Healthy ageing of cloned sheep

The health of cloned animals generated by somatic-cell nuclear transfer (SCNT) has been of concern since its inception; however, there are no detailed assessments of late-onset, non-communicable diseases. Here we report that SCNT has no obvious detrimental longterm health effects in a cohort of 13 cloned sheep. We perform musculoskeletal assessments, metabolic tests and blood pressure measurements in 13 aged (7–9 years old) cloned sheep, including four derived from the cell line that gave rise to Dolly. We also perform radiological examinations of all main joints, including the knees, the joint most affected by osteoarthritis in Dolly, and compare all health parameters to groups of 5- and 6-year-old sheep, and published reference ranges. Despite their advanced age, these clones are euglycaemic, insulin sensitive and normotensive. Importantly, we observe no clinical signs of degenerative joint disease apart from mild, or in one case moderate, osteoarthritis in some animals. Our study is the first to assess the long-term health outcomes of SCNT in large animals

Calcium entry blockade and adrenergic vascular reactivity in hypertensives: differences between nicardipine and diltiazem.

The interference of nicardipine and diltiazem infused into the brachial artery at systemically ineffective rates, with the forearm vascular response to graded exogenous norepinephrine, was evaluated in hypertensive patients. Nicardipine (1 and 3 micrograms/dl forearm tissue/min in both absence and presence of propranolol) increased forearm blood flow (venous plethysmography) and antagonized dose dependently the vasoconstrictor effect of norepinephrine, suggesting that functional alpha-antagonism may participate in the vasodilating and possibly the antihypertensive effect of the drug. On the contrary, no antagonism but rather potentiation of the responses to norepinephrine occurred after diltiazem (0.5 and 1 microgram/dl forearm tissue/min). Because intra-arterial propranolol abolished that potentiating action of the drug, whereas the local vasodilation to isoproterenol was clearly reduced, diltiazem probably interfered with beta-adrenergic receptor-mediated vasorelaxing mechanisms in human forearm arterioles. The data further stress the heterogeneity of calcium entry blockers in humans

Verapamil antagonizes forearm vasoconstriction mediated by selective alpha 1- and alpha 2-agonists in hypertensive patients.

Calcium channel blocking agents preferentially antagonize alpha 2-mediated pressor responses in various animal species. Whether the same happens in man is not clear. For this reason we studied the interference exerted by verapamil, a calcium entry blocker, on forearm vasoconstriction mediated by selective alpha 1- (methoxamine) and alpha 2- (B-HT 933) adrenergic agonists in untreated mild-to-moderately hypertensive patients (n = 22). Each patient underwent a single study. Forearm blood flow was recorded by strain gauge venous plethysmography; all drugs were infused into the brachial artery at systemically ineffective rates. Cumulative dose-response curves to intra-arterial methoxamine or B-HT 933 were obtained during saline or two different rates of verapamil infusion (0.9 and 3.1 micrograms/100 ml forearm tissue per min) which increased forearm blood flow dose-dependently without changing systemic blood pressure or heart rate. Either methoxamine or B-HT 933 decreased forearm blood flow during saline infusion, but their effect was blunted in a dose-dependent manner during verapamil. No evidence of preferential alpha 2-antagonism was present. At variance with animal data, calcium entry blockade by verapamil antagonizes either alpha 1- or alpha 2-mediated vasoconstriction in human forearm vessels

Calcium entry blockade and agonist-mediated forearm vasoconstriction in hypertensive patients. Difference between nicardipine and verapamil.

The interference by nicardipine and verapamil with the response to vasoactive stimuli, such as lower body negative pressure and angiotensin II, has been evaluated in the forearm of hypertensive patients. Forearm blood flow was monitored during the intraarterial infusion of either drug at rates equieffective on basal flow. Nicardipine blunted the peak forearm vasoconstrictor action of lower body negative pressure and a comparable result was obtained when angiotensin II was administered intraarterially. In spite of a comparable increase in forearm flow, nicardipine was more potent than verapamil in inhibiting vasoconstriction following both stimuli. Thus, nicardipine suppressed regional vascular reactivity, probably by blockade of the influx of extracellular calcium, in response to receptor activation, since both alpha-adrenergic and angiotensin II receptor-mediated vasoconstrictor responses were attenuated. However, the results of the comparison with an unrelated calcium entry blocker, such as verapamil, may suggest that nicardipine, and possibly other dihydropiridine derivatives, preferentially antagonize agonist-mediated vasoconstriction in the human forearm