Biochemical, functional and morphologic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the hearts of female rats were examined. Six days after the treatment of rats with TCDD, the blood pressures and resting heart rates were significantly less than in control animals. Treated animals were also less responsive to the effects of the beta-1 agonist, (-)isoproterenol. No histopathologic changes were observed in the heart although extensive centrilobular necrosis occurred in the liver after TCDD administration. Serum levels of thyroxine were 66% less than in control animals. Marked lipid peroxidation was produced in the liver with small but significant increases occurring in the heart. TCDD administration had no effect on catalase activity in the heart, but produced a 20% decrease in superoxide dismutase activity relative to control animals. The effects of TCDD on cardiac function do not appear to be due to a direct action of the xenobiotic on the heart but possibly to a down-regulation of beta-receptors in the heart as a result of the hypothyroid state.

Histamine released within walls of resistance blood vessels is suggested to mediate an active portion of baroreceptor-mediated neurogenic vasodilatation in skeletal muscle vasculature. Studies were undertaken to examine the possibility that histamine-mediated active vasodilatation could be effected, in part, by an inhibitory presynaptic action of histamine on vascular sympathetic varicosities. All experiments were conducted in constant-flow autoperfused rat hindquarters in which vasoconstrictor responses were evoked by sympathetic chain (L2-4) stimulation at varying frequencies or intraarterial norepinephrine (0.5 microgram) administration. Intraarterial histamine infusion resulted in a significant inhibition of nerve-stimulated hindquarter vasoconstriction, with the greatest reduction (20%) occurring at the 82.5-ng/ml/min dose. The inhibitory effect of histamine was not stimulation frequency dependent, and occurred when the vasoconstrictor responses to intraarterial norepinephrine and dilator responses to intraarterial nitroglycerin (1 microgram) were unaltered by the histamine infusions. The H2 agonist impromidine produced a significant inhibition of nerve-stimulated hindquarter vasoconstrictor responses without altering perfusion pressure responsiveness to either intraarterial norepinephrine or nitroglycerin. The magnitude of this inhibition of nerve-stimulated vasoconstrictor response was equivalent to or greater than that produced by histamine. The alpha 2-agonist clonidine produced a significant inhibitory effect on neurogenic vasoconstrictor responses with a maximum of 54%. Cimetidine infusion (10 mg/kg i.a.) essentially abolished the inhibitory effect of histamine on nerve-stimulated hindquarter vasoconstriction. These results are consistent with the existence of inhibitory presynaptic histamine receptors on sympathetic varicosities in the hindquarter vascular bed. Furthermore, evidence supports these inhibitory receptors being of the H2 class and the possibility that histamine-mediated active vasodilatation in rat hindquarters involves inhibitory presynaptic histamine receptors.

The innervated, constant flow perfused hindquarters of the rat have been used to evaluate post-stimulation vasodilatation, which is a model of active reflex vasodilatation in this species. The vasodilatation resulting from lumbar sympathetic stimulation was dependent on stimulation frequency and duration. Maximal vasodilatation (16 +/- 2%) was at 8 Hz for 15 s, while markedly reduced vasodilatation was seen after stimulation for longer than 30 s at all frequencies tested. The vasodilatation was transient. Atropine (2.0 mg kg-1 i.v.) failed to attenuate post-stimulation vasodilatation at a time when hindquarter vasodilatation to i.a. acetylcholine had been abolished. The H1 antihistamine, tripelennamine (2.5 mg kg-1 i.v.) significantly reduced (77%) post-stimulation vasodilatation relative to controls at a time when hindquarter vasodilatation due to i.a. histamine was essentially abolished. Reactive hyperaemia is an unlikely cause of vasodilatation since it is not blocked by H1 antihistamines; 60 s post-occlusion hyperaemia also, was not demonstrable. These data suggest that there is an active component of baroreceptor-mediated vasodilatation in the rat and that histamine, rather than acetylcholine, could be a mediator of this vasodilatation.

Experiments were conducted to determine if substrate-specific changes in microsomal metabolism and liver proteins occurred in young (12-13 weeks) spontaneously hypertensive rats (SHR) fed ad libitum compared to age-matched normotensive Wistar Kyoto (WKY) control rats. The hepatic microsomal protein content in SHR rats was significantly increased compared to WKY rats while cytosolic and total liver protein levels did not differ between the two groups. Liver microsomal ethylmorphine-N-demethylase activity was substantially enhanced in SHR rats with only slight increases in cytochrome P-450 content and aniline hydroxylase activity compared to WKY rats. The substrate-specific increases in the microsomal drug metabolism in SHR rats were accompanied by an increase in the prominence of a protein with molecular weight 55,000 in the cytochrome P-450 region. These preliminary observations may be clinically relevant in that alterations in hepatic drug metabolism may be associated with endogenous biochemical processes underlying the hypertensive state.

