Bisquaternary ligands of the common allosteric site of M2 acetylcholine receptors: search for the minimum essential distances between the pharmacophoric elements.

Structurally diverse molecules, such as alcuronium, gallamine, and tubocurarine as well as W84 and WDUO, are known to interact allosterically with ligand binding to muscarinic M2 acetylcholine receptors. Preliminary molecular modeling studies revealed two positive charges in the middle and two lateral aromatic areas to be essential elements of a high allosteric potency. To find out the optimum distances between these pharmacophoric elements, a systematic variation of the spacer in the series of W84, WDUO, and IWDUO compounds was performed. The allosteric reduction of the rate of dissociation of the antagonist [3H]-N-methylscopolamine from porcine heart M2 receptors served as a test system. The minimal essential distance between the positive charges was found to be 10 A. The length of the peripheral spacers connecting the positive charge and the lateral aromatic moiety appears to depend on the chemical functionality; the peripheral spacers have to be long and flexible enough to position the aromatic skeletons in the spatial neighborhood of the alkane middle chain: in the case of an oxime ether containing peripheral spacer, six atoms are required, and in the case of an alkane chain, four carbon atoms are necessary to adopt the pharmacophoric S-shape conformation.

A new technique for study of impact of arterial elasticity on left ventricular mass in rats.

We investigated possible links between left ventricular mass and central arterial elasticity in the adult spontaneously hypertensive rat (SHR) and in a subgroup of SHR in which blood pressure was normalized by chronic antihypertensive drug treatment; results were compared with those of age-matched normotensive Wistar-Kyoto rats. Two indexes of arterial elasticity, based on the measurement of aortic pressure pulse wave velocity, were used. First, the slope relating carotidofemoral pulse wave velocity to blood pressure in the phenylephrine-infused pithed preparation was used as a pressure-independent index of wall elasticity. Second, to account for hypertension- and treatment-induced aortic remodeling, elastic modulus was determined from the pulse wave velocity recorded when blood pressure reached that measured in awake animals before anesthesia and pithing, together with values for wall thickness and lumen diameter evaluated by histomorphometric analysis after in situ fixation at the same pressure. In control SHR, regression analysis of variance revealed significant correlations between left ventricular mass and both wave velocity/pressure slope and elastic modulus. Chronic antihypertensive treatment normalized all three parameters. In conclusion, this new technique provides experimental evidence of a link between left ventricular mass and central arterial elasticity.

Aortic stiffness and left ventricular mass in a rat model of isolated systolic hypertension.

We tested whether cardiac mass can be related to decreased aortic stiffness in an original rat model of isolated systolic hypertension. Increased aortic stiffness was produced by calcium overload of elastic arteries after vitamin D3 plus nicotine treatment. Half of the animals were chronically treated with the angiotensin-converting enzyme inhibitor perindopril (1 mg/kg per day PO). Rats were pithed, and lower body vascular resistance was measured. Blood pressure was then increased by phenylephrine infusion, and carotidofemoral pulse wave velocity was measured. This value together with those for thoracic aorta internal diameter and medial thickness (determined after in situ fixation and histomorphometry) were used to calculate elastic modulus. Vitamin D3 plus nicotine treatment produced parallel increases in cardiac mass and elastic modulus, with a significant correlation between the two. There was no significant change in resistance. Treatment with perindopril reversed the changes in cardiac mass and elastic modulus but had no effect on resistance after calcium overload of the elastic arteries. In this model of isolated systolic hypertension, we showed that cardiac mass is related to arterial elasticity.

Effect of chronic ANG I-converting enzyme inhibition on aging processes. IV. Cerebral blood flow regulation.

Age-related changes in systemic arterial blood pressure, basal cerebral blood flow (CBF), and CBF regulatory capacity were investigated in awake 6-, 12-, 24-, and 30-mo-old male Wistar (WAG/Rij) rats, one-half of which received the angiotensin I-converting enzyme inhibitor (ACEI) perindopril from 6 mo onward. There was no age-dependent change in mean arterial blood pressure, basal CBF, or cerebrovascular reactivity to hypercapnia, but the lower limit of CBF autoregulation rose from 70 mmHg at 6 and 12 mo to 90 mmHg in 24- and 30-mo-old animals. ACEI lowered mean arterial blood pressure but had no effect on basal CBF or on cerebrovascular reactivity to hypercapnia. ACEI shifted the lower limit of CBF autoregulation to a 20-mmHg-lower level in 12- and 24-mo animals but not in rats treated for 2 yr, i.e., from the ages of 6 to 30 mo. In conclusion, the main age-related change in CBF regulation was an increase in the lower limit of CBF autoregulation to a higher blood pressure level. Treatment with ACEI partially restored the lower limit of CBF autoregulation.

