Renal Hypertensive Dogs Research Articles

Pharmacology of Lacidipine, a Vascular-Selective Calcium Antagonist

Lacidipine is a new 1,4-dihydropyridine (DHP) that induces a potent calcium antagonistic activity on vascular preparations. It has a markedly slow rate of onset, but its effect is still apparent after 9 h of drug washout. Calcium antagonistic activity has been evaluated on nonvascular smooth muscle, and lacidipine has proved to be more vascular-selective than standard DHP derivatives. In cardiac preparations, the concentrations required to induce negative inotropic effects are approximately 100 times higher than concentrations needed to antagonize calcium-induced contractions in vascular smooth muscle. In addition, lacidipine exhibits antioxidant properties in tests based on the autoperoxidation of rat cerebral cortical membranes. In spontaneously hypertensive rats (SHRs), lacidipine induces a potent and long-acting blood pressure reduction (ED25 = 0.19 mg/kg orally and 0.006 mg/kg intravenously, with durations greater than 12 and 3 h, respectively). In saline-loaded SHRs and at antihypertensive dosages, lacidipine increases urine volume as well as urinary excretion of sodium. In one-clip, two-kidney renal hypertensive dogs, the antihypertensive properties of lacidipine after both oral and intravenous administration were confirmed. The marked vascular selectivity of lacidipine was clearly evident both in pithed rats infused with angiotensin II and in anesthetized dogs, in which preferential and long-lasting coronary and vertebral blood flow increases were also observed.

SD-3211, a Novel Benzothiazine Calcium Antagonist, Alone and in Combination with a Beta-Adrenoceptor Antagonist, Produces Antihypertensive Effects Without Affecting Heart Rate and Atrioventricular Conduction in Conscious Renal Hypertensive Dogs

We compared the effects of SD-3211, a novel calcium antagonist, on blood pressure, heart rate, and atrioventricular conduction with those of diltiazem using conscious renal hypertensive dogs (one-kidney, one-clip type). We also examined the combined effects of these calcium antagonists with a beta-adrenoceptor antagonist, propranolol, on these variables. Oral administration of SD-3211 (1.25, 2.5, and 5 mg/kg) resulted in a dose-dependent decrease in blood pressure without affecting heart rate. SD-3211 at all three doses significantly decreased systolic blood pressure. At 2.5 and 5 mg/kg the compound elicited significant decreases in mean blood pressure and diastolic blood pressure. Hypotension obtained with the highest dose of SD-3211 lasted for at least 9 h. No significant alteration in PR interval was observed in electrocardiograms after administration of SD-3211. Diltiazem, given orally at doses of 2.5 and 5 mg/kg but not 1.25 mg/kg, produced significant hypotension with little change in heart rate. The duration of hypotension induced by the highest dose of diltiazem was only 3 h. Diltiazem prolonged PR interval in a dose-dependent manner, causing second-degree atrioventricular block in some dogs. Combined administration of SD-3211 or diltiazem (2.5 mg/kg) with propranolol (30 mg/kg) resulted in enhanced hypotension with no alteration in heart rate. SD-3211 plus propranolol had little effect on the PR interval, whereas diltiazem plus propranolol caused a markedly enhanced prolongation. These results indicate that SD-3211 is an antihypertensive agent with long-lasting action and little effect on heart rate and atrioventricular conduction and, when administered alone or in combination with propranolol, may be useful in the treatment of hypertension.

Altered responsiveness of peripheral presynaptic alpha 2 and vascular postsynaptic alpha 1 adrenoceptors in renal hypertensive dogs

Altered responsiveness of peripheral presynaptic alpha 2 and vascular postsynaptic alpha 1 adrenoceptors in renal hypertensive dogs

