Joseph P. Buckley

Evidence for a Central Mechanism in Angiotensin Induced Hypertension.

Summary Angiotensin II appears to produce an increase in blood pressure by 2 mechanisms: 1. A direct peripheral action on the vascular smooth musculature producing a marked increase in peripheral resistance, which is not blocked by piperoxan. 2. A central hypertensive effect, probably due to stimulation of central sympathetic structures and evoking peripheral sympathetic discharges, which are blocked by administration of a sympatholytic agent into the peripheral circulation.

Role of the central autonomic nervous system in the hypotension and bradycardia induced by (-)-Δ9-trans-tetrahydrocannabinol

(‐)‐Δ9‐trans‐Tetrahydrocannabinol (Δ9‐THC), when given intravenously (2 mg kg−1) to cats, produced marked decreases in blood pressure and heart rate which developed gradually and were of prolonged duration. Cervical spinal transection (C1‐C2) abolished these effects whereas surgical removal of neurogenic tone to the myocardium selectively eliminated the bradycardia. Bilateral vagotomy alone did not modify the action of Δ9‐THC upon heart rate or blood pressure. Recordings of spontaneous sympathetic outflow in the inferior cardiac nerve indicated a rapid reduction in neural discharge rate after Δ9‐THC administration. These observations support the hypothesis that Δ9‐THC produces a cardiodecellerator and hypotensive effect by acting at some level within the sympathetic nervous system. Experiments conducted to investigate transmission in the superior cervical and stellate ganglia demonstrated that Δ9‐THC did not alter ganglionic function. Also, responses to intravenous isoprenaline and noradrenaline were unchanged which suggested that Δ9‐THC did not interact with α‐ or β‐ adrenoceptors. The possible action of Δ9‐THC on central sympathetic structures was investigated by perfusion of Δ9‐THC into the lateral cerebral ventricle. Δ9‐THC so administered produced a significant reduction in heart rate without a substantial lowering of blood pressure. Tritiated or 14C‐Δ9‐THC perfused into the lateral ventricle demonstrated that the amount of radioactive compound passing into the peripheral circulation was insignificant and could not account for the decrease in heart rate. The current data are in agreement with the proposal that Δ9‐THC produces cardiovascular alterations by an action on the central nervous system which results in a decrease in sympathetic tone.

Relationships between brain catecholamine synthesis, pituitary adrenal function and the production of hypertension during prolonged exposure to environmental stress

Abstract Male rats were subjected to environmental stresses consisting of flashing lights, audiogenic stimulation and oscillation for 20 weeks on a randomized schedule. The mean systolic blood pressure in the stressed animals rose to 150mm Hg±1.01 by week 8 and ranged between 150 and 160 mm Hg for the remaining 12 weeks, whereas the mean systolic pressure of the non-stressed animals fluctuated between 110 and 120mm Hg throughout this same period of time. Serum corticosterone level in the stressed animals were approximately 3 times higher than controls for the first 4 weeks of exposure; however, by the end of week 5. serum corticosterone declined dramatically in the stressed group and was significantly lower than controls, after which serum corticosterone levels exhibited a cyclic pattern at approximately 6-week intervals. No significant alterations were observed in brain NE and DA and serum FFA throughout the 20-week stress exposure. In a second study, rats received 100 mg kg p.o. of L -α-methyltyrosine. At the end of weeks 2 and 4, brain NE was depleted by more than 80° in the stressed treated group, whereas brain NE in the non-stressed treated animals was depleted by approximately 45°. indicating a significant increase in the turnover of brain NE The elevated turnover of brain NE returned to control values by the end of the 6th week. In addition, a-MT prevented the stress-induced elevation in systolic blood pressure. These data indicate a close temporal relationship between brain NE synthesis rate and adrenocortical steroid secretion as well as demonstrating that a-MT is an effective antihypertensive agent in stress-induced hypertension.

On the central hypertensive effect of angiotensin II.

Abstract It was the purpose of this study to investigate further the mechanism by which angiotensin II produces central hypertensive effects. When administered into the perfused lateral ventricle of the cat, the peptide consistently produced neural presser effects which were essentially abolished by lesions at high midbrain levels. Presser activity was apparently not generated by bulbar efferent or afferent mechanisms, as topical application of the peptide at the termination of the cerebral aqueduct during perfusion produced little or no change in femoral blood pressure when compared with the intraventricular responses in the same animals. Similar pressor activity was observed in perfused dog lateral ventricle experiments but was not detected in experiments in which only subarachnoid structures of the dog brain were perfused.

Evidence for a central hypotensive mechanism of 2-(2,6-dichlorophenylamino)-2-imidazoline (catapresan, ST-155)☆

Abstract 2-(2, 6-dichlorophenylamino)-2 imidazoline (ST-155) when administered into the arterial inflow (IA-R) of neurally intact vascularly isolated heads of recipient non-debuffered and debuffered dogs resulted in a depressor response in both the recipient and donor dogs and markedly increased cerebral vascular resistance. In contrast, intravenous injection to intact dogs was found to reduce peripheral vascular resistance. These data are consistent with the hypothesis that ST-155 produces a central hypotensive effect mediated by a reduction in sympathetic tone.

