Comparison of lisinopril versus atenolol for mild to moderate essential hypertension.

The antihypertensive effects and safety profiles of lisinopril (10 to 40 mg) and atenolol (50 to 100 mg) were compared in a randomized, double-blind, parallel group trial in 144 patients with essential hypertension. After 8 weeks of therapy, seated blood pressure (BP) decreased by 26/15 mm Hg with lisinopril and by 19/14 mm Hg with atenolol. Lisinopril produced a greater reduction (p less than 0.05) in sitting systolic BP than did atenolol. Standing BP decreased by 25/15 mm Hg with lisinopril and by 19/14 mm Hg with atenolol. No important changes in hematologic and biochemical profiles were seen with either drug. Eleven patients, 7 receiving lisinopril and 4 receiving atenolol, were withdrawn because of adverse experiences; another 3 patients defaulted during treatment, 1 in the lisinopril group and 2 in the atenolol group. Both drugs were well-tolerated and are therefore suitable for first-line therapy in essential hypertension.

Carotid chemoreceptor function and structure in the atherosclerotic rabbit: respiratory and cardiovascular responses to hyperoxia, hypoxia and hypercapnia.

We tested the following hypothesis: if carotid body blood flow, and hence the relationship of the frequency of discharge in chemoreceptor afferent fibres to arterial PO2, were affected by atherosclerotic change, then a modification of the control of the respiratory and cardiovascular systems might result. Carotid body reflexes were therefore studied in conscious atherosclerotic rabbits and a control group of normal animals breathing 100% O2, three hypoxic gas mixtures to which was added sufficient CO2 to maintain the arterial PCO2 constant, and 2% and 4% CO2 in 21% O2 and N2. When breathing room air, the atherosclerotic rabbits breathed at a higher respiratory frequency and lower tidal volume than the normal animals, although there was no difference in the respiratory minute volume. The respiratory and cardiovascular responses to hyperoxia, isocapnic hypoxia and hypercapnia were essentially the same in both groups of animals. Serial sections of the carotid bodies showed pathological changes including interstitial fibrosis in the caudal part with interstitial haemorrhages. The proximal part of the ascending pharyngeal artery, the vessel supplying the organ, and its origin from the external carotid, and the arterioles in the caudal part of the carotid body were nearly always occluded to a varying extent by atheromatous plaques. The capillaries appeared normal under light microscopy. The rostral-caudal lengths of the carotid bodies were similar in the two groups. We conclude that the peripheral arterial chemoreceptor responses in atherosclerotic rabbits are relatively normal even though the arteries to, and arterioles within, the carotid body are partly occluded.

Long-term effect of carotid endarterectomy on carotid sinus baroreceptor function and blood pressure control.

In order to assess whether carotid endarterectomy had any long-term hypotensive effect, by altering the function of the carotid sinus baroreceptors, blood pressure and carotid sinus baroreceptor function were recorded in 25 patients undergoing carotid endarterectomy. No overall change in blood pressure was recorded 6 months after surgery. Sinus function was shown to decrease in 2 (8 per cent), to remain unchanged in 15 (60 per cent) and to increase in 8 (32 per cent) patients 6 months postoperatively. There was no relationship between changes in sinus function and changes in blood pressure over the 6 months period. Thus, carotid endarterectomy has no long-term hypotensive effect.

Respiratory and cardiovascular responses to hyperoxia, hypoxia and hypercapnia in the renal hypertensive rabbit: role of carotid body chemoreceptors.

We tested the hypothesis that in renal hypertension the increased peripheral vascular resistance of neurogenic origin might be due to a reflex through resetting of the carotid body chemoreceptors. The reflex respiratory and cardiovascular functions of the carotid bodies were studied in a one-kidney wrapped hypertension model in conscious rabbits, and compared with a control group of animals, by breathing 100% oxygen, three hypoxic gas mixtures to which were added sufficient CO2 to maintain the PaCO2 constant, and 2 and 4% CO2 in 21% O2 and N2. In the control state (breathing room air) the renal hypertensive animals had a slightly higher respiratory minute volume, a higher level of arterial blood pressure and increased calculated systemic vascular resistance, compared with the normal group, but there was no difference in cardiac output. Hyperoxia had no consistent effect on respiration, heart rate or arterial blood pressure. Increasing degrees of isocapnic hypoxia caused the same degree of hyperventilation and bradycardia in both groups of animals. The arterial blood pressure did not change in either group but there was a transient increase in systemic vascular resistance in the renal hypertensives breathing 9 and 7.5% O2. The respiratory responses to 2 and 4% CO2 were similar in the two groups of animals. In the renal hypertensive animals, serial sections of the carotid bodies showed pathological changes, including subendothelial proliferation in vessels supplying the carotid bodies with narrowing of their lumens, fragmentation of the elastic laminae of the media, hypertrophy of the smooth muscle and extensive fibrosis with occasional haemorrhages. The capillaries, however, were normal. The rostral-caudal lengths of the carotid bodies were similar in the two groups. In view of our findings we conclude that the relatively normal carotid chemoreceptor responses in renal hypertensive rabbits may, in part at least, be the result of the carotid body blood flow through the partially occluded vessels being maintained at near normal levels by the elevated blood pressure.