Lacidipine

Lacidipine, currently being evaluated as a once-daily antihypertensive agent, acted as a calcium entry blocker on rabbit ear artery (pA2 = 9.4) with a markedly slower onset of action than that of nitrendipine; this effect was not reversed after 9 h of drug washout. Calcium entry blocker activity was also evaluated on nonvascular smooth muscles: Lacidipine showed a more pronounced vascular selectivity than nitrendipine; for both drugs, concentrations required to induce negative inotropic effects in guinea pig ventricular strip were approximately 100 times higher than concentrations needed to antagonize calcium contraction in vascular smooth muscle. In spontaneously hypertensive rats (SHR), by the tail-cuff method, lacidipine (ED25 = 0.35 mg/kg orally, p.o.) proved approximately 30 times more potent, slower in onset, and longer-acting than nitrendipine in reducing blood pressure. These features were confirmed in chronically implanted SHR after oral and intravenous (i.v.) administration (ED25 = 0.19 mg/kg p.o. and 0.006 mg/kg i.v.). A short-lasting tachycardia was detected with both drugs. No evidence of acquired tolerance emerged after repeated oral administrations over a 3-week period. Lacidipine induced a natriuretic effect in saline-loaded SHR at antihypertensive doses. In renal hypertensive dogs, lacidipine proved more potent (three to seven times), slower in onset, and longer-lasting than nitrendipine after p.o. (ED25 = 0.22 mg/kg) and i.v. (ED25 = 0.004 mg/kg) administrations.

心選択性β‐遮断薬Ｂｅｔａｘｏｌｏｌの腎性高血圧犬における抗高血圧作用

The antihypertensive effect of betaxolol, a highly selective beta 1-adrenoceptor antagonist, was investigated in renal hypertensive dogs, and the mechanism was also studied. A single oral administration of betaxolol (1 and 10 mg/kg) lowered blood pressure dose-dependently. The hypotensive effect of betaxolol was enhanced by daily oral administration for 10 days. In anesthetized dogs, intraarterial injection of betaxolol produced a dose-dependent increase in femoral artery flow; and in this test, betaxolol was 3 times less potent than papaverine. The increase in blood flow with betaxolol was not affected by pretreatment with propranolol. These findings indicate that a certain vasodilating activity may contribute to the antihypertensive mechanism of betaxolol.

新しいα，β‐遮断薬，（±）‐４‐〔２‐Ｈｙｄｒｏｘｙ‐３‐（３‐（２‐ｍｅｔｈｏｘｙｐｈｅｎｏｘｙ）‐２‐ｐｒｏｐｙｌａｍｉｎｏ）ｐｒｏｐｏｘｙ〕‐１（２Ｈ）‐ｉｓｏｑｕｉｎｏｌｉｎｏｎｅ（Ｎ‐１５１８）の薬理作用

The alpha, beta-adrenergic blocking, antihypertensive and vasodilating properties of N-1518 were compared with those of labetalol. N-1518 blocked alpha- and beta-adrenoceptors competitively as indicated by parallel rightward displacement of the dose-response curve of each agonist in isolated organs and in anesthetized dogs. As judged by pA2 values and DR10 values, N-1518 was as potent as labetalol in blocking alpha- and beta-adrenoceptors. The beta 1/alpha 1 ratio of N-1518 was 8.3 for pA2 values in isolated organs and 13.6 for DR10 values in anesthetized dogs, respectively. N-1518 inhibited dose-dependently the pressor response to intravenous administration of noradrenaline, but labetalol did not depress the response to noradrenaline in anesthetized dogs. N-1518 is composed of four optical isomers. The SR-isomer was the most potent in blocking beta-receptors, and the RR-isomer was the most potent in blocking alpha-receptors. N-1518 has no intrinsic sympathomimetic activity in reserpinized rats and has no local anesthetic activity in guinea pigs. Single oral administration of N-1518 produced a fall in blood pressure in conscious SHR and renal hypertensive dogs without causing tachycardia. Intra-arterially administered N-1518 in the dog hindlimb resulted in vasodilation as indicated by the increase in blood flow. The magnitude of the responses was approximately 3 times more potent than that of labetalol.

Nonpeptide Angiotensin II Receptor Antagonists: A Novel Class of Antihypertensive Agents

The most direct approach to block the function of the renin-angiotensin system would be to antagonize angiotensin II (AII) at the level of its receptor. However, the AII receptor antagonists currently available, such as saralasin, are peptides which still retain agonistic activity and lack oral bioavailability. We have identified the N-benzylimidazoles, S-8307 and S-8308, as weak, but selective nonpeptide AII receptor antagonists. These initial leads were subsequently converted into more potent compounds, such as EXP6155, EXP6803 and EXP7711, while maintaining the selectivity. The compounds displace 3H-AII from its specific binding sites in adrenal cortical membranes and smooth muscle cells. They competitively inhibit the vasoconstrictor response to AII in various in vivo and in vitro preparations, but do not influence those to KCl, norepinephrine, and vasopressin. Converting enzyme and renin are not affected by these agents. In renal hypertensive rats and sodium-depleted dogs our compounds cause a sustained decrease in arterial pressure following intravenous and oral (EXP7711) administration, and are devoid of agonistic properties. Taken together, these nonpeptide structures are true competitive AII receptor antagonists and represent a new class of effective antihypertensive agents.

