+ antagonist, on cardiac function, ultrastructure, and high-energy phosphate stores in the myocardium were evaluated in rats made diabetic by an intravenous injection of streptozocin (65 mg/kg). Four weeks after the induction of diabetes, the animals were treated with three doses (2, 4, or 8 mg.kg-1.day-1) of verapamil for 4 wk until they were used for the measurement of different parameters. Untreated diabetic animals had slower heart rates, depressed rate of contraction and rate of relaxation, lower peak left ventricular systolic pressure, and elevated left ventricular diastolic pressure. All of these changes were significantly improved in diabetic rats receiving verapamil treatment. The beneficial effects of verapamil were more evident with higher doses (8 mg.kg-1.day-1) than with the lower doses (2 mg.kg-1.day-1). The diabetic animals also showed alterations in myocardial high-energy phosphate stores and exhibited evidence of ultrastructural damage; these abnormalities were improved by verapamil treatment without affecting their hyperglycemic status. Our results demonstrate that verapamil is capable of preventing diabetes-induced myocardial changes and support the involvement of Ca2+ in the cardiac pathology during diabetes.

Neuropeptide Y modulation of sympathetic activity in myocardial infarction.

OBJECTIVES: We examined the possible effect of neuropeptide Y in modulating central sympathetic activity after myocardial infarction in rats. BACKGROUND: Previous studies have shown the coexistence of neuropeptide Y and norepinephrine in the brain and a possible functional interaction between the two. Neuropeptide Y inhibits the release of norepinephrine at the presynaptic level and can be considered to act as a neuromodulator. METHODS: Two groups of rats were examined in this study-an experimental group, defined as those rats undergoing left coronary artery ligation, and a sham group without coronary artery ligation, serving as the control group. The animal in both groups underwent microdialysis in the paraventricular nucleus at 2, 4 and 8 weeks after operation. Microdialysis samples were collected with and without injecting neuropeptide Y in the paraventricular nucleus. The concentration of norepinephrine was determined by injecting purified microdialysate samples during high performance liquid chromatography. To explore the receptor's possible role, autoradiographic localization of neuropeptide Y receptors in the paraventricular nucleus was also carried out in the experimental and sham groups. RESULTS: The concentration of norepinephrine measured in the samples was decreased by 50% with neuropeptide Y in 2- and 4-week old rats after infarction, but by only 20% (p < 0.05) in 8-week old rats after infraction. The diminished inhibitory effects of neuropeptide Y on norepinephrine release was associated with increased sympathetic activity, as reflected by plasma norepinephrine; 8-week old rats after infarction had almost a 100% (p < 0.05) increase in their plasma norepinephrine level compared with the sham group. Autoradiography revealed a significant decrease in density of neuropeptide Y receptors in the paraventricular nucleus in 8-week old rats after infarction (p < 0.05). CONCLUSIONS: The data presented in this report suggest that the reduction of the inhibitory activation of neuropeptide Y on sympathetic release may contribute to elevated norepinephrine levels after myocardial infarction.

Endoscope-assisted inguinal hernia repair.

BACKGROUND: Since the advent of laparoscopic inguinal hernia repair, the procedure has invited numerous controversies, and although the procedure has some definitive advantages, no definitive indications for its use have been formulated. The objective of this study was to investigate a novel method for inguinal hernia repair (through a small 2 cm to 2.5 cm) single skin incision that combines the time-tested fundamentals of Lichtenstein's tension-free repair with the advantages of laparoscopic assistance. METHODS: The study was conducted as a randomized, controlled trial over a 1-year period and included 50 patients. Only patients with simple reducible hernias without associated comorbid conditions were included. The patients were randomized into 2 groups of 25 patients each. One group underwent conventional tension-free meshplasty, while the other group underwent the repair through a single 2-cm to 2.5-cm skin incision with laparoscopic assistance. This repair was carried out with the help of an indigenously designed steel retractor, 10-mm laparoscope, and conventional instruments; the mesh was fixed with the help of endotacks. Univariate analysis of variance techniques using SPSS 7.5 software was used for data analysis. RESULTS: Two groups were compared for time taken for the procedure, size of skin incision, postoperative pain, complications, return to work, and cosmetic appearance. The results showed a significant decrease in postoperative pain and an earlier return to work, along with much improved cosmesis for the new procedure. CONCLUSIONS: Although the study was conducted with a limited number of patients and a very short follow-up, it is worth considering this method over laparoscopic and conventional techniques, especially in reducible hernias.

