Effect of atorvastatin on hemorheologic-hemostatic parameters and serum fibrinogen levels in hyperlipidemic patients.

Plasma fibrinogen and hemorheologic-hemostatic factors contribute to dyslipidemia-induced morbidity. Some of these parameters can be favorably affected when abnormal serum lipoprotein levels are corrected. Thus, we investigated whether treatment with atorvastatin would result in changes in plasma viscosity and other hemorheologic and hemostatic parameters. Twenty-two hyperlipidemic men at a university lipid clinic were treated single-blinded with atorvastatin 80 mg/day for 12 weeks to determine hemostatic-hemorheologic parameters including blood viscosity, fibrinogen levels, whole blood platelet aggregation, tissue plasminogen activator antigen, hematocrit, plasminogen activator inhibitor activity, factor VII activity, red blood cell (RBC) deformity and lipid ratio, sedimentation rate, and fasting serum lipoprotein levels. Atorvastatin treatment provided significant lowering of serum lipoprotein levels: low-density lipoprotein -53% (p = 0.0001), very low density lipoprotein -43% (p = 0.0001), and triglycerides -35% (p < 0.0001). These effects were accompanied by changes in plasma viscosity -10% (p = 0.0007), arachidonic acid-induced whole blood platelet aggregation -11% (p = 0.006), factor VII -8% (p = 0.001), RBC lipid composition +5% (p = 0.0003), and RBC sedimentation -33% (p = 0.0002). Plasma fibrinogen levels were not affected. Thus, atorvastatin 80 mg/day produced marked reductions in serum low-density lipoprotein cholesterol (-53%), very low density lipoprotein cholesterol (-43%), and triglycerides levels (-35%), and significant changes in plasma viscosity as well as other hemorheologic-hemostatic parameters, but no changes in plasma fibrinogen levels.

Evidence for NO involvement in regulating vascular reactivity in balloon-injured rat carotid artery.

The present study evaluated the influence of this newly formed intima on vascular reactivity in balloon-injured carotid arteries and the regulatory role of the vasodilator, nitric oxide (NO). Balloon injury was performed using a 2-F Fogarty catheter. After 2 and 4 wk, carotid artery segments were removed for both histomorphometric analysis and determination of in vitro contractile responses. Histomorphometric analysis showed a marked intimal thickening with an intima-to-media ratio of 126 +/- 19% (n = 5). The lack of factor VIII staining in injured carotid arteries revealed the absence of endothelium, since factor VIII-related antigen is a glycoprotein synthesized by endothelial cells. Functionally, maximal contractile responses to norepinephrine, angiotensin II (ANG II), endothelin-1, and serotonin were all attenuated in the injured vessels compared with the uninjured carotid arteries [0.38 +/- 0.11 vs. 0.73 +/- 0.10 g (n = 5), norepinephrine; 0.15 +/- 0.06 vs. 0.38 +/- 0.05 g (n = 4), ANG II; 0.60 +/- 0.14 vs. 1.05 +/- 0.12 g (n = 4), endothelin-1; 0.23 +/- 0.07 vs. 0.60 +/- 0.06 g (n = 12), serotonin]. Contractile responses induced by KCl were not affected by the balloon injury (0.62 +/- 0.10 vs. 0.64 +/- 0.09 g, n = 4). Interestingly, carbachol, a muscarinic agonist and vasodilator, caused concentration-dependent relaxations in 2- as well as 4-wk postinjured vessels despite the absence of endothelium. The NO synthase inhibitors, N omega-L-arginine methyl ester (L-NAME) and N omega-nitro-L-arginine (L-NNA), blocked the relaxation responses evoked by carbachol. Exogenously administered L-arginine reversed this blockade of the NOS inhibitors on the carbachol-induced relaxations. In addition, L-NAME partially reversed in a concentration-dependent manner the reduced maximal contractile force elicited by serotonin in the injured carotid artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional studies but not receptor binding can distinguish surmountable from insurmountable AT1 antagonism.

Our study demonstrated that inhibition of angiotensin II- (Ang II) mediated contractions of rabbit aorta by structurally diverse nonpeptide AT1 antagonists could distinguish surmountable from insurmountable AT1 antagonism. CI-996, L158809, EXP 3174 and SKF 108834 produced concentration-related rightward shifts in Ang II response curves and reduced the maximal contraction to Ang II, characteristic of insurmountable antagonism. In contrast, DuP 753 and SKF 108566, produced parallel rightward shifts in Ang II contractile curves without affecting the maximal response which is consistent with the definition of surmountable or competitive antagonism. In addition, CI-996 demonstrated potent inhibition of Ang II-stimulated inositol phosphate accumulation in rat aortic smooth muscle cells, behaving as an insurmountable antagonist. However, DuP 753 was a surmountable antagonist of Ang II-stimulated inositol phosphate accumulation. Repeated washing of rabbit aorta preincubated with either CI-996 or EXP 3174 did not restore the blunted Ang II contractions. In contrast, both DuP 753 and the structurally dissimilar SKF 108566 at a concentration of 100 nM showed complete recovery of Ang II responses within 2 hr of repeated washing. Surprisingly, repeated rinsing of rabbit aorta for up to 5 hr after incubation with 1 microM DuP 753 failed to restore responses to Ang II. In addition, Scatchard analysis of [125I] Ang II saturation binding experiments revealed a competitive and rapidly reversible nature of AT1 receptor antagonism for all the AT1 antagonists examined. Taken together, the results of this study provide evidence for a competitive and rapidly reversible binding interaction of structurally diverse non-peptide antagonists at the AT1 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Antisense-designed peptides: a comparative study focusing on possible complements to angiotensin II.

