cholecystokinin and Hypertension

Cerebral capillary endothelium forms a barrier limiting and controlling the movement of ions and solutes between blood and brain. Recent anatomical, physiological and biochemical studies have suggested the possibility that capillary function may be directly controlled by neuronal structures. Alterations in neuronal systems involved in the regulation of microcirculation may account for microvascular dysfunctions which occur in different pathologic conditions.

Topics: Acetylcholine; Aging; Animals; Biological Transport, Active; Blood-Brain Barrier; Brain; Capillaries; Capillary Permeability; Cerebrovascular Circulation; Cholecystokinin; Diabetes Mellitus; Dopamine; Endothelium; Histamine; Hypertension; Hypoxia, Brain; Locus Coeruleus; Microcirculation; Neural Pathways; Neurons; Norepinephrine; Receptors, Neurotransmitter; Serotonin; Substance P; Vasoactive Intestinal Peptide

We studied the effect of CCK-8 on BP and blood content of CGRP in rats with hypertension caused by fructose or inhibition of NO synthase with L-NAME. The decrease in the CGRP content was found during the development of fructose-induced hypertension, but not L-NAME-caused hypertension. Administration of CCK-8 to fructose-fed animals reduced BP and increased the content of CGRP. In rats with hypertension caused by NO deficit, CCK-8 lowered BP, but did not affect the content of CGRP. These findings suggest that CGRP mediates the hypotensive effect of CCK-8 in fructose-induced hypertension, but not in NO-deficient hypertension.

Topics: Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Cholecystokinin; Fructose; Hypertension; Insulin Resistance; Male; Nitric Oxide; Nitric Oxide Synthase; Peptide Fragments; Rats; Rats, Wistar; Signal Transduction

To understand the changes in physiological responses due to aging, a number of bioactive probes based on different signal transduction pathways are necessary. In this study, we comprehensively and systematically investigated changes in blood vessel function with age using a 336-dipeptide library. In the early stage of hypertension, the most potent vasorelaxant dipeptide was Ser-Tyr (SY) in the mesenteric artery isolated from spontaneously hypertensive rats (SHR). SY-induced vasorelaxation and anti-hypertensive effects were blocked by L-NAME, an inhibitor of nitric oxide synthase (NOS), suggesting that SY activates the NO system. On the other hand, the patterns of dipeptides with vasorelaxation activity in early and advanced stages of hypertension were different. In the advanced stage, the most potent vasorelaxing dipeptide was Asn-Ala (NA). Orally administered NA (1.5 mg/kg) reduced the blood pressure in the advanced stage, at which drugs were sometimes less effective, and the anti-hypertensive effects lasted for 6 hr. The NA-induced vasorelaxation and anti-hypertensive activity was blocked by lorglumide, an antagonist of the cholecystokinin CCK

Topics: Aging; Amino Acid Sequence; Animals; Antihypertensive Agents; Blood Pressure; Cholecystokinin; Dipeptides; Drug Evaluation, Preclinical; Hypertension; Male; Mesenteric Arteries; Nitric Oxide; Peptide Library; Proglumide; Rats; Rats, Inbred SHR; Receptors, Cholecystokinin; Vasodilation; Vasodilator Agents

Exact cause of the metabolic syndrome [MS], a global epidemic, is still unclear. Man has same fundamental needs to live as animals but modern man's life-style compels him to acquire certainty of resources for all his needs in a complex social network. Today money has become the sole life essential need. Contrarily none of the animals needs to earn money. Brain is also an organ of the human body with a unique thought process to define logical actions to achieve a person's goals. This way life is a flow of desires followed by logical actions. The person struggles to attain desired goals via the allostatic load but a perceived insurmountable threat can make his flow of life stalled to freeze him. Published data from varied branches of medical science indicates role of hormones in overall homeostasis. Particularly multifaceted role of serotonin is well documented. Adrenalin being the primary mediator of Cori cycle is also well known. From the integration of observations from published data with reference to common human's modern lifestyle, it is hypothesized that a perceived trapped situation in life creates acute chaos of thoughts in brain, which results in acute excess of stress hormones and concurrent depletion of resting hormones, which in turn triggers MS. In global terms, MS indicates an acute imbalance of a few hormones and implies psychosomatic roots of the disorder. This may pave a better way in deciding a personalized holistic protocol with combination of counter regulatory psychoactive medications.

