THE SEARCH for natriuretic hormones or factors by studies of negative pressure breathing, atrial distension experiments, head-out water immersion, expansion of blood volume, Na+/K+-ATPase inhibitors and parabiosis experiments in Dahl rats has led to the finding that the atria are a peptide-secreting endocrine gland. This new natriuretic hormone has now been purified, sequenced and synthetized, and its cDNA and gene have been cloned. The native and synthetic hormones exert identical wide ranging effects (possibly through particulate guanylate cyclase stimulation and adenylate cyclase inhibition) on the kidney, blood vessels, adrenal cortex, and pituitary. Physiopathologic implications of the hormone in experimental hypertension, congestive heart failure, and expansion of blood volume are beginning to emerge.

The Heart and the Atrial Natriuretic Factor

The Bezold-Jarisch reflex revisited: Clinical implications of inhibitory reflexes originating in the heart

Neurally mediated hypotension and bradycardia are believed to be common causes of syncope. We used the "upright-tilt test" (duration, less than or equal to 10 minutes) with or without an infusion of exogenous catecholamine (isoproterenol [1 to 5 micrograms per minute], given intravenously) to elicit bradycardia, hypotension, or both in 24 patients with recurrent syncope and in 18 control subjects. A conventional electrophysiologic test performed before the tilt test was positive in 9 of the 24 patients, revealing arrhythmias that may have caused recurrent syncope, but was negative and thus nondiagnostic in 15 patients. The tilt test alone (i.e., without isoproterenol) induced symptomatic bradycardia or hypotension in 1 of the 9 patients with positive electrophysiologic tests (11 percent), 4 of the 15 patients with negative electrophysiologic tests (27 percent), and none of the controls. When the isoproterenol infusion was administered during the tilt test, 9 of the 11 patients with negative electrophysiologic and tilt tests had syncope, marked slowing of the heart rate, and hypotension. In contrast, isoproterenol was associated with tachycardia and only a slight decline in arterial pressure in the 8 remaining patients with positive electrophysiologic tests and the 18 control subjects, and syncope developed in only 1 of the 8 patients with positive electrophysiologic tests and negative tilt tests (13 percent) and 2 of the 18 control subjects (11 percent). We conclude that an isoproterenol infusion administered in conjunction with the upright-tilt test may be useful for identifying susceptibility to neurally mediated recurrent syncope.

Provocation of bradycardia and hypotension by isoproterenol and upright posture in patients with unexplained syncope.

Systemic osmoregulation is a vital process whereby changes in plasma osmolality, detected by osmoreceptors, modulate ingestive behaviour, sympathetic outflow and renal function to stabilize the tonicity and volume of the extracellular fluid. Furthermore, changes in the central processing of osmosensory signals are likely to affect the hydro-mineral balance and other related aspects of homeostasis, including thermoregulation and cardiovascular balance. Surprisingly little is known about how the brain orchestrates these responses. Here, recent advances in our understanding of the molecular, cellular and network mechanisms that mediate the central control of osmotic homeostasis in mammals are reviewed.

http://www.med.uottawa.ca/courses/nsc5104/assets/documents/dr_renaud2009/nrn2400.pdf

Central mechanisms of osmosensation and systemic osmoregulation.

IN 1963, Okamoto and Aoki introduced a new model of experimental hypertension that required no physiological, pharmacological, or surgical intervention. This spontaneously hypertensive rat (SHR) was developed by meticulous genetic (brother-to-sister) inbreeding that uniformly resulted in 100% of the progeny having naturally occurring hypertensive disease (Okamoto and Aoki, 1963; Okamoto et al., 1966a). Since then, several expert panels have reported that the SHR is an excellent model of experimental hypertension that could serve as a counterpart for clinical essential hypertension (Undenfriend and Spector, 1972; ILAR, 1976). In this discourse we take the affirmative position that the SHR is, indeed, an excellent model for the study of essential hypertension. We do so, however, with four important caveats. First, we recognize that it is unlikely that both forms of naturally occurring hypertension (man and rat) are identical expressions of genetically determined hypertensive disease. Second, we take the position that both forms of hypertension are polygenic in origin and that both are influenced by environmental factors. Thirdly, since the control of normal arterial pressure in both man and rat is multifactorial, it follows that certain pressor mechanisms might well operate in one form of genetic hypertension that do not necessarily occur in the other (although in both, some similar factors could be involved). This same reasoning also may be applied to hypertensive in-

Similarities of genetic (spontaneous) hypertension. Man and rat.

Impulse activity in vagal afferent fibres and changes in heart rate were simultaneously recorded during rapid hemorrhage or blood pooling in cats in order to elucidate whether the sudden reflex bradycardia, sometimes evoked with the mentioned interventions, was correlated to an increased activity in any type of heart receptors. The results show that the slowing of the heart, resulting from an emptying of the central blood reservoirs was correlated to, and preceded by, an increased activity in receptors located in the left ventricle and signalling in non-medullated afferents. The receptors were found to be activated also by obstructions of the ascending aorta and mechanical stimulation of the heart, and therefore seem to operate as mechanorecepton, stimulated by a “distortion” of the myocardium. - It is conceivable that with rapid bleeding or pooling of blood, the receptors are excited by an improper squeezing of the myocardium when the ventricles contract vigorously around an almost empty chamber, and then induce a reflex bradycardia. This reflex mechanism, resembling the so-called vaso-vagal syncope reaction in man, may therefore serve as a protective system causing a break on the heart and allowing for an improved diastolic filling in situations when venous return is critically reduced.