Reduced vascular histamine content is postulated to contribute to increased peripheral vascular resistance in experimental hypertension in rats. Experiments were conducted to examine histamine content, in vitro uptake ability and in vitro catabolism of histamine in blood vessels from 12-week-old spontaneously hypertensive rats (SHR) and age-matched normotensive controls. Histamine content of mesenteric artery and abdominal aorta from SHR was significantly reduced (P less than .05) when compared to Wistar-Kyoto normotensive controls. This finding confirms a similar observation of reduced vascular histamine content in deoxycorticosterone acetate salt hypertensive rats reported from our laboratory. This reduction in histamine content may be more prevalent in arteries because the decrease was not observed in the portal vein from SHR. Uptake of [14C]histamine into mesenteric artery and abdominal aorta was unchanged in SHR compared to Wistar-Kyoto controls. No significant differences between slopes for uptake regression lines were observed for either mesenteric artery or abdominal aorta. Mesenteric artery exhibited a greater capacity of [14C]histamine accumulation than aorta and significant reductions in accumulation of labeled histamine after 20 and 60 min were found in this vessel from SHR. Because metabolism of histamine was inhibited by aminoguanidine, this reduction may reflect diminished retention by histamine storage sites. In vitro I-[14C]histidine uptake was significantly increased in abdominal aorta and iliac artery but not mesenteric artery from SHR. These differences were also present at the later accumulation periods of 20 and 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Cupreidine 96'-hydroxycinchonine) is a recently synthesized analog of quinidine (6'-methoxycinchonine). Previous studies in mice have shown that quinidine and cupreidine have equivalent antiarrhythmic potencies, whereas the acute toxicity of cupreidine is about 50% less than that of quinidine. Many of the serious adverse effects of quinidine are due to undesirable cardiovascular properties. We have, therefore, compared the effects of the two drugs on blood pressure, heart rate, and peripheral vasodilation in rats, and on myocardial contractility in isolated rabbit hearts at a series of comparable doses. Quinidine produces a more marked bradycardia and depression of blood pressure than does cupreidine. The vasodilation produced by intraarterial administration of quinidine was significantly greater than cupreidine. Furthermore, quinidine elicited a greater negative inotropic effect. Cupreidine exhibited a much more favorable hemodynamic profile than quinidine with regard to the properties that were examined. These results, coupled with the fact that cupreidine has significant antiarrhythmic activity and a lower acute toxicity profile, suggest that this drug may be useful in the therapy of cardiac arrhythmias.

SUMMARY1. The autoperfused hindlimb technique in the rat was used to determine the effects of atropine upon the peripheral vasculature.2. Injection of atropine (0.1–0.8 μmoles) into the hindlimb perfusion circuit resulted in a dose‐dependent decrease in perfusion pressure which was immediate in onset and always preceded systemic pressure changes. The duration of vasodilation lengthened with increasing doses of atropine and ranged from 1.5 to 9 min.3. During atropine‐induced vasodilation, challenging doses of acetylcholine did not alter the perfusion pressure.4. These experiments suggest that atropine is capable of direct vasodilator activity upon the peripheral vasculature in which a muscarinic mechanism appears unlikely.

We have compared the ED50 value for antiarrhythmic activity and the acute toxicities in mice of quinidine and 4 recently synthesized analogs. For the ED50 studies, groups of mice were treated intravenously with equally spaced logarithmic doses of 6'-methoxycinchonine (quinidine), 6'-hydroxycinchonine (cupreidine), 6'-isovaleryloxycinchonine, 6'-acetyloxycinchonine and 6'-benzoyloxycinchonine. For the actue toxicity studies, mice were treated intraperitoneally with quinidine and the 4 analogs. Mice were observed over a 24-h period, and thereafter for each additional 24-h period for a total of 120 h. Tests for parallelism of acute toxicity indicated that with the exception of the 6'-isovaleryloxy derivative the drug treatment regression lines were parallel to that of quinidine (P > 0.05). The results indicated decreases of 50% (843 mumol/kg), 52% (857 mumol/kg), and 61% (910 mumol/kg) in the acute toxicities of the 6'-acetyloxy, 6'-hydroxy, and 6'-benzoyloxycinchonine, respectively. The 6'-acetyloxy (18.5 mumol/kg) and 6'-benzoyloxy (14.6 mumol/kg) derivatives had significantly lower ED50 values than quinidine (60.1 mumol/kg). The results suggest that the 6'-acetyloxy and 6'-benzoyloxy derivatives may have much greater antiarrhythmic effectiveness than quinidine.

