tetrodotoxin and Hypertension

Calcium antagonists (slow channel blocking agents) are a very heterogeneous group of agents with dissimilar structural, electrophysiologic and pharmacologic properties. Nifedipine is a potent, long-acting vasodilator that has proved highly efficacious in relieving anginal symptoms caused by coronary vasospasm. In vivo, it exerts no myocardial depressant effects and has no antiarrhythmic properties. Treatment with nifedipine can safely be combined with administration of a beta receptor blocking agent. VErapamil prolongs atrioventricular (A-V) conduction (A-H interval) in a dose-dependent manner. It is the drug of choice for the treatment of reentrant supraventricular arrhythmias, irrespective of whether reentry occurs within the A-V node or through an accessory pathway (the Wolff-Parkinson-White syndrome). Verapamil is only moderately effective as an antianginal agent. Diltiazem is efficacious for the treatment of angiospastic angina, but its value as an antiarrhythmic agent remains to be delineated.

Topics: Angina Pectoris; Angina Pectoris, Variant; Animals; Arrhythmias, Cardiac; Benzazepines; Calcium; Cardiovascular System; Diltiazem; Dogs; Electrophysiology; Humans; Hypertension; Ion Channels; Kinetics; Muscle, Smooth, Vascular; Myocardial Contraction; Myocardial Infarction; Nifedipine; Pyridines; Sheep; Tetrodotoxin; Vasodilator Agents; Verapamil

Diastolic dysfunction can lead to heart failure with preserved ejection fraction, for which there is no effective therapeutic. Ranolazine has been reported to reduce diastolic dysfunction, but the specific mechanisms of action are unclear. The effect of ranolazine on diastolic function was examined in spontaneously hypertensive rats (SHRs), where left ventricular relaxation is impaired and stiffness increased. The objective of this study was to determine whether ranolazine improves diastolic function in SHRs and identify the mechanism(s) by which improvement is achieved. Specifically, to test the hypothesis that ranolazine, by inhibiting late sodium current, reduces Ca(2+) overload and promotes ventricular relaxation and reduction in diastolic stiffness, the effects of ranolazine or vehicle on heart function and the response to dobutamine challenge were evaluated in aged male SHRs and Wistar-Kyoto rats by echocardiography and pressure-volume loop analysis. The effects of ranolazine and the more specific sodium channel inhibitor tetrodotoxin were determined on the late sodium current, sarcomere length, and intracellular calcium in isolated cardiomyocytes. Ranolazine reduced the end-diastolic pressure-volume relationship slope and improved diastolic function during dobutamine challenge in the SHR. Ranolazine and tetrodotoxin also enhanced cardiomyocyte relaxation and reduced myoplasmic free Ca(2+) during diastole at high-stimulus rates in the SHR. The density of the late sodium current was elevated in SHRs. In conclusion, ranolazine was effective in reducing diastolic dysfunction in the SHR. Its mechanism of action, at least in part, is consistent with inhibition of the increased late sodium current in the SHR leading to reduced Ca(2+) overload.

Topics: Acetanilides; Aging; Animals; Blood Pressure; Calcium; Cells, Cultured; Diastole; Disease Models, Animal; Dobutamine; Enzyme Inhibitors; Hypertension; In Vitro Techniques; Male; Myocytes, Cardiac; Piperazines; Ranolazine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrodotoxin; Ventricular Dysfunction, Left

Genetic factors that induce essential hypertension have been examined using genome-wide linkage analyses. A quantitative trait locus (QTL) region that is closely linked to hypertension has been found on chromosome 1 in stroke-prone spontaneously hypertensive rats (SHRSPs). We used 2 congenic rats in which the blood pressure QTL on rat chromosome 1 was introgressed from SHRSP/Izm to Wistar-Kyoto (WKY)/Izm (WKYpch1.0) and from WKY/Izm to SHRSP/Izm (SHRSPwch1.0) rats by repeated backcrossing. Previous studies reported that the intermediate phenotype of this QTL for hypertension is characterized by the hyperactivity of the sympathetic nervous system in response to physiological and psychological stress. We performed intracellular patch-clamp recordings of rostral ventrolateral medulla (RVLM) neurons from WKY, WKYpch1.0, SHRSPwch1.0, and SHRSPs and compared the basal electrophysiological activities of RVLM neurons and the responses of these neurons to angiotensin II. The basal membrane potential of RVLM neurons from WKYpch1.0 was significantly "shallower" than that of the neurons from WKY. The depolarization of RVLM neurons from WKYpch1.0 in response to angiotensin II was significantly larger than that in neurons from WKY rats, whereas the depolarization of RVLM neurons from SHRSPwch1.0 was significantly smaller than that in neurons from SHRSPs. The response to angiotensin II of RVLM neurons from WKYpch1.0 and SHRSPs was sustained even after the blockade of all of the synaptic transmissions using tetrodotoxin. The QTL on rat chromosome 1 was primarily related to the postsynaptic response of RVLM bulbospinal neurons to brain angiotensin II, whereas both the QTL and other genomic regions influenced the basal activity of RVLM neurons.