Noradrenaline turnover and metabolism in myocardium following aortic constriction in rats.

STUDY OBJECTIVE: The aim was to provide meaningful information on the function of the sympathetic system soon after an increased pressure overload on the heart. DESIGN: Noradrenaline storage, turnover, uptake, and synthesis were investigated at 3, 14, and 28 d after aortic banding in rats. Sham operated rats without aortic banding were used as control group. EXPERIMENTAL MATERIAL: Left ventricle, spleen, and kidney from male Sprague-Dawley rats (175-200 g) were used in this study. MEASUREMENTS AND MAIN RESULTS: Cardiac noradrenaline concentration was decreased at 3 d and 28 d after banding and increased at 14 d; left ventricular mass was increased from 14 d onwards. The rate of change in the specific activity of myocardial noradrenaline (noradrenaline turnover) as well as dopamine beta hydroxylase, an enzyme for noradrenaline synthesis, was unaltered at 3 d, increased at 14 d, and decreased at 28 d after aortic banding. Myocardial [3H]noradrenaline uptake, on the other hand, was decreased at all time points studied. The changes observed in the myocardium at day 14 were specific since noradrenaline turnover rate was unaltered in other peripheral organs such as spleen and kidney. Furthermore, after ganglionic blockade with pentolinium, both sham operated control and banded animals had identical, low noradrenaline turnover rate constants, and significant restoration of cardiac weight and noradrenaline stores was observed in the hearts from banded animals. CONCLUSIONS: Noradrenaline turnover and metabolism are altered soon after imposing increased workload on heart. Whether or not the changes in the sympathetic activity are a prerequisites for hypertrophy still remains to be seen.

Beneficial effects of propionyl L-carnitine on sarcolemmal changes in congestive heart failure due to myocardial infarction.

OBJECTIVE: Earlier studies have revealed sarcolemmal (SL) defects in congestive heart failure due to myocardial infarction; however, the mechanisms of SL changes in the failing heart are poorly understood. Since congestive heart failure is associated with various metabolic abnormalities including a deficiency of carnitine, we examined the effects of propionyl L-carnitine, a carnitine derivative, in animals with congestive heart failure. METHODS: For this purpose, heart failure in rats was induced by occluding the coronary artery and 3 weeks later the animals were treated with 100 mg/kg (i.p. daily) propionyl L-carnitine for 4 weeks. The sham control group received saline injections. The animals were assessed for their left ventricular function. SL membranes were examined for Na(+)-K+ ATPase, Na(+)-Ca2+ exchange and adenylate cyclase activities. RESULTS: A marked improvement in the attenuated left ventricular function of the experimental animals was seen upon treatment with propionyl L-carnitine. The SL adenylyl cyclase activities in control, untreated failing hearts and treated failing hearts were 590 +/- 36, 190 +/- 22 and 320 +/- 21 pmol cAMP/mg/10 min, whereas the SL Na(+)-K+ ATPase activities were 35.7 +/- 2.8, 22.5 +/- 2.4 and 30.1 +/- 2.8 mumol Pi/mg/h, respectively. Furthermore, the SL Na(+)-dependent Ca(2+)-uptake activity, which decreased in the failing hearts (4.6 +/- 0.4 vs. 9.3 +/- 0.7 nmol Ca2+/mg/2 s for control), was improved (6.8 +/- 0.5 nmol Ca2+/mg/2 s) significantly following treatment with propionyl L-carnitine. CONCLUSION: These results indicate that metabolic therapy with propionyl L-carnitine may attenuate defects in the SL membrane and thus may improve heart function in congestive heart failure due to myocardial infarction.

Neuropeptide Y prevents agonist-stimulated increases in contractility.