Studies on the bradycardia induced by (−)-Δ9-trans-tetrahydrocannabinol in anesthetized dogs

Abstract (−)-Δ9-trans-tetrahydrocannabinol (Δ9-THC) (39 μg-5 mg/kg, i.v.) decreased heart rate in a dose related manner in dogs under pentobarbital anesthesia. This cardiac effect of Δ9-THC was neither due to an impairment of transmission across the sympathetic ganglia nor to a specific stimulation of parasympathetic ganglia. Selective blockade of either parasympathetic (atropine, bilateral vagotomy) or sympathetic (propranolol, spinal section at C2C4 neurogenic activity to the heart partially prevented the negative chronotropic effect of Δ9-THC. However the bradycardic effect of Δ9-THC was completely abolished in animals in which the autonomic pathways to the heart were pharmacologically or surgically inactivated. Administration of Δ9-THC into the vascularly isolated, neurally intact cross-perfused head of dogs significantly slowed the heart rate in intact as well as debuffered recipients. This bradycardia was reduced in recipients in which the trunk was atropinized prior to cerebral administration of Δ9-THC into the femoral vein of the recipient in the dog cross circulation preparation also caused a significant decrease in heart rate which was essentially abolished either by bilateral vagotomy or by atropinization of the recipients. These results are compatible with the hypothesis that the negative chronotropic effects of Δ9-THC in dogs under pentobarbital anesthesia is of central origin and involves both a direct and reflexogenic alteration of central autonomic outflow regulating the heart rate.

Effects of chlorpromazine and three metabolites on behavioral responses in rats

Effects of chlorpromazine (CPZ) and three metabolites (3,7-dihydroxy-CPZ; 7,8-dihydroxy-CPZ; 7-hydroxy-CPZ) on behavioral performance of rats were tested by three methods: (a) continuous nondiscriminative lever-pressing shock-avoidance response without a warning signal; (b) discriminative pole-climbing shock avoidance and escape; (c) discriminative control of behavior by drug states. Both types of avoidance were much more impaired by CPZ than by the metabolites. The metabolite producing the most consistent impairment was 7-hydroxy-CPZ and the least consistent was 7,8-dihydroxy-CPZ. In the test for discriminative control of behavior by drug states, the 7-hydroxy-CPZ was the only metabolite which evoked the CPZ stimulus characteristics whereas the 7,8-dihydroxy-CPZ produced a generalized depressant effect.

Central and reflexogenic cardiovascular actions of prostaglandin E1

The centrally mediated cardiovascular effects of prostaglandin E1 (PGE1) were investigated using cross-circulation procedures. PGE1 was injected into the arterial inflow (IA-R) of vascularly isolated, ncurally intact heads of anesthetized recipient dogs. Following the administration of 5 and 10 μg/kg of PGE1 (IA-R) consistent depressor responses occurred in the donor dogs and in the recipients isolated trunk. The administration of 5 and 10 μg/kg of PGE1 (IA-R) to debuffered recipients (carotid sinus-body areas bilaterally denervated) elicited centrally mediated pressor responses in the recipients trunk paralleled by depressor effects in the donor and a decline in the recipients perfusion pressure. Centrally mediated pressor responses of angiotensin II were inhibited by PGE1 only in the non-debuffered recipients. Pressor responses to PGE1 in debuffcrcd recipients were blocked by the ganglionic blocking agent, hexamethonium. These data plus results from the intra-artcrial administration of PGE1 into the carotid sinus area before and after denervation suggest that the carotid sinusbody structures, most likely the baroreceptors, are primarily implicated in the hypotensive response to PGE1 in the non-debuffered recipients trunk. On the other hand, the central nervous systemper se appears to be involved in mediation of the central pressor responses obtained in the debuffered preparations. This study provides evidence for the involvement of the carotid sinus-body structures and the central nervous system as additional loci for the cardiovascular effects of PGE1.

Hemodynamic and myocardial effects of (−)-Δ9-trans-tetrahydrocannabinol in anesthetized dogs

Abstract (−)- Δ 9 - trans -tetrahydrocannabinol ( Δ 9 -THC) (39 μg–2.5 mg/kg, i.v.) decreased blood pressure, heart rate, cardiac output and right ventricular contractile force in a dose-related manner in intact dogs under pentobarbital anesthesia. The Δ 9 -THC-induced hypotension appeared to result mainly from a consistent and reproducible attenuation of cardiac output since no marked alteration in total peripheral resistance occured. In these animals the decrease in cardiac output appeared to be related to the bradycardia since there was no change in stroke volume following Δ 9 -THC. However, when the change in heart rate was prevented by atrial pacing or cardiac denervation, a less but significant reduction in cardiac output was induced by Δ 9 -THC. Under these experimental conditions Δ 9 -THC also significantly attenuated stroke volume. In contrast, Δ 9 -THC did not induce any significant changes in cardiac output, blood pressure, and heart rate of dogs pretreated with a ganglionic blocker. Δ 9 -THC appeared to be devoid of any measurable direct effect on the myocardium since the compound neither significantly altered right ventricular contractile force of the denervated or ganglionic blocker-pretreated hearts nor interfered with the positive inotropic responses to i.v. calcium and isoproterenol. In the major vessel occlusion preparation administration of Δ 9 -THC was followed by a reduction in venous tone. Furthermore, measurements of blood and plasma volume excluded an effect of Δ 9 -THC in these parameters. From these findings it is suggested that the reduction in cardiac output induced by Δ 9 -THC is the result of the action of this compound on cardiac rate as well as venous return; no evidence could be documented for a direct effect of this compound on the myocardium.

Parasympatholytic activity of (-)-Δ9-trans- Tetrahydrocannabinol in mongrel dogs

Abstract (-)-Δ 9 - trans -Tetrahydrocannabinol (Δ 9 -THC) (0.312–5 mg/kg) shifted the frequency-response curves of vagal stimulation to the right and attenuated salivation induced by chorda tympani stimulation in dogs. This parasympatholytic activity of Δ 9 -THC was neither atropine-like in nature nor was it due to ganglionic blockade. It is postulated that Δ 9 -THC may interfere with the release of acetylcholine.