Topics: Angiotensin II; Animals; Animals, Congenic; Blood Pressure; Chromosomes; Electrophysiological Phenomena; Hypertension; Hypothalamus; Medulla Oblongata; Membrane Potentials; Neurons; Patch-Clamp Techniques; Quantitative Trait Loci; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium Channel Blockers; Tetrodotoxin; Vasoconstrictor Agents

We analysed the influence of aging on the acute effect of clenbuterol, a beta(2)-adrenoceptor agonist, on the vasoconstrictor response induced by electrical field stimulation in mesenteric arteries from young and old spontaneously hypertensive rats (SHRs). Clenbuterol increased the contraction elicited by electrical field stimulation in arteries from both groups, and this was prevented by propranolol. N(G)-nitro-L-arginine methyl ester (L-NAME) also increased the electrical field stimulation-elicited contractions in arteries from both age groups. However, pretreatment with capsaicin increased the electrical field stimulation-induced contractions in young SHRs, but did not modify it in old SHRs. In segments from young SHRs, the treatment with the calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP-(8-37), induced an increase in the electrical field stimulation-induced vasoconstrictor response that was not modified by the subsequent addition of capsaicin. Addition of clenbuterol to L-NAME-treated segments from both groups further increased the response to electrical field stimulation. In segments from young SHRs, clenbuterol failed to increase the electrical field stimulation-induced response in the capsaicin-treated segments, but the response was increased by the subsequent addition of L-NAME. The addition of L-NAME to the clenbuterol-treated segments from old SHRs did not modify the enhanced electrical field stimulation response. Electrical field stimulation induced a similar tritium release in arteries from young and old SHRs preincubated with [3H]noradrenaline. In arteries from young SHRs, isoproterenol increased this release and the increase was abolished by propranolol. Clenbuterol increased the stimulated tritium overflow and exogenous noradrenaline response only in segments from old SHRs, and both effects were abolished by propranolol. To summarize and conclude, clenbuterol increased the electrical field stimulation-induced contraction in segments from both age groups. In young SHRs, clenbuterol seems to inhibit CGRP release, while in old SHRs, it increases the release of and response to noradrenaline and decreases neuronal nitric oxide (NO) release.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Agonists; Aging; Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Capsaicin; Clenbuterol; Dose-Response Relationship, Drug; Electric Stimulation; Enzyme Inhibitors; Hypertension; In Vitro Techniques; Male; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroprusside; Norepinephrine; Phentolamine; Propranolol; Rats; Rats, Inbred SHR; Tetrodotoxin; Tritium; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

Primary cultured human coronary myocytes, derived from patients with end-stage heart failure (NYHA, classes III and IV) caused by an ischemic disease and undergoing heart transplantation, express a voltage-gated tetrodotoxin-sensitive sodium current (INa). This current has atypical electrophysiological and pharmacological properties and regulates intracellular sodium ([Na+]i) and calcium ([Ca2+]i). Our work is aimed at identifying its role and regulation of expression during pathophysiology. We currently investigate whether INa is expressed in vascular smooth muscles cells (VSMCs) isolated from either healthy or diseased (atheromatous) arteries in human and, in parallel, in pig, rabbit and rat. Cells were enzymatically isolated, primary cultured and macroscopic INa were recorded using the whole cell patch clamp technique. We found that INa is expressed in VSMCs grown from human aortic (90%; n = 48) and pulmonary (44%; n = 16) arteries and in the human aortic cell line HAVSMC (94%; n = 27). INa was also detected in pig coronary (60%; n = 25) and rabbit aortic (47%; n = 15) VSMCs, but not in rat aortic myocytes (n = 30). These different INa were activated at similar range of potentials (approximately -45 mV), had similar sensitivity to tetrodotoxin (IC50 around 5 nM) and similar density (2 to 4 pA/pF). Their expression was related to cell dedifferentiation in vitro. However, INa was observed more frequently in human myocytes derived from diseased arteries (ischemic cardiopathy) than in those derived from healthy tissues (dilated cardiopathy). In conclusion, INa may contribute to increase the basal arterial contractility and play a role in pathological situations including hypertension.

