Changes of ischemic heart disease in Utsunomiya, Japan, over 10 years: a survey of primary care physicians.

A total of 502 patients presenting in Utsunomiya city and its suburbs during a 10-year period were studied to determine the clinical features of ischemic heart disease and to identify coronary risk factors. The male/female ratio was 1.21, but the ratio decreased with increasing age. The duration of chest pain showed a continuous spectrum between angina and infarction, with a short duration of chest pain not being useful for excluding the diagnosis of myocardial infarction. Hypertension was more common than hypercholesterolemia in this study, although the prevalence of the latter increased slightly with time, along with the shift towards a modernized occupational pattern. Smoking was a more important risk factor for ischemic heart disease in younger individuals than in the elderly, and diabetes mellitus was highly associated with the development of myocardial infarction. The incidence of radiologically diagnosed cardiac hypertrophy and aortic calcification decreased over time. These changes may have resulted in part from improved blood pressure control and the development of new anti-hypertensive and cholesterol-lowering agents.

Central respiratory drive-related activity in sympathetic nerves of the rat: the regional differences.

In halothane-anaesthetized, vagotomized, SA-denervated rats, the activity of various sympathetic nerves has been analyzed with respect to phrenic nerve discharge (an indicator of central respiratory drive (CRD)). The cervical and lumbar sympathetic nerves had maximal activity following, and were least active during phrenic nerve discharge. In contrast, the splanchnic, cardiac, renal and adrenal nerves exhibited their activity peak during phrenic nerve discharge (i.e. inspiration). Similar activity profiles were observed after ganglion blockade in the mixed pre- and postganglionic fibre preparations. These observations indicate that it is the subpopulations of preganglionic neurones and the proportional contribution of each to whole-nerve activity which give rise to the differences in CRD-related activity profiles between nerves.

Effects of aortic nerve stimulation on cervical sympathetic preganglionic neurones in the rat.

The effects of aortic nerve stimulation on the activity of single cervical sympathetic preganglionic neurones have been studied. Based upon the relationship of their firing patterns to central respiratory drive the neurones were categorized as either expiratory-related, inspiratory-related or non-modulated. Aortic nerve stimulation depressed the activity of each type of neurone indicating that irrespective of their respiratory modulation they are amenable to baroreceptor control.

Absence of sustained hypertension in sinoaortic-denervated rabbits.

In 21 conscious unrestrained rabbits, arterial pressure was continuously recorded up to 11 wk by an indwelling catheter placed in the thoracic aorta. The average and standard deviation of the 24-h mean arterial pressure (MAP) were calculated and compared before and after sinoaortic denervation, sham operation, or cervical sympathectomy. At the time of sinoaortic denervation, the cervical sympathetic nerve was always disrupted bilaterally to remove possible arterial barosensory afferents contained in it. Subsequent to sinoaortic denervation performed on 12 rabbits, the average 24-h MAP was initially elevated but invariably returned to the predenervation level in 5-36 days (average 14 days). Meanwhile, the standard deviation remained elevated in all but one animal. In five sham-operated or four cervical-sympathectomized animals, neither the average 24-h MAP nor the standard deviation was significantly altered from that of controls. Our results are consistent with the view that the arterial baroreceptor reflex by itself does not play a critical role in determining the long-term level of arterial pressure.

Discharge patterns of cervical sympathetic preganglionic neurones related to central respiratory drive in the rat.

The central respiratory-drive-related inputs to antidromically identified cervical sympathetic preganglionic neurones have been investigated, in the rat, using extracellular recording techniques, the ionophoretic application of an excitatory amino acid (glutamate) to increase their excitability, and phrenic nerve discharge as an indicator of central respiratory drive. Three distinct firing patterns of sympathetic preganglionic neurones are described: maximal discharge during phrenic nerve activity, maximal discharge during phrenic silence, and a firing pattern unrelated to phrenic nerve discharge. Both spontaneously active and glutamate-activated silent cervical sympathetic preganglionic neurones had similar, if not identical, firing patterns. The application of glutamate, using ionophoretic currents of up to 100 nA, did not disrupt central respiratory-drive-related discharge patterns indicating that these inputs are an important contribution in the regulation of the firing pattern of a proportion of sympathetic preganglionic neurones. On the basis of these observations it is proposed that some sympathetic preganglionic neurones may receive central respiratory drive potentials similar to those received by respiratory motoneurones.