Topics: Acidosis, Lactic; Allostasis; Animals; Brain; Cardiovascular Diseases; Cholecystokinin; Cholesterol; Diabetes Mellitus, Type 2; Diet; Dopamine; Epinephrine; Exercise; Homeostasis; Hormones; Humans; Hypertension; Life Style; Metabolic Syndrome; Microbiota; Models, Theoretical; Motivation; Obesity; Oxytocin; Psychophysiologic Disorders; Risk Factors; Serotonin

We have previously demonstrated that a number of rats fed a moderately high-fat diet (MHFD) become obese and hypertensive and had compromised sympathoinhibitory and vasodilator responses to the gut hormones cholecystokinin (CCK) and gastric leptin. This has implications for increased resistance in vascular beds that attract a large proportion of cardiac output after a meal and may be an important mechanism underlying the development of hypertension in obesity in which food consumption is greatly increased. The aim of this study was to determine whether swapping a MHFD for a low-fat diet (LFD) would induce weight loss in obese animals, reverse the signs of hypertension and restore sympathoinhibitory reflexes. Male Sprague-Dawley rats were placed on a LFD (controls; n = 8) or a MHFD (n = 24) for 11 weeks after which the latter displayed either an obesity-prone (OP) or obesity-resistant (OR) phenotype. All animals were fed a LFD for a further 6 weeks after which they were anaesthetised with isoflurane and artificially ventilated for evaluation of resting arterial pressure (AP) and renal sympathetic nerve responses to CCK (0.1-4 μg/kg) and leptin (15 μg/kg). Weight gain in OP animals remained higher than OR or controls following diet switch (P < 0.05 for both). Resting AP was not significantly different between OP (103 ± 4 mmHg), OR (102 ± 3 mmHg) or control (104 ± 3 mmHg) animals and sympathoinhibitory responses to CCK or leptin were not different between the groups (P > 0.05). These results demonstrate that diet modification can have beneficial effects on sympathetic function and restore normotension without the need for weight reduction.

Topics: Animals; Arterial Pressure; Autonomic Agents; Body Weight; Cholecystokinin; Diet, Fat-Restricted; Diet, High-Fat; Disease Models, Animal; Gastrointestinal Agents; Genetic Predisposition to Disease; Hypertension; Leptin; Male; Obesity; Rats, Sprague-Dawley; Sympathetic Nervous System

The gut hormone cholecystokinin (CCK) acts at subdiaphragmatic vagal afferents to induce renal and splanchnic sympathoinhibition and vasodilatation, via reflex inhibition of a subclass of cardiovascular-controlling neurons in the rostroventrolateral medulla (RVLM). These sympathoinhibitory and vasodilator responses are blunted in obese, hypertensive rats and our aim in the present study was to determine whether this is attributable to (i) altered sensitivity of presympathetic vasomotor RVLM neurons, and (ii) aberrant peripheral or central signalling mechanisms. Using a diet-induced obesity model, male Sprague-Dawley rats exhibited either an obesity-prone (OP) or obesity-resistant (OR) phenotype when placed on a medium high fat diet for 13-15 weeks; control animals were placed on a low fat diet. OP animals had elevated resting arterial pressure compared to OR/control animals (P < 0.05). Barosensitivity of RVLM neurons was significantly attenuated in OP animals (P < 0.05), suggesting altered baroreflex gain. CCK induced inhibitory responses in RVLM neurons of OR/control animals but not OP animals. Subdiaphragmatic vagal nerve responsiveness to CCK and CCK1 receptor mRNA expression in nodose ganglia did not differ between the groups, but CCK induced significantly less Fos-like immunoreactivity in both the nucleus of the solitary tract and the caudal ventrolateral medulla of OP animals compared to controls (P < 0.05). These results suggest that blunted sympathoinhibitory and vasodilator responses in obesity-related hypertension are due to alterations in RVLM neuronal responses, resulting from aberrant central but not peripheral signalling mechanisms. In obesity, blunted sympathoinhibitory mechanisms may lead to increased regional vascular resistance and contribute to the development of hypertension.

Topics: Animals; Arterial Pressure; Baroreflex; Cholecystokinin; Disease Models, Animal; Hypertension; Male; Medulla Oblongata; Neural Inhibition; Nodose Ganglion; Obesity; Proto-Oncogene Proteins c-fos; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Signal Transduction; Sympathetic Nervous System

The gut and kidney command >50% of cardiac output postprandially, highlighting the importance of these vascular beds in cardiovascular homeostasis. The gastrointestinal peptide cholecystokinin (CCK) induces vagally mediated splanchnic sympathoinhibition that is attenuated in animals fed a medium high-fat diet (MHFD); therefore, our aim was to determine whether renal sympathetic nerve discharge (RSND) responses to CCK are also affected by this diet, and whether these changes are associated with obesity and hypertension. Another aim was to determine whether regional vasodilator responses to CCK are affected in obesity-related hypertension. In two separate studies, Sprague-Dawley rats were fed either a low-fat diet (LFD; control) or a MHFD for 13 weeks, after which MHFD animals were classified as obesity prone (OP) or obesity resistant (OR) based on their weight gain falling into the upper or lower tertile, respectively. Arterial pressure and heart rate were monitored in isoflurane-anaesthetized, artificially ventilated animals, and either RSND or regional vascular responses to CCK (0.1-8 μg kg(-1)) were evaluated. The OP rats had higher baseline arterial pressure compared with control/OR rats (P < 0.05). Administration of CCK inhibited RSND and increased renal vascular conductance in control/OR rats, and these responses were significantly blunted in OP rats (P < 0.05 for all). Baseline arterial pressure was positively correlated with weight gain and inversely correlated with CCK-induced vasodilatation (P < 0.05 for both). We hypothesize that in obesity-related hypertension, disruption of the sympathoinhibitory signals elicited by CCK reduces vasodilatation in the splanchnic/renal regions, leading to increased postprandial vascular resistance.