Topics: Action Potentials; Animals; Aorta; Aortic Diseases; Arterial Occlusive Diseases; Arteriosclerosis; Cardiomyopathy, Dilated; Cell Differentiation; Cells, Cultured; Coronary Artery Disease; Coronary Vessels; Disease Models, Animal; Humans; Hypertension; Ion Channel Gating; Muscle, Smooth, Vascular; Myocardial Ischemia; Patch-Clamp Techniques; Pulmonary Artery; Rabbits; Rats; Rats, Wistar; Sodium Channels; Swine; Tetrodotoxin; Vasomotor System

The arteries of aged spontaneously hypertensive rats (SHR) exhibit spontaneous electrical activity together with membrane depolarization. Vascular eicosanoid production is increased in SHR, which is further accelerated with aging. We tested the hypothesis that eicosanoids are involved in spontaneous electrical activity, membrane depolarization or both in mesenteric arteries of aged SHR.. Membrane potentials were recorded with microelectrodes from the mesenteric arteries of aged (24 months and older) SHR, aged Wistar-Kyoto (WKY) rats and adult (6- to 8-month-old) SHR.. The membrane potential was less negative in aged SHR (-38.5 +/- 0.9 mV) than in either aged WKY rats or adult SHR (-49.8 +/- 0.5 and -47.2 +/- 0.6 mV, respectively; P < 0.05 for both). Spontaneous electrical activity (5-20 mV, 1-7/min) was present only in arteries of aged SHR. Spontaneous electrical activity was not affected by phentolamine, atropine or tetrodotoxin, but was abolished by indomethacin, a cyclooxygenase inhibitor, and ONO-3708, a thromboxane A2/prostaglandin H2 receptor antagonist. Furthermore, indomethacin and ONO-3708 hyperpolarized the membrane by about 5 mV in aged SHR but not in the other two groups. Spontaneous electrical activity was enhanced by a thromboxane A2 analog and prostaglandin H2, and was abolished by a Ca2+ antagonist, nicardipine, and Ca(2+)-free solution.. These findings suggest that cyclooxygenase-dependent eicosanoids contribute importantly to both spontaneous electrical activity and membrane depolarization, presumably through activation of the thromboxane A2/prostaglandin H2 receptor, in mesenteric arteries of aged SHR, and that spontaneous electrical activity is mediated by a Ca2+ influx through voltage-dependent Ca2+ channels.

Topics: Aging; Animals; Atropine; Blood Pressure; Calcium Channels; Cyclooxygenase Inhibitors; Eicosanoids; Hypertension; Indomethacin; Male; Membrane Potentials; Mesenteric Artery, Superior; Microelectrodes; Muscle, Smooth, Vascular; Phentolamine; Platelet Aggregation Inhibitors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrodotoxin; Thromboxane A2

The objective was to test the hypothesis that the effects of the sodium channel blockers lignocaine and tetrodotoxin are modified in the presence of hypertension-induced hypertrophy. We describe the effects of lignocaine and tetrodotoxin on the action potentials and contractions of left ventricles isolated from 6-month-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The upstroke velocity, amplitude, and overshoot of the action potential were reduced; action potentials were prolonged; and the contractions were reduced on the hypertrophied left ventricles of the SHRs. Lignocaine and tetrodotoxin reduced the upstroke velocity, amplitude, and overshoot and prolonged the left ventricular action potentials. These effects of lignocaine and tetrodotoxin on the SHR were less than those on the WKY left ventricle, possibly because the action potential was already modified by hypertrophy. Lignocaine also reduced the left ventricular contractions and the concentrations producing this reduction were lower for the hypertrophied than those for the normal left ventricle. Tetrodotoxin at 3 x 10(-6)-10(-5) M caused similar attenuation of the WKY and SHR left ventricle contractions. Our study shows that the effects of lignocaine on contraction are enhanced in the hypertrophied left ventricle of the SHR, which suggests that the binding is increased or the access of lignocaine to the receptor is enhanced in hypertrophy. In contrast, the effects of tetrodotoxin on contractions are similar, and thus the binding or access of tetrodotoxin to the receptor is not altered in the hypertrophied left ventricle of the SHR.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Hypertension; Hypertrophy, Left Ventricular; Lidocaine; Myocardial Contraction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium Channels; Tetrodotoxin; Ventricular Function, Left

Topics: Afferent Pathways; alpha-Methyltyrosine; Animals; gamma-Aminobutyric Acid; Hypertension; Levodopa; Microdialysis; Neurotransmitter Agents; Phenylephrine; Potassium; Pressoreceptors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Solitary Nucleus; Tetrodotoxin

