Bhagavan S. Jandhyala

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.

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.

Influence of pentobarbital anesthesia on the effects of certain autonomic blocking agents on heart rate.

Abstract The nature of neurogenic control of the myocardium was profoundly altered by pentobarbital anesthesia in mongrel dogs. Since the pharmacological responses of various autonomic blocking agents depend essentially upon this neurogenic control, their effects on cardiac rate were significantly different in conscious animals from those under pentobarbital anesthesia. The intrinsic heart rate was significantly attenuated by pentobarbital suggesting that it had direct depressant effect on S-A node.

Effects of prolonged hydrochlorothiazide administration on neurogenic tone in the hind limb vasculature

Abstract Prolonged oral administration of hydrochlorothiazide, (HCT) 10 mg/kg/day, to beagle dogs for a period of 12 months did not produce significant changes in body weight, blood pressure and heart rate. After 10 months of treatment, animals were anesthetized with sodium pentobarbital and pressure-flow relationships were established in the perfused hind limb prior to and following acute denervation and after α-adrenergic blockade. Denervation of the limb resulted in a marked decrease in perfusion pressures in the control animals while there were only slight changes in the HCT-treated dogs. Responses of the hind limb vasculature to lumbar sympathetic stimulation at L-5 level, and to intra-arterial administration of norepinephrine were similar in both groups. Blood pressure responses to bilateral carotid occlusion were also indentical in both treated and control groups. The data obtained suggested that there was a significant reduction in the neurogenic tone to hind limb vasculature of the animals treated with HCT and this inhibition was not due to any alterations in the peripheral adrenergic mechanisms. It is postulated that chronic hydrochlorothiazide treatment attenuated neurogenic tone to vasculature of the hind limb by an action mediated via the central nervous system.

Cardiovascular effects of chronic reserpine administration in mongrel dogs

Abstract Twenty-four mongrel dogs received small oral doses of reserpine daily for 12–13 months. Chronic administration of low doses of reserpine did not induce significant alterations in arterial blood pressures; however, there was a gradual, significant decrease in heart rate. Studies on autonomic function revealed a certain degree of impairment of cardiovascular reflexes and sympathetic tone. Hypotensive response to hexamethonium was inhibited in reserpine-treated dogs. At the termination of the study, left ventricular work was significantly lower and cardiac output decreased in the reserpine-treated group under pentobarbital anesthesia. Although the right ventricular contractile force and rate of tension development were significantly greater in the reserpine-treated group, the stroke volumes were not. Greater pressor responses obtained to intravenous administration of epinephrine and norepinephrine in the reserpine group were due to a greater elevation of total peripheral resistance rather than cardiac output. It is concluded that the efficiency of the right ventricular myocardium was attenuated in the dogs treated with reserpine.

Effects of (−)-Δ9-trans-tetrahydrocannabinol on regional blood flow in anesthetized dogs

Abstract Distribution of cardiac output to various organs was studied utilizing 85Sr-labelled microspheres in dogs. In the group receiving Δ9-THC, 2.5 mg/kg, i.v., there was a significant reduction in the fractional blood flow accompanied by an increase in resistance in the splanchnic vasculature. Net total peripheral resistance was unchanged.

Prolonged Administration of Hydrochlorothiazide on Cardiac Function in Beagle Dogs

Conclusions Chronic administration of hydrochlorothiazide (10 mg/kg, po for 12 months) to beagle dogs failed to produce any alterations in blood pressure and heart rate, despite a significant reduction in cardiac output, stroke volume, and stroke work. Analysis of ventricular function curves indicates a diminution in contractility of the myocardium in the treated animals. It is concluded from this investigation that the adverse effects of HCT on the myocardium in the face of increased total peripheral resistance noted in this study may warrant careful reevaluation of this agent in cardiovascular therapy. This study was supported by Public Health Service Grant GM-15587. The authors express their appreciation to Dr. John E. Baer of Merck Institute of Therapeutic Research, West Point, PA, for generously supplying hydrochlorothiazide, and to Messrs. Charles Parham and David Snyder for their valuable technical assistance.