sincalide and Hypertension

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

Acupuncture or electroacupuncture (EA) potentially offers a nonpharmacological approach to reduce high blood pressure (BP). However, ~70% of the patients and animal subjects respond to EA, while 30% do not. EA acts, in part, through an opioid mechanism in the rostral ventrolateral medulla (rVLM) to inhibit sympathoexcitatory reflexes induced by gastric distention. CCK-8 opposes the action of opioids during analgesia. Therefore, we hypothesized that CCK-8 in the rVLM antagonizes EA modulation of sympathoexcitatory cardiovascular reflex responses. Male rats anesthetized with ketamine and α-chloralose subjected to repeated gastric distension every 10 min were examined for their responsiveness to EA (2 Hz, 0.5 ms, 1-4 mA) at P5-P6 acupoints overlying median nerve. Repeated gastric distension every 10 min evoked consistent sympathoexcitatory responses. EA at P5-P6 modulated gastric distension-induced responses. Microinjection of CCK-8 in the rVLM reversed the EA effect in seven responders. The CCK1 receptor antagonist devazepide microinjected into the rVLM converted six nonresponders to responders by lowering the reflex response from 21 ± 2.2 to 10 ± 2.9 mmHg (first vs. second application of EA). The EA modulatory action in rats converted to responders with devazepide was reversed with rVLM microinjection of naloxone (n = 6). Microinjection of devazepide in the absence of a second application of EA did not influence the primary pressor reflexes of nonresponders. These data suggest that CCK-8 antagonizes EA modulation of sympathoexcitatory cardiovascular responses through an opioid mechanism and that inhibition of CCK-8 can convert animals that initially are unresponsive to EA to become responsive.

Topics: Animals; Blood Pressure; Devazepide; Disease Models, Animal; Electroacupuncture; Enkephalins; Hormone Antagonists; Hypertension; Male; Mechanotransduction, Cellular; Medulla Oblongata; Microinjections; Narcotic Antagonists; Pressure; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Reflex; Sincalide; Stomach; Time Factors

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

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.

Topics: Animals; Autoradiography; Corpus Striatum; Hypertension; Male; Nucleus Accumbens; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Cholecystokinin; Reference Values; Sincalide; Tissue Distribution; Up-Regulation

The regional brain and spinal cord concentrations of cholecystokinin-octapeptide (CCK-8) were measured in age-matched normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats. The relative order of distribution of CCK-8 in the WKY strain was hippocampus (20.5 +/- 1.3 pmol/g) greater than cortex greater than striatum = hypothalamus greater than midbrain = thalamus greater than spinal cord greater than medulla oblongata/pons (MO/P, 1.6 +/- 0.2 pmol/g) whereas in the SH strain this order was hippocampus (12.9 +/- 0.8 pmol/g) greater than cortex = striatum greater than hypothalamus greater than midbrain greater than thalamus = spinal cord greater than MO/P (1.4 +/- 0.2 pmol/g). The concentrations of CCK-8 in the cerebellum were at the level of assay sensitivity (0.5 pmol/g in both strains). In comparison to the WKY rats, the SH strain had significantly lower levels of CCK-8 in the hippocampus (-37%), cortex (-28%), spinal cord (-23%) and pituitary (-57%). The lowered levels of CCK-8 in the brain of the SH rat may be causally related to, or result from, the cardiovascular, behavioural or morphological abnormalities of this strain.

Topics: Age Factors; Animals; Brain Chemistry; Female; Hypertension; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sincalide; Spinal Cord

In the present study, the mean arterial pressures (MAP) and heart rates (HR) were measured in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) that had received a 10-day continuous subcutaneous infusion of either saline or the centrally acting alpha-adrenoceptor agonist clonidine (10 micrograms/kg/h). In separate groups of similarly treated rats, the concentrations of neurotensin (NT), vasoactive intestinal polypeptide (VIP), cholecystokinin octapeptide (CCK-8), calcitonin gene-related peptide (CGRP), and neuropeptide Y (NPY) were measured in the cortex (COR), hypothalamus (HYP), medulla oblongata/pons (MO/P), and cervical (CSC) and thoracic (TSC) spinal cord. In comparison to the WKY rats, the SHR had significantly lower neuropeptide concentrations within the COR (NPY, CCK-8), HYP (NT), MO/P (NPY, NT, and CCK-8), CSC (all neuropeptides), and TSC (NPY, NT, CCK-8, and VIP). The infusion of clonidine lowered the MAP of the WKY and SHR rats (-10 and -35 mm Hg, as compared with respective saline controls) and HR in the WKY rats (-45 beats/min). In general, the infusion of clonidine produced decreases in neuropeptide levels within the CNS of the WKY rather than the SHR strain. When there was a strain difference (i.e., SHR less than WKY), it was evident, particularly within the spinal cord, that clonidine reduced the levels of the neuropeptides in the WKY rats to those levels in the SHR. These findings suggest that the reduced neuropeptide concentrations of the SHR (particularly those within the CSC) and TSC may be a result of, rather than a causal factor in, hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Chemistry; Clonidine; Female; Hypertension; Infusion Pumps; Infusions, Parenteral; Neuropeptide Y; Neuropeptides; Neurotensin; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sincalide; Spinal Cord