1. The aim of the present study was to analyse the noradrenergic transmission in the tail artery of hypertensive rats transgenic for the mouse renin gene Ren-2 (TGR) in comparison with its control, the Sprague-Dawley (SD) rat. 2. Electrical field stimulation (EFS) of vascular segments produced frequency-dependent vasoconstrictions that were significantly greater in TGR arteries. 3. These contractions were abolished by tetrodotoxin (0.1 microM). Phentolamine (50 nM) and prazosin (1 - 10 nM) produced an inhibition of these responses that was significantly greater in SD arteries, whereas that produced by yohimbine (0.5-1 microM) was higher in TGR arteries. In both strains, propranolol (1 microM) potentiated the responses to EFS, and this increase was observed at lower frequencies in TGR arteries. 4. The EFS-evoked [3H]-noradrenaline (NA) release was significantly greater in TGR than in SD rats. However, NA (10 nM-10 microM) reduced and yohimbine and phentolamine (10 nM-10 microM) increased the tritium outflow to a similar degree in both strains. 5. Exogenous NA also induced greater vasoconstriction in TGR arteries. 6. These results suggest the existence in TGR tail artery of an increase in: (a) NA-release and alpha 2-adrenoceptor-mediated contractions, which could contribute to the elevated blood pressure in these rats; and (b) beta-adrenoceptor-mediated vasodilatations, which may be a mechanism to counteract high blood pressure.

Topics: Animals; Animals, Genetically Modified; Arteries; Electric Stimulation; Hypertension; Male; Mice; Norepinephrine; Phentolamine; Prazosin; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Receptors, Adrenergic, beta; Renin; Synaptic Transmission; Tetrodotoxin; Vasoconstriction; Yohimbine

Tetrodotoxin, a violent neurotoxin, is present in puffer fish and may occur in a variety of marine animals. Outbreaks of human tetrodotoxin poisoning, following consumption of marine organisms other than puffer fish, has been rare. We here report an outbreak of tetrodotoxin poisoning following ingestion of gastropod molluscs and its clinical features are discussed. A 71-year-old woman was admitted with hypertension and other neurological symptoms developing after ingestion of some molluscs. A further 16 cases were also found to have typical symptoms of tetrodotoxication after mollusc consumption. Clinical features in these 17 cases were similar to those conventionally found in tetrodotoxin poisoning, except that there was hypertension in eight cases (47%). All except one case had mild poisoning and recovered well. The molluscs consumed comprised two different species: Nassarius castus and Nassarius conoidalis, both of which were shown to contain various amounts of tetrodotoxin. It is concluded that tetrodotoxin poisoning following mollusc consumption is a possibility. Hypertension, as an unusual feature in tetrodotoxication, is frequent in this outbreak, and should be looked for in future cases. The explanation of hypertension in tetrodotoxication may come either from an exaggerated response to sympathetic stimuli, or due to various responses of the vasomotor centre to a small dose of tetrodotoxin. Further studies are required to answer this question.

Topics: Adolescent; Adult; Aged; Animals; Child; Disease Outbreaks; Female; Foodborne Diseases; Humans; Hypertension; Male; Middle Aged; Mollusca; Paresthesia; Shellfish Poisoning; Taiwan; Tetrodotoxin

The present study investigates sympathetic cotransmission and its alpha-adrenoceptor-mediated modulation in kidneys of spontaneously hypertensive rats (SHR, 12 to 14 weeks) and age-matched normotensive Wistar-Kyoto rats (WKY). In the presence of cocaine and corticosterone, renal nerve stimulation at 1 Hz (30 seconds) induced a greater outflow of norepinephrine in SHR (4.2 +/- 0.2 pmol/g kidney) than in WKY (3.0 +/- 0.2 pmol/g kidney). The alpha 2-adrenoceptor antagonist rauwolscine (0.01 to 1 mumol/L) increased the stimulation-induced norepinephrine outflow to a greater extent in SHR than in WKY. In contrast, the alpha 1-adrenoceptor antagonist prazosin (0.03 to 3 mumol/L) increased the stimulation-induced norepinephrine outflow to a greater extent in WKY than in SHR. This difference was not observed in the presence of the P1-purinoceptor antagonist 8-(p-sulfophenyl)theophylline (100 mumol/L). Stimulation at 4 Hz (30 seconds) induced an outflow of ATP (SHR, 12.7 +/- 3.3 pmol/g kidney; WKY, 16.7 +/- 2.1 pmol/g kidney; perfusion solution without cocaine and corticosterone). Prazosin (0.03 mumol/L) markedly reduced pressor responses to stimulation and inhibited the induced ATP outflow by 60% to 70%. When prazosin (0.03 mumol/L) was present, rauwolscine (0.1 mumol/L) increased the induced outflow of norepinephrine and ATP and markedly enhanced prazosin-resistant pressor responses. These pressor responses were abolished by the P2-purinoceptor antagonist suramin (300 mumol/L). The results demonstrate an increased alpha 2-adrenoceptor-mediated automodulation of norepinephrine release in SHR kidneys caused by increased intrasynaptic norepinephrine levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Electric Stimulation; Hypertension; Kidney; Norepinephrine; Prazosin; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic, alpha; Suramin; Tetrodotoxin; Theophylline; Yohimbine

