Marc D. Thames

Preferential distribution of inhibitory cardiac receptors with vagal afferents to the inferoposterior wall of the left ventricle activated during coronary occlusion in the dog.

The purpose of this study was to determine the relative magnitudes of the reflex effects mediated by cardiac receptors during anterior as opposed to inferoposterior ischemia of the left ventricle of the dog. Cessation of perfusion (coronary ‘occlusion’) of the circumflex coronary artery (Cx) in 29 chloralose-anesthetized dogs with common carotids ligated (group I) resulted in significant bradycardia and hypotension, but in no significant change in perfusion pressure in the gracilis muscle perfused at constant flow. Occlusion of the left anterior descending coronary artery (LAD) produced less hypotension, no change in heart rate, and vasoconstriction in the gracilis. After vagotomy and aortic nerve section, no significant change in heart rate or gracilis perfusion pressure was observed during LAD or Cx occlusion, and the blood pressure responses to LAD and Cx occlusion were not different. In nine dogs with sinoaortic denervation (group II), brief Cx occlusion resulted in bradycardia, hypotension, and vasodilation in the gracilis muscle. LAD occlusion in group II dogs caused less hypotension and no change in heart rate or gracilis perfusion pressure. After vagotomy, the bradycardia and vasodilation resulting from Cx occlusion were abolished and the blood pressure responses to LAD and Cx occlusion were not different. The weights of left ventricle perfused by each occluded vessel were not different. These data show that left ventricular receptors with vagal afferents which are activated during coronary occlusion and which mediate cardioinhibitory and vasodepressor responses are located mainly in the inferoposterior left ventricle of the dog heart.

Renal adrenoceptor mediation of antinatriuretic and renin secretion responses to low frequency renal nerve stimulation in the dog.

We evaluated renal adrenoceptor mediation of the renin secretion and antinatriuretic responses to low frequency (1.0 Hz) electrical stimulation of the renal nerves in the dog using renal a-adrenoceptor blockade with phentolamine {α-i/α-i), prazosin (α,), yohimbine (α2), and rauwolscine (α2), and β-adrenoceptor blockade with d,β-propranolol Oβ1//β2) and atenolol (β,). In all animals studied, renal blood flow and glomerular filtration rate remained constant throughout the experiment. In 11 dogs, low frequency renal nerve stimulation decreased urinary sodium excretion (119 ± 13 to 86 ± 18 μEq/min) and increased renin secretion (79 ± 22 to 348 ± 73 μg/ min). Renal arterial infusion of phentolamine (2–10 μg/kg per min) prevented the antinatriuresis but did not change the response of renin secretion (96 ± 46 to 412 ± 93 μg/min). In six dogs, renal arterial infusion of prazosin (0.7 μg/kg per min) similarly blocked the antinatriuretic but not the renin secretion responses to low frequency renal nerve stimulation. Renal arterial infusion of either yohimbine or rauwolscine did not affect the antinatriuretic or renin secretion responses to low frequency renal nerve stimulation. Intrarenal /S]-adrenoceptor blockade with low dose atenolol (0.5 μg/kg per min, n = 9) had no effect on the antinatriuretic responses to low frequency renal nerve stimulation (—47 ± 12 vs. —37 ± 8 μEq/min) but significantly decreased the increment in renin secretion during low frequency renal nerve stimulation (636 ± 249 vs. 305 ± 157 μg/ min; P < 0.05). Renal arterial infusion of d,β-propranolol (0.5 μgAg per min, n = 4) or a high dose of atenolol (5.0 μg/kg per min, n = 8) abolished the renin secretion but not the antinatnuretic responses to low frequency renal nerve stimulation. These results demonstrate that: antinatriuresis during 1.0 Hz renal nerve stimulation (where renal blood flow and glomerular filtration rate are unchanged) is mediated by renal oα-adrenoceptors and not by α2- or β-adrenoceptors, that renin secretion elicited by low frequency renal nerve stimulation is mediated by renal βi-adrenoceptors and not by a-adrenoceptors, and that the renin secretion response to low frequency renal nerve stimulation is evoked by direct stimulation of juxtaglomerular granular cell β-adrenoceptors and not indirectly by stimulation of the macula densa receptor through decreased urinary sodium excretion.

Reflex inhibition of renal sympathetic nerve activity during myocardial ischemia mediated by left ventricular receptors with vagal afferents in dogs.