Topics: Animals; Blood Pressure; Cholecystokinin; Diet, Fat-Restricted; Diet, High-Fat; Heart Rate; Hypertension; Kidney; Male; Obesity; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System; Vasodilation

D(1)-like (D(1), D(5)) and D(2)-like (D(2), D(3), D(4)) dopamine receptors interact in the kidney to produce a natriuresis and a diuresis. Disruption of D(1) or D(3) receptors in mice results in hypertension that is caused, in part, by a decreased ability to excrete an acute saline load. We studied D(1)-like and D(2)-like receptor interaction in anesthetized spontaneously hypertensive rats (SHR) by the intrarenal infusion of Z-1046 (a novel dopamine receptor agonist with rank order potency of D(3)> or =D(4)>D(2)>D(5)>D(1)). Z-1046 increased glomerular filtration rate (GFR), urine flow, and sodium excretion in normotensive Wistar-Kyoto rats but not in SHRs. The lack of responsiveness to Z-1046 in SHRs was not an epiphenomenon, because intrarenal cholecystokinin infusion increased GFR, urine flow, and sodium excretion to a similar extent in the two rat strains. We conclude that renal D(1)-like and D(2)-like receptor interaction is impaired in SHRs. The impaired D(1)-like and D(2)-like receptor interaction in SHRs is not caused by alterations in the coding sequence of the D(3) receptor, the D(2)-like receptor expressed in rat renal tubules that has been shown to be involved in sodium transport. Because the diuretic and natriuretic effects of D(1)-like receptors are, in part, caused by an interaction with D(2)-like receptors, it is possible that the decreased Z-1046 action in SHRs is secondary to the renal D(1)-like receptor dysfunction in this rat strain.

Topics: Animals; Biological Transport; Cholecystokinin; Disease Models, Animal; Diuresis; Dopamine Agonists; Glomerular Filtration Rate; Hypertension; Infusions, Intra-Arterial; Kidney; Kidney Function Tests; Male; Naphthols; Natriuresis; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Sequence Analysis, DNA; Sodium

1. The cardiovascular actions of cholecystokinin and related peptides were investigated in the pithed rat. The receptors and the mechanisms involved in these experiments were characterized. 2. Sulphated cholecystokinin octapeptide (sCCK-8, 0.1-100 nmol kg-1, i.v.) elicited a dose-dependent bradycardia and increase in mean arterial blood pressure. Neither gastrin-17 nor pentagastrin had any effect at concentrations up to 100 nmol kg-1. 3. Both the pressor response and bradycardia elicited by sCCK-8 were reduced by the selective CCKA receptor antagonists, devazepide (0.5-50 nmol kg-1) and lorglumide (1-7 mumol kg-1). The selective CCKB receptor antagonists, CI-988 (1 mumol kg-1) and L-365,260 (15 mumol kg-1) did not inhibit the effects of sCCK-8. 4. The pressor response induced with sCCK-8 was reduced by treatment with either phentolamine (3 mumol kg-1) or guanethidine (2 mumol kg-1) and was unaffected by treatment with propranolol, atropine or hexamethonium. The pressor response also persisted following bilateral adrenalectomy. 5. The bradycardia induced with sCCK-8 was unaffected by treatment with phentolamine, propranolol, guanethidine, atropine, hexamethonium or bilateral adrenalectomy. 6. The tetrapeptide of cholecystokinin (CCK-4) elicited a dose-dependent pressor response but did not induce bradycardia. The pressor response was unaffected by devazepide (50 nmol kg-1), L-365260 (15 mumol kg-1) or phentolamine (3 mumol kg-1). 7. In the pithed rat, sCCK-8 acted via CCKA receptors to increase arterial blood pressure indirectly, at least in part, through activation of alpha-adrenoceptors. The observed bradycardia was also mediated byCCKA receptors but possibly through a direct action on the heart.

Topics: Adrenalectomy; Adrenergic Agents; Animals; Benzodiazepinones; Blood Pressure; Bradycardia; Cholecystokinin; Decerebrate State; Devazepide; Dose-Response Relationship, Drug; Gastrins; Guanethidine; Heart Rate; Hormone Antagonists; Hormones; Hypertension; Indoles; Male; Meglumine; Pentagastrin; Phentolamine; Proglumide; Rats; Receptors, Cholecystokinin; Sincalide; Tetragastrin

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.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Blood Pressure; Cholecystokinin; Dopamine; Histocytochemistry; Homovanillic Acid; Hydroxyindoleacetic Acid; Hypertension; Male; Nucleus Accumbens; Rats; Rats, Inbred SHR; Rats, Inbred WKY