Experiments were designed to clarify whether a tonic L-DOPA system is altered in the caudal ventrolateral medulla (CVLM) of adult spontaneously hypertensive rats (SHR), compared to age-matched Wistar-Kyoto rats (WKY). By microdialysis in CVLM, basal L-DOPA release was constantly detectable and was lower in SHR than that in WKY. This release was reduced by tetrodotoxin perfusion (1 microM) in WKY to a basal level in SHR, whereas no modification occurred with tetrodotoxin in SHR. No difference of tyrosine hydroxylase and DOPA decarboxylase activities in the CVLM region was seen between the two strains. By microinjections into depressor sites of CVLM, L-DOPA (10-300 ng) or L-glutamate (3-300 ng) elicited dose-dependent depressor and bradycardic responses and greater depressor responses to both amino acids were seen at high doses in SHR, compared to WKY. Tonic neuronal activity to release L-DOPA is lost in the CVLM of adult SHR and this loss may contribute to maintenance of hypertension in SHR.

Topics: Animals; Aromatic-L-Amino-Acid Decarboxylases; Blood Pressure; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Levodopa; Male; Medulla Oblongata; Microdialysis; Neurons; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrodotoxin; Tyrosine 3-Monooxygenase

1. L-DOPA as a probable neurotransmitter of baroreceptor afferents functions as a tonic to mediate cardiodepressor control in the nucleus tractus solitarii (NTS). We attempted to clarify further whether a transmitter-like L-DOPA system is altered in NTS of adult spontaneously hypertensive rats (SHR). 2. By microdialysis of left NTS area, the basal L-DOPA release was lower in SHR than in Wistar-Kyoto (WKY) rats. This release was partially inhibited by tetrodotoxin (TTX, 1 mu mol/L) to a similar degree in both strains. TTX-sensitive L-DOPA release was lower in SHR than in WKY. 3. L-DOPA (10-300 ng) and L-glutamate (3-100 ng) microinjected into left NTS produced dose-dependent hypotension and bradycardia. No difference of responses to L-glutamate was seen in either strain. However, depressor but not bradycardic responses to L-DOPA at higher doses were slightly greater in SHR than in WKY. 4. In caudal dorsomedial medulla including NTS, tyrosine hydroxylase activity was increased in SHR compared to WKY, while there was no difference in either strain of L-aromatic amino acid decarboxylase activity. 5. Impaired tonic neuronal activity to release L-DOPA in NTS may be involved in the maintenance of hypertension in SHR. An increase in sensitivity of a recognition site for L-DOPA seems to occur as a compensatory mechanism for impairment of the neuronal activity.

Topics: Animals; Dopamine; Dopamine Agents; Hypertension; Levodopa; Male; Microdialysis; Microinjections; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Solitary Nucleus; Tetrodotoxin; Tyrosine

1. Transmitter-like L-DOPA functions as a tonic to produce postsynaptic cardiopressor responses in the rostral ventrolateral medulla (RVLM) of rats. We attempted to clarify whether a transmitter-like L-DOPA system is altered in the RVLM of spontaneously hypertensive rats (SHR) to maintain the hypertension. 2. By microdialysis of left RVLM area, the basal L-DOPA release was higher in SHR than in Wistar-Kyoto (WKY) rats. This release was partially inhibited by tetrodotoxin (TTX, 1 mu mol/L) to a similar degree in both strains. TTX-sensitive L-DOPA release was higher in SHR than in WKY. 3. L-DOPA (10-600 ng) and L-glutamate (10-300 ng) microinjected into left RVLM produced dose-dependent hypertension and tachycardia. Pressor but not tachycardiac responses to L-DOPA at lower doses were slightly greater in SHR than in WKY, whereas no difference to L-glutamate was observed in either strain. 4. In RVLM regions, there was no difference of tyrosine hydroxylase activity in SHR or WKY; however, L-aromatic amino acid decarboxylase activity was lower in SHR than in WKY. 5. Enhanced presynaptic neuronal L-DOPA release, including a decrease in decarboxylation and sensitization of postsynaptic pressor sites to L-DOPA in RVLM, may be involved in the maintenance of hypertension in SHR.