Neuropeptide Y has been shown to inhibit contractility in the rat heart. Although the reasons for this effect are not known, it is possible that postsynaptic adrenergic mechanisms involving neuropeptide Y may be responsible. To ascertain whether this neuromodulatory effect is possible for decreasing contractility, we investigated the effect of neuropeptide Y on agonist-stimulated contractility of the isolated rat myocardium. Receptor binding studies of purified cardiac membranes showed that incubating membrane in the presence of neuropeptide Y (10(-7) mol/L) decreased the number of alpha-/beta-adrenoceptor binding sites without affecting the affinity of these receptors. Isolated hearts perfused with phenylephrine (10(-5) to 10(-10) mol/L) or isoproterenol (10(-5) to 10(-10) mol/L) in a nonrecirculating Langendorff setup demonstrated a significant increase in contractility over control values, whereas no change in contractility was observed when the hearts were perfused with neuropeptide Y (10(-7) mol/L). However, in the presence of both agonist and neuropeptide Y the increase in contractility previously seen with agonist alone was not evident. Comparisons made with hearts taken from aortic banded rats yielded similar results. Although neuropeptide Y itself was ineffective in decreasing contractility, it prevented the agonists from stimulating contractility when perfused together. We conclude that neuropeptide Y does not directly decrease contractility but prevents agonist-stimulated increases in contractility through alpha-/beta-adrenoceptor pathways. This neuromodulatory effect of neuropeptide Y is unchanged in situations of increased sympathetic activity, such as hypertension.

Extracorporeal liver perfusion system for successful hepatic support pending liver regeneration or liver transplantation: a pre-clinical controlled trial.

BACKGROUND: There is a well recognized need for a system capable of providing effective support for patients with hepatic failure pending liver regeneration or liver transplantation. Recent attempts of using bioartificial liver containing encapsulated porcine hepatocytes, the deployment of emergency whole liver, or hepatocyte transplantation are complex and not consistently successful. The technique of ex vivo hepatic perfusion developed and used clinically by Abouna in the 1970s, has now been redesigned in a perfusion circuitry that mimics the physiological conditions of a normal liver. Before clinical application of this system, a preclinical trial was carried out in dogs with induced hepatic failure. METHODS: Acute hepatic failure was induced in dogs by an end-to-side porto caval shunt, followed 24 hr later, by a 2-hr occlusion of the hepatic artery. All animals (n=18) were medically supported and were divided into three groups. In the control group (n=6) only medical support was used. In the experimental group (n=12) the animals were connected to the ex vivo liver support apparatus during acute hepatic failure via an AV shunt using a dog liver (n=6) or calf liver (n=6) (after a temporary extracorporeal bovine kidney transplant to remove preformed xeno antibody). Hepatic perfusion was carried out at 37 degrees C through the hepatic artery and portal vein at physiological pressures, and blood flow rate for 6-8 hr. RESULTS: All control animals died of progressive hepatic failure at 14-19 hr after clamping the hepatic artery. The animals treated with ex vivo liver showed remarkable clinical and biochemical improvement. Five animals survived for 36-60 hr. Another seven animals recovered completely and became long-term survivors with biochemical and histological evidence of regeneration of their own liver. Biopsy of the allogeneic ex vivo liver at the end of perfusion showed some interstitial edema. Similar biopsy of the xenogeneic calf liver showed only mild and delayed xenograft rejection, which was most likely due to removal of preformed xeno antibody by temporary transplantation of the calf kidney before liver perfusion. CONCLUSIONS: The observations and results obtained in this trial strongly confirm that extracorporeal perfusion through a whole liver, using the system described, is very successful and cost effective for the treatment of acute, but reversible hepatic failure, as well as serving as a bridge to liver transplantation. The time has come for this form of liver support technology to be reintroduced and widely used.

Topographical organization in the nucleus accumbens of afferents from the basolateral amygdala and efferents to the lateral hypothalamus.