A1 noradrenergic neurons tonically inhibit sympathoexcitatory neurons of C1 area in rat brainstem.

In rats anesthetized with urethane and paralyzed, bilateral microinjections of kainic acid (KA) into the region of caudal ventrolateral medulla (CVL) containing noradrenergic neurons of the A1 group (A1 area) elicited a decrease followed by an increase in arterial pressure (AP), heart rate (HR) and sympathetic renal nerve activity (RNA). The sympathoinhibitory and sympathoexcitatory effects of KA were prevented by bilateral microinjection of tetrodotoxin into an area of the rostral ventrolateral medulla (RVL) containing C1 adrenergic neurons (the C1 area). In contrast, the autonomic responses were not altered by interruption of the two other principal projections of A1 area neurons, namely to the hypothalamus or to the nucleus tractus solitarii. Bilateral microinjections of tyramine, clonidine, alpha-methylnoradrenaline or histamine into the C1 area elicited a dose-dependent, anatomically specific and reversible decrease in AP, HR and RNA. The effect of tyramine was blocked by previous microinjection of reserpine, 6-hydroxydopamine (6-OHDA), or phentolamine into the C1 area. Pretreatment with phentolamine unveiled a hypertensive effect of alpha-methylnoradrenaline. All effects of alpha-methylnoradrenaline were blocked by pretreatment of the C1 area with phentolamine plus DL-propranolol, whereas those elicited by histamine prevailed. Pretreatment of the C1 area with 6-OHDA abolished all changes in AP and HR elicited by microinjections of KA into the A1 area. We conclude that (1) neurons of the CVL tonically inhibit sympathetic activity, (2) this effect is mediated by an action upon vasomotor neurons of the C1 area of RVL, (3) the inhibition is mediated by noradrenergic projections from A1 neurons into the C1 area, and (4) this tonic sympathoinhibitory effect is independent of the baroreceptor reflex.

The aortic nerve-sympathetic reflex in the rat.

The effects of stimulation of aortic nerve A- and C-fibers on the renal and cardiac sympathetic nerve activities in anesthetized and immobilized Sprague-Dawley rats were investigated. A separate aortic nerve was found in 46 rats (90%) out of 51. Activation of A- and C-fiber groups, alone or in combination, resulted in an inhibition of renal and cardiac nerve activities. However, an excitatory component preceding the inhibitory component, representing the reflex response to stimulation of non-barosensory afferent fibers contained in the carotid sinus or aortic nerve, was never observed. This result provides electrophysiological evidence supporting the view that the rat's aortic nerve does not contain a significant amount of functionally active non-barosensory afferents. As with the aortic nerve reflex in the rabbit and cat, the sympatho-inhibitory action of C-fibers was more powerful and longer-lasting than that of A-fibers. Furthermore, the C-fiber reflex was elicited at stimulus frequencies as low as 2 Hz. No significant difference was found between the reflex response of cardiac and renal nerves. On the other hand, stimulation of the superior laryngeal nerve, which constitutes an important pathway carrying arterial baroreceptor fibers, caused a reflex sympathetic response typically consisting of excitatory and inhibitory components. Thus, the rat's aortic nerve provides a useful experimental means to activate selectively central neural structures associated with barosensory afferents and to elicit the reflex response homologous to that in the arterial baroreceptor reflex in rabbits and cats.

Physiological and pharmacological properties of the three subsystems constituting the aortic nerve-renal sympathetic reflex in rabbits.