Topics: Animals; Aromatic-L-Amino-Acid Decarboxylases; Blood Pressure; Dopamine Agents; Glutamic Acid; Heart Rate; Hypertension; Levodopa; Male; Medulla Oblongata; Microdialysis; Microinjections; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrodotoxin; Tyrosine; Tyrosine 3-Monooxygenase

We report an outbreak of tetrodotoxin poisoning resulting from consumption of ovaries of an unidentified species of fish. Thirty victims manifested the typical neurologic symptoms of tetrodotoxin poisoning. Although hypotension is the classically described blood pressure reaction, eight individuals developed hypertension (average blood pressure 192/110 mm Hg); one died of acute pulmonary edema. Semi-quantitative tetrodotoxin bioassay of two uneaten ovaries revealed tetrodotoxin concentrations of 54 Mouse Units/gm and 287 Mouse Units/gm, respectively. To gain insight into the unusual phenomenon of hypertension observed in our outbreak, we interviewed the victims, performed a funduscopic exam for hypertensive retinopathy and checked their blood pressure periodically in the ensuing year. Mild hypertension evidenced by retinopathy and elevated blood pressure was found in all seven who manifested hypertension during the acute event and survived. We postulate that individuals with pre-existing hypertension responded to the relatively small doses of tetrodotoxin with a dramatic rise in blood pressure. This resulted in the fatal outcome for one individual with severe coronary artery disease. Hypertension should be recognized as a possible feature of tetrodotoxin poisoning, especially in predisposed individuals.

Topics: Adult; Animals; Blood Pressure; Coronary Artery Disease; Disease Outbreaks; Female; Fishes, Poisonous; Foodborne Diseases; Humans; Hypertension; Male; Middle Aged; Tetrodotoxin

The in vitro membrane properties of neurons from superior cervical ganglia (SCG) of neonatal spontaneously hypertensive (SH), Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats were studied with microelectrodes. Neurons were obtained by enzymatic dissociation, plated, irradiated, and studied after 2-5 wk. Most SH neurons showed multiple action potentials in response to an intracellular long-duration depolarizing pulse (multiple firing), whereas most neurons from WKY or SD rats generated only one or two action potentials. Multiple firing was inhibited by low concentrations of cobalt (10(-5) M) but not by tetrodotoxin (TTX) (3 x 10(-6) M). Neither high calcium (5-10 x 10(-3) M) nor the Ca2+(-)channel opener BAY K 8644 (10(-6) M) could induce multiple firing in SD or WKY neurons. However, multiple firing was readily induced by apamin (10(-6) M) or tetraethylammonium chloride (5 x 10(-3) M) (Ca2+(-)activated K+(-)channels blockers), with cobalt and TTX sensitivities similar to native multiple-firing neurons. We conclude that 1) multiple firing is characteristic of neonate SH rats SCG neurons in vitro and depends on regenerative Ca2+ currents; 2) multiple firing in SH neurons results from a lack of activation of a Ca2+(-)activated K+ conductance and not from a lack of internal Ca2+ availability; and 3) multiple firing in SCG neurons mirrors a default in K+ conductance common to all cells in genetically hypertensive individuals.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Action Potentials; Animals; Animals, Newborn; Apamin; Calcium; Cell Membrane; Cobalt; Ganglia, Sympathetic; Hypertension; In Vitro Techniques; Membrane Potentials; Neurons; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Tetraethylammonium; Tetraethylammonium Compounds; Tetrodotoxin

The purpose of this study was to compare the responsiveness of the rostral and caudal ventrolateral medulla in spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats to microinjection of L-glutamate, and to estimate tonic output of these areas by microinjecting the neurotoxin tetrodotoxin. Rats were anesthetized with 1.25 g/kg urethane s.c., implanted with arterial (femoral) and venous (femoral) catheters, artificially ventilated and paralyzed with gallamine triethiodide (10 mg/kg). Using a ventral approach to the brainstem, the mean arterial pressure and heart rate responses to microinjection (30 nl) of L-glutamate (1, 10 and 100 mM) and tetrodotoxin (10 microM) into the rostral and caudal ventrolateral medulla were compared in SH (n = 7) and WKY (n = 7) groups. Microinjection of L-glutamate into the rostral ventrolateral medulla produced equivalent increases in mean arterial pressure (maximum +33 +/- 3 and +36 +/- 6 mm Hg, SH and WKY groups respectively) and minimal changes in heart rate. Similar administration of L-glutamate into the caudal ventrolateral medulla caused decreases in mean arterial pressure and heart rate; changes in mean arterial pressure were significantly greater in the SH group than in the WKY group (-52.3 +/- 2.9 mm Hg for SH, -22.6 +/- 2.6 mm Hg for WKY). Bilateral microinjection of tetrodotoxin into the caudal ventrolateral medulla produced significantly larger increases of mean arterial pressure in WKY rats (+8 +/- 4 vs +46 +/- 8 mm Hg for SH vs WKY). These data indicate that SH rats may have a lower tonic activity of neurons in the caudal ventrolateral medulla, resulting in a lower restraining influence on sympathetic outflow in the SH rat.