The basolateral region of the amygdala and the lateral hypothalamic area are involved in cardiovascular regulation. The aim of the present investigation was to determine if the terminal field of afferent projections from the basolateral nucleus of the amygdala to the nucleus accumbens overlap with the origin of the efferent projections from the nucleus accumbens to the lateral hypothalamic area. Neurons projecting from the nucleus accumbens to the lateral hypothalamic area were labeled by injecting the retrograde tracer Fluoro-Gold in the lateral hypothalamus of rats. In the same rats, fiber terminals from the amygdala to the nucleus accumbens were labeled by injecting the anterograde tracer Fluoro-Ruby in the basolateral region of the amygdala. Injections of Fluoro-Gold in the lateral hypothalamus labeled neurons in the posteromedial portion of the nucleus accumbens. Injections of Fluoro-Ruby in the basolateral amygdala labeled fibers and terminals in all parts of the nucleus accumbens with the highest density being found in the posteromedial part of the nucleus accumbens where Fluoro-Gold-labeled neurons were located. When regions of the posteromedial nucleus accumbens were examined under high-magnification, Fluoro-Ruby-labeled terminals appeared to make contact on Fluoro-Gold-labeled dendrites and cell bodies. This investigation demonstrates that there is a distinct overlap in the posteromedial region of the nucleus accumbens between the terminal field from neurons originating in the amygdala and neurons which project to the lateral hypothalamus. In addition, neurons in the basolateral amygdala appear to make synaptic contact with neurons in the nucleus accumbens that project to the lateral hypothalamic area.(ABSTRACT TRUNCATED AT 250 WORDS)

Up-regulation of dopamine receptors in the brain of the spontaneously hypertensive rat: an autoradiographic analysis.

Recent evidence points to a dysfunction of brain dopaminergic mechanisms in the spontaneously hypertensive rat. Using in vitro receptor autoradiography, we assessed the density of D1 and D2 dopamine receptors in the brain of spontaneously hypertensive rats and their normotensive controls the Wistar-Kyoto rat. Brain sections from five- and 15-week-old rats were incubated with 1 nM [3H]SCH 23390 (D1 receptor antagonist) or 15 nM [3H]sulpiride (D2 receptor antagonist), and exposed along with radioactive standards to 3H-Hyperfilm. The binding density of selected brain regions (anteromedial prefrontal cortex, cingulate cortex, lateral septal nucleus, nucleus accumbens, caudate-putamen, globus pallidus, amygdaloid complex) were quantified using computer-assisted densitometry. These experiments showed a significant increase in the binding density of [3H]SCH 23390 in the nucleus accumbens and caudate-putamen of five- and 15-week-old spontaneously hypertensive rats. The binding density of [3H]SCH 23390 was increased in the lateral septal nucleus of five-week-old and globus pallidus of 15-week-old spontaneously hypertensive rats. The binding density of [3H]sulpiride was also greater in the nucleus accumbens of five-week-old spontaneously hypertensive rats. The present investigation demonstrates an up-regulation of D1 dopamine receptors in spontaneously hypertensive rats with established hypertension. More importantly, up-regulation of D1 and D2 dopamine receptors in the striatum of young prehypertensive spontaneously hypertensive rats suggests that dopamine may be involved in the pathogenesis of hypertension in this strain of genetically hypertensive rats.

Evidence against the involvement of nonenzymatic glycosylation in diabetic cardiomyopathy.

There is evidence to suggest that increased nonenzymatic glycosylation (NEG) occurs in hyperglycemic states such as seen in diabetes mellitus. In order to examine the hypothesis that the development of cardiomyopathy in diabetes results from an increased nonenzymatic glycosylation of cardiac sarcolemmal proteins, rats were made diabetic by an intravenous (IV) injection of streptozotocin (65 mg/kg). Twelve weeks after the induction of diabetes, animal showed significantly lower heart rate, left ventricular systolic pressure, rate of contraction (+dp/dt), and rate of relaxation (-dp/dt), whereas left ventricular diastolic pressure was markedly increased. Furthermore, cardiac sarcolemmal Na+, K+ adenosine triphosphatase (ATPase) activity was significantly decreased in diabetic rats. When examined in cardiac crude membranes, as well as in purified sarcolemmal membranes prepared by two different procedures, the levels of NEG did not differ between control and diabetic animals; however, NEG levels were increased in kidney and skeletal muscle. These results indicate that chronic diabetes is associated with functional and biochemical alterations in cardiac muscle and suggest that NEG of cardiac sarcolemma may not play any role in the development of diabetic cardiomyopathy.

Cholecystokinin-induced release of dopamine in the nucleus accumbens of the spontaneously hypertensive rat.