O-209 - Antihypertensive effects of SD-3211, a novel calcium antagonist in conscious renal hypertensive dogs

O-209 - Antihypertensive effects of SD-3211, a novel calcium antagonist in conscious renal hypertensive dogs

P-360 - Antihypertensive effects of NZ-105, a novel dihydropyrldine calcium antagonist, in conscious renal hypertensive dogs

P-360 - Antihypertensive effects of NZ-105, a novel dihydropyrldine calcium antagonist, in conscious renal hypertensive dogs

無麻酔・無拘束実験高血圧動物における，新規α１‐アドレナリン受容体遮断薬，Ｎａｆｔｏｐｉｄｉｌ（ＫＴ‐６１１）の抗高血圧作用

The antihypertensive effect of naftopidil (KT-611) following single oral administration was investigated in normotensive Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), DOCA-Salt hypertensive rats (DHR), 2-kidney 1-clip renal hypertensive rats (RHR) and Grollman type renal hypertensive dogs with 1-kidney (RHD); and it was compared with that of the selective alpha 1-adrenoceptor antagonist prazosin. The blood pressure and heart rate were measured under the unanesthetized, unrestrained state through an arterial catheter that was chronically implanted into the abdominal aorta. In SHR and WKY, both KT-611 (10 and 30 mg/kg, p.o.) and prazosin (1 and 3 mg/kg, p.o.) markedly inhibited the pressor response to the alpha 1-adrenoceptor agonist phenylephrine (3 micrograms/kg, i.v.). KT-611 (10 to 100 mg/kg, p.o.) showed a dose-dependent hypotensive effect in SHR, DHR and RHR but not in WKY. The hypotensive effect of KT-611 reached maximum at 0.5-1 hr, lasted for 4-6 hr and was more potent in DHR and RHR than in SHR. The potency of KT-611 was 1/10-1/30 weaker than that of prazosin. In RHD, single oral administration of KT-611 (1 to 10 mg/kg) caused a dose-dependent and long-lasting hypotensive effect. These results suggest that KT-611 has a long-lasting hypotensive effect in experimental hypertensive animal models.

Cycle time effect of sinus nerve stimulation on variabilities of heart rate and blood pressure of normotensive and renal hypertensive dogs

Wackermann (1999) [Wackermann, J., 1999. Towards a quantitative characterization of functional states of the brain: from the non-linear methodology to the global linear description. Int. J. Psychophysiol. 34, 65–80] proposed ∑–ϕ–Ω system for describing the global brain macro-state, in which Ω complexity was used to quantify the degree of synchrony between spatially distributed EEG processes. In this paper the effect of signal power on Ω complexity is discussed, which was not considered in Wackermann's paper (1999). Then an improved method for eliminating the effect of signal power on Ω complexity is proposed. Finally a case study on the degree of synchrony between two-channel EEG signals over different brain regions during hand motor imagery is given. The results show that the improved Ω complexity measure would characterize the true degree of synchrony among the EEG signals by eliminating the influence of signal power.

Altered agonist-activated 86Rb+ efflux from arteries in canine renal hypertension.

Basal rate constants for 86Rb+ efflux from renal arteries of renal hypertensive dogs were lower than those of control animals whereas no differences were found for coronary arteries. Norepinephrine produced parallel increases in efflux rate constants for hypertensive and control renal arteries, but serotonin produced smaller responses in hypertensive compared to control coronary arteries.

A review of the preclinical cardiovascular pharmacology of cilazapril, a new angiotensin converting enzyme inhibitor.