Topics: Action Potentials; Animals; Blood Pressure; Glutamates; Glutamic Acid; Heart Rate; Hypertension; Medulla Oblongata; Rats; Rats, Inbred SHR; Tetrodotoxin

We previously demonstrated that the mesenteric resistance blood vessels have nonadrenergic, noncholinergic vasodilator innervation in which calcitonin gene-related peptide (CGRP) is a possible neurotransmitter. The role of CGRP-containing vasodilator nerves in hypertension was investigated in perfused mesenteric vascular beds isolated from spontaneously hypertensive rats (SHR). The adrenergic vasoconstrictor responses to perivascular nerve stimulation in both SHR (8-, 15-, and 30-week-old) and age-matched Wistar-Kyoto (WKY) rat preparations increased with aging, but the response was greater in SHR than in WKY rats at all ages. The preparation isolated from SHR and WKY rats was precontracted by continuous perfusion of Krebs' solution containing 7 x 10(-6) M methoxamine plus 5 x 10(-6) M guanethidine. In both SHR and WKY rats, perivascular nerve stimulation (1-8 Hz) produced frequency-dependent vasodilation, which was blocked by 1 x 10(-7) M tetrodotoxin, pretreatment with 5 x 10(-7) M capsaicin, and denervation by cold storage (4 degrees C for 72 hours). The vasodilation induced by perivascular nerve stimulation in SHR greatly decreased with age, whereas a slight decrease in the response with age was found in WKY rats. The neurogenic vasodilation in the young SHR preparation was similar in magnitude to the vasodilation in age-matched WKY rats, whereas the vasodilation in 15- and 30-week-old SHR was significantly smaller than that in age-matched WKY rats. In both SHR and WKY rats, perfusion of rat CGRP (1 x 10(-10) to 3 x 10(-8) M) produced marked vasodilation in a concentration-dependent manner. The CGRP-induced vasodilation in SHR increased with age, whereas an age-related decrease in vasodilation was found in WKY rats. Perivascular nerve stimulation (4 and 8 Hz) of the perfused mesenteric vascular bed evoked an increased release of CGRP-like immunoreactive substance in the perfusate, which was significantly less in 15-week-old SHR than in age-matched WKY rats. Immunohistochemical studies showed an age-related decrease in CGRP-like immunoreactive fibers in SHR but not in WKY rats. These results suggest that CGRP-containing vasodilator innervation is greatly decreased when SHR develop and maintain hypertension. It is also suggested that the decreased vasodilator mechanism by CGRP-containing nerves contributes to the development and maintenance of hypertension.

Topics: Aging; Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Guanethidine; Hypertension; Immunohistochemistry; In Vitro Techniques; Male; Mesenteric Arteries; Methoxamine; Nerve Fibers; Peripheral Nerves; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrodotoxin; Vascular Resistance; Vasodilation

Resistance-sized branches of posterior cerebral arteries from Wistar-Kyoto (WKY), spontaneously hypertensive (SHR), spontaneously hypertensive stroke-prone (SHRSP), and antihypertensive-treated SHRSP (SHRSP-TRT) rats were studied in vitro. After the rats were killed, arterial segments were excised, mounted on microcannulas, and pressurized. After equilibration, intravascular pressure was increased in a stepwise fashion from 30 to 150-200 mmHg. All vessels developed a myogenic tone, which resulted in diameter reductions of 31-37% at 100 mmHg when compared with fully relaxed diameters [approximately 200 micron in 1 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid]. Differences in the extent of tone were not significant between animal groups (P greater than 0.05). Rhythmic vasomotion was present in 94% SHRSP and 100% SHRSP-TRT, 83% SHR, and only 6% of the WKY arteries. At higher pressures, the amplitude of the diameter oscillations decreased and frequency increased. Vasomotion was unaltered by tetrodotoxin or indomethacin, but could be abolished by cooling to 34 degrees C, ouabain (a depolarizing solution containing 125 mM K+), potassium-free physiological saline solution, or by calcium entry blockade with diltiazem or MnCl2. In normally quiescent WKY arteries, vasomotion, which was qualitatively similar to that observed in the hypertensive strains, could be induced by the addition of 5 mM tetraethylammonium chloride. Thus intrinsic oscillations in membrane calcium and potassium conductance may underlie the rhythmic contractile activity of rat cerebral arteries. This property appears to have a major genetic component, the expression of which is relatively independent of blood pressure history and is not related to the myogenic properties of the preparation.