Changes in dopamine neurotransmission in the nucleus accumbens of the spontaneously hypertensive rat (SHR) may be involved in the pathogenesis of hypertension. This investigation tested the hypothesis that the sulfated octapeptide cholecystokinin (CCK8S) induced release of dopamine is greater in the SHR than in its normotensive control, the Wistar-Kyoto rat (WKY). Dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were sampled using microdialysis in the caudal half of the nucleus accumbens of 10-week-old anesthetized SHRs and WKYs. Samples were collected in the following order: 3 baseline, 3 CCK8S (10 mumol/l), and 3 postdrug samples. The samples were then analyzed using high pressure liquid chromatography with electrochemical detection. CCK8S increased dopamine and DOPAC levels in both the SHR and WKY with a larger increase in basal dopamine in the SHR (greater than 200%). Perfusion of the nucleus accumbens with 1 mumol/l of CCK8S or the nonsulfated form of CCK8 (CCK8US, 10 mumol/l) produced no significant increase in the release of dopamine in the SHR. These results indicate that CCK8S-induced release of dopamine in the nucleus accumbens is greater in the SHR. Changes in CCK8S neurotransmission/receptor function may be responsible for the alterations in dopaminergic function of the SHR and the pathogenesis of hypertension.

Cholecystokinin receptor density in the striatum of the spontaneously hypertensive rat.

The possibility that cholecystokinin in the striatum may be involved in hypertension was investigated using in vitro receptor autoradiography. The binding density of 125I-Bolton Hunter labeled cholecystokinin octapeptide (125I-BH-CCK8) was determined using computer-assisted densitometry in the striatum of the spontaneously hypertensive rat (SHR) and its control the Wistar-Kyoto rat (WKY). A significant increase in 125I-BH-CCK8 binding density was found in the lateral part of the caudate-putamen of the SHR. In contrast, a significant decrease in 125I-BH-CCK8 binding density was found in the posteromedial nucleus accumbens of the SHR. These results indicate that CCK8 receptor density is altered in the striatum of the SHR and suggest a role for CCK8 receptors in the pathophysiology of hypertension.

Up-regulation of cholecystokinin receptors in the nucleus accumbens of the young prehypertensive spontaneously hypertensive rat.

We employed receptor autoradiography to test the hypothesis that changes in cholecystokinin neurotransmission in the striatum of the young spontaneously hypertensive rat (SHR) is involved in the development of hypertension. The binding density of 125I-Bolton Hunter labelled cholecystokinin octapeptide (125I-BH-CCK8) in the striatum of 5-week-old prehypertensive SHRs and its normotensive control the Wistar-Kyoto rat (WKY) was determined using computer-assisted densitometry. We found a significant increase in 125I-BH-CCK8 binding density in the nucleus accumbens of the SHR. No difference between the binding density of 125I-BH-CCK8 was found in the caudate-putamen and the prefrontal cortex of SHRs and WKYs. These results suggest that changes in CCK8S neurotransmission or receptor function are not secondary to an increase in arterial blood pressure and, therefore, may be involved in the development of hypertension.

Role of atrial natriuretic peptide in congestive heart failure due to chronic diabetes.

OBJECTIVE: It is now believed that diabetes sensitizes the myocardium so that superimposed hypertension with its attendant vascular changes results in progressive myocyte damage leading ultimately to congestive heart failure. In this regard, remarkable progress has been made within the past few years with a family of closely related peptides, the atrial natriuretic peptides (ANPs), which are involved in the regulation of plasma volume. Any changes in their levels and/or action can be seen to participate in the development of diabetes-induced congestive heart failure. While the literature reasonably supports the evidence for a defect in the ANP-receptor coupling system in hypertensive and diabetic animals, it is not as clear that this is the cause for heart failure. The present article attempts to demonstrate evidence for causality. DESIGN: The present article summarizes existing knowledge on the involvement of ANP in the induction of fluid imbalance. In particular, the role of ANP in congestive heart failure, hypertension, diabetes and congestive heart failure in diabetes is examined. Recent data in experimental hypertensive-diabetic rats, obtained from this laboratory have also been described here. MAIN RESULTS: There are now several reports which indicate high plasma ANP concentrations in both patients and animals with heart failure, thus implicating a role for this peptide. The present paper deals with ANP-induced molecular changes in kidney basolateral membranes in congestive heart failure due to chronic diabetes. CONCLUSION: Congestive heart failure in diabetes with hypertension may be due to uncoupling of the ANP-receptor effector system in the kidney basolateral membrane. It is possible that other neurohumoral agents through a wide variety of activities may also contribute to the pathophysiology of this disease.