The major goal of this investigation was to determine if activation of cardiac receptors during coronary artery occlusion could inhibit efferent renal sympathetic nerve activity. In nine chloralose anesthetized dogs with only carotid (n = 3) or with sinoaortic (n = 6) baroreceptors operative, anterior descending coronary artery (LAD) occlusion resulted in a small decrease in mean arterial pressure (-9.8+/-5.1 mm Hg, NS) and in a significant (P < 0.05) increase in renal nerve activity (24.0+/-4.1%). In these dogs, circumflex coronary artery (Cx) occlusion resulted in greater hypotension (-18.4+/-4.0 mm Hg), and yet no change (1.1+/-9%) in renal nerve activity was noted. Changes in left atrial pressure during LAD and Cx occlusion were not different. In seven dogs with carotid sinus denervation, coronary occlusions resulted in decreases both in arterial pressure and in renal nerve activity which were consistently greater during Cx occlusion. The responses to coronary occlusion in six dogs after sinoaortic deafferentation were similar to those observed with only carotid sinuses denervated. In all experiments, vagotomy abolished the difference in the blood pressure responses and the decreases in renal sympathetic nerve activity during Cx occlusion. Vagotomy also abolished the decrease in nerve activity during LAD occlusion in dogs with carotid or sinoaortic denervation. These data show that Cx occlusion and, to a lesser degree, LAD occlusion resulted in reflex withdrawal of renal sympathetic nerve activity mediated by left ventricular receptors with vagal afferents. The reflex withdrawal of renal nerve activity during Cx occlusion occurred in spite of hypotension and the presence of functioning sinoaortic baroreceptors.

Behavior of left ventricular mechanoreceptors with myelinated and nonmyelinated afferent vagal fibers in cats.

The purpose of this study was to determine the behavior of left ventricular mechano-receptors with myelinated vagal afferents and to compare them with endings with nonmyelinated vagal afferents. Single unit activity was recorded from 13 endings with nonmyelinated vagal afferents (conduction velocity 2.1 ± 0.3 m/sec) and from 16 endings with myelinated vagal afferents (conduction velocity 7.3 ± 1.3 m/sec). Resting discharge frequencies of nonmyelinated afferents and of myelinated vagal afferents were 1.7 ± 0.3 and 2.7 ± 0.5 imp/sec (P < 0.1), respectively (at left ventricular end diastolic pressure of 6 mm Hg for both groups). Ten of 16 myelinated vagal afferents had pulse synchronous discharge under basal condition, whereas only 3 of 13 nonmyelinated vagal afferents had such activity. During aortic occlusion, the discharge of myelinated vagal afferents increased 1.7 ± 0.3 imp/sec per mm Hg, whereas nonmyelinated vagal afferents increased signifi-cantly (P < 0.05) less (0.5 ± 0.1 imp/sec per mm Hg). Discharge for both groups was linearly related to left ventricular end-diastolic pressure but not to left ventricular systolic pressure. Increases in left ventricular systolic pressure alone did not increase firing for either group. During aortic occlusion, the maximum discharge rates of myelinated vagal afferents (43 ± 7 imp/sec) were significantly higher than those of nonmyelinated vagal afferents (14 ± 3 imp/sec) at left ventricular end-diastolic pressure of 30 ± 2 and 24 ± 2 mm Hg, respectively. Both groups increased their discharge during volume expansion with myelinated vagal afferents showing greater sensitivity than nonmyelinated vagal afferents. All endings studied were in the inferoposterior wall of the left ventricle. All nonmyelinated vagal afferents were in or near the epicardium. In contrast, myelinated vagal afferents were equally distributed between the endocardium and the epicardium. Myelinated vagal afferents had discrete receptive fields (1–2 mm2) whereas those of nonmyelinated vagal afferents were much larger (1 cm2). In conclusion, the discharge of left ventricular endings with nonmyelinated vagal afferents and myelinated vagal afferents both appear to be determined mainly by changes in left ventricular end-diastolic pressure. They may be located at different depths in the left ventricular wall. Myelinated vagal afferents have greater sensitivity and maximum firing frequencies than nonmyelinated vagal afferents.

Interaction of Cardiopulmonary and Somatic Reflexes in Humans

Activation of cardiopulmonary receptors with vagal afferents results predominantly in reflex inhibition of efferent sympathetic activity, whereas activation of somatic receptors reflexly increases sympathetic activity to the heart and circulation. Previous studies in experimental animals indicate that there is an important interaction between these excitatory and inhibitory reflexes in the control of the renal circulation. The purpose of this study was to determine whether there is a similar interaction between somatic and cardiopulmonary reflexes in humans. The activity of the cardiopulmonary receptors was altered (reduced) with lower body negative pressure (-5 mm Hg), which causes a decrease in cardiac filling pressure and a small reflex increase in forearm vascular resistance without accompanying changes in arterial pressure. Activation of somatic receptors by isometric handgrip for 2 min at 10 and 20% of maximum voluntary contraction resulted in reflex vasoconstriction in the nonexercising arm. Lower body negative pressure at -5 mm Hg produced a threefold augmentation in the forearm vasoconstrictor response to isometric handgrip in the nonexercising arm. This increase in resistance was significantly greater (P < 0.05) than the algebraic sum of the increases in resistance resulting from lower body suction alone plus isometric handgrip alone. Furthermore, it occurred despite a greater rise in arterial pressure, which would be expected to decrease forearm vascular resistance through activation of arterial baroreceptors and through passive dilatation of forearm vessels. Thus, removal of the inhibitory influence of cardiopulmonary receptors by pooling blood in the lower extremities enhances the somatic reflex. These data suggest an interaction between cardiopulmonary and somatic reflexes in the control of forearm vascular resistance in man.