1. Cilazapril is the monoethyl ester prodrug form of the di-acid cilazaprilat, a new angiotensin converting enzyme (ACE) inhibitor. Cilazaprilat has an IC50 of 1.9 nM as an inhibitor of rabbit lung ACE in vitro making it one of the most potent ACE inhibitors currently available. Studies on a wide range of other enzymes show that the inhibition is highly specific. 2. An oral dose of 0.1 mg kg-1 cilazapril evoked the same maximum degree of plasma ACE inhibition (approximately 76%) in the rat as 0.25 mg kg-1 enalapril. Cilazapril (0.25 mg kg-1 p.o.) inhibited plasma ACE by greater than 95%. The rate of recovery of ACE activity was slower with cilazapril (5-6% h-1) than with enalapril (10% h-1). 3. In anaesthetised rats cilazaprilat was equipotent with ramiprilat and slightly more potent (1.5x) than enalaprilat as an inhibitor of the angiotensin I pressor response. 4. Following oral administration to conscious rats and intravenous administration to anaesthetised dogs, cilazapril was 2-4.5x more potent than enalapril as an ACE inhibitor. 5. In cats cilazapril (0.1 and 0.3 mg kg-1 p.o.) dose dependently decreased plasma ACE activity and the angiotensin pressor response. Peak effects occurred at 2 h after dosing and plasma ACE inhibition was maintained at greater than or equal to 50% for up to 18 h. Mean arterial pressure was also decreased dose dependently with a peak effect at 3-4 h. 6. Daily oral dosing of cilazapril (30 mg kg-1 p.o.) to spontaneously hypertensive rats evoked a progressive and prolonged (24 h) antihypertensive response with a maximum decrease in systolic blood pressure of 110 mm Hg. 7. Cilazapril (10 mg kg-1 p.o. twice daily for 3.5 days) progressively decreased blood pressure in volume depleted renal hypertensive dogs. The maximum fall in systolic pressure was 39 +/- 6 mm Hg. 8. Haemodynamic studies in open chest anaesthetised dogs showed that the hypotensive response to intravenous cilazapril was accompanied by a reduction in total peripheral resistance. Small decreases in cardiac output and myocardial contractile force were seen at high doses. 9. Cilazapril had no adverse effect on cardiovascular reflexes. There was no impairment of the baroreflex in rats. Exercise-induced tachycardia and pressor responses in conscious cats were unchanged. 10. Cilazapril is exceptionally well absorbed by the oral route (98% in rats).

Effects of carotid sinus nerve stimulation at different times in the respiratory and cardiac cycles on variability of heart rate and blood pressure of normotensive and renal hypertensive dogs

It was the purpose of the present study to determine (1) whether or not there exists a common respiratory and cardiac cycle time effect of the baroreceptor control of heart rate (HR) and blood pressure (BP) in spontaneously breathing anaesthetized dogs and (2) whether this effect, if present, is abnormal in dogs with renal hypertension. The baroreflex responses were evoked by brief low-intensity electrical carotid sinus nerve stimulation (CSNS) triggered by the R-wave in the electrocardiogram with an adjustable delay (0–210 ms) and positioned in either inspiration or expiration. All baroreceptor afferent nerves were intact. Brief CSNS had no noticeable effect on breathing. The responses of means of HR, respiratory sinus arrhythmia (RSA), and systolic and diastolic respiratory blood pressure waves (RBPW syst, RBPW diast) to CSNS were not different for normotensive and hypertensive dogs. No cardiac, but a small respiratory cycle time effect on means of HR, BP syst and BP diast was observed. The magnitude of RSA and RBPW diast was markedly enhanced for expiratory CSNS at each delay after the R-wave. Inspiratory CSNS diminished the magnitude of RSA and RBPW only if applied during systole, and become ineffective for delays greater than 200 ms after the R-wave. During both respiratory phases, CSNS was elevated at times of central presentation of the natural sinoaortal baroreceptor discharges (120 ms and 70 ms, respectively). The magnitudes of RSA and RBPW were influenced simultaneously and in the same way by CSNS throughout. It is concluded that, under the present experimental conditions, RSA and RBPW have a common central origin.

5-(1-piperazinyl)-1H-1,2,4-triazol-3-amines as antihypertensive agents.

A series of 5-(1-piperazinyl)-1H-1,2,4-triazol-3-amines was synthesized and screened for antihypertensive and diuretic activity in spontaneously hypertensive rats (SHR). One compound, 5-[4-[(3-chlorophenyl)methyl]-1-piperazinyl]-1H-1,2,4-triazol-3-am ine (8), was selected to define the mechanism of its antihypertensive activity. Studies in SHR suggest ganglionic blocking activity. Short-lived antihypertensive activity was observed in conscious renal hypertensive dogs.