A comprehensive study of antisense peptides possibly complementary to angiotensin II (AII) is described. Antisense peptides of AII were designed using two different procedures outlined by Blalock and Root-Bernstein. Also, peptide complements designed to interact as homologs of AII were investigated. Three methods were used to detect binding between these peptides and AII. Several antisense-designed peptides were studied with unprotected termini to compare the effects of protected vs. unprotected termini. It was determined that the protected antisense-designed peptides derived from Root-Bernstein's methods interacted (high micro-molar range) directly with AII, while those protected antisense peptides derived from Blalock's method interacted only with the AII receptor. Two novel AII antagonists were discovered using this technology, a Root-Bernstein derived unprotected complementary peptide (H2N-K-G-V-Y-M-H-A-L-CO2H) and a Blalock derived unprotected antisense peptide (H2N-E-G-V-Y-V-H-P-V-CO2H), which exhibited 5 microM and 70 nM affinity toward the AII receptor, respectively.

Effects of quinapril, a new angiotensin-converting enzyme inhibitor, on vasoconstrictor activity in the isolated, perfused mesenteric vasculature of hypertensive rats.

Previously, we had reported that 7-day administration of the angiotensin-converting enzyme inhibitor quinapril markedly reduced electrically evoked pressor responses in the isolated, perfused mesenteric vascular bed of the spontaneously hypertensive rat (SHR). In the present study, we investigated the possibility that quinapril alters postsynaptic vasoconstrictor activity to a variety of vasoconstrictive agents. Quinapril (10 mg/kg/day), administered orally to SHR for 7 days, significantly reduced the potency and the maximal vasopressor response to phenylephrine (2.5-fold and 40%, respectively) and the maximal response to serotonin (50%) compared with the responses from vehicle treated SHR. In contrast, quinapril had no significant effect on the pressor responses to KCl or phorbol ester. Furthermore, an equipotent antihypertensive dose of hydralazine (5 mg/kg/day, p.o., for 7 days) exerted no inhibitory effect on the pressor responses elicited by phenylephrine, KCl phorbol ester, but significantly reduced the maximal response to serotonin. In addition, vasopressor responses to phenylephrine were not affected by an acute (i.e., 75 min) infusion of quinaprilat, the active metabolite of quinapril. The results suggest that 7-day quinapril administration, and not acute treatment, reduces alpha 1 adrenoceptor and S2-serotonergic receptor-mediated vasoconstriction. However, quinapril did not reduce the vasoconstrictor responses induced by KCl or phorbol ester, indicating that those pressor responses that are due to depolarization or protein kinase C activation are, in part, independent of angiotensin-converting enzyme inhibition. This inhibition of vascular alpha 1 adrenoceptor and S2-serotonergic receptor pressor activity may underlie, in part, the long-term antihypertensive activity of quinapril in the SHR.

Effects of quinapril, a new angiotensin converting enzyme inhibitor, on left ventricular failure and survival in the cardiomyopathic hamster. Hemodynamic, morphological, and biochemical correlates.

The effect of chronic therapy with quinapril on the temporal progression of left ventricular failure and survival was assessed in the CHF 146 cardiomyopathic (CM) hamster, which is an idiopathic model of congestive heart failure. Age-matched Golden Syrian (GS) hamsters served as normal controls. Quinapril was administered in the drinking water at average daily doses of 10.2, 112.4, and 222.4 mg/kg/day. In untreated CM hamsters, in vitro left ventricular performance progressively deteriorated with increasing age beginning at roughly 180 days. This decline in left ventricular performance was accompanied by a decrease in coronary flow and an increase in left ventricular volume. Administration of quinapril from 180 to 300 days of age prevented the decline of in vitro left ventricular contractile performance and coronary flow and also reduced the age-dependent increases in left ventricular volume. The cardioprotective effects of quinapril were observed at doses of 112.4 and 222.4 mg/kg/day but not at 10.2 mg/kg/day. Lung angiotensin converting enzyme activity was significantly inhibited by quinapril in GS and CM hamsters at 240 and 300 days of age at all dose levels. In contrast, significant inhibition of ventricular angiotensin converting enzyme activity was observed consistently at doses of 112.4 and 222.4 mg/kg/day quinapril but not at 10.2 mg/kg/day. In the survival protocol, CM and GS hamsters were treated with vehicle or quinapril (100 mg/kg/day) from 180 to 522 days of age. During the initial 210 days of treatment (from 180 to 390 days of age) 78.3% of the vehicle-treated CM hamsters died compared with 27.7% of quinapril-treated CM hamsters. Quinapril increased the median survival time of CM hamsters by 32.9% (112 days). It is concluded that chronic quinapril therapy exerts a significant cardioprotective effect and also increases survival.