Increased arterial distensibility induced by the angiotensin-converting enzyme inhibitor, lisinopril, in normotensive rats.

1. We investigated possible structural correlates of the beneficial effect of chronic angiotensin-converting enzyme inhibition (ACEI) with lisinopril on the aortic distensibility of normotensive rats. 2. Experiments were performed in young (4-month old), normotensive, Wistar rats which received lisinopril in their drinking water (0.9 or 9 mg kg-1 day-1) for 9 months. 3. Following ACEI treatment, rats were pithed and aortic pulse wave velocity was measured during the progressive rise in mean arterial blood pressure produced by i.v. infusion of the alpha 1-adrenoceptor agonist, phenylephrine. The slope of the regression line relating aortic pulse wave velocity to mean arterial blood pressure was taken as an index of aortic distensibility. Following this, the aorta was fixed in situ at a normotensive pressure level and histomorphometry was performed. We also measured the calcium content of the aortic wall by atomic absorption. 4. The lower dose of lisinopril failed to lower systolic arterial blood pressure (unanaesthetized rat) or mean arterial blood pressure (pithed rat). Chronic ACEI with the higher dose of lisinopril lowered both systolic arterial blood pressure (104 +/- 6 mmHg, controls 133 +/- 4 mmHg, unanaesthetized), and mean arterial blood pressure (27 +/- 1 mmHg, controls 34 +/- 2 mmHg, pithed). 5. Although the lower dose of lisinopril did not lower blood pressure, it did improve aortic distensibility as revealed by a fall in the slope relating aortic pulse wave velocity (Y) to mean arterial blood pressure (X). Values were 5.7 +/- 0.7, 3.8 +/- 0.6 and 2.7 +/- 0.3 in controls, and in low and high ACEI groups, respectively. 6. Lisinopril treatment did not modify the calcium content, the internal and external diameters or the medial thickness of the aorta. Chronic ACEI did, however, increase the thickness of the medial elastic fibres (controls 3.55 +/- 0.05 microm, low dose ACEI 4.05 +/- 0.15 gm (P<0.05), and high dose ACEI4.18 +/- 0.15 microm (P<0.05)).7. In conclusion, we would suggest that ACEI treatment with a low dose of lisinopril can decrease aortic stiffness via a pressure-independent mechanism which possibly involves an effect of ACEI on elastic fibres.

Haemodynamic effects of a new dihydropyridine calcium entry blocker, S-12968-(-), in a rat model of cardiovascular calcium overload.

1. The haemodynamic effects of S-12968-(-), a new dihydropyridine calcium entry blocker (enantiomer of S-11568), were compared with those of the stereoisomer, S-12967-(+), nifedipine, and sodium nitroprusside. 2. A first experiment was performed in conscious, young male rats chronically implanted with femoral artery and vein cannula and repeated in rats previously treated with vitamin D3 and nicotine. Such treatment produces marked vascular calcium overload, especially of the compliance arteries, with no overt sign of toxicity as far as can be judged from the plasma profile. 3. In conscious rats the hypotensive effects of S-12968-(-), nifedipine and sodium nitroprusside were of similar potency. The falls in blood pressure produced by nifedipine and sodium nitroprusside were accompanied by reflex tachycardia which was less marked in the vascular calcium overload model. S-12968-(-) did not induce reflex tachycardia. S-12967-(+) increased blood pressure in both models. 4. A second experiment was performed in open-chest pentobarbitone-anaesthetized rats with electromagnetic flowprobes on the ascending aorta. In controls the falls in blood pressure produced by low doses (0.1 and 0.3 mg kg-1, i.v.) of S-12968-(-) were accompanied by falls in total peripheral resistance. The higher dose (1 mg kg-1, i.v.) of S-12968-(-) produced no change in total peripheral resistance, and in rats pretreated with vitamin D3 and nicotine, cardiac output fell. 5. In conclusion, S-12968-(-) appears to have a dual action and to lower blood pressure at higher doses at least in part by a cardiac effect. This phenomenon is more pronounced in rats pretreated with vitamin D3 and nicotine.6. S-12967-(+) resembles a calcium channel activator in this model.