Electrical stimulation of the aortic nerve of anesthetized rabbits reflexly evoked both excitation and inhibition of renal nerve activity. The excitatory component of the reflex, observed in about 75% of the animals, was elicited by activation of aortic C-fibers. It was selectively suppressed by chronic treatment of the animal with capsaicin. Intracisternal injection of either [D-ala2]-met-enkephalinamide or beta-endorphin markedly attenuated this excitatory component, although neither affected the excitatory component mediated by chemoreceptor fibers in response to stimulation of the carotid sinus nerve. It seems most likely that nociceptive C-fibers of the rabbit's aortic nerve were responsible for the excitatory component. On the other hand, the inhibitory component was reflexly elicited by stimulation of the aortic A- or C-fiber group activated separately or in combination. In agreement with previous reports, the sympatho-inhibitory action of C-fibers was more powerful and longer-lasting than that of A-fibers. We found that the inhibitory component induced by C-fibers was markedly attenuated by the two opioid peptides mentioned above, but was resistant to pentobarbital. On the contrary, the component mediated by A-fibers was suppressed by pentobarbital but was relatively resistant to the opioid peptides. Thus, the rabbit's aortic nerve-renal sympathetic reflex consists of the following 3 subsystems characterized by different physiological and pharmacological properties: sympatho-inhibitory systems activated by barosensory A- or C-fibers and a sympatho-excitatory system attributable to C-fibers probably of nociceptive modality.

Two types of hypotensive effect of beta-blocking agents.

In anesthetized and immobilized rats, an hour-long continuous intravenous injection of dl-propranolol (PR; 3 mg/kg), pindolol (PI; 1 mg/kg), oxprenolol (OX; 3 mg/kg) or atenolol (AT; 3 mg/kg) invariably resulted in moderate hypotension. When the drug-induced hypotension was plotted against the control arterial pressure (AP), two types of correlation were found. The hypotension induced by PR or PI, both known to accumulate in the brain at a high concentration was positively correlated to the control AP, whereas the hypotension produced by OX or AT, both known to penetrate the blood-brain-barrier poorly, was not. To test the hypothesis that the observed difference was attributable to the presence or lack of sympathoinhibitory action of the drug, the effect of these agents on the renal nerve activity (RNA) was examined. PR or PI diminished the tonic and reflexly evoked RNA, when the evoked RNA was elicited by sciatic nerve stimulation. No such changes were induced by OX or AT. These results demonstrate a modulatory role of sympathoinhibitory effect of beta-blocking agents in their hypotensive action.

Identification of the primary afferent fiber group and adequate stimulus initiating the trigeminal depressor response.

In anesthetized and immobilized rabbits we sought to identify the adequate stimulus and the primary afferent fiber group initiating hypotension and inhibition of sympathetic vasoconstrictor discharges in the trigeminal depressor response (TDR). In the first series of experiments we investigated the effects of electrical stimulation of different fiber groups of the infraorbital nerve on arterial pressure (AP) and renal sympathetic nerve activity (RNA). Stimulation of A-beta-fibers at frequencies between 1 and 200 Hz caused little or no reduction in AP or RNA. Recruitment of A-delta-fibers at stimulus frequencies between 1 and 30 Hz always resulted in falls in AP and RNA (by up to 30 mm Hg, and 75% of control, respectively). Decreases in AP and RNA were augmented to some extent by additional excitation of C-fibers over the same frequency range. In the second series of experiments we applied noxious or innocuous mechanical or thermal stimuli to the hairy skin of the upper lip. Hypotension and inhibition of RNA were elicited by any of the following noxious stimuli of the facial skin: (a) pricking by pins; (b) pinching by serrated forceps, (c) heating above 43% C by a contact thermoprobe; and (d) actual burning of the skin. In contrast, innocuous mechanical or thermal (below 40 degrees C) stimuli failed to diminish AP and RNA. These results indicate that noxious stimuli to the face initiate hypotension and inhibition of the sympathetic nerve activity in the TDR through activation of the A-delta primary afferent fiber group, alone or in combination with the C-fiber group.

Hypotensive effects of pentobarbital and diuretics on sympathectomized spontaneously hypertensive rats.

The upper abdominal sympathetic chain with the splanchnic nerve was removed bilaterally in spontaneously hypertensive rats(Okamoto-Aoki). After recovery from the operation, the sympathectomized spontaneously hypertensive rats were as hypertensive as intact or sham operated ones. However, anesthesia with pentobarbital or administration of diuretics induced a significantly greater fall of pressure in the sympathectomized hypertensive rats. The hypotensive effect of either drug was insignificant or considerably small, if present at all, in sympathectomized normotensive control rats. It seems that, in intact spontaneously hypertensive rats, the hypotensive effects of pentrobarvital and diuretics are compensated for by a reflex activation of the abdominal sympathetic nerves.