Topics: Animals; Cerebral Arteries; Chlorides; Hypertension; Indomethacin; Manganese; Manganese Compounds; Ouabain; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetraethylammonium; Tetraethylammonium Compounds; Tetrodotoxin; Vascular Resistance; Vasomotor System

The effect of arginine-vasopressin (AVP) on potassium ion-evoked release of [3H]noradrenaline (NA) from rat brainstem slices was investigated. In normotensive Sprague-Dawley (SD) and Wistar Kyoto (WKY) rats, AVP inhibited release of [3H]NA in a dose-dependent fashion, the magnitude and time course of inhibition at 10(-12)M AVP being similar to that observed using the alpha 2-adrenoceptor agonist, clonidine at 10(-7) M. However, it is unlikely that AVP functions through alpha-receptors since its effect is not blocked by phentolamine (10(-6) M). When brainstems from spontaneously-hypertensive (SH) rats (stroke-prone strain) were used, AVP was found to be without effect on [3H]NA-release at concentrations up to 10(-8) M. The potassium ion-evoked release appeared to have two components. The early phase of release was tetrodoxotin (TTX)-sensitive and was probably due to action potential conduction within the slices. The later phase, which was unaffected by tetrodotoxin, was probably a result of potassium-induced depolarization of nerve endings. AVP appeared to affect principally the early, TTX-sensitive release. In the presence of TTX (0.3 microM) the inhibitory effects of AVP were no longer seen. Thus, AVP may affect generation or conduction of action potentials within this tissue. There is published evidence that central vasopressinergic neurons may play a role in controlling the baroreceptor reflex arc. The present study provides a possible biochemical basis for this effect and is consistent with a neuromodulatory role of AVP in the CNS.

Topics: Animals; Arginine Vasopressin; Brain Stem; Drug Interactions; Hypertension; Male; Norepinephrine; Potassium; Rats; Rats, Inbred Strains; Tetrodotoxin

Comparative in situ (innervation and circulation intact) and in vitro measurements of transmembrane potential (Em) were made in vascular smooth muscle cells (VSM) of small (300-500 micrometers) veins of an externalized intestinal mesenteric loop in 13- to 15-wk-old anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive controls (WKY). During suffusion with physiological salt solution (PSS), the mean in situ Em in SHR was significantly lower (-34 +/- 0.8 mV) than in WKY (-49 +/- 1.3 mV). In situ neural blockade with 1 microgram/ml tetrodotoxin (TTX) in PSS hyperpolarized venous Em in SHR (-45 +/- 1.7 mV) but not in WKY. In vitro Em in SHR (-51 +/- 1.0 mV) and WKY (-54 +/- 1.1 mV), though significantly elevated above respective in situ values, did not differ significantly from each other and were not altered by TTX. Increasing norepinephrine (NE) concentrations in the PSS gradedly depolarized the venous VSM of WKY in situ to a plateau Em of -32 +/- 0.9 mV at 6 microM (1 micrograms/ml) NE but had no significant depolarizing effect on the less-polarized venous VSM of SHR. However, after addition of 1 micrograms/ml TTX to the PSS, the in situ Em in SHR followed a depolarizing NE dose-response curve similar to that observed in WKY (with or without TTX). These results support the hypothesis that the neurogenic vasoconstrictor component of VSM tone is significantly elevated in mesenteric veins of the SHR model of essential hypertension.

Topics: Animals; Blood Pressure; Heart Rate; Hypertension; Male; Membrane Potentials; Mesenteric Veins; Muscle, Smooth, Vascular; Norepinephrine; Rats; Rats, Inbred Strains; Tetrodotoxin

Pre- and postjunctional control mechanisms of the portal vein of spontaneously hypertensive rats (SHR) were characterized. Emphasis was placed on the influence of the presynaptic beta-adrenoceptor mediated mechanism for regulation of neuronal noradrenaline (NA) release (studied as tritium overflow) and its consequences for the contractile response under in vitro conditions. It was found that isoprenaline increased, whereas dl-propranolol decreased the release of neuronal NA during transmural nerve stimulation, while effector responses remained unaltered. d-Propranolol and the beta-1 selective adrenoceptor antagonist, metoprolol, did not affect these two variables. It is concluded that the presynaptic beta-adrenoceptors in the rat portal vein are mainly of the beta-2 type and mediate facilitation of neuronal transmitter release and that concomitant changes of the effector responses of this tissue are below the level of detection under the present experimental conditions.

Topics: Animals; Autacoids; Electric Stimulation; Female; Hypertension; Isoproterenol; Male; Metoprolol; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Phenoxybenzamine; Portal Vein; Propranolol; Rats; Receptors, Adrenergic; Receptors, Adrenergic, beta; Tetrodotoxin; Vasoconstriction