Inhibition of cardiac sympathetic nerve activity during intravenous administration of lidocaine.

The antiarrhythmic action of lidocaine has been attributed solely to its direct electrophysiological effects on the heart. However, lidocaine is particularly effective in treating ventricular arrhythmias associated with increased sympathetic activity, e.g., in myocardial infarction and digitalis toxicity. We tested the hypothesis that lidocaine administered intravenously depressed cardiac sympathetic nerve activity (CSNA). We measured CSNA in six dogs in control state and after lidocaine in doses of 0.625, 1.25, and 2.5 mg/kg i.v. over 2 min. These doses of lidocaine produced graded decreases of CSNA of -8 +/- 2, -18 +/- 1, and -41 +/- 5%, respectively (P less than 0.05, mean +/- SE). In six additional experiments the bolus of lidocaine was followed by an infusion for 20 min (1.25 mg/kg followed by 100 micrograms/kg per min and 2.5 mg/kg followed by 200 micrograms/kg per min). Infusion of lidocaine maintained depression of CSNA at a level that was 23 +/- 3 and 35 +/- 5% less than control (P less than 0.05), respectively, at plasma lidocaine levels of 5.2 +/- 0.6 and 7.5 +/- 1.4 micrograms/ml, respectively. CSNA returned to control during recovery periods. CSNA did not decrease with the passage of time or administration of vehicle. In five dogs with vagi intact, carotid sinuses isolated and held at a pressure of 100 mmHg, and aortic baroreceptors denervated, administration of lidocaine (2.5 mg/kg followed by 200 micrograms/kg per min) decreased renal nerve activity to 71 +/- 8% of control. Increases in left ventricular systolic pressure and maximum derivative of pressure with respect to time (dP/dtmax) resulting from electrical stimulation of preganglionic sympathetic nerves were not significantly altered by lidocaine, but were markedly attenuated by hexamethonium, a ganglionic blocker. In conclusion, lidocaine administered intravenously produces dose-dependent and sustained decreases in cardiac sympathetic nerve activity. These decreases can occur with therapeutic plasma levels. We speculate that this effect is due to central nervous system effects of the drug and that this effect may contribute to the antiarrhythmic actions of lidocaine.

Renal Nerves Modulate Renin Secretion during Autoregulation

Abstract Efferent stimulation of the renal nerves at a very low frequency (0.25 Hz) which is subthreshold for changes in renal blood flow (RBF), urinary sodium excretion (UNaV), and renin secretion has been shown to augment the renin secretion response to reduction in renal arterial pressure to 50 mm Hg by aortic constriction. The present experiments determined whether this modulating influence on renin secretion could be demonstrated during aortic constriction when both RBF and glomerular filtration rate (GFR) were autoregulated. In 9 dogs with renal nerves sectioned, aortic constriction reduced renal arterial pressure from 131 to 98 mm Hg and UNaV from 68 ± 15 to 29 ± 6 μeq/min, did not change RBF or GFR, and significantly increased renin secretion (82 ± 26 to 606 ± 206 ng/min). Aortic constriction during low frequency renal nerve stimulation (0.25 Hz) resulted in similar increases in renin secretion (245 ± 130 to 691 ± 298 ng/min). In 10 dogs with innervated and contralateral dener-vated filtering kidneys, aortic constriction reduced renal arterial pressure from 131 to 99 mm Hg without changing RBF or GFR and equally decreasing UNaV in innervated and dener-vated kidneys. Renin secretion increased significantly more (P < 0.05) from innervated (1363 ± 669 ng/min) than from denervated kidneys (647 ± 399 ng/min). These results support the view that the prevailing nerve activity which passes to the kidney during aortic constriction exceeds 0.25 Hz of electrical nerve stimulation and is sufficient to augment the renin secretion response to aortic constriction when RBF and GFR are autoregulated.

Neural Control of Renin Secretion

The renal sympathetic nerves have been shown to be an important pathway regulating renin1 and prostaglandin2 release from the kidney. We recently reported that direct electrical stimulation of the kidney nerves at 0.5 Hz increases renin secretion rate without altering mean arterial pressure, renal blood flow, glomerular filtration rate, or urinary sodium excretion.3 We have interpreted this result as evidence for a direct action of the renal nerves on the juxtaglomerular granular cells to increase renin secretion. In addition to a direct influence on renin secretion, subthreshold levels of renal nerve stimulation augment the renin secretion rate response to nonneural stimuli and innervated kidneys have a higher renin secretion rate response to suprarenal aortic constriction than denervated kidneys.4 Since renal nerve stimulation results in the release of renal prostaglandins, we hypothesized that intrarenal prostaglandins may be an important mediator of renin secretion during renal nerve stimulation.