Effects of cord section and pithing on spontaneously hypertensive rats.

In spontaneously hypertensive rats and normotensive control rats the spinal cord was transected between the vertebrae C7 and Th 1 under ether anesthesia. When the animals recovered from anesthesia in two hours, the blood pressure was significantly higher in the hypertensive rats, indicating that the hypertensive factors are not confined to the supraspinal centers. The blood pressure was also significantly higher in spontaneously hypertensive rats than in normotensive control rats even after pithing the spinal cord below the vertebra of Th 1. In either case subsequent pentobarbital anesthesia abolished the significant difference in pressure between the two groups of rats. The blood pressure after either cord section or pithing tended to increase with age in spontaneously hypertensive rats but not in normotensive control rats. These findings indicate the presence of certain age-dependent peripheral hypertensive factors which are susceptible to pentobarbital and probably myogenic in nature.

Effect of cardiac output on circulatory blood volume.

In anesthetized dogs venous return was drained into a blood reservoir from which blood was pumped to the right atrium at a variable perfusion rate, which was equal to cardiac output in the steady state. When cardiac output was decreased or increased by 25 or 50 percent of the control, the blood volume in the dog's body was changed in the same direction in the intact reflexic state as well as in the areflexic state prepared by hexamethonium and norepinephrine infusion. The volume change in the reflexic state was twice that in the areflexic state when compared 5 min after stepwise changes in cardiac output. When only the flow through the right heart and lungs was changed by-50 percent, with systemic flow unchanged, the decrease in blood volume was about one-fifth of that observed on a 50 percent decrease of cardiac output and not affected by ablation of the reflexes. It is concluded that, on a change in cardiac output, the passive change in blood volume is as large as the active or reflexic change, that the majority of the change in blood volume takes place in the systemic circulation rather than in the pulmonary circulation, and that the receptors for the reflexic change are located in the systemic circulation.

Correlative changes in total vascular capacity and resistance in carotid sinus reflex.

To attain a quantitative understanding of carotid sinus reflex control of circulation, we studied the correlation between changes in total vascular capacity (V) and total peripheral resistance (R). We used a newly devised, accurate and simple method to measure changes in V while both mean central venous and arterial pressures being kept constant. In 7 open chest dogs (7-11 Kg, mean 8.9 Kg), bilateral carotid occlusion after vagotomy reduced V by as much as 58 +/- 9 (SE) ml or approximately 8% of total blood volume while R increased by 36 +/- 5% from 0.08 +/- 0.01 mmHg-min/ml. Similar responses were obtained either in the reflex before vagotomy or with infusion of norepinephrine. Mathematical analysis with Poiseuille's law suggested that internal radius of an average resistance vessel decreased approximately 1.5 to 3 times as much as that of an average capacitance vessel. The wall to lumen ratio of the average resistance vessel estimated from the correlation was 0.3 to 0.6, being within physiological range. Therefore, the difference in vascular sensitivity may be partly owing to the wall to lumen ratio of resistance vessels. Moreover, the correlative changes in the capacitance and resistance vessels were elucidated to be significantly responsible for the characteristic hemodynamic changes in carotid sinus reflex.

Hemodynamics of experimentally hypertensive rats in conscious and anesthetized states.

Cardiac output was measured by a pulse contour method in reno-vascular hypertensive rats, deoxycorticosterone (DOC) hypertensive rats and normotensive control Wistar rats in the conscious state. All rats were male in sex and 12-13 weeks of age (2-3 weeks after operation in the hypertensive rats). Cardiac output per body weight was not significantly different among the groups. Therefore, the hypertension in the experimentally hypertensive rats in the conscious state was ascribable to an increased total peripheral resistance. After anesthesia with pentobarbital and thoracotomy, the DOC rats were no longer hypertensive. However, in the renovascular hypertensive rats, the hypertensive state due to an increase in vascular resistance persisted after anesthesia, thoracotomy, and even ganglion blockade with hexamethonium bromide, indicating the importance of non-neural factors in the renovascular hypertension. Aortic compliance measured in vivo under anesthesia was smaller in either the renovascular or DOC hypertensive rats than in the control rats before and after ganglion blockade, which suggests a non-neural hardening of elastic vessels in the experimental hypertensions.