The efficacy of mexiletine used alone, and in combination with a class la antiarrhythmic drug, was assessed in 159 previously drug-refractory patients with ventricular tachycardia (VT) during serial electrophysiologic studies and during long-term (5-year) clinical follow-up. Electrically-inducible ventricular tachycardia was suppressed by mexiletine alone in 23% of patients tested, and a combined antiarrhythmic drug regimen was effective in 29% of the trials performed. Mexiletine was much more likely to be effective in patients presenting with nonsustained VT or ventricular fibrillation than in patients with sustained VT (p < 0.005). After 1 and 4 years of treatment, 18% and 42% of the patients treated with mexiletine alone had died suddenly or suffered recurrent symptomatic VT, compared to 11% and 25% of patients treated with the combined antiarrhythmic drug regimens (p=NS). Mexiletine therapy was associated with frequent, though readily reversible, adverse reactions. However, mexiletine treatment had to be discontinued permanently in 8 of 92 patients (9%) because of intolerable side effects. We conclude that the added efficacy and possible improved arrhythmia-free survival associated with combining mexiletine with a class la agent should be further investigated.

Journal Article The antiarrhythmic activities of 6′-hydroxycinchonine, 6’-benzyloxycin-chonine and 6′-allyloxycinchonine compared with quinidine in mice Get access P U Nwangwu, P U Nwangwu College of Pharmacy, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, Nebraska 68105, Canada Search for other works by this author on: Oxford Academic Google Scholar T L Holcslaw, T L Holcslaw College of Pharmacy, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, Nebraska 68105, Canada Search for other works by this author on: Oxford Academic Google Scholar H Rosenberg, H Rosenberg College of Pharmacy, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, Nebraska 68105, Canada Search for other works by this author on: Oxford Academic Google Scholar L D Small, L D Small College of Pharmacy, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, Nebraska 68105, Canada Search for other works by this author on: Oxford Academic Google Scholar S J Stohs S J Stohs College of Pharmacy, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, Nebraska 68105, Canada Correspondence: College of Pharmacy, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, Nebraska 68105, Canada Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 31, Issue 1, September 1979, Pages 488–489, https://doi.org/10.1111/j.2042-7158.1979.tb13566.x Published: 12 April 2011 Article history Received: 11 August 1978 Published: 12 April 2011

Atropine sulfate causes bradycardia in doses which are greater than the usual anticholinergic doses producing tachycardia (Shucard and Andrew, 1977, Res. Comm. Chem. Path. Pharmacol. 16, 401-410). The present study was designed to evaluate the effects of large doses of atropine sulfate on heart rate and systemic blood pressure in rats. Six groups of urethane anesthetized, male, Sprague Dawley rats (200-450 g) were injected with varying doses of atropine via the jugular vein. Groups I through IV received 5 mg/kg, 20 mg/kg, 40mg/kg and 80 mg/kg, respectively. Group V was bilaterally vagotomized before the injection of 80 mg/kg of atropine. Animals in Group VI were bilaterally vagotomized and pretreated with propranolol-HCl before injection of 40 mg/kg of atropine. Atropine caused a significant (p less than 0.005) dose-dependent reduction in both heart rate and blood pressure. The negative chronotropic property of atropine shown in these experiments is in agreement with recent in vitro and in vitro studies. The cause of bradycardia in these doses appears to be an intrinsic property of atropine rather than being centrally mediated. Possible direct action by atropine on peripheral vascular resistance is discussed.

The synthesis of 6'-hydroxycinchonine [8R,9S)-cinchonan-6',9-diol] was achieved by demethylating quinidine with boron tribromide in dichloromethane at -75 degrees C. The antiarrhythmic activities of 6'-hydroxycinchonine and quinidine were compared following the infusion of aconitine into the tail veins of mice to induce arrhythmias. Comparative ED50 and LD50 studies for quinidine and 6'-hydroxycinchonine revealed equivalent antiarrhythmic potencies for the two drugs but a smaller acute toxicity for 6'-hydroxycinchonine.

Methods currently used to quantitate myocardial damage and necrosis produced by chemicals are usually time consuming and subjective. These studies were conducted to evaluate the utility of 3H-tetracycline as a means of quantitating myocardial necrosis produced by isoproterenol. Male, Sprague-Dawley derived rats (180-200 g) were treated with (+/-)-isoproterenol HCl (0.1-100 mg/kg, s.c.) or equivalent volumes of saline. After 90 minutes, all rats received 50 uCi/kg of 3H-tetracycline. Rats were sacrificed 3 hours after 3H-tetracycline administration and the hearts were removed and rinsed free of blood. The degree of radioactivity of the heart as determined by liquid scintillation counting was directly proportional to the dose of isoproterenol. Propranolol pretreatment decreased the accumulation of radioactivity in a dose-dependent fashion. Determination of 3H-tetracycline accumulation appears to be a rapid and reliable method for quantitating isoproterenol-induced myocardial necrosis.