Increased Activity in Left Ventricular Receptors during Hemorrhage or Occlusion of Caval Veins in the Cat. ‐ A Possible Cause of the Vaso‐vagal Reaction

Left ventricular receptors, signalling in non-medullated vagal fibres and displaying a low, irregular spontaneous activity, have been analysed by recordings of impulse activity in cardiac afferent nerves. The receptors were distributed diffusely all over the ventricle and in both superficial and deep layers of the myocardium. They were activated by occlusions of the ascending aorta, by substantial elevations of arterial blood pressure and by rapid infusions of saline or dextran, whenever these procedures produced a clearcut increase of intraventricular diastolic pressure and end-diastolic volume. The endings were also excited by veratrum alkaloids, nicotine and digitalis alkaloids. When activated, the receptors usually displayed a cardiac rhytm, but with intense stimulation the activity usually became continuous. The receptors evidently function as mechano- or deformation receptors, responding primarily to a distension of the ventricle. Activation of the receptors causes a reflex bradycardia and, in all probability, vasodilatation and blood pressure fall. They may contribute to the homeostatic control of blood pressure and blood volume, but their main function seems to be to protect the heart from e.g. imminent overloading. The endings are probably of main importance for the emergence of the Bezold-Jarisch reflex.

Studies on left ventricular receptors, signalling in non-medullated vagal afferents.

Recordings of the evoked compound potentials in the right main cardiac nerve in the cat demonstrated the presence of both medullated and non-medullated fibres. The circulatory responses to afferent stimulation of these two fibre populations were followed in terms of changes in blood pressure, heart rate and skeletal muscle and renal flow resistances. A selective stimulation of the medullated afferents, which probably arise mainly from atrial receptors, induced a moderate reflex rise of blood pressure, an increased heart rate and a vasoconstriction in the skeletal muscle and kidney. Clearcut effects were observed first with high stimulation frequencies, and then only in case the buffering influences from other receptor sites were minimized. Stimulation of the non-medullated fibres, which probably emanate from ventricular receptors, caused a very marked reflex blood pressure fall, slowing of the heart and vasodilatation in the muscle and the kidney, already with very low stimulation rates. These results suggest that the powerful reflex influence from cardiac receptors on the cardiovascular system is exerted by receptors with non-medullated afferents, while endings firing in medullated pathways as e.g. atrial receptors, have very small direct effects on the cardiovascular system and then rather of an excitatory nature.

Circulatory Responses to Stimulation of Medullated and Non-medullated Afferents in the Cardiac Nerve in the Cat

The activity in unmyelinated afferents from left ventricular receptors was examined in cats during shortlasting general asphyxia and during transient occlusion of one coronary artery. After 40–70 s of asphyxia the receptors increased their activity. The firing initially displayed a cardiac rhythm but became continuous when the asphyxia was prolonged and intensified. This increased activity was closely related to a mechanical distension of the left ventricle when the nutritional supply was compromised suggesting a mechanoreceptor rather than a chemo-receptor function of the recepton. Coronary occlusion also caused an activation of the ventricular receptors after a latency of about 35 s with an initial cardiac rhythmicity which became continuous with prolonged occlusions. The receptor activation appeared also in this situation to be caused by the mechanical bulging of the ischemic area of the left ventricular wall, rather than by chemical factors.

Left ventricular receptors activated by severe asphyxia and by coronary artery occlusion.

The left atrial pressure in adult spontaneously hypertensive rats (SHR) of the Okamoto strain and normotensive control rat (NCR) was measured via chronically implanted catheters. In SHR left atrial pressure in end-expiration was more than twice as high (10.3 +/- 0.4 mmHg) as in NCR (4.6 +/- 0.3 mmHg). There was no difference in the intrapleural pressure between the two groups of rats, therefore the enhanced left atrial pressure in SHR represents a real rise in the diastolic filling pressure of its left ventricle. This is considered to be the most important compensation for the earlier reported rightward shift of the Frank-Starling curve in SHR (Hallback, Isaksson & Noresson 1975, Noresson et al. 1979a). Without this compensation the stroke volume would have been drastically reduced for the hypertrophied heart.

Peter Thorén

Papers

Increased Activity in Left Ventricular Receptors during Hemorrhage or Occlusion of Caval Veins in the Cat. ‐ A Possible Cause of the Vaso‐vagal Reaction

Studies on left ventricular receptors, signalling in non-medullated vagal afferents.

Circulatory Responses to Stimulation of Medullated and Non-medullated Afferents in the Cardiac Nerve in the Cat

Left ventricular receptors activated by severe asphyxia and by coronary artery occlusion.

Left atrial pressure in normotensive and spontaneously hypertensive rats.