Effects of hypertension and its reversal on canine arterial wall properties.

Segments of carotid, femoral, saphenous, and left circumflex coronary arteries were obtained from control, renal hypertensive, and nephrectomized hypertensive dogs for in vitro study of mechanical properties. Hypertension was produced in two-kidney dogs by unilateral renal artery constriction. After 3 months, the compromised kidney was removed in half of the dogs. Mean arterial pressure was significantly elevated in the hypertensive dogs after 3 months (127 +/- 2 vs 94 +/- 1 mm Hg for controls) and partially returned toward normal 3 months after nephrectomy (105 +/- 2 mm Hg). Pressure-diameter relations were determined under conditions of maximum active and passive smooth muscle activation. Contiguous segments were used for the determination of water and connective tissue content. Hypertension was associated with increased passive arterial wall stiffness at most sites, with a partial return toward normal after nephrectomy. Maximum responses to smooth muscle activation (active stress and constriction response) were augmented in arteries from hypertensive dogs and partially returned toward normal in the nephrectomized hypertensive group. The elastin content of these arteries was unchanged, while collagen content was nonuniformly decreased in renal hypertensive dogs. Small decreases were found in the radius-wall thickness ratio of some arteries. No significant mechanical changes occurred in the saphenous artery. The largest hypertension-related changes were found in the coronary arteries, which also exhibited the smallest recovery toward normal properties after nephrectomy. Considerable regional variability of changes in arterial wall in renal hypertensive and nephrectomized hypertensive dogs was found. Incomplete resolution of the hypertension and arterial wall changes by nephrectomy was found in this animal model.

Cardiovascular effects of the novel arteriovenous dilator agent, flosequinan in conscious dogs and cats.

1. Flosequinan (BTS 49 465, 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) a novel arteriovenous dilator agent was orally effective in conscious renal hypertensive dogs and normotensive cats. The hypotensive potency of flosequinan was approximately ten times less than that of hydralazine in renal hypertensive dogs, 10 mg kg-1 and 20 mg kg-1 flosequinan causing similar falls in mean blood pressure to 1 mg kg-1 and 3 mg kg-1 hydralazine respectively. In normotensive cats, 5 mg kg-1 flosequinan caused similar falls to 0.5 and 1.0 mg kg-1 hydralazine. The onset of hypotensive effect after flosequinan appeared to be slightly slower than after hydralazine in the dog and slightly faster than hydralazine in the cat. 2. The degree of tachycardia and increase in plasma renin activity (PRA) for equivalent falls in mean blood pressure in both species was significantly less for flosequinan than for hydralazine (P less than 0.05). 3. In normotensive dogs, flosequinan, 10 and 20 mg kg-1 orally, caused a small but non-significant increase in sodium and chloride excretion and had little effect on urine volume whereas hydralazine, 1 and 3 mg kg-1 orally, caused a marked retention of sodium and chloride ions and a reduction in urine volume (P less than 0.01). 4. Neither flosequinan, 10 mg kg-1 orally, nor hydralazine 1 mg kg-1 orally, affected either glomerular filtration rate measured as creatinine clearance or effective renal plasma flow measured as p-aminohippuric acid clearance in normotensive dogs. 5. The lesser degree of tachycardia and increase in plasma renin activity together with a lack of sodium retaining activity associated with flosequinan suggest that this agent may have potential advantages over existing therapy as an antihypertensive in man.

Vascular and cardiac effects of HP 406 and nifedipine in vitro and in conscious spontaneously hypertensive rats and renal hypertensive dogs