Lung inflation: effects on heart rate, respiration, and vagal afferent activity in seals.

In the anesthetized harbor seal, Phoca vitulina, the Hering-Breuer inflation reflex was weak and comparable to that in humans. Single inflations of the lungs from a syringe during the expiratory phase of normal breathing caused temporary inhibition of breathing and an immediate tachycardia dependent on the integrity of the cervical vagosympathetic nerves. A similar cardiac response occurred when the lungs were artificially inflated during an experimental dive and under conditions in which apnea and bradycardia were reflexly induced by a combination of stimulation of the carotid body chemoreceptors and of the trigeminal or laryngeal input. Recordings from single vagal afferent nerve fibers innervating presumptive pulmonary stretch receptors showed a close relationship between the increase in impulse frequency and increase in lung volume or transpulmonary pressure. It appears that in diving the decrease in pulmonary stretch receptor activity during apnea, combined with cessation of central inspiratory neuronal drive, is an important integrative mechanism that helps development of the reflex bradycardia of trigeminal, carotid, chemoreceptor, and baroreceptor origin.

Carotid sinus baroreceptor reflex control of the circulation in medial sclerotic and renal hypertensive rabbits and its modification by the aortic baroreceptors.

We studied the reflex control of blood pressure, heart rate, and hindlimb vascular resistance by the carotid sinus baroreceptors in normal (N), experimental renal hypertensive (RH, one kidney renal wrap model), and medial sclerotic (MS) rabbits under urethane anaesthesia using an isolated perfused carotid sinus preparation and auto-perfused hindlimb. The contralateral carotid sinus was denervated. Compared to N rabbits, the blood pressure and hindlimb vascular resistance of RH and MS rabbits were significantly elevated at all carotid sinus pressures 15 weeks after inducing the disease process. The maximum gains of the curves relating carotid sinus pressure to vascular resistance were significantly elevated in the MS and RH rabbits, but those relating carotid sinus pressure to heart rate were significantly reduced. The changes were greatest in the RH group in which the responses also were set to a higher carotid sinus pressure. In the three groups, division of the aortic nerves produced different changes in the sigmoid curves relating carotid sinus pressure to heart rate, blood pressure, and vascular resistance. There was a linear relationship between blood pressure and basal vascular resistance (correlation coefficient 0.88).

Baroreflex sensitivity in rabbits during the development of experimental renal hypertension and medial sclerosis.

Baroreflex sensitivity was assessed in 9 normotensive (N), 8 renal wrap (one kidney model, RH) and 16 medial sclerotic rabbits (MS, fed on calciferol 50,000 i.u. and calcium lactate 1g for 10 days) before (mean BP;N, 79 +/- 3.3 mm Hg; RH, 80 +/- 7.4 mm Hg; and MS, 83 +/- 1.0 mm Hg) and at monthly intervals for up to 16 weeks after the induction of the disease processes (mean BP;N, 87 +/- 3.9 mm Hg; RH, 127 +/- 7.2 mm Hg and MS, 99 +/- 3.8 mm Hg). Blood pressure was elevated by i.v. phenylephrine (5 and 10 micrograms.kg-1) or angiotensin (250 ng.kg-1) and baroreflex sensitivity assessed by the increase of pulse interval per unit rise of pressure. The pressor response was greater in the RH and MS than in the N rabbits. The baroreflex sensitivity showed a progressive reduction with time and with the elevation of blood pressure in both MS and RH rabbits. The difference was significantly greater (P < 0.01) than in the aged related control rabbits (P < 0.05). There was an inverse relationship between baroreflex sensitivity and the pressor response in MS rabbits. Results indicated progressive baroreceptors dysfunction in hypertensive and medial sclerotic rabbits.

Role of carotid-body chemoreceptors and their reflex interactions in bradycardia and cardiac arrest.

Stimulation of the carotid-body chemo-receptors by asphyxia during an apnoeic episode may contribute to the vagally mediated cardiac arrest and sudden death that sometimes occurs in man. Apnoeic asphyxia may be induced centrally or reflexly by stimulation of upper airways receptors. Conditions associated with apnoeic asphyxia and in which the risk is likely to be greatest include intubation, laryngoscopy and bronchoscopy; accidents involving underwater swimming; inhalation of sympathomimetic amines in aerosols by asthmatic patients; and chronic hypoventilation syndromes. These reflexes may be responsible for some victims of sudden infant death syndrome. Stimulation of the carotid bodies normally produces hyperventilation and bradycardia. When apnoea occurs centrally or reflexly, carotid chemoreceptor excitation resulting from asphyxia now causes a much enhanced bradycardia and even cardiac arrest, but paradoxically does not usually affect respiration. These reflexes and their interactions normally serve protective and purposeful functions, but may under certain circumstances become exaggerated and put the patient's life at risk.

Cardiovascular and respiratory effects of carotid body stimulation in the monkey.

1. The carotid bodies were stimulated in the anaesthetized pig-tailed macaque monkey (M. nemestrina) using (i) brief injections of cyanide or CO2-equilibrated bicarbonate solution into a common carotid artery, and (ii) longer perfusion with hypoxic hypercapnic blood in vascularly isolated chemoreceptor preparations. 2. In spontaneously breathing animals brief stimuli (thirty-one tests, seven monkeys) consistently increased pulmonary ventilation (by 97 +/- 10% of control), slowed the heart rate (the pulse interval increasing by 36 +/- 7.5%), and increased femoral vascular resistance (by 44 +/- 7%). 3. More sustained chemoreceptor stimulation with asphyxial blood (nineteen tests, five monkeys) increased ventilation by 187 +/- 23%, but transient bradycardia occurred in only eight of nineteen tests and was followed by tachycardia; in the remaining tests, only tachycardia occurred. After 20--40s, the pulse interval was 5.8 +/- 0.9% below the control level. Femoral vascular resistance either increased (five tests, two animals) or decreased (six tests, two animals). 4. Evidence is presented that in the monkey the autonomic effects of chemoreceptor stimulation are influenced by the level of respiratory activity with bradycardia and vasoconstriction occurring when the level is low, and tachycardia and vasodilatation when it is high. 5. The interaction of autonomic responses resulting from carotid body stimulation and from mechanisms initiated by the concomitant hyperventilation are qualitatively similar in the monkey and in subprimate species, although there may be quantitative differences such as would account for the species differences to distrubances produced, for instance, by arterial hypoxia.

Cardiovascular-respiratory reflex interactions between carotid bodies and upper-airways receptors in the monkey.

The carotid bodies were stimulated in the anesthetized pig-tailed macaque monkey (Macaca nemestrina) using i) brief injections of cyanide or CO2-equilibrated bicarbonate solution into a common carotid artery, and ii) longer perfusion with hypoxic hypercapnic blood in vascularly isolated chemoreceptor preparations. In spontaneously breathing animals, brief stimulations of the chemoreceptors consistently caused an increase in pulmonary ventilation, bradycardia, and an increase in femoral vascular resistance. When the same chemoreceptor stimulus was superimposed during the apneic period, reflexly evoked by stimulating either the central ends of the superior laryngeal nerves or the nasopharynx, the respiratory stimulation was absent or minimal, but the bradycardia and vasconstriction were greatly enhanced and exceeded the summed responses of separate stimulation of the chemoreceptors and one or the other of the upper-airways inputs. With sustained stimulation of the carotid bodies, hyperventilation, tachycardia, and femoral vasodilatation occurred due to overriding respiratory mechanisms. When superior laryngeal nerve stimulation was superimposed on this response, apnea occurred and tachycardia was reversed to bradycardia, and femoral vascular resistance increased above resting level. The interaction of autonomic responses resulting from chemoreceptor stimulation and from increases in the upper-airways inputs are qualitatively similar in the monkey and in subprimate species. Those involving specifically cardioinhibitory vagal responses are, in part at least, dependent on mechanisms related to the concomitant changes in respiration.

The effects of artificial lung inflation on reflexly induced bradycardia associated with apnoea in the dog.

1. The cardiac effects of artificial inflation of the lungs were studied during reflexly induced apnoea and bradycardia in anaesthetized dogs.2. Reflex apnoea and bradycardia were induced (a) by stimulation of the larynx with water or by electrical stimulation of afferent fibres in the superior laryngeal nerve, or (b) by combined stimulation of the superior laryngeal nerve and carotid body chemoreceptors.3. During combined stimulation of the laryngeal and carotid body inputs, the activation of respiration normally evoked by chemoreceptor stimulation was inhibited whereas the chemoreceptor cardio-inhibitory reflex was facilitated leading to periods of temporary cardiac arrest.4. In spontaneously breathing animals and in those artificially ventilated, lung inflation invariably caused tachycardia.5. Rhythmic artificial inflation of the lungs during the apnoeic period produced by the laryngeal input or by a combination of the laryngeal and chemoreceptor inputs wholly or partly reversed the bradycardia. This occurred using lung inflation volumes within the range of the normal tidal volume and inflation pressures of less than 12 mmHg; the response was independent of the composition of the gas used for inflating the lungs, and occurred at constant P(a, O2) and P(a, CO2). Lung inflation carried out during a reflexly induced arrest of the heart immediately restarted the heart and was accompanied by an exaggerated sinus arrhythmia.6. Evidence is presented that the observed effects of artificial lung inflation are reflex in origin with the vagus nerves as the main afferent and efferent pathways.7. Electrical stimulation of the central end of the cut pulmonary branches of the thoracic vagosympathetic nerves also caused tachycardia and had the same effects as lung inflation in modifying the reflexly induced bradycardia.8. Some clinical implications of these results are discussed.

Carotid body chemoreceptor reflexes and their interactions in the seal.

In the anesthetized spontaneously breathing harbor seal Phoca vitulina stimulation of the carotid body chemoreceptors by intracarotid injections of sodium cyanide or by hypoxic hypercapnic blood causes an increase in tidal volume, respiratory frequency, and respiratory minute volume. The heart rate invariably decreased. Experimental dives caused apnea and bradycardia. When the carotid bodies are stimulated within 10 s of the commencement of a dive, the chemoreceptor-respiratory response is abolished, but the chemoreceptor-cardioinhibitory response is considerably enhanced. Electrical stimulation of the central cut end of a superior laryngeal nerve also causes apnea and bradycardia; stimulation of the carotid body now fails to produce a respiratory response but the cardioinhibitory effect is enhanced. These results indicate that the carotid bodies cause reflexly hyperventilation and bradycardia, and that these responses are considerably modified by other inputs to the central nervous system.

Cardiorespiratory control by carotid chemoreceptors during experimental dives in the seal.

The diving responses of apnea and bradycardia, produced experimentally by immersing the face in water, were successfully elicited in the harbor seal Phoca vitulina anesthetized with urethan. The role of the carotid body chemoreceptors in the production of the diving bradycardia was studied in isolated carotid sinus-body preparations autoperfused with blood from the arterial circulation. When asphyxia was well developed during a dive the chemoreceptor drive was withdrawn by temporarily perfusing the chemoreceptors with blood of high PO2 (greater than 400 mmHg) and normal PCO2 from a disk oxygenator. The heart rate immediately rose to its predive value. Reestablishing hypoxic hypercapnic blood perfusion of the chemoreceptors from the animal's own circulation caused bradycardia with persistence of the apnea. Breathing restarted only on emersion. Substitution of normal arterialized blood from the oxygenator before or at the onset of a dive had no effect on the existing heart rate. It is concluded that the carotid bodies play an important part in maintaining the diving bradycardia during developing asphyxia without affecting respiration.

Time-course of the reduction of baroreceptor sensitivity in experimental hypertensive rabbits.

1. Hypertension was produced experimentally in three groups of rabbits by atherosclerosis, meical sclerosis and renal encapsulation. 2. The sensitivity of afferent baroreceptor fibre recordings, obtained from an isolated perfused aortic arch preparation, was reduced in all three treated groups. 3. The reduction of baroreceptor sensitivity was directly related to the increase in the lability of the blood pressure in the intact animal and to the reduction of the distensibility of the perfused region. 4. There was a closer relationship between the length of time of rabbits had been hypertensive and the reduction in the baroreceptor sensitivity, than to the level of their blood pressure. 5. The reduction of baroreflex sensitivity obtained by the infusion of phenylephrine was also directly correlated with the period of the hypertension. 6. Baroreceptor resetting occurred to a higher pressure in the renal hypertensive group.