AbstractThe cardiovascular effects of the calcium antagonists HP 406 and nifedipine were assessed in a series of in vitro and in vivo studies. HP 406 was found to display moderate affinity for dihydropyridine binding sites, as determined by the inhibition of [3H]‐nitrendipine binding on rat ventricular membranes. HP 406 was found to have an IC50 of 1.3 × 10−7 M as compared to nifedipine with an IC50 of 7.0 × 10−9 M. Additional in vitro studies were conducted with isolated spontaneously contracting and electrically paced guinea pig atria and rabbit aortic rings. HP 406 was found to have minimal effects on cardiac chronotropic and inotropic activity in isolated guinea pig atria. In contrast, nifedipine caused significant dose‐related reductions in heart rate and myocardial contractile force. Rabbit aortic rings were precontracted with potassium chloride (KCI) or norepinephrine (NE), and HP 406 or nifedipine was added to tissue baths in a cumulative dose range. HP 406 and nifedipine both caused dose‐related relaxation of KCI‐ and NE‐contracted rings; however, the IC50's against KCI were found to be significantly lower than those against NE for both compounds. The IC50's against NE were found to be 4.8 × 10−8 M and 5.9 × 10−8 M for HP 406 and nifedipine, respectively. The IC50's against NE were 1.9 × 10−5 M for HP 406 and 4.4 × 10−5M for nifedipine. Finally, the antihypertensive activity of HP 406 and nifedipine were compared in the spontaneously hypertensive rat (SHR) and renal hypertensive dog. Both compounds produced significant reductions in mean arterial pressure at 1 mgikg p.o. in the SHR and at 3 mgikg p.o. in the renal hypertensive dog. Nifedipine was also found to cause a significantly greater tachycardia compared to HP 406. The results of this study show that HP 406 is a potent antihypertensive agent with minimal direct or reflex‐mediated chronotropic effects. The mechanism of this antihypertensive activity appears to result from calcium‐channel antagonism and vascular dilation.

Pinacidil

Peripheral vasodilation has proved to be a successful method to control hypertension in recent years, as illustrated by the increasing number of marketed vasodilators like calcium antagonists, alpha-adrenergic antagonists, and angiotensin-converting enzyme inhibitors. A novel group of vasodilators showing excellent antihypertensive activity in spontaneously hypertensive rats and renal hypertensive dogs has been discovered. The first compounds of the group were pyridylthioureas. Chemical modification based on structure-activity studies involving a substitution of N-cyanoguanidine for the less active thiourea function has led to the synthesis of pinacidil, N'-cyano-N-(4-pyridyl)-N"-(1,2,2-trimethylpropyl) guanidine, recently introduced as the new antihypertensive drug, Pindac. Preclinical studies showed that pinacidil does not relax vascular smooth muscle by any known mechanism, but recent investigations indicate that the compound opens potassium channels in the cell membranes. The hyperpolarization that follows is responsible for the relaxation. Pinacidil is rapidly and almost completely absorbed after oral administration and produces a dose-dependent blood pressure fall in hypertensive animals and humans. The therapeutic plasma concentrations are in the range of those producing relaxation of isolated, noradrenalin-contracted human blood vessels in vitro. In dogs, pinacidil decreases vascular resistance in most tissues proportionally to the blood pressure fall, but elicits a specific increase in coronary blood flow at antihypertensive doses. The compound shows a selectivity for precapillary vessels. It is mainly eliminated by hepatic metabolism to pinacidil-N-oxide followed by renal excretion, and the N-oxidation is partly reversible. Pinacidil is relatively free of toxicity, and action-related side effects such as fluid retention and tachycardia are readily controlled with diuretics and beta-blockers.(ABSTRACT TRUNCATED AT 250 WORDS)

Partition of carotid baroreceptor response in two-kidney renal hypertensive dogs.

This study evaluated the mechanism of carotid sinus baroreceptor resetting in two-kidney one-clip Goldblatt hypertension in dogs by partitioning the resetting between carotid sinus wall compliance and receptor neural elements. With dogs under halothane anesthesia, the left renal artery was constricted 70-80% with a Goldblatt clamp without disturbing the contralateral kidney. Ten weeks later, when mean blood pressure had risen to 151 +/- 6 mmHg (means +/- SE) compared with 105 +/- 5 mmHg in controls, we measured simultaneously whole nerve action potentials (N) and carotid sinus volume (V) during step changes in intrasinus pressure (P). Hypertensive N vs. P relationship was sigmoid shaped and shifted toward the P-axis compared with controls. Hypertensive V vs. P relationship was not significantly different from controls. The hypertensive N vs. V relationship derived from the composite plots of N vs. P and V vs. P was sigmoid shaped and shifted toward the V-axis compared with controls. These results suggest that the resetting of baroreceptors is due to changes in receptor properties rather than